記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Introduction: Chemotherapy for breast cancer can cause neutropenia, increasing the risk of febrile neutropenia (FN) and serious infections. The use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis has been explored to mitigate these risks. To evaluate the efficacy and safety of primary G-CSF prophylaxis in patients with invasive breast cancer undergoing chemotherapy. Methods: A systematic literature review was conducted according to the “Minds Handbook for Clinical Practice Guideline Development” using PubMed, Ichushi-Web, and the Cochrane Library databases. Randomized controlled trials (RCTs) and cohort studies assessing using G-CSF as primary prophylaxis in invasive breast cancer were included. The primary outcomes were overall survival (OS) and FN incidence. Meta-analyses were performed for outcomes with sufficient data. Results: Eight RCTs were included in the qualitative analysis, and five RCTs were meta-analyzed for FN incidence. The meta-analysis showed a significant reduction in FN incidence with primary G-CSF prophylaxis (risk difference [RD] = 0.22, 95% CI: 0.01–0.43, p = 0.04). Evidence for improvement in OS with G-CSF was inconclusive. Four RCTs suggested a tendency for increased pain with G-CSF, but statistical significance was not reported. Conclusions: Primary prophylactic use of G-CSF is strongly recommended for breast cancer patients undergoing chemotherapy, as it has been shown to reduce the incidence of FN. While the impact on OS is unclear, the benefits of reducing FN are considered to outweigh the potential harm of increased pain.

DOI： 10.1007/s10147-024-02570-8

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語  

DOI： 10.21873/cdp.10355

PubMed

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Multidrug chemotherapy for Ewing sarcoma can lead to severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, “Does primary prophylaxis with G-CSF benefit chemotherapy for Ewing sarcoma?” and CQ #2, “Does G-CSF-based intensified chemotherapy improve Ewing sarcoma treatment outcomes?”. Methods: A comprehensive literature search was conducted in PubMed, Cochrane Library, and Ichushi web databases, including English and Japanese articles published from 1990 to 2019. Two reviewers assessed the extracted papers and analyzed overall survival (OS), febrile neutropenia (FN) incidence, infection-related mortality, quality of life (QOL), and pain. Results: Twenty-five English and five Japanese articles were identified for CQ #1. After screening, a cohort study of vincristine, ifosfamide, doxorubicin, and etoposide chemotherapy with 851 patients was selected. Incidence of FN was 60.8% with G-CSF and 65.8% without; statistical tests were not conducted. Data on OS, infection-related mortality, QOL, or pain was unavailable. Consequently, CQ #1 was redefined as a future research question. As for CQ #2, we found two English and five Japanese papers, of which one high-quality randomized controlled trial on G-CSF use in intensified chemotherapy was included. This trial showed trends toward lower mortality and a significant increase in event-free survival for 2-week interval regimen with the G-CSF primary prophylactic use compared with 3-week interval. Conclusion: This review indicated that G-CSF’s efficacy as primary prophylaxis in Ewing sarcoma, except in children, is uncertain despite its common use. This review tentatively endorses intensified chemotherapy with G-CSF primary prophylaxis for Ewing sarcoma.

DOI： 10.1007/s10147-024-02572-6

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

Background: Granulocyte colony-stimulating factor (G-CSF) is an essential supportive agent for chemotherapy-induced severe myelosuppression. We proposed two clinical questions (CQ): CQ #1, “Does primary prophylaxis with G-CSF benefit chemotherapy for non-round cell soft tissue sarcoma (NRC-STS)?” and CQ #2, “Does G-CSF-based intensified chemotherapy improve NRC-STS treatment outcomes?” for the Clinical Practice Guidelines for the Use of G-CSF 2022 of the Japan Society of Clinical Oncology. Methods: A literature search was performed on the primary prophylactic use of G-CSF for NRC-STSs. Two reviewers assessed the extracted papers and analyzed overall survival, incidence of febrile neutropenia, infection-related mortality, quality of life, and pain. Results: Eighty-one and 154 articles were extracted from the literature search for CQs #1 and #2, respectively. After the first and second screening, one and two articles were included in the final evaluation, respectively. Only some studies have addressed these two clinical questions through a literature review. Conclusion: The clinical questions were converted to future research questions because of insufficient available data. The statements were proposed: “The benefit of primary G-CSF prophylaxis is not clear in NRC-STS” and “The benefit of intensified chemotherapy with primary G-CSF prophylaxis is not clear in NRC-STSs.” G-CSF is often administered as primary prophylaxis when chemotherapy with severe myelosuppression is administered. However, its effectiveness and safety are yet to be scientifically proven.

DOI： 10.1007/s10147-024-02569-1

Web of Science

Scopus

PubMed

Web of Science

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The outcomes of relapsed or refractory acute myeloid leukemia (AML) remain poor. Although the concomitant use of granulocyte colony-stimulating factor (G-CSF) and anti-chemotherapeutic agents has been investigated to improve the antileukemic effect on AML, its usefulness remains controversial. This study aimed to investigate the effects of G-CSF priming as a remission induction therapy or salvage chemotherapy. METHODS: We performed a thorough literature search for studies related to the priming effect of G-CSF using PubMed, Ichushi-Web, and the Cochrane Library. A qualitative analysis of the pooled data was performed, and risk ratios (RRs) with confidence intervals (CIs) were calculated and summarized. RESULTS: Two reviewers independently extracted and accessed the 278 records identified during the initial screening, and 62 full-text articles were assessed for eligibility in second screening. Eleven studies were included in the qualitative analysis and 10 in the meta-analysis. A systematic review revealed that priming with G-CSF did not correlate with an improvement in response rate and overall survival (OS). The result of the meta-analysis revealed the tendency for lower relapse rate in the G-CSF priming groups without inter-study heterogeneity [RR, 0.91 (95% CI 0.82-1.01), p = 0.08; I2 = 4%, p = 0.35]. In specific populations, including patients with intermediate cytogenetic risk and those receiving high-dose cytarabine, the G-CSF priming regimen prolonged OS. CONCLUSIONS: G-CSF priming in combination with intensive remission induction treatment is not universally effective in patients with AML. Further studies are required to identify the patient cohort for which G-CSF priming is recommended.

DOI： 10.1007/s10147-023-02461-4

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Febrile neutropenia represents a critical oncologic emergency, and its management is pivotal in cancer therapy. In several guidelines, the use of granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapy-induced febrile neutropenia is not routinely recommended except in high-risk cases. The Japan Society of Clinical Oncology has updated its clinical practice guidelines for the use of G-CSF, incorporating a systematic review to address this clinical question. METHODS: The systematic review was conducted by performing a comprehensive literature search across PubMed, the Cochrane Library, and Ichushi-Web, focusing on publications from January 1990 to December 2019. Selected studies included randomized controlled trials (RCTs), non-RCTs, and cohort and case-control studies. Evaluated outcomes included overall survival, infection-related mortality, hospitalization duration, quality of life, and pain. RESULTS: The initial search yielded 332 records. Following two rounds of screening, two records were selected for both qualitative and quantitative synthesis including meta-analysis. Regarding infection-related mortality, the event to case ratio was 5:134 (3.73%) in the G-CSF group versus 6:129 (4.65%) in the non-G-CSF group, resulting in a relative risk of 0.83 (95% confidence interval, 0.27-2.58; p = 0.54), which was not statistically significant. Only median values for hospitalization duration were available from the two RCTs, precluding a meta-analysis. For overall survival, quality of life, and pain, no suitable studies were found for analysis, rendering their assessment unfeasible. CONCLUSION: A weak recommendation is made that G-CSF treatment not be administered to patients with febrile neutropenia during cancer chemotherapy. G-CSF treatment can be considered for patients at high risk.

DOI： 10.1007/s10147-024-02541-z

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

INTRODUCTION: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

DOI： 10.1007/s10147-024-02499-y

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JCO Precision Oncology  

PURPOSE

The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer.

METHODS

We conducted a retrospective study using real-world clinical data and next-generation sequencing–based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment.

RESULTS

In 114 patients with human epidermal growth factor receptor-2 (HER2)–positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were TP53 (82%), ERBB2 (80%), and CCNE1 (36%). Multivariate Cox regression analysis revealed CCNE1 amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days v 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; P = .044). Analyses of 1,450 G/GEJ cancers revealed significant CCNE1/ ERBB2 coamplification (41% relative to 11% CCNE1 amplification in ERBB2-nonamplified tumors; P < .0001). ERBB2-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with ERBB2-mutated tumors showed shorter PFS than those without ERBB2 mutations after T-DXd treatment (mPFS, 105 v 180 days; P = .046).

CONCLUSION

CCNE1 amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in CCNE1/ERBB2 coamplified tumors. ERBB2-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.

DOI： 10.1200/po.23.00681

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.

DOI： 10.1007/s10147-024-02501-7

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

DOI： 10.1007/s10147-024-02491-6

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

DOI： 10.1007/s10147-023-02465-0

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

DOI： 10.1007/s10147-024-02502-6

Web of Science

Scopus

PubMed

researchmap

その他リンク： https://link.springer.com/article/10.1007/s10147-024-02502-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. METHODS: We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. RESULTS: A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. CONCLUSION: Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.

DOI： 10.1007/s10147-024-02469-4

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/μL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

DOI： 10.1007/s10147-024-02504-4

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

出版者・発行元：メディカルレビュー社  

DOI： 10.34449/j0001.41.01_0048-0049

CiNii Research

記述言語：英語   出版者・発行元：Scientific Reports  

The original version of this Article contained an error in the Supplementary Information File, where the Kaplan–Meier curves and numbers at risk were incorrect. The original Supplementary Information file is provided below. The original Article has been corrected.

DOI： 10.1038/s41598-024-55673-7

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Breast Cancer  

Liquid biopsy using circulating tumor DNA (ctDNA) has been reported to be less invasive and effective for comprehensive genetic analysis of heterogeneous solid tumors, including decision-making for therapeutic strategies, predicting recurrence, and detecting genetic factors related to treatment resistance in various types of cancers. Breast cancer, colorectal cancer, and lung cancer are among the most prevalent malignancies worldwide, and clinical studies of liquid biopsy for these cancers are ongoing. Liquid biopsy has been used as a companion diagnostic tool in clinical settings, and research findings have accumulated, especially in cases of colorectal cancer after curative resection and non-small cell lung cancer (NSCLC) after curative chemoradiotherapy, in which ctDNA detection helps predict eligibility for adjuvant chemotherapy. Liquid biopsy using ctDNA shows promise across a wide range of cancer types, including breast cancer, and its clinical applications are expected to expand further through ongoing research. In this article, studies on liquid biopsy in breast cancer, colorectal cancer, and NSCLC are compared focusing on ctDNA.

DOI： 10.1007/s12282-024-01556-8

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：World Journal of Gastroenterology  

BACKGROUND: Metastatic cardiac tumors are known to occur more frequently than primary cardiac tumors, however, they often remain asymptomatic and are commonly discovered on autopsy. Malignant tumors with a relatively high frequency of cardiac metastasis include mesothelioma, melanoma, lung cancer, and breast cancer, whereas reports of esophageal cancer with cardiac metastasis are rare. CASE SUMMARY: The case of a 60-year-old man who complained of dysphagia is presented. Upper gastrointestinal endoscopy showed a submucosal tumor-like elevated lesion in the esophagus causing stenosis. Contrast-enhanced computed tomography showed left atrial compression due to the esophageal tumor, multiple liver and lung metastases, and a left pleural effusion. Pathological examination of a biopsy specimen from the esophageal tumor showed spindle-shaped cells, raising suspicion of esophageal sarcoma. The disease progressed rapidly, and systemic chemotherapy was deemed necessary, however, due to his poor general condition, administration of cytotoxic agents was considered difficult. Given his high Combined Positive Score, nivolumab was administered, however, the patient soon died from the disease. The autopsy confirmed spindle cell carcinoma (SCC) of the esophagus and cardiac metastasis with similar histological features. Cancer stem cell markers, ZEB1 and TWIST, were positive in both the primary tumor and the cardiac metastasis. CONCLUSION: To the best of our knowledge, there have been no prior reports of cardiac metastasis of esophageal SCC. This case highlights our experience with a patient with esophageal SCC who progressed rapidly and died from the disease, with the autopsy examination showing cardiac metastasis.

DOI： 10.3748/wjg.v30.i11.1636

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Clinical Oncology  

Epithelioid hemangioendothelioma (EHE) is a remarkably rare tumor arising from endothelial cells that is classified as a vascular tumor in the WHO classification. The tumor is predominantly characterized by the presence of fusion genes, such as WWTR1-CAMTA1 or YAP1-TFE3, with a minority of cases exhibiting other rare fusion genes. EHE exhibits a broad age of onset, typically presenting at ~50 years, but it is not uncommon in pediatric populations. It manifests in a variety of organs, including the liver, lung, soft tissue and bone. Initial multiple-organ involvement is also observed. The tumor's biological behavior and prognosis vary substantially based on the primary site of manifestation. From a therapeutic perspective, initial active surveillance might be considered in selected cases, although surgical intervention remains the mainstay of treatment, especially for localized single-organ involvement. Chemotherapy is administered to patients with progressive unresectable tumors. Recent advances in the biological analysis of EHE fusion genes have elucidated their diverse functions. Additionally, next-generation sequencing has facilitated the identification of other mutations beyond the fusion genes. These continuous efforts to understand the biology of the fusion genes themselves and/or the dysregulated signaling by fusion genes are expected to lead to the development of novel therapeutic strategies for EHE. This article aims to provide a comprehensive review of EHE, encompassing its historical context, clinical manifestations, molecular biology and the current state of treatment.

DOI： 10.1093/jjco/hyae037

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. METHODS: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. FINDINGS: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. INTERPRETATION: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. FUNDING: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

DOI： 10.1016/j.eclinm.2024.102447

記述言語：英語   出版者・発行元：Frontiers in Oncology  

Here, we present the case of a 42-year-old female who developed acute pancreatitis due to dexamethasone during adjuvant chemotherapy for early triple negative breast cancer (TNBC). The patient received partial mastectomy and sentinel lymph node biopsy for early TNBC (cT1N0M0, cStage I) of the left breast. Dose-dense doxorubicin plus cyclophosphamide (ddAC) was administered as the adjuvant-chemotherapy; however, epigastralgia appeared on the fifth day of the first administration. A blood test showed a remarkable increase of serum pancreatic enzyme levels and computed tomography (CT) showed the swelling of pancreas and surrounding effusion, and she was diagnosed with moderate acute pancreatitis. As she had no history of excessive alcohol consumption or complication of cholelithiasis, dyslipidemia, or pancreatic neoplasm, drug-induced pancreatitis was suspected. Dexamethasone, which was administered as an antiemetic, was the suspected drug based on the drug administration history and previous report, and dexamethasone was discontinued from the second administration of ddAC. There was subsequently no recurrence of pancreatitis with no increase in serum pancreatic enzyme levels, and it was possible to complete adjuvant-chemotherapy. Alcohol, gallstones, dyslipidemia, and drugs have been reported as causes of pancreatitis; however, steroid-induced acute pancreatitis is extremely rare. We present the first case of acute pancreatitis induced by dexamethasone as the antiemetic.

DOI： 10.3389/fonc.2024.1340419

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：ESMO Open  

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

DOI： 10.1016/j.esmoop.2023.102226

Web of Science

Scopus

PubMed

DOI： 10.1200/JCO.2024.42.3_suppl.TPS423

Web of Science

記述言語：日本語   出版者・発行元：日本臨床薬理学会  

セッションID: 44_3-C-S37-2

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.Methods and Results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133-567) and 170 (72-358) days, respectively, compared with 146 (70-309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50-0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73-0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62-0.76; P<0.001). CONCLUSIONS: This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.

DOI： 10.1253/circj.CJ-22-0628

記述言語：英語   出版者・発行元：(一社)日本循環器学会  

記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

<p>A 75-year-old man diagnosed with esophageal cancer and lung metastasis received a combination of fluorouracil, cisplatin, and pembrolizumab. During pembrolizumab maintenance therapy, lymphoproliferative lesions at the lips and mouth and multiple lymph node swellings appeared. Histologically, Epstein-Barr virus (EBV)-encoded RNA was positive, and EBV-DNA was detected in the blood. The patient was diagnosed with other iatrogenic immunodeficiency-associated lymph proliferative disorders (OIIA-LPDs) related to EBV activation induced by pembrolizumab. Rituximab was administered, resulting in the improvement of the OIIA-LPD. The emergence of an OIIA-LPD merits close attention in patients receiving immune checkpoint inhibitors. </p>

DOI： 10.2169/internalmedicine.3743-24

Web of Science

PubMed

CiNii Research

記述言語：英語   出版者・発行元：Case Reports in Oncology  

Here, we present a 69-year-old female with advanced neuroendocrine carcinoma (NEC) of colon with multiple liver, bone, and kidney metastases who developed Trousseau's syndrome. The patient received etoposide plus cisplatin (EP) as the first-line therapy; however, after single administration of EP, she developed the severe lower-limb edema and EP was considered to be intolerable. Etoposide plus carboplatin was administered as the second-line therapy and after 3 cycles of administration, the progressive disease (PD) was confirmed and 5-fluorouracil + leucovorin + irinotecan (FOLFIRI) plus ramucirumab was administered as the third-line therapy. However, PD was confirmed after 3 cycles of the therapy, and she was to receive the best supportive care and was hospitalized in our hospital. Four weeks after hospitalization, mild impaired consciousness and dysarthria were observed. Blood tests showed coagulation abnormalities including elevation of plasma fibrin/fibrinogen degradation products (FDPs) and D-dimer levels, and the diffusion-weighted image of magnetic resonance imaging (MRI) of the head showed multiple cerebral infarcts. She was diagnosed with Trousseau's syndrome due to the progression of NEC and intravenous unfractionated heparin was administered as anticoagulant therapy. After the administration of heparin, plasma FDP and D-dimer levels decreased; however, due to the progression of NEC, the patient died 6 weeks after hospitalization. This is the first report of NEC of the colon that developed Trousseau's syndrome.

DOI： 10.1159/000530927

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

BACKGROUND: Comprehensive genomic profiling (CGP) has become generally accepted practice in cancer care since CGP has become reimbursed by national healthcare insurance in Japan in 2019. However, its usefulness for cancer patients is insufficient for several reasons. METHODS: In an observational clinical study of FoundationOne® CDx, potential biomarkers were explored and the cause of testing failure was investigated. A total of 220 cancer patients were enrolled in the study during the period from 2018 to 2019 at Kyushu University Hospital. RESULTS: The primary tumor sites of the 220 cases were breast (115), colon (29), stomach (19), and pancreas (20). The present dataset suggested that homologous recombination repair (HRR) gene alterations were positively associated with tumor mutational burden-high (TMB-high) (p = 0.0099). A public dataset confirmed that patients with HRR gene alterations had a higher TMB and showed significantly longer survival of immunotherapy. In the present study, 18 cases failed sequencing. A lower percentage of tumor cell nuclei was the most common reason for testing failures (p = 0.037). Cases that received neoadjuvant chemotherapy before sampling tended to fail testing. CONCLUSIONS: HRR gene alterations can be a potential biomarker predicting TMB-high and a good response to immunotherapy. For successful sequencing, samples with lower percentages of tumor cell nuclei and previous neoadjuvant chemotherapy should be avoided.

DOI： 10.3390/cancers15235608

Web of Science

Scopus

PubMed

researchmap

DOI： 10.1016/j.annonc.2023.09.323

Web of Science

DOI： 10.1016/j.annonc.2023.09.141

Web of Science

DOI： 10.1016/j.annonc.2023.09.205

Web of Science

DOI： 10.1016/j.annonc.2023.09.197

Web of Science

DOI： 10.1016/j.annonc.2023.09.209

Web of Science

DOI： 10.1016/j.annonc.2023.09.212

Web of Science

DOI： 10.1016/j.annonc.2023.09.349

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The anti-programmed cell death-1 (PD-1) antibody nivolumab has been shown to significantly prolong the survival of patients with unresectable advanced or recurrent gastric cancer (AGC). However, immune-related adverse events (irAEs), which show different profiles from those of cytotoxic agents or conventional molecular-targeted drugs including tyrosine kinase inhibitors, have been reported. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare autoimmune disorder with acute-onset, rheumatoid factor-negative, symmetric synovitis associated with limb edema observed in elderly persons. A case of RS3PE syndrome that developed after administration of nivolumab for advanced gastric cancer is reported. This is the first report of a case of RS3PE syndrome as an irAE caused by nivolumab in a patient with gastric cancer.

DOI： 10.3389/fonc.2023.1260818

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Cancer  

Abstract

Background

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy.

Methods

We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy.

Results

Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 – 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95&#37;CI: 6.0 – 25.8 months): 17.1 months (95&#37;CI: 6.0 – not reached (NR)) for patients with stage I-III and 8.5 months (95&#37;CI: 5.2 – 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5&#37; and 11.3&#37; for all patients. Median OS in all patients was 40.8 months (95&#37;CI: 12.1 months–NR): 40.8 months (95&#37;CI: 12.1 – NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5&#37; for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions.

Conclusion

The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions.

DOI： 10.1186/s12885-023-11528-4

Web of Science

Scopus

PubMed

researchmap

その他リンク： https://link.springer.com/article/10.1186/s12885-023-11528-4/fulltext.html

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：日本語   出版者・発行元：医学図書出版(株)  

がん発症のリスクファクターとして生活習慣や環境要因などが報告されており,複数のがん種が共通のリスクファクターを有することが知られている。胆道癌については膵・胆管合流異常や肝内結石症などが,膵癌では家族歴(遺伝性膵癌症候群)や膵管内乳頭粘液性腫瘍などが特徴的なリスクファクターである。また近年がん遺伝子パネルが保険診療で用いられ標的治療や臨床試験へのアクセスを高める試みがなされているが,偶発的に遺伝性腫瘍に関連する生殖細胞系列変異が検出されることもある。リスクファクターに応じた胆道癌や膵臓癌に対する適切なサーベイランスの頻度,期間について確立されたものは限られている。またサーベイランスが長期となる場合は患者の精神的,経済的負担も考慮して行う。(著者抄録)

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Immunology, Immunotherapy  

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

DOI： 10.1007/s00262-023-03505-4

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02360-8

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

DOI： 10.1007/s10147-023-02397-9

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s10147-023-02397-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s10147-023-02345-7

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

大腸癌幹細胞の中で増殖状態にあるものの特徴を決定するため、オルガノイドと大腸癌組織を材料に、それらのトランスクリプトミクスを解析した。その結果、CD44陽性を示す通常のヒト大腸癌幹細胞の分画の中に、ヒアルロン酸媒介運動性受容体(RHAMM)を発現している亜集団があることを発見した。細胞種の多様性を再構成することで腫瘍組織のミニチュア版としたオルガノイドを材料に、単一細胞トランスクリプトミクス解析を施行したところ、増殖性を示し、様々な細胞種の中にあって独特の特徴を示すRHAMM陽性細胞があることに注目された。ヒト大腸癌組織からRHAMM陽性CD44陽性の細胞を予期的に分離した結果、分離された同細胞は他の癌細胞と比較して高い増殖特性と自己新生能を現した。RHAMMを阻害するとin vitroでのオルガノイド形成は強く抑制され、in vivoでは腫瘍成長が阻害された。RHAMMは、通常の癌幹細胞分画内に含まれる増殖性の亜集団への特異的マーカーになりうると考えられた。

Web of Science

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1016/j.esmoop.2023.101558.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1007/s10147-023-02360-8.

DOI： 10.1016/j.annonc.2023.04.136

Web of Science

記述言語：英語   出版者・発行元：ESMO Open  

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer (mCRC), published in late 2022, were adapted in December 2022, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with mCRC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with mCRC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian countries. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with mCRC across the different countries of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation, coupled with a disparity in the drug approvals and reimbursement strategies, between the different countries.

DOI： 10.1016/j.esmoop.2023.101558

Web of Science

Scopus

PubMed

記述言語：英語   出版者・発行元：Scientific Reports  

There are limited absolute biomarkers for determining the prognosis before first- and second-line palliative chemotherapy in unresectable pancreatic cancer (urPC) patients. To find the best prognostic inflammatory marker, we investigated relationships between overall survival (OS) and six inflammatory markers; C-reactive protein/albumin ratio (CAR), neutrophil–lymphocyte ratio (NLR), prognostic nutrition index (PNI), platelet–lymphocyte ratio (PLR), Glasgow prognostic score (GPS), and prognostic index (PI). We examined 255 patients who received gemcitabine + nab-paclitaxel or FOLFIRINOX as first-line chemotherapy and 159 patients who subsequently underwent second-line chemotherapy. First-line patients with lower CAR had better OS compared to those with a higher CAR (hazard ratio 0.57; 95% confidential index 0.42–77; P < 0.01). Similarly, lower NLR (P = 0.01), higher PNI (P = 0.04), lower PLR (P = 0.03), GPS score of 0 (P < 0.01) and PI score of 0 (P < 0.01) were all associated with better OS. CAR demonstrated the best superiority for determining survival prognosis through the use of area under the curve of time-dependent receiver-operating characteristic curves. Furthermore, a lower CAR before second-line therapy exhibited better OS versus higher CAR (P < 0.01). Therefore, CAR might be a useful biomarker for predicting urPC patient prognosis in both first- and second-line chemotherapy.

DOI： 10.1038/s41598-023-34962-7

Web of Science

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1038/s41598-023-34962-7.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.

DOI： 10.1007/s10147-023-02345-7

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

The cancer stem cell (CSC) theory features typically rare self-renewing subpopulation that reconstitute the heterogeneous tumor. Identification of molecules which characterize the feature of CSCs is a key imperative for further understanding of tumor heterogeneity and for the development of novel therapeutic strategies. However, the use of conventional markers of CSCs is still insufficient for the isolation of bona fide CSCs. We investigated organoids which are miniature forms of tumor tissues with reconstructing cellular diversity to identify specific marker to characterize CSCs in heterogeneous tumors. Here, we report that receptor for hyaluronan-mediated motility (RHAMM) expresses in a subpopulation of CD44+ conventional human colorectal CSC fraction. Single-cell transcriptomics of organoids highlighted RHAMM positive proliferative cells that revealed distinct characteristics among the various cell types. Prospectively isolated RHAMM+ CD44+ cells from the human colorectal cancer tissues showed highly proliferative character with self-renewal ability in comparison with the other cancer cells. Furthermore, inhibition of RHAMM strongly suppressed organoids formation in vitro and inhibited the tumor growth in vivo. Our findings suggest that RHAMM is a potential therapeutic target because it is a specific marker of the proliferative subpopulation within the conventional CSC fraction.

DOI： 10.1111/cas.15795

Web of Science

Scopus

PubMed

researchmap

Web of Science

Web of Science

Web of Science

Web of Science

Web of Science

Web of Science

記述言語：英語  

Here, we present a 59-year-old female with recurrent malignant phyllodes tumor with multiple lung and lymph node metastases who developed a pneumothorax after the administration of pazopanib. The patient received pazopanib as the second-line chemotherapy. After 2.5 months of the therapy, computed tomography (CT) showed a decrease in the sizes and cavitation of lung lesions; however, a left pneumothorax was newly observed. It was difficult to distinguish the pneumothorax by upright chest X-ray. Typical symptom or physical finding of pneumothorax, such as dyspnea, chest pain or decreased breath sound was not observed. As the pneumothorax was small and asymptomatic, the administration of pazopanib was discontinued and follow-up chest X-ray and CT were performed. After 1 week, CT showed an improvement in the pneumothorax. Chemotherapy was switched to eribulin; however, a rapid increase in sizes of lung lesions was observed after the first administration of eribulin, pazopanib was reintroduced. Careful follow-up by chest X-ray and CT was performed and the pneumothorax has not recurred.

DOI： 10.1007/s13691-022-00572-9

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gastric Cancer  

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

DOI： 10.1007/s10120-022-01349-y

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

測定可能病変を有し、日本の24施設で2ライン以上の化学療法後にニボルマブ療法を受けた症例を検討対象として、後方視的研究を行った。腫瘍増大(hyperprogressive disease、HPD)は測定可能病変の増殖率が2倍以上に増加した場合と定義した。病勢進行パターンは、異なった臓器での新規病変の出現および腹水の出現や増加に分類した。245名のうち、ニボルマブ単剤治療中に最も奏効した場合が病勢進行(PD)であった症例は147名(60.0%)、HPDを示したのは41名(16.7%)であった。HPD症例とHPD以外のPD症例との間で全生存期間(OS)に有意差は認められなかった(OS中央値5.0ヵ月対4.8ヵ月、ハザード比(HR)1.0、95%信頼区間(CI)0.6-1.5、P=1.0)。53名の患者で異なる臓器に新たな病変が出現し、58名で腹水の出現や増加を認めた。これらの患者は、それ以外の患者よりもOSが短かった(OS中央値3.3月対7.1ヵ月、新規病変出現症例HR 1.8、95%CI 1.2-2.7、P=0.0031、腹水出現および増加例HR 2.6、95%CI 1.8-3.8、P<0.0001)。新規病変と腹水出現ないし増加の両方が認められた31名の患者は、予後が最も悪かった(OS中央値2.6ヵ月)。ニボルマブ療法に対する奏効度がPDまでであった進行胃癌(AGC)患者において、新規病変の出現と腹水の出現や増加は、従来のHPDの定義よりも予後不良に関連する疾患進行のパターンである可能性が示された。

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

症例は59歳女性で、他院にてトリプルネガティブ乳癌(cT3NXM0、cStage IIIB、浸潤性乳管癌)と診断され、左乳房切除術と腋窩リンパ節郭清を受けた。手術検体の病理組織学的検査では悪性葉状腫瘍に一致していた。術後4ヵ月、左胸A・B領域の悪性葉状腫瘍再発、最大径5cmの多発性肺転移、リンパ節転移と診断され、当院で全身化学療法を受けることになった。二次化学療法としてパゾパニブを投与した。治療開始2.5ヵ月後、CT検査で肺病変のサイズと空洞が減少したが、新たに左気胸を認めた。立位胸部X線では気胸の鑑別が困難であった。気胸の典型的な症状や身体所見である呼吸困難、胸痛、呼吸音減弱は認めなかった。気胸は小さく無症状であったため、パゾパニブ投与を中止し、胸部X線とCTで経過観察を行った。1週間後、CTで気胸の改善を確認した。化学療法をエリブリンに変更したが、エリブリン初回投与後に肺病変の急速な増大を認めたため、パゾパニブを再投与した。胸部X線とCTによる慎重な経過観察を行った結果、気胸の再発は認めなかった。

DOI： 10.1007/s10120-022-01331-8

Web of Science

PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本臨床薬理学会  

<p>近年のがんゲノム研究の発展により、新規標的に対する抗腫瘍薬の開発が増すと共に、異なる臓器に生じたがんでも共通の遺伝子異常を有する場合には、同じ抗腫瘍薬の効果が期待できることから、臓器横断的治療の概念が示された。がんゲノムプロファイリング検査の拡大に伴い実臨床での臓器横断的治療の機会は増加している。高頻度マイクロサテライト不安定性や高い腫瘍遺伝子変異量を有するがん、NTRK融合遺伝子を有するがんに対しては、保険診療で免疫チェックポイント阻害薬やTRK阻害薬の使用が可能となった。さらにBRAFやBRCAなどの遺伝子異常も臓器横断的治療の対象として検討可能である。この臓器横断的ながん治療を、特にがんゲノム医療に携わる機関において適切かつ円滑に実施するためには、これまでの臓器特異的な治療主体の診療体制とは異なり、多診療科・部門が協力して対応することが重要である。毎週開催されるエキスパートパネルでは、臓器横断的治療の対象となる遺伝子異常も明らかとなるため、この場において当該遺伝子異常の臨床的意義や治療薬候補について各診療科の視点からの議論が行われている。担当診療科では日常診療で投与しない薬剤が推奨された場合は、主に腫瘍内科が薬物療法を担う場合がある。臓器横断的治療として用いられる免疫チェックポイント阻害薬の免疫関連有害事象は未だ注意を要するため、薬剤部を中心としたチーム会合で支援を行う体制を構築している。さらに胚細胞系列遺伝子異常が同定された場合には、遺伝医療部が説明、カウンセリング、遺伝子検査を担っている。臓器横断的治療は遺伝子異常を有する腫瘍に対する治療選択肢が増す点で期待されているが、臓器毎の臨床的意義や治療薬の効果の差については今後も研究が必要と考えられる。</p>

DOI： 10.50993/jsptsuppl.44.0_3-c-s37-2

CiNii Research

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown. OBJECTIVES: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension. METHOD: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint. RESULTS: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584). CONCLUSIONS: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive.

DOI： 10.1136/openhrt-2022-002135

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1253/circj.CJ-22-0628.

記述言語：英語   出版者・発行元：Oxford University Press  

原発不明癌患者を対象とした多施設共同観察研究を実施し、サブセットごとの治療効果を明らかにするとともに、特に予後不良サブセットにおける経験的治療と部位特異的治療の有効性を比較検討した。2006年から2018年までに8ヶ所の施設で第一選択治療として化学療法または化学放射線療法を受けた原発不明癌患者177例を対象とした。そのうち33例(年齢36～83歳)が予後良好サブセット、144例(年齢35～84歳)が予後不良サブセットに分類された。予後不良サブセットの84例(58.3%)が経験的治療を受け、60例(41.7%)が部位特異的な治療を受けた。全生存期間の中央値は、部位特異的治療群と経験的治療群でそれぞれ10.0ヵ月および10.1ヵ月であり、有意差はなかった(ハザード比1.01、95%CI 0.70～1.45、P=0.95)。多変量解析により、パフォーマンスステータス、転移部位数、低アルブミン血症が、予後不良サブセットにおける全生存期間の独立した予後因子であることが示された。以上より、原発不明癌の予後不良サブセットにおける部位特異的治療群と経験的治療群の全生存期間はほぼ同様であった。

記述言語：日本語   出版者・発行元：(有)科学評論社  

researchmap

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

クロイソカイメンから発見されたハリコンドリンBの誘導体である微小管標的薬エリブリン(Eri)に対する耐性のメカニズムについて検討した。Eri耐性大腸癌由来SW480細胞におけるインスリン様成長因子-1受容体(IGF-1R)/インスリン受容体(INSR)活性化に対するEri処理の影響を分析した。その結果、Eriへの曝露により、リン酸化されたIGF-1R/INSRとその下流エフェクターにおけるAktの蓄積量が増加し、IGFシグナルが活性化された。Eri処理はIGF-1Rの活性化とそれに続く核移行を誘導したが、IGF-1Rの活性化や核移行を阻害した場合、EriはDNA損傷を誘導し、G2/M停止を促進した。さらに、Eri耐性細胞株であるSW480を用いた異種移植マウスモデルにおいて、EriとIGF-1R阻害剤であるリンシチニブの併用は、いずれの単剤よりも腫瘍増殖を抑制した。以上より、EriとIGF-1R阻害剤の併用はEri耐性を克服することが示唆された。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese journal of clinical oncology  

BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

DOI： 10.1093/jjco/hyac103

Web of Science

Scopus

PubMed

researchmap

記述言語：英語  

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

researchmap

記述言語：英語   出版者・発行元：Oxford University Press  

癌関連血栓症を有する進行消化器癌患者に対する抗凝固療法の患者選択を改善するため、出血の発生率や危険因子を後方視的に検討した。2014～2018年に化学療法を受けた進行消化器癌患者194例(年齢31～84歳)を対象とした。消化器癌の内訳は胃癌74例、大腸癌120例であった。194例のうち、静脈血栓塞栓症と診断された患者は40例(20.6%)、肺血栓塞栓症を併発した患者は10例(5.2%)であった。出血は29名(15%)に認められた。出血部位は、原発巣17例、転移巣9例、出血性胃潰瘍3例であり、静脈血栓塞栓症群40例のうち10例(25%)に出血が認められた。多変量解析により、International Medical Prevention Registry on Venous Thromboembolism(IMPROVE)出血スコア7以上と大出血は有意に相関していた(P=0.01)。出血リスクの低い患者では大出血は3例のみであった。以上より、IMPROVE出血スコアは静脈血栓塞栓症を有する消化器癌患者における出血リスクを予測する可能性があった。

出版者・発行元：日本メディカルセンター  

DOI： 10.19020/cg.0000002384

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abstract

Background

Patients with cancer of unknown primary site are divided into two distinct groups, favourable and unfavourable subsets. For the unfavourable subset, empiric treatment or site-specific treatment is recommended, but limited knowledge exists about the efficacy of site-specific treatment compared with empiric treatment in clinical practice.

Methods

In this multicentre retrospective study, we reviewed the medical records of patients with cancer of unknown primary site treated with chemotherapy (or chemoradiotherapy) as first-line treatment from eight institutions during 2006–18. We investigated the workup modality and categorized the patients into favourable and unfavourable subsets, which were further divided into site-specific and empiric treatment groups. Site-specific treatment is defined as a standard chemotherapy for an estimated primary site. We examined the efficacy in the favourable and unfavourable subsets and performed multivariable analysis for estimating the overall survival in the unfavourable subset.

Results

Of 177 patients with cancer of unknown primary site, 33 and 144 were categorized into favourable and unfavourable subsets, respectively. In the unfavourable subset, 84 patients (58.3&#37;) received empiric therapy, and 60 patients (41.7&#37;) received site-specific treatment. Median overall survival was 10.0 and 10.1 months in site-specific and empiric treatment groups, respectively, with no significant difference (hazard ratio 1.01, 95&#37; confidence interval 0.70–1.45, P = 0.95). Multivariable analysis revealed performance status, number of metastatic sites and hypoalbuminaemia as independent prognostic factors for overall survival in the unfavourable subset.

Conclusions

Overall survival in site-specific and empiric treatment groups was similar in the unfavourable cancer of unknown primary site subset in this study. Further research is needed to prolong overall survival in patients in the unfavourable cancer of unknown primary site subset.

DOI： 10.1093/jjco/hyac143

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

BACKGROUND: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. METHODS: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. RESULTS: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07). CONCLUSION: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

DOI： 10.1007/s10147-022-02208-7

Web of Science

Scopus

PubMed

researchmap

記述言語：英語  

記述言語：日本語  

＜文献概要＞胃がんは,わが国で罹患率,死亡者数ともに高い悪性腫瘍の一つである.胃がんに対するがん薬物療法は,治癒切除例における再発予防目的および切除不能・再発症例に対する延命・症状緩和目的で選択される.近年薬物療法の開発が進み,pStage III症例に対する術後補助化学療法としてS-1+ドセタキセル(DTX)併用療法の有効性が示された.また切除不能・再発症例の一次治療でニボルマブが化学療法との併用でup-frontに使用されるようになり,またHER2陽性例に対するトラスツズマブ・デルクステカンなど,三次治療においても延命効果が期待される薬剤が開発されている.胃がんにおける薬物療法について解説していく.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Microtubule targeting agents (MTAs) such as taxanes are broadly used for the treatment of patients with cancer. Although MTAs are not effective for treatment of colorectal cancer (CRC), preclinical studies suggest that a subset of patients with CRC, especially those with cancers harboring the BRAF mutation, could benefit from such agents. However, two MTAs, eribulin (Eri) and vinorelbine, have shown limited clinical efficacy. Here, we report that insulin-like growth factor 1 receptor (IGF-1R) signaling is involved in Eri resistance. Using CRC cell lines, we showed that Eri induces activation and subsequent translocation of IGF-1R to the nucleus. When the activation and/or nuclear translocation of IGF-1R was inhibited, Eri induced DNA damage and enhanced G2 /M arrest. In a xenograft model using the Eri-resistant SW480 cell line, the combination of Eri and the IGF-1R inhibitor linsitinib suppressed tumor growth more efficiently than either single agent. Thus, our results indicated that combination dosing with Eri and an IGF-1R inhibitor could overcome Eri resistance and offer a therapeutic opportunity in CRC.

DOI： 10.1111/cas.15558

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：(一社)日本癌学会  

researchmap

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

ファーストライン治療として抗血管内皮増殖因子抗体製剤ベバシズマブ(BEV)または抗上皮成長因子受容体抗体製剤セツキシマブやパニツムマブ(CET/PAN)を受けたRAS野生型転移性大腸癌(mCRC)患者において、原発巣の部位別に実臨床での有効性を検討した。2013年1月から2016年12月までに日本国内24施設において、BEVまたはCET/PAN+5-フルオロウラシルベースの2剤併用化学療法を開始したRAS野生型mCRC患者935例を対象とした。その結果、右側mCRCの213例の全生存期間(OS)中央値は、BEVで24.6ヵ月、CET/PANで20.9ヵ月であり(調整後HR 0.73、95%CI 0.50～1.06)、左側mCRCの722例のOS中央値は、BEVで35.7ヵ月、CET/PANで30.0ヵ月であった(調整後HR 0.92、95%CI 0.74～1.13)。傾向スコアをマッチさせたコホートでは、右側mCRCではBEV群がCET/PAN群よりもOSが有意に良好であったが、左側mCRCでは有意差はなかった。以上より、実臨床において、右側mCRCに対してはBEV投与の方がCET/PAN投与よりも有効であるが、左側mCRCに対する有効性には差が認められないことが示された。

記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

＜文献概要＞胃がんは,わが国で罹患率,死亡者数ともに高い悪性腫瘍の一つである.胃がんに対するがん薬物療法は,治癒切除例における再発予防目的および切除不能・再発症例に対する延命・症状緩和目的で選択される.近年薬物療法の開発が進み,pStage III症例に対する術後補助化学療法としてS-1+ドセタキセル(DTX)併用療法の有効性が示された.また切除不能・再発症例の一次治療でニボルマブが化学療法との併用でup-frontに使用されるようになり,またHER2陽性例に対するトラスツズマブ・デルクステカンなど,三次治療においても延命効果が期待される薬剤が開発されている.胃がんにおける薬物療法について解説していく.

researchmap

DOI： 10.1016/j.annonc.2022.07.527

Web of Science

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

E-カドヘリン欠損胃印環細胞癌(SRCC)における新規治療標的を同定することを目的とした。E-カドヘリンをコードするCDH1遺伝子をノックアウト(KO)したヒト胃オルガノイド(hGO)を用いて、in vitroのE-カドヘリン欠損胃癌モデルを作製し、新規治療標的を探索した。CDH1 KO hGO細胞は、SRCCに類似した特徴的な形態変化と高い細胞運動性を示した。RNA配列解析の結果、CDH1 KO hGO細胞では、野生型と比較して、マトリックスメタロプロテアーゼ(MMP)遺伝子の発現が増加していた。MMP阻害剤は、in vitroでCDH1 KO hGO細胞およびSRCC細胞株の細胞運動を抑制した。95例の臨床胃癌組織を用いた免疫蛍光分析により、MMP-3はE-カドヘリン異常のSRCCに特異的に多く存在することが示された。また、CDH1 KO後、CXCR4分子が細胞膜上に移行した。CXCR4のリガンドであるCXCL12を培養液に添加すると、CDH1 KO hGO細胞の細胞生存率が延長し、CXCR4アンタゴニストであるAMD3100によってその効果が消失した。SRCCの臨床サンプルでは、CXCL12を分泌する線維芽細胞が癌領域に著しく浸潤していることを確認した。以上より、MMPとCXCL12/CXCR4軸は、E-カドヘリン欠損SRCCの新規治療標的として有望な候補であると考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemistry and Biophysics Reports  

Epithelial-mesenchymal plasticity (EMP) refers to the reversible cellular transition between epithelial and mesenchymal status. Spontaneous EMP is also reported in breast and prostate cancer, leading to the acquisition of stem-cell properties and chemoresistance. However, the presence of spontaneous EMP is still not reported in esophageal cancer. We screened 11 esophageal squamous cancer cell (ESCC) cell lines by CD44 isoform expression. KYSE520 was found to comprise heterogenous populations consisting of CD44v+ and CD44v- subpopulations. CD44v+ and CD44v- cells showed the expression of epithelial and mesenchymal markers, respectively. Single-cell sorting of CD44v+ and CD44v- cells revealed both cells gave rise to cell populations consisting of CD44v+ and CD44v- cells, indicating CD44v+ epithelial-like and CD44v- mesenchymal-like cells can generate counterparts, respectively. The ablation of Epithelial splicing regulatory protein 1 (ESRP1), a major regulator of CD44 mRNA splicing, resulted in the shift from CD44v+ to CD44v- cells in KYSE520. However, the expression of epithelial-mesenchymal transition (EMT)-related markers or transcriptional factors were almost not affected, suggesting ESRP1 functions downstream of EMP. Our results revealed the presence of spontaneous EMP in esophageal cancer and KYSE520 is useful model to understand spontaneous EMP.

DOI： 10.1016/j.bbrep.2022.101246

Web of Science

Scopus

PubMed

researchmap

記述言語：日本語  

記述言語：日本語   出版者・発行元：(有)科学評論社  

researchmap

出版者・発行元：Gan to kagaku ryoho. Cancer &amp; chemotherapy  

While it is necessary to provide a detailed cancer treatment according to patient's life stages which are childhood, adolescence and young adulthood, and senior years, there is shortage of human resources who can meet these needs because of few opportunities to train in clinical experience including rare cancers. In addition, since Kyushu has a lot of remote islands and remote areas, it is also important to take measures against elderly cancer patients in such places. On the other hand, the practical application of cancer genomic medicine is accelerating in Japan, however, there is an overwhelming shortage of medical staff who can appropriately apply genomic medicine clinically and who can contribute to the research development of this field. The purpose of"Kyushu Promotion Plan for the Platform of Human Resource Development for Cancer"is to promote the growth of the medical staff specialized for cancer genomic medicine, adolescent and young adult oncology, rare cancers, and measure for cancer depending on the patient's life stage. This plan is consisted with ten universities in Kyushu and we have carried out a variety of events along with these themes above by collaborating with each other for 5 years. These events include lectures, conferences, presentation of their researches, training at the medical center abroad or isolated island, the support system for trainees to get the specialized license for oncologist in Japan. We have run these events successfully and the response from the trainees belonging to this plan was satisfactory. I have confidence that the number of medical staffs who have learned cancer genomic medicine and the cancer treatments depending on the patient's life stage has increased through this project, and they will play an important role as the professional medical staff in the future. We are planning to continue these events even after the end of this plan to keep the number and quality of professional medical staff for cancer.

Scopus

Web of Science

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

While it is necessary to provide a detailed cancer treatment according to patient's life stages which are childhood, adolescence and young adulthood, and senior years, there is shortage of human resources who can meet these needs because of few opportunities to train in clinical experience including rare cancers. In addition, since Kyushu has a lot of remote islands and remote areas, it is also important to take measures against elderly cancer patients in such places. On the other hand, the practical application of cancer genomic medicine is accelerating in Japan, however, there is an overwhelming shortage of medical staff who can appropriately apply genomic medicine clinically and who can contribute to the research development of this field. The purpose of"Kyushu Promotion Plan for the Platform of Human Resource Development for Cancer"is to promote the growth of the medical staff specialized for cancer genomic medicine, adolescent and young adult oncology, rare cancers, and measure for cancer depending on the patient's life stage. This plan is consisted with ten universities in Kyushu and we have carried out a variety of events along with these themes above by collaborating with each other for 5 years. These events include lectures, conferences, presentation of their researches, training at the medical center abroad or isolated island, the support system for trainees to get the specialized license for oncologist in Japan. We have run these events successfully and the response from the trainees belonging to this plan was satisfactory. I have confidence that the number of medical staffs who have learned cancer genomic medicine and the cancer treatments depending on the patient's life stage has increased through this project, and they will play an important role as the professional medical staff in the future. We are planning to continue these events even after the end of this plan to keep the number and quality of professional medical staff for cancer.

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gastric Cancer  

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

DOI： 10.1007/s10120-022-01307-8

Web of Science

Scopus

PubMed

researchmap

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

While it is necessary to provide a detailed cancer treatment according to patient's life stages which are childhood, adolescence and young adulthood, and senior years, there is shortage of human resources who can meet these needs because of few opportunities to train in clinical experience including rare cancers. In addition, since Kyushu has a lot of remote islands and remote areas, it is also important to take measures against elderly cancer patients in such places. On the other hand, the practical application of cancer genomic medicine is accelerating in Japan, however, there is an overwhelming shortage of medical staff who can appropriately apply genomic medicine clinically and who can contribute to the research development of this field. The purpose of"Kyushu Promotion Plan for the Platform of Human Resource Development for Cancer"is to promote the growth of the medical staff specialized for cancer genomic medicine, adolescent and young adult oncology, rare cancers, and measure for cancer depending on the patient's life stage. This plan is consisted with ten universities in Kyushu and we have carried out a variety of events along with these themes above by collaborating with each other for 5 years. These events include lectures, conferences, presentation of their researches, training at the medical center abroad or isolated island, the support system for trainees to get the specialized license for oncologist in Japan. We have run these events successfully and the response from the trainees belonging to this plan was satisfactory. I have confidence that the number of medical staffs who have learned cancer genomic medicine and the cancer treatments depending on the patient's life stage has increased through this project, and they will play an important role as the professional medical staff in the future. We are planning to continue these events even after the end of this plan to keep the number and quality of professional medical staff for cancer.

PubMed

researchmap

記述言語：日本語  

PubMed

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Monitoring proteinuria is important for the management of patients with cancer treated with anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR) inhibitors (VEGF/Ri). Here we investigated the difference between the urine protein/creatinine ratio (UPCR) and a qualitative value test (QV) on the decision making of treatment continuation and the usefulness of UPCR testing in patients with gastrointestinal cancer treated with anti-VEGF/Ri. METHODS: From January 2017 to December 2018, a survey was conducted based on the medical records of patients with gastrointestinal cancer with a QV of ≥2+ during the use of anti-VEGF/Ri at seven Japanese institutions participating in the Onco-nephrology Consortium. The primary endpoint was the ratio of the worst UPCR < 2.0 (low UPCR) in cases with a QV2+ at the point of the first proteinuria onset. The secondary endpoints were a comparison of low UPCR and worst UPCR ≥2.0 (high UPCR), the concordance rate between UPCR and QV in the Common Terminology Criteria for Adverse Events (CTCAE) grading, and the differences in the decision making for anti-VEGF/Ri continuation. RESULTS: Among the 71 patients enrolled, the proportion of low UPCR in onset QV2+ (n = 53) was 66% (n = 35). In a comparison between low (n = 36) and high UPCR cases (n = 24), body weight (P = 0.036), onset QV status (P = 0.0134), and worst QV status (P < 0.0001) were significantly associated with UPCR levels. The concordance rate for CTCAE Grade 2 of both the QV and UPCR was 83%. Regarding the judgment of anti-VEGF/Ri continuation, treatment was continued in 42.4% of cases when the QV became 3+, whereas only 25% continued treatment when the UPCR value became high. CONCLUSION: Urine dipstick test results may overestimate proteinuria, and the UPCR result tended to be more critical than the QV when deciding the treatment policy. TRIAL REGISTRATION: This study is a multiple institutional retrospectively registered observational trial. CLINICAL TRIAL NUMBER: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (protocol ID UMIN000042545 ).

DOI： 10.1186/s12885-022-09611-3

記述言語：日本語  

記述言語：日本語   出版者・発行元：(有)科学評論社  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD9.0000000000000196

researchmap

出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28104305

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Letters  

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

DOI： 10.1016/j.canlet.2022.215597

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   出版者・発行元：International Journal of Clinical Oncology  

The article, Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2 written by Akiko Tozawa, Fuminori Kimura, Yasushi Takai, Takeshi Nakajima, Kimio Ushijima, Hiroaki Kobayashi, Toyomi Satoh, Miyuki Harada, Kohei Sugimoto, Shigehira Saji, Chikako Shimizu, Kyoko Akiyama, Hiroko Bando, Akira Kuwahara, Tatsuro Furui, Hiroshi Okada, Koji Kawai, Nobuo Shinohara, Koichi Nagao, Michio Kitajima, Souichi Suenobu,Toshinori Soejima, Mitsuru Miyachi, Yoko Miyoshi, Akihiro Yoneda, Akihito Horie,Yasushi Ishida, Noriko Usui, Yoshinobu Kanda, Nobuharu Fujii, Makoto Endo, Robert Nakayama, Manabu Hoshi, Tsukasa Yonemoto, Chikako Kiyotani, Natsuko Okita, Eishi Baba, Manabu Muto, Iwaho Kikuchi, Ken‑ichirou Morishige, Koichiro Tsugawa, Hiroyuki Nishiyama, Hajime Hosoi, Mitsune Tanimoto, Akira Kawai, Kazuhiko Sugiyama, Narikazu Boku, Masato Yonemura, Naoko Hayashi, Daisuke Aoki, Nao Suzuki, Yutaka Osuga was originally published Online First without Open Access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on February 14, 2022 to © Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0. The original article has been corrected.

DOI： 10.1007/s10147-022-02137-5

Web of Science

Scopus

PubMed

researchmap

DOI： 10.1200/JCO.2022.40.4_suppl.280

Web of Science

DOI： 10.1200/JCO.2022.40.4_suppl.258

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

DOI： 10.1007/s10147-021-02081-w

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Clinical Oncology  

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

DOI： 10.1007/s10147-021-02076-7

Web of Science

Scopus

PubMed

researchmap

Web of Science

Web of Science

Web of Science

Web of Science

Web of Science

記述言語：英語   出版者・発行元：Case Reports in Oncology  

Desmoid tumors are clonal fibroblastic neoplasms that arise in soft tissues. Patients with familial adenomatous polyposis (FAP) can develop intra-abdominal desmoid tumors. However, metachronous appearance of intra-abdominal desmoid tumor is rare, and its clinical course is not well known. Here, we report a case of spontaneous regression of metachronous intra-abdominal desmoid tumor in a 36-year-old man with FAP. The patient was diagnosed with FAP and underwent laparoscopic total colorectomy. Intra-abdominal desmoid tumor appeared 2 years later and progressed despite treatment with tamoxifen and sulindac. He received four cycles of combinatory therapy with dacarbazine and adriamycin, resulting in shrinkage and stabilization of the desmoid tumor even after cessation of chemotherapy. A new intra-abdominal desmoid tumor developed 2 years later at a different site from the first lesion and progressed from 65 mm to 70 mm in diameter within a month. The size of the first lesion, however, remained unchanged. We prepared for chemotherapy because the second lesion progressed, but follow-up computed tomography showed spontaneous shrinkage of the second lesion. The patient still has not needed additional therapy as of more than 4 years after the appearance of the second lesion. Immunohistochemical staining showed the presence of macrophages in the second lesion. Although metachronous intra-abdominal desmoid tumor is rare and management protocols have yet to be established, this case suggests that an active surveillance approach may be applicable under careful follow-up in asymptomatic patients.

DOI： 10.1159/000521920

Web of Science

Scopus

PubMed

researchmap

記述言語：英語  

Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.

DOI： 10.3892/mco.2021.2379

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94-18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10-0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin.

DOI： 10.3390/jcm10214972

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Approximately 12-15% of gastric cancers (GCs) are human epidermal growth factor receptor-2 (HER2)-positive (HER2 immunohistochemistry 3 + or 2 + /in situ hybridization + [ERBB2/CEP17 ≥ 2.0]). While the anti-HER2 monoclonal antibody trastuzumab, in combination with chemotherapy, is the standard treatment for HER2-positive GC, other HER2-targeted therapies have not demonstrated survival benefits in patients with GC, despite showing efficacy in patients with HER2-positive breast cancer. This indicates that there are unique challenges to the use of currently available HER2-targeted therapies for the treatment of HER2-positive GC. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 human monoclonal IgG1 antibody with the same amino acid sequence as trastuzumab, an enzymatically cleavable peptide-based linker, and DXd, a novel topoisomerase I inhibitor, as its released payload. T-DXd has a high drug-antibody ratio (approximately 8) and a demonstrated bystander antitumor effect. It has demonstrated significant efficacy when compared with standard therapies and is approved as third- or later-line treatment for HER2-positive GC in Japan and second- or later-line treatment in the US. T-DXd treatment is associated with gastrointestinal and hematological adverse events, and a risk of interstitial lung disease (ILD), with the ILD risk being higher in Japan than in countries other than Japan. However, most adverse events, including ILD, can be managed with proactive monitoring and T-DXd dose modification, and initiation of adequate treatment. In this review, we summarize the discovery and development of T-DXd and provide guidance for T-DXd safety management, including ILD monitoring, for patients with HER2-positive GC.

DOI： 10.1007/s10120-021-01196-3

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Kyushu University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine since February 2018. Our institution promotes cancer genomic medicine collaborating with 10 Cooperative Hospitals for Cancer Genomic Medicine among Kyushu region. Over 500 solid tumor cases have been examined by cancer genomic profiling tests and the results have been intensively evaluated and discussed in the expert panel meetings. To expand cancer genomic medicine for Kyushu region, we have started a consultation desk for the cancer patients in the local community and began educating programs as cancer genomic medicine seminars for the medical staff of Cooperative Hospitals for Cancer Genomic Medicine. A consultation system has been established to discuss the indication of"Patient requested medical care system". Kyushu University Hospital is now focusing on rare cancer care and medical genetics. Thus close cooperation with cancer genomic medicine and each department has been started. We would like to look back on current progress and issues of cancer genomic medicine in Kyushu University Hospital.

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly published "Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment" in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made. METHODS: A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020. RESULTS: The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines. CONCLUSION: We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.

DOI： 10.1007/s10147-020-01831-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

DOI： 10.1007/s10147-020-01803-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the neutrophil to lymphocyte ratio (NLR) was reported to be a predictive biomarker for clinical outcomes in various types of cancer, including recurrent or metastatic head and neck cancer (R/M HNSCC) treated with nivolumab, the usefulness of the pretreatment C-reactive protein/albumin ratio (CAR) as a prognostic marker remains to be clarified. This study aimed to analyze the clinical usability of the CAR in comparison with that of the NLR. 46 R/M HNSCC patients treated with nivolumab were retrospectively analyzed. The optimal cutoff value for the CAR was calculated using receiver operating characteristic curve analysis. The optimal cutoff value for the CAR was set to 0.30. On multivariate analyses, a high CAR was significantly associated with poor overall survival (adjusted HR, 2.19; 95% CI, 1.42-3.47; p < 0.01) and progression-free survival (adjusted HR, 1.98; 95% CI, 1.38-2.80; p < 0.01). The overall response rate and disease control rate for the high CAR patients were lower than for the low CAR patients. The CAR had significantly higher area under the curve values than the NLR at 2 and 4 months. The pretreatment CAR might be an independent marker for prognosis and efficacy in R/M HNSCC patients treated with nivolumab.

DOI： 10.1038/s41598-021-82448-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide™ NCC Oncopanel System and FoundationOne® CDx (F1CDx). Our purpose was to identify potentially actionable genetic alterations in breast cancer with this comprehensive tumor profiling test. We enrolled 115 patients with pathologically diagnosed advanced or metastatic breast cancer. Comprehensive tumor genomic profiling, microsatellite instability, and tumor mutational burden (TMB) were determined using F1CDx. Testing was successful in 109/115 cases (94.8&#37;). Clinically actionable alterations were identified in 76&#37; of advanced breast cancer patients. The most frequent short variants were in TP53 (48.6&#37;), PIK3CA (38.5&#37;), GATA3 (11.0&#37;), PTEN (11.0&#37;), and BRCA1 (10.1&#37;), and structural variants were in ERBB2 (24.8&#37;), MYC (21.1&#37;), RAD21 (21.1&#37;), CCND1 (11.9&#37;), FGF19 (10.1&#37;), and PTEN (10.1&#37;). Regarding human epidermal growth factor receptor (HER)2 status, 106/109 samples (97.2&#37;) were concordant between F1CDx and HER2 testing with immunohistochemistry/fluorescence in situ hybridization. However, ERBB2 amplification was newly detected in four samples and ERBB2 mutations were detected in five HER2-negative breast cancer samples. Oncogenic BRCA mutations were found in three samples with F1CDx among 27 germline testing-negative samples. The mean TMB in all samples was 6.28 mut/Mb and tended to be higher in luminal B and triple-negative breast cancer (mean = 8.1 and 5.9 mut/Mb, respectively) compared with other subtypes. In conclusion, we established a system for precision oncology and obtained preliminary data with NGS as the first step. The information in this clinical sequencing panel will help guide the development of new treatments for breast cancer patients.

DOI： 10.1002/cam4.3619

記述言語：英語   掲載種別：研究論文（学術雑誌）  

<title>Abstract</title>Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95&#37; CI: 1.0-not reached) and 3.9 months (95&#37; CI: 2.7–5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.

DOI： 10.1038/s41598-020-77898-y

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fat mass and obesity-associated protein (FTO) is an enzyme that demethylates N6-methyladenosine (m6A), the most abundant RNA modifications in a cell. The upregulated expression of FTO promotes the progression of various types of cancer by modulating cell-intrinsic genes which relate to malignant potential. However, the impact of FTO on the expression of immune-checkpoint molecules in the tumor cells, which are important for immune escape, has not been well understood. We examined the relevance of FTO to programmed cell death-ligand 1 (PD-L1) expression in colon cancer cells. HCT-116 cells showed high expression of both FTO and PD-L1 proteins. The knockdown of FTO by small interfering RNA decreased mRNA and protein levels of PD-L1 in HCT-116 cells. To elucidate the underlying mechanism by which FTO regulates the expression of PD-L1, we depleted FTO in HCT-116 in the presence of IFN-γ, which is a major stimulus to upregulate PD-L1 expression. Depletion of FTO reduced PD-L1 expression in an IFN-γ signaling-independent manner. RNA immunoprecipitation assay revealed the m6A modification of the PD-L1 mRNA and the binding of FTO to the PD-L1 mRNA in HCT-116. Taken together, our results indicated that FTO could regulate PD-L1 expression in colon cancer cells and provides new insights into the regulation of PD-L1 expression by RNA modification.

DOI： 10.1016/j.bbrc.2020.06.153

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tyrosine kinase inhibitors (TKI) work against various types of cancer by inhibiting angiogenic signaling. Little is understood about the incidence, characteristics, and risk factors associated with thromboembolism induced by TKI in routine clinical practice. We retrospectively analyzed data derived from 29 patients with thyroid cancer or soft tissue sarcoma (STS) treated with lenvatinib (n=10) and pazopanib (n=19). Eight (arterial n=4; venous n=4) thromboembolic events developed in 6 (20%) patients. Thromboembolisms occurred during a mean of 149 (range, 42-847) days from starting TKI. The primary disease progressed in all patients with thromboembolism. The overall survival durations of patients with and without improved thromboembolism were 572 [95% confidence interval (CI), 225- 918] and 176 (95% CI, 84-394) days, respectively, which did not significantly differ (P=0.33). Patients with and without improved thromboembolism survived after onset for 122 (95% CI, 71-173) versus 27 (95% CI, 21-42) days (P=0.049), which significantly differed. Univariate analysis and variate selection for multivariate analysis selected a history of thromboembolism as the most powerful risk factor for new thromboembolism. In summary, the frequency of thromboembolism in clinical practice was higher than that in previous clinical trials. Furthermore, a history of thromboembolism was a risk factor for the development of new thromboembolism in patients treated with TKI. Thromboembolism developed particularly as the primary disease progressed. Our findings require validation in a large-scale study.

DOI： 10.1097/IJ9.0000000000000089

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. PATIENTS AND METHODS: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. RESULTS: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). CONCLUSION: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.

DOI： 10.1016/j.ejca.2020.04.014

記述言語：日本語  

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.annonc.2020.03.299

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated. Results: After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040). Conclusions: Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.

DOI： 10.1038/s41416-020-0810-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

<title>Abstract</title>
In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa−/− mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.

DOI： 10.1182/blood.2019002194

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously proposed using a hydrolysis enzyme for fluorescent signal amplification in flow cytometric detection of antigen proteins, which was named the catalyzed reporter penetration (CARP) method. In this method, antigen proteins are labeled with enzyme-modified antibodies, and then fluorophore-modified substrates stain cells by penetrating the cell membrane upon hydrolysis of the substrate. We proved the concept by using alkaline phosphatase (AP) as the hydrolysis enzyme. However, a required prior inactivation process of endogenous AP activity on the cell surface risked disrupting recognition of antigen proteins by antibodies. In this report, the CARP method was extended to β-galactosidase (β-gal) as an amplification enzyme, which circumvented the requirement of an initial inactivation process because endogenous β-gal activity on the surface of examined cells was found to be negligible. The substrate structure for β-gal was optimized and used for the CARP method. The CARP method showed significantly higher fluorescent signals than a conventional method using fluorophore-modified antibodies. Moreover, the degree of amplification of the fluorescence signal was higher for antigens with low expression levels, showing that the CARP method is a suitable signal amplification method over current conventional approaches.

DOI： 10.1021/acs.analchem.9b04471

記述言語：その他   掲載種別：研究論文（学術雑誌）  

35

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95% CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.

DOI： 10.1200/jco.2020.38.5_suppl.35

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Novel therapeutic agents have improved survival outcomes in patients with advanced solid tumors. In parallel, the development of predictive biomarkers to identify patients who are likely to benefit from a certain treatment has also contributed to the improvement of survival. Recently, clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. In Japan, a PD-1 inhibitor for dMMR advanced solid tumors, regardless of the primary tumor site, has been approved. However, there are some issues related to administering immune checkpoint inhibitors in the clinical practice setting, making it necessary to develop the guidelines. Methods: Clinical questions (CQs) regarding medical care were formulated for patients with dMMR advanced solid tumors, and evidence to the CQs was collected by manual search to prepare recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. Results: The current guideline, which we consider a provisional clinical opinion at this point, describes the 11 requirements to be considered in terms of patients for whom dMMR testing is recommended, the timing and methods of dMMR testing, and clinical care systems required to perform dMMR testing properly and to administer immune checkpoint inhibitors safely. Conclusion: This provisional clinical opinion proposes the requirements for performing dMMR testing properly to select patients who are likely to benefit from immune checkpoint inhibitors and administering them safely.

DOI： 10.1007/s10147-019-01498-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tertiary lymphoid structures (TLSs), clusters of immune cells found around tumor tissue, have been shown to be associated with anti-tumor immunity, but the cellular composition within each TLS and whether the cellular composition of a TLS affects a patient’s prognosis are poorly understood. In the present study, each TLS was categorized according to its cellular composition determined by a system of multiplex immunohistochemical staining and quantitative analysis, and the correlation between the category and prognosis was examined. Sixty-seven patients with curatively resected stage II/III colorectal cancer (CRC) were enrolled. A TLS, consisting of germinal center B cells, follicular dendritic cells, T helper (Th) cells, B cells, cytotoxic T cells, and macrophages, was confirmed in the tumor tissue of 58 patients (87%). The densities of Th cells and macrophages were significantly higher in relapsed patients than in not-relapsed patients (p = .043 and p = .0076). A higher ratio of Th cells was the most significant independent risk factor for disease relapse on multivariate analysis. The subset increasing in Th cells was GATA3⁺ Th2. A total of 353 TLSs was divided into five clusters according to immune cell composition. Among them, the Th-rich type TLS was significantly increased (p = .0009) in relapsed patients. These data suggest the possibility that Th cell-dominant composition might disturb the anti-tumor immune response, and the function of each TLS might differ depending on its composition.

DOI： 10.1080/2162402X.2020.1724763

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epstein–Barr virus (EBV)-associated gastric cancer (GC) is associated with a high degree of DNA methylation. However, the association between chemotherapy susceptibility and tumor DNA methylation in advanced diseases remains unclear. The comprehensive DNA methylation status of GC cells obtained from an advanced EBV-associated GC (EBVGC) case, in which complete response to S-1 plus cisplatin chemotherapy was achieved, was analyzed using a DNA methylation microarray. We compared DNA methylation of GC cells with public data and identified genes with higher methylation in EBVGC cell lines than in normal gastric cells, and genes in which methylation was increased by EBV. Of these genes, ABCG2, AHNAK2, BCL2, FZD1, and TP73 are associated with published evidence for resistance to 5-fluorouracil and cisplatin. Silencing of these genes may be associated with hypersensitivity to chemotherapy.

DOI： 10.1002/2211-5463.12765

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Response Evaluation Criteria in Solid Tumors (RECIST) is used to assess the objective response of solid tumors to treatment. However, it remains unclear to what extent the response rate assessed by RECIST reflects a reduction of tumor size in multiple organs in patients with unresectable advanced or recurrent colorectal cancer (CRC) with multiple organ metastases. It is also unclear whether the management of liver metastases with systemic chemotherapy in CRC patients with multiple organ metastases improves their prognosis, although surgical resection has been shown to be the most effective treatment approach to CRC cases with liver metastases. A total of 38 CRC patients who underwent systemic chemotherapy in Kyushu Medical Center Hospital between January 2013 and April 2016 were examined. The patients had measurable lesions in multiple organs, including the liver, and did not undergo curative surgery for metastatic lesions after initiation of chemotherapy. The association between the total reduction ratio (TRR) of all lesions and liver lesion reduction ratio (LRR) was retrospectively analyzed. A total of 18 patients (47&#37;) had H3 liver metastases, and the median liver lesion occupancy rate in the sum of the measured lesions with RECIST was 76&#37;. TRR and LRR were strongly correlated, regardless of the volume of the liver metastases. Although a TRR of >30&#37; was significantly associated with improved overall survival (OS), this improvement was not observed in patients with H3 liver metastases. TRR was correlated with LRR and was associated with a better OS. CRC patients with both multiple organ and H3 liver metastases exhibited poor survival, even with a high reduction ratio by chemotherapy.

DOI： 10.3892/mco.2019.1894

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. Methods: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. Results: Thirty-four patients (18&#37;) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate–severe ascites (32&#37; versus 17&#37;, 32&#37; versus 14&#37;, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85&#37;) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45&#37;) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). Conclusion: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.

DOI： 10.1007/s10120-019-00930-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Dose modification of chemotherapy for metastatic colorectal cancer (MCRC) is often needed, especially in second-line and later-line treatments due to adverse events of previous treatment and poor patient condition. No study has focused on ramucirumab plus modified dose of FOLFIRI for MCRC, and whether low relative dose intensity (RDI) affects treatment efficacy has not been clarified. Methods: MCRC patients who received ramucirumab plus FOLFIRI, which consisted of 150 mg/m ² of irinotecan, at six institutions were retrospectively analyzed. Results: A total of 43 patients were assessed. Median age was 63 years, and 22 patients (51%) were women. Twenty-six patients (60%) were given ramucirumab plus FOLFIRI as second-line therapy, and 17 (40%) as third or later-line. The median relative dose intensity (RDI) of irinotecan was 60.6%, which is lower than that in the pivotal phase 3 study (RAISE), and other agents showed the same trend. Median progression-free survival was 4.8 [95% confidence interval (CI) 3.2–5.7] months for all patients, 5.4 (95% CI 3.5–7.2) months for second-line patients, and 2.8 (95% CI 1.6–5.8) months for third or later-line patients. Median overall survival was 17.3 (95% CI 11.5–22.4) months for all patients. Patients with irinotecan RDI less than 60% showed similar treatment efficacy. Hematological toxicities of grade 3 or worse were observed in 21 patients, but all were manageable. Conclusion: Low RDI did not compromise the treatment efficacy of ramucirumab plus modified FOLFIRI for MCRC patients.

DOI： 10.1007/s10147-018-01391-w

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The randomized phase III study (WJOG4407G) showed equivalent efficacy between FOLFOX and FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (mCRC). We studied whole genome copy number profiles using array-based comparative genomic hybridization (aCGH) analysis of tumor tissue samples obtained in this study. The aim of this study was to identify gene copy number alterations that could aid in selecting either FOLFOX or FOLFIRI in combination with bevacizumab for patients with mCRC. Materials and Methods: DNA was purified from 154 pretreatment formalin-fixed paraffin-embedded tissue samples (75 from the FOLFOX arm and 79 from the FOLFIRI arm) of 395 patients enrolled in the WJOG4407G trial and analyzed by aCGH. Genomic regions greater than 1.2-fold were regarded as copy number gain (CNG). Results: Patient characteristics between the treatment arms were well balanced except for tumor laterality (left side; 64% in FOLFOX arm and 80% in FOLFIRI arm, p =.07). FOLFIRI showed a trend toward better response rate (RR), progression-free survival (PFS) and overall survival (OS) than FOLFOX in the patients with CNG of chromosome 8q24.1 (Fisher's exact test, p =.134 for RR; interaction test, p =.102 for PFS and p =.003 for OS) and 8q24.2 (Fisher's exact test, p =.179 for RR; interaction test, p =.144 for PFS and p =.002 for OS). Conclusion: Chromosome 8q24.1–q24.2 may contain genes that could potentially serve as predictive markers for selecting either FOLFOX or FOLFIRI in combination with bevacizumab for treatment of patients with mCRC. Implications for Practice: Bevacizumab has been used as a standard first-line treatment for patients with metastatic colorectal cancer (mCRC) in combination with either oxaliplatin-based or irinotecan-based chemotherapy. Until now, there has been no predictive marker to choose between the two combination chemotherapies. This array-based comparative genomic hybridization analysis revealed that the difference in therapeutic effect between the two combination chemotherapies is prominent in patients with mCRC with gene copy number gain in chromosome 8p24.1–p24.2. Such patients showed more favorable response and survival when treated with irinotecan-based combination chemotherapy. Overlapping genes commonly found in this region may be predictive biomarkers of the efficacy of the combination chemotherapy with bevacizumab.

DOI： 10.1634/theoncologist.2018-0119

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 ⁺ CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 ⁺ CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 ⁻ non-CSCs into the undifferentiated CD44 ⁺ CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.

DOI： 10.1038/s41388-018-0480-0

記述言語：その他   掲載種別：研究論文（学術雑誌）  

54

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95% CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

DOI： 10.1200/jco.2019.37.4_suppl.54

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/annonc/mdy502

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of oesophageal cancer was published in 2016, and covered the management and treatment of local/ locoregional disease, limited disease, locally advanced disease and the management of advanced/metastatic disease. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting immediately after the JSMO Annual Meeting in 2018. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic oesophageal cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic oesophageal cancer representing the oncological societies of Japan (JSMO), China (CSCO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

DOI： 10.1093/annonc/mdy498

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autocrine and paracrine factors, including glutamate and epidermal growth factor (EGF), are potent inducers of brain tumor cell invasion, a pathological hallmark of malignant gliomas. System xc(-) consists of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. We previously showed that the EGF receptor (EGFR) interacts with xCT and thereby promotes the activity of system xc(-) in a kinase-independent manner, resulting in enhanced glutamate release in glioma cells. However, the molecular mechanism underlying EGFR-mediated glioma progression in a glutamate-rich microenvironment has remained unclear. Here we show that the GluN2B subunit of the N-methyl-d-aspartate-sensitive glutamate receptor (NMDAR) is a substrate of EGFR in glioma cells. In response to EGF stimulation, EGFR phosphorylated the COOH-terminal domain of GluN2B and thereby enhanced glutamate-NMDAR signaling and consequent cell migration in EGFR-overexpressing glioma cells. Treatment with the NMDAR inhibitor MK-801 or the system xc(-) inhibitor sulfasalazine suppressed EGF-elicited glioma cell migration. The administration of sulfasalazine and MK-801 also synergistically suppressed the growth of subcutaneous tumors formed by EGFR-overexpressing glioma cells. Furthermore, shRNA-mediated knockdown of xCT and GluN2B cooperatively prolonged the survival of mice injected intracerebrally with such glioma cells. Our findings thus establish a central role for EGFR in the signaling crosstalk between xCT and GluN2B-containing NMDAR in glioma cells.

DOI： 10.1111/cas.13826

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Assessment of patient factors is essential for selecting later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). The efficacy, prognosis, and safety of each treatment regimen according to nutritional and inflammatory status still remain to be elucidated. PATIENTS AND METHODS: A total of 550 patients with mCRC who were registered in the REGOTAS study (Regorafenib versus TAS-102 as Salvage-line in patients with colorectal cancer refractory to standard chemotherapies: a multicenter observational study, UMIN 000020416) and treated with trifluridine/tipiracil (TFTD) or regorafenib as a later-line therapy were retrospectively stratified according to the modified Glasgow Prognostic Score (mGPS), which divided patients into mGPS 0 to 2 by serum albumin and C-reactive protein, and compared. RESULTS: The median overall survival (OS) of patients with mGPS 0, 1, and 2 was 10.0 months (95&#37; confidence interval [CI], 9.2-11.6 months), 6.5 months (95&#37; CI, 5.3-7.1 months), and 3.9 months (95&#37; CI, 3.3-4.9 months), respectively. The median progression-free survival (PFS) with mGPS 0, 1, and 2 was 2.5 months (95&#37; CI, 2.1-3.0 months), 2.0 months (95&#37; CI, 1.9-2.3 months), and 1.7 months (95&#37; CI, 1.4-1.9 months), respectively. There were significant differences by mGPS in both OS and PFS (all P < .001). No significant differences in OS and PFS were observed between the patient groups treated with TFTD and regorafenib in each mGPS group. In patients aged ≥ 65 years with mGPS 2, the OS and PFS were worse with regorafenib than with TFTD (OS: hazard ratio, 1.45; 95&#37; CI, 0.93-2.25; P = .097; PFS: hazard ratio, 1.57, 95&#37; CI, 1.01-2.44; P = .047), but there were no consistent trends observed as mGPS increased. The frequency of grade 3 and more adverse events was generally similar in each mGPS group. The multivariate analyses showed that mGPS was the strongest predictive factor for OS. CONCLUSIONS: The mGPS before later-line chemotherapy is strongly correlated with survival in patients with mCRC.

DOI： 10.1016/j.clcc.2018.07.004

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Disseminated cancer cells in malignant ascites possess unique properties that differ from primary tumors. However, the biological features of ascites tumor cells (ATC) have not been fully investigated. By analyzing ascites fluid from 65 gastrointestinal cancer patients, the distinguishing characteristics of ATC were identified. High frequency of CD44+ cells was observed in ATC using flow cytometry (n = 48). Multiplex quantitative PCR (n = 15) showed higher gene expression of epithelial-mesenchymal transition (EMT)-related genes and transforming growth factor beta (TGF-beta)-related genes in ATC than in the primary tissues. Immunohistochemistry (n = 10) showed that ATC also had much higher expression of phosphorylated SMAD2 than that in the corresponding primary tissues. TGF-beta 1 was detected in all cases of malignant ascites by enzyme-linked immunoassay (n = 38), suggesting the possible interaction of ATC and the ascites microenvironment. In vitro experiments revealed that these ATC properties were maintained by TGF-beta 1 in cultured ATC(n = 3). Here, we showed that ATCrevealed high frequencies of CD44 and possessed distinct EMT features from primary tissues that were mainly maintained by TGF-beta 1 in the ascites.

DOI： 10.1111/cas.13777

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of central/effector memory T cells and T-helper 1 polarization in malignant melanoma patients treated with anti-programmed death-1 antibody.
Human anti-programmed death-1 (PD-1) antibody possesses the capability to revitalize host T cells and has been an effective therapy for metastatic malignant melanoma (MM). The precise subsets of T cells predominantly activated by anti-PD-1, however, have not yet been clarified. In this study, peripheral blood mononuclear cells obtained from MM patients scheduled to receive anti-PD-1 (nivolumab) therapy, and healthy subjects (HS), were systematically examined on flow cytometry to identify changes in the proportion of immune cell subsets. Compared with HS, MM patients prior to therapy had an increased proportion of activated CD8+ T cells with effector memory phenotypes (Tem), and PD-1 positive subsets of CD4+ central memory T cells (Tcm) and T-helper (Th)17 cells. After a single course of anti-PD-1 therapy, MM patients had an increase in activated Tem and Tcm subsets of CD4+ and CD8+ T cells, and activated Th1 plus T-helper follicular 1 cells. There was no consistent change in the proportion of Tfh cells, B cells, natural killer cells, or dendritic cells. The observed activated phenotypes were attenuated during the course of therapy, but regulatory T cells belonging to the CD3+CD4+CD45RO+CD25high fraction increased at disease progression. Taken together, anti-PD-1 therapy modulates systemic immune reactions and exerts anti-tumor effects, not only by revitalizing Tem and Tcm of CD4+ and CD8+ T cells, but also via a shift to a Th1 phenotype.

DOI： 10.1111/cas.13758

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study. METHODS: AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent. RESULTS: A total of 60 patients including 39 males and 21 females were examined. The median age was 66 years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or < 100 mg/m2 oxaliplatin was administered to 12, 39, and 9 patients, respectively. S-1 or capecitabine as a concomitant drug was administered in 54 and 6 patients, respectively. In multivariate analysis, the comorbidity of diabetes mellitus was associated with ≥ grade 2 thrombocytopenia (p = 0.035). No significant risk factor was associated with ≥ grade 2 PSN. However, the accumulated dose of oxaliplatin exhibited a strong correlation with ≥ grade 2 PSN (p = 0.0043), and the predicted accumulated dose of oxaliplatin in which 10&#37; of patients developed ≥ grade 2 PSN was 800 mg/m2. The frequency of PSN in subsequent paclitaxel therapy in patients with ≥ grade 2 or worse PSN in oxaliplatin-based chemotherapy did not increase compared to those with none or grade 1 PSN in oxaliplatin. CONCLUSION: Thrombocytopenia in AGC patients with diabetes mellitus should be carefully monitored during oxaliplatin-based therapy.

DOI： 10.1007/s00280-018-3652-2

記述言語：英語  

DOI： 10.1093/annonc/mdy281.151

記述言語：英語  

DOI： 10.1093/annonc/mdy281.058

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metastatic esophageal carcinosarcoma comprising neuroendocrine carcinoma, squamous cell carcinoma, and sarcoma: A case report.
RATIONALE: Esophageal carcinosarcoma generally comprises 2 histological components: squamous cell carcinoma (SqCC) and sarcoma. Esophageal carcinosarcoma comprising 3 components is extremely rare and no reports have described therapeutic effects for this disease with metastasis. PATIENT CONCERNS: A 76-year-old man with dysphagia presented to a local clinic. Gastrointestinal endoscopy revealed a polypoid tumor in the middle esophagus and he was referred to our hospital. DIAGNOSIS AND INTERVENTIONS: Thoracoscopic esophagectomy with super-extended (D3) nodal dissection and gastric tube reconstitution was performed, which resulted in carcinosarcoma comprising neuroendocrine carcinoma (NEC), SqCC, and sarcoma. Pathological stage was T1bN1M0 stage IIB according to the TNM Classification of Malignant Tumors-7th edition. The NEC component was observed in lymph node. At 47 days after surgery, lymph nodes, liver, and bone metastasis appeared, and tumor markers such as ProGRP and NSE were elevated. Combination chemotherapy with cisplatin and etoposide (EP) adapted to NEC was performed. OUTCOMES: The patient showed complete response within 4 cycles of chemotherapy. However, the disease recurred 5.5 months after the final course of EP chemotherapy. LESSONS: A therapeutic strategy based on assessment of which component caused metastasis might be important for metastatic carcinosarcoma comprising 3 components, although more accumulation of data about the efficacy of chemotherapy is necessary. Moreover, elucidation of the mechanisms underlying generation of carcinosarcoma is expected in the future.

DOI： 10.1097/MD.0000000000012796

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer.
The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.

DOI： 10.1111/cas.13723

記述言語：英語   掲載種別：研究論文（学術雑誌）  

E‑cadherin regulates proliferation of colorectal cancer stem cells through NANOG.
Cancer stem cells (CSCs) possess a self‑renewal ability and display tumorigenic potential in immunodeficient mice. Colorectal CSCs are thought to be a uniform population and no functionally distinct subpopulations have been identified. Because E‑cadherin is an essential molecule for self‑renewal of embryonic stem cells, we examined E‑cadherin expression, which may play a role in maintaining the properties of CSCs, in EpCAMhigh/CD44+ colorectal CSCs from human primary colorectal cancers. We obtained 18 surgical specimens of human primary colorectal cancer. CD44, EpCAM, and E‑cadherin expression were analyzed by fluorescence‑activated cell sorting. Sorted EpCAMhigh/CD44+ colorectal CSCs were injected into immunodeficient mice to estimate the tumorigenic potential. Genetic profiles were analyzed by cDNA microarray. Notably, colorectal CSCs could be divided into two populations based on the E‑cadherin expression status, and they exhibited different pathological characteristics. Compared to E‑cadherin‑negative colorectal CSCs, E‑cadherin‑positive (EC+) colorectal CSCs demonstrated higher tumor growth potential in vivo. EC+ colorectal CSCs revealed a higher expression of the pluripotency factor NANOG, which contributed to the higher tumor growth potential of EC+ colorectal CSCs through control of cyclin D1 expression. These findings are the first demonstration of functionally distinct subpopulations of colorectal CSCs in human clinical samples.

DOI： 10.3892/or.2018.6464

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug. METHODS: To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course. RESULTS: Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3&#37;) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70&#37; (95&#37; confidence interval [CI]: 55&#37;-83&#37;) in the overall phase and 91&#37; (95&#37; CI: 78&#37;-97&#37;) in the acute phase and 70&#37; (95&#37; CI: 55&#37;-83&#37;) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed. CONCLUSIONS: These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

DOI： 10.1097/MD.0000000000011042

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rationale:Metastatic littoral cell angioma (LCA) is extremely rare. No standard therapeutic strategy has been established, and the impact of chemotherapy has not yet been evaluated.Patient concerns:A 61-year-old woman was admitted because of bicytopenia. She had a splenectomy for LCA of the spleen 10 years earlier. Bone marrow aspiration was normal, and a computed tomography (CT) scan showed hepatomegaly with multiple liver tumors. Diagnoses:Liver biopsy samples showed macrophage-like cell infiltration in the hepatic sinusoids. Metastatic LCA was diagnosed based on immunohistochemistry, imaging tests, and the clinical course.Interventions:Immunosuppressive agents, such as prednisolone and cyclosporine, were ineffective. Next, cytotoxic agents, such as etoposide, paclitaxel, and vincristine, were administered.Outcomes:Cytotoxic agents showed a prominent effect against LCA. CT showed improvement of the hepatomegaly, and fluoro-deoxyglucose (FDG) uptake decreased markedly at a follow-up FDG- positron emission tomography (PET) scan.Lessons:Chemotherapeutic treatment based on hemophagocytic syndrome or angiosarcoma might have anti-tumor activity against metastatic LCA. Analysis of the molecular characteristics of this tumor is needed to develop better treatment options.

DOI： 10.1097/MD.0000000000010378

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. Patients and methods The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Results Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1-60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Conclusion Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.

DOI： 10.1136/esmoopen-2017-000301

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. Methods: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. Results: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210
SP group, 234)
the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients’ characteristics were comparable between groups, except the male ratio (S-1 group, 64.2&#37;
SP group, 77.1&#37;
p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p &lt
0.001 each). Conclusion: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.

DOI： 10.1007/s10120-018-0797-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Oxaliplatin + S-1 is a recognized treatment regimen in Japan, but there are no Japanese clinical data on an oxaliplatin dose of 130 mg/m2. The current research involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg/m2 to treat HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy in Japan. METHODS/DESIGN: The primary endpoint of this trial will be the response rate, and the secondary endpoints will be the safety profile of oxaliplatin + S-1, progression-free survival, the response rate in subjects under the age of 75, overall survival, time to treatment failure, duration of treatment, time to failure of strategy, and dose intensity. The threshold response rate is 45&#37; and the expected response rate is 60&#37;. Assuming that a one-tailed score test will be performed with an α of 0.05, 68 patients are needed to ensure a statistical power of 80&#37;. Planned enrollment is 70 subjects and the total duration of this trial is expected to be 3 years. DISCUSSION: Since replacing cisplatin with oxaliplatin should provide the same level of therapeutic efficacy while limiting adverse events and simplifying treatment, oxaliplatin + S-1 may be increasingly used to treat gastric cancer in Japan. Verifying the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg is an important task that the current trial has set out to achieve. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000017550) on May 29, 2015. The details are available at the following web address: http://www.umin.ac.jp/ctr/ .

DOI： 10.1186/s12885-017-3937-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment. MATERIALS AND METHODS: The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics. RESULTS: A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95&#37; confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95&#37; CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95&#37; CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95&#37; CI, 0.98-1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78; 95&#37; CI, 0.59-1.03). CONCLUSION: No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies. IMPLICATIONS FOR PRACTICE: Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.

DOI： 10.1634/theoncologist.2017-0275

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Despite the expanding use of flow cytometry, its detection limit is not satisfactory for many antigen proteins with low copy numbers. Herein, we describe an alkaline phosphatase (AP)-based technique to amplify the fluorescence signal for cell staining applications. We designed a fluorescent substrate that acquires membrane permeability upon dephosphorylation by AP. By using the substrate, the fluorescence signal of cells in flow cytometry could be successfully amplified to give a much stronger signal than the cells labeled using a conventional fluorophore-modified antibody.

DOI： 10.1021/acs.analchem.7b03893

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rationale: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. Patient concerns: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. Diagnosis: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. Interventions: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. Outcomes: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. Lessons: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

DOI： 10.1097/MD.0000000000008987

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Readministration of anti-epidermal growth factor receptor (EGFR) antibody for metastatic colorectal cancer (mCRC) after disease progression remains to be determined. Patients and Methods: Readministration of anti-EGFR antibody in mCRC patients previously refractory to anti-EGFR antibody was prospectively observed. Results: A total of thirteen patients with a median age of 60-years old and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled. The median number of previous chemotherapies was 3 (range 2-5). Prior anti-EGFR antibody in combination with cytotoxic drugs was administered in 12 patients. Anti-EGFR antibody readministration regimens were cetuximab/panitumumab plus capecitabine/S-1 (seven patients), panitumumab plus FOLFOX (three patients), cetuximab plus irinotecan (two patients), and panitumumab monotherapy (one patient). Seven patients showed stable disease following readministration and six patients showed progressive disease. The median overall survival (OS) following readministration was 228 days and the median PFS was 102 days. Patients with intervals longer than 90 days between anti-EGFR therapies exhibited more favorable survival than those with intervals shorter than 90 days. Switching of anti-EGFR antibody between treatments was observed to contribute survival. Conclusion: Anti-EGFR antibody readministration could show a modest survival benefit in mCRC patients, with the length of therapy interval and switching of antibody being important contributory factors.

DOI： 10.21873/anticanres.12101

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66&#37;) patients. The median EETS, DPR, progression-free survival, and OS were 16.1&#37;, 27.2&#37;, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R-2= 0.429), whereas EETS and DPR were less correlated with OS (R-2= 0.0682, 0.186). EETS was well correlated with DPR (R-2=0.659). Patients with EETS greater than 16.12&#37; were predicted to achieve tumor shrinkage of more than 30&#37; at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy. Copyright (c) 2017 Wolters Kluwer Health, Inc. All rights reserved.

DOI： 10.1097/CAD.0000000000000562

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rationale:The multi-targeted tyrosine kinase inhibitors such as cediranib, sunitinib and pazopanib have been reported to be effective for alveolar soft part sarcoma (ASPS). The efficacy of pazopanib for the patient with lingual ASPS has yet to be reported.Patient concerns:A 23-year old man presented with articulation disorder and swelling of the tongue. Diagnosis of lingual ASPS was made after incisional biopsy and complete excision of the mass was performed. Three months later, he presented with a protruding mental region.Diagnoses:Computed tomography revealed mental region mass and lung metastasis.Interventions:After the failure of combination therapy of doxorubicin and ifosfamide, pazopanib was administered.Outcomes:Shrinkage of both the mental region and lung mass continued for more than two months, but regrowth was confirmed at the fourth month.Lessons:Lingual ASPS is an exceedingly rare subset of ASPS with distinct molecular and histological characteristics and appropriate therapy remains to be established. Our findings suggest a possible therapeutic strategy for lingual ASPS.

DOI： 10.1097/MD.0000000000008470

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA.
This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20-80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety.
Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31-79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58&#37;) and jejunum in 10 patients (42&#37;). The median follow-up time was 14.7 months (3.7-40.3). The 1-year PFS was 23.3&#37;. The ORR was 9/20 (45&#37;). The median PFS and OS times were 5.9 months (95&#37; confidence interval [CI] 3.0-10.2) and 17.3 months (95&#37; CI 11.7-19.0), respectively. Major grade 3/4 toxicities were neutropenia (38&#37;), anemia/peripheral neuropathy (25&#37;), and stenosis (17&#37;). There were no treatment-related deaths.
Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

DOI： 10.1007/s10147-017-1138-6

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Rationale:Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known.Patient concerns:Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50&#37; dose reduction due to liver dysfunction.Diagnoses:Fundus examination revealed hemorrhage of the retinal vein.Interventions:Regorafenib treatment was discontinued and observational therapy was pursued.Outcomes:Retinal and gastrointestinal hemorrhage resolved in 1 week.Lessons:Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified.

DOI： 10.1097/MD.0000000000008285

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Irinotecan monotherapy as third-line or later treatment in advanced gastric cancer
BACKGROUND: Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated. METHODS: Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed. RESULTS: A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3&#37; had prior platinum therapy. The median age was 66 (range 27-81) years, and 102 males (69.9&#37;) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0&#37;) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5&#37;/7.5&#37;). The median number of administrations was 4 (range 1-62). Forty-six patients (31.5&#37;) required initial dose reduction at the physician's discretion. The overall response rate was 6.8&#37;, and the disease control rate was 43.1&#37;. The median PFS was 3.19 months [95&#37; confidence interval (CI) 2.30-4.08 months], and the median OS was 6.61 months (95&#37; CI 5.94-7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5&#37;) and non-hematological toxicity (50 patients, 34.2&#37;). Hospitalization due to adverse events was required in 31 patients (21.2&#37;). Patients with relative dose intensity (RDI) less than 80&#37; showed similar survival to those with RDI 80&#37; or higher. CONCLUSIONS: Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival.

DOI： 10.1007/s10120-017-0759-9.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Analysis of a Questionnaire Survey regarding Current Conditions against Exposure to Anticancer Drugs and Reports of Cancer Chemotherapy at Outpatient Departments in Japan

記述言語：英語   掲載種別：研究論文（学術雑誌）  

An advanced granulocyte-colony stimulating factor (G-CSF)-producing tumor is rare, and it exhibits leukocytosis in association with high serum G-CSF levels. A 67-year-old male with a 1-month history of bloody emesis and black stools was revealed to exhibit leukocytosis, anemia and a high serum concentration of G-CSF. During a gastrointestinal endoscopy, an ulcerating tumor was identified in the stomach. Computed tomography and a fluorodeoxyglucose-positron emission tomography scan demonstrated direct invasion of the gastric tumor into the transverse colon, regional lymphadenopathy, lung nodules and diffuse high uptake of FDG in bone marrow. The histological diagnosis was a G-CSF-producing neuroendocrine carcinoma (NEC) (tumor 4b, node 2, metastasis 1, pulmonary, clinical stage IV). Systemic chemotherapy consisting of cisplatin and irinotecan was started. Common terminology criteria of adverse events grade 3 tumor lysis syndrome and gastric penetration appeared. Grade 4 neutropenia lasted for 10 days despite intensive G-CSF administration. Prominent shrinkage of the primary and the metastatic tumors was observed subsequent to 3 cycles of chemotherapy. Total gastrectomy and resection of the transverse colon were subsequently performed. Systemic chemotherapy was effective for a G-CSF-producing advanced gastric NEC with careful monitoring and appropriate supportive care for severe adverse events.

DOI： 10.3892/ol.2017.6299

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA.
Methods The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome.
Results Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67&#37;), the ampulla of Vater in three patients (9&#37;), the jejunum in seven patients (21&#37;) and the ileum in one patient (3&#37;). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61&#37;) and nine (27&#37;) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25&#37; and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed.
Conclusions The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.

DOI： 10.1007/s00280-017-3371-0

記述言語：英語  

xCT promotes malignant phenotypes in EGFR-expressing glioma

DOI： 10.1158/1538-7445.AM2017-LB-334

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerise chain reaction (dPCR)-based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation).
Materials and Methods: Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations.
Results: The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1&#37; (range, 90.0-100&#37;). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7&#37; (range, 89.1-99.5&#37;). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner.
Conclusions: Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment. (C) 2017 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.lungcan.2017.02.019

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic acinar cell carcinoma (PACC) is a rare tumor of the exocrine pancreas, representing only 1% of all pancreatic malignancies. A 50-year-old man presented with edema of the thumb joints bilaterally, followed by an appearance of masses in the bilateral lower extremities and fever (38°C). The masses were diagnosed as panniculitis by skin biopsy, and multiple intraperitoneal masses were incidentally detected on pelvic magnetic resonance imaging performed to investigate the leg abnormalities. The patient was referred to the Kyushu University Hospital for further investigation, and fluorodeoxyglucose-positron emission tomography/computed tomography (CT) revealed high-uptake tumors in the pancreatic tail, in the periphery of the liver, and in the pelvis. Laboratory examinations revealed high serum concentrations of pancreatic exocrine enzymes, such as lipase, trypsin, elastase 1 and pancreatic phospholipase A2. Histological examination of a bioptic specimen obtained from a hepatic lesion revealed proliferation of atypical cells arranged in a tubular or glandular pattern. Immunohistochemical staining revealed that the atypical cells were positive for cytokeratin (CK)7, CK19 and lipase, but negative for CK20 and thyroid transcription factor-1, leading to a final diagnosis of acinar cell carcinoma of the pancreatic tail (T4bN0M1, stage IV according to the 7th edition of the TNM Classification of Malignant Tumors). Combined chemotherapy with oxaliplatin, irinotecan and fluorouracil (FOLFIRINOX) was administered and fever was soon alleviated. The serum levels of lipase also declined and panniculitis completely resolved. As of the start of the 8th course of chemotherapy, the levels of the pancreatic exocrine enzymes were within normal ranges and CT revealed partial response. Therefore, the severe lipase hypersecretion syndrome was well controlled by the FOLFIRINOX regimen and shrinkage of the mass was also achieved. Thus, the FOLFIRINOX regimen may represent an effective treatment option for advanced PACC.

DOI： 10.3892/mco.2017.1240

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear. Patients and Methods: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined. Results: The median age was 67 years and oxaliplatin was administered to 39 (71&#37;) patients as first-line and in 16 (29&#37;) patients as second-line therapy. An initial dose of 130 or 100 mg/m(2) of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33&#37;, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m(2), the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m(2). A total of 10 patients (18&#37;) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14&#37; and the mPFS was 6.1 months. Conclusion: An initial oxaliplatin dose of 130 mg/m(2) resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.

DOI： 10.21873/anticanres.11614

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Inflammation is considered to be a prognostic factor for renal cell carcinoma (RCC). An inflammation-based prognostic score (modified Glasgow Prognostic Score; mGPS) is widely used for preoperative patients; however, little information is available regarding its prognostic value in patients with RCC treated with molecular-targeted drugs. A total of 32 advanced and recurrent RCC patients initially treated with molecular-targeted drugs from October, 2009 to August, 2015 were retrospectively investigated. Information on patient characteristics prior to treatment initiation and the clinical course were retrieved from clinical records. The correlation between survival and patient variables was analyzed. Survival was compared among patient groups according to the mGPS score. The median patient age was 66 years. The percentage of patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 was 87.5, and 65.6% of the RCCs were clear cell carcinomas. A Memorial Sloan-Kettering Cancer Center index of good or intermediate was determined for 75% of the patients. Sunitinib, pazopanib or sorafenib was administered to 56, 22 and 13% of the cases, respectively. An mGPS score of 0, 1 and 2 was calculated for 66, 9 and 25% of the cases, respectively. Patients in the mGPS low group (score 0) exhibited significantly better progression-free survival (PFS) and overall survival (OS) compared with patients in the mGPS high group (score 1 or 2) (median PFS, 307 vs. 70 days and median OS, 1,081 vs. 140 days, respectively). In conclusion, inflammatory status as assessed by the mGPS score was closely associated with the prognosis of RCC patients treated with molecular-targeted therapy.

DOI： 10.3892/mco.2017.1205

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Inflammation is considered to be a prognostic factor for renal cell carcinoma (RCC). An inflammation-based prognostic score (modified Glasgow Prognostic Score; mGPS) is widely used for preoperative patients; however, little information is available regarding its prognostic value in patients with RCC treated with molecular-targeted drugs. A total of 32 advanced and recurrent RCC patients initially treated with molecular-targeted drugs from October, 2009 to August, 2015 were retrospectively investigated. Information on patient characteristics prior to treatment initiation and the clinical course were retrieved from clinical records. The correlation between survival and patient variables was analyzed. Survival was compared among patient groups according to the mGPS score. The median patient age was 66 years. The percentage of patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 was 87.5, and 65.6% of the RCCs were clear cell carcinomas. A Memorial Sloan-Kettering Cancer Center index of good or intermediate was determined for 75% of the patients. Sunitinib, pazopanib or sorafenib was administered to 56, 22 and 13% of the cases, respectively. An mGPS score of 0, 1 and 2 was calculated for 66, 9 and 25% of the cases, respectively. Patients in the mGPS low group (score 0) exhibited significantly better progression-free survival (PFS) and overall survival (OS) compared with patients in the mGPS high group (score 1 or 2) (median PFS, 307 vs. 70 days and median OS, 1,081 vs. 140 days, respectively). In conclusion, inflammatory status as assessed by the mGPS score was closely associated with the prognosis of RCC patients treated with molecular-targeted therapy.

DOI： 10.3892/mco.2017.1205

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A phase II study of 5-FU/l-LV/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma.

DOI： 10.1007/s10147-017-1138-6.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Patients with advanced gastric cancer (AGC) often suffer weight loss, which can be used to predict prognosis. Few reports have assessed the correlation between weight loss during chemotherapy and survival in patients with AGC. Methods: Fifty-three patients with histologically proven AGC, who started systemic chemotherapy from September 2010 to March 2014, were retrospectively examined for body weight, inflammatory status, and survival. Correlation analyses were performed between weight change and survival. Correlations between weight loss and the patient characteristics were analyzed by stepwise multiple regression analyses. Results: The mean age of the patients was 64.4 years; 64% of the patients were males. Initial chemotherapy included fluoropyrimidine plus cisplatin (62%), fluoropyrimidine alone (26%), and other medications (12%); 72% of the patients exhibited weight loss during the initial therapy. Poorer mean overall survival and mean progression-free survival were observed in patients with weight loss of higher-than-average values than in those with weight loss of lower-than-average values. Serum C-reactive protein levels were significantly correlated with weight loss. Conclusions: Weight loss during initial chemotherapy for AGC may predict survival. Systemic inflammation is suggested to be associated with weight loss.

DOI： 10.1080/01635581.2017.1267774

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Appropriate antiemetic prophylaxis for moderately emetogenic chemotherapy in patients with non-round cell soft-tissue sarcomas (NRC-STS) remains unclear. We retrospectively investigated efficacy and safety of aprepitant-combined antiemetic prophylaxis in patients with NRC-STS receiving adriamycin plus ifosfamide (AI) therapy. Forty NRC-STS patients were enrolled, their median age was 50 years (range 18-74), and 13 (32.5&#37;) were female. Median cycle number of AI therapy was 4. Twenty patients received the doublet antiemetic prophylaxis (5-hydroxytryptamine-3 receptor antagonist and dexamethasone), and 20 received triplet (5-hydroxytryptamine-3 receptor antagonist, dexamethasone, and aprepitant). In the overall period, complete response rate for nausea and emesis in the triplet group was significantly higher than that in the doublet group (70&#37; vs 35&#37;; P=0.027). Patients with no-emesis in the overall period were more frequently observed in the triplet group than in the doublet group (90&#37; vs 65&#37;; P=0.058). All toxicities other than emesis were almost equivalent in both the groups. These results suggest that a triplet antiemetic prophylaxis may be optimal in the treatment with AI therapy for NRC-STS.

DOI： 10.1097/MD.0000000000005460

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Favorable control of advanced colon adenocarcinoma with severe bone marrow metastasis: A case report.
Colorectal cancer (CRC) has a propensity to metastasize to the liver, lungs and regional abdominal lymph nodes, but rarely to the bone marrow. A 60-year-old man presented to the National Hospital Organization Kyushu Cancer Center with a 4-week history of persistent lower back pain, anorexia and difficulty defecating. Complete blood count revealed severe thrombocytopenia and erythroblastosis, suggesting a hematological malignancy. However, the bone marrow examination demonstrated involvement by a moderately to poorly differentiated adenocarcinoma, but no hematopoietic abnormalities. A computed tomography scan revealed thickening of the wall of the sigmoid colon, with para-aortic, hilar, mediastinal and supraclavicular lymphadenopathy. The patient was thus diagnosed with sigmoid colon adenocarcinoma with lymph node and bone marrow metastasis. Modified FOLFOX6 was promptly initiated, with concurrent therapy for disseminated intravascular coagulation (DIC). An increased number of thrombocytes was observed on day 6. After 3 cycles of treatment, the patient recovered from DIC and the levels of serum carcinoembryonic antigen and cytokeratin 19 fragment were decreased. Tumor biopsy during colonoscopy following recovery from DIC demonstrated poorly differentiated adenocarcinoma with mucin production, without mutations in the RAS, BRAF or PIK3CA genes, and a cytokeratin (CK) 7-negative, CK20-positive phenotype. The patient has been treated with chemotherapy for 150 days without disease progression. However, the efficacy of chemotherapy for rarely encountered bone marrow metastasis from CRC is poor. The present case was favorably maintained on chemotherapy and survived for 10 months.

DOI： 10.3892/mco.2016.1029

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Appropriate management of cardiovascular diseases (CVDs) related to chemotherapy for solid tumors is important for safe oncologic treatment. However, prediction of the onset and progression of CVDs has not generally been established in Japan. We carried out a retrospective analysis of advanced or recurrent solid tumor patients who received chemotherapies in a single institution. Patient characteristics, chemotherapy regimens, adverse events, CVDs before chemotherapy, and diagnosis of CVDs in association with chemotherapy were assessed. During the period from April 2006 to March 2012, 394 patients were examined. Cardiac diseases (CDs), hypertension (HT), or arterial thrombosis or venous thromboembolism were prevalent in 37 (9.4&#37;), 22 (5.6&#37;), five (1.3&#37;), and 14 (3.5&#37;) cases, respectively. HT (14.5&#37;) and venous thrombosis (5.8&#37;) were frequent in patients who received bevacizumab-containing chemotherapy. Four cases with left ventricular dysfunction experienced a decrease of ejection fraction and early filling/atrial filling (E/A) and E/A tended to decrease before ejection fraction. Ninety (62.1&#37;) of 145 cases showed an increase in the d-dimer (DD) level before chemotherapy, and a further increase in DD level was found when venous thrombosis occurred. Relative risks of the disease progression of HT, CD, and thromboembolism because of chemotherapy were 1.3, 1.9, and 3.6, respectively. A decrease in E/A and an increase in DD were suggested to be valuable for early diagnosis of the respective onsets of left ventricular dysfunction and venous thrombosis related to chemotherapy. We conclude that patients with previous CD tend to have disease progression of CD during chemotherapy.

DOI： 10.1097/CAD.0000000000000392

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Characteristics of Smoking Patients with Lung Cancer with Emphysematous Bullae.
INTRODUCTION: Emphysema is thought to be a risk factor for lung cancer in smokers, with emphysematous bullae (EBs), which are believed to have the potential to give rise to lung cancer. The clinical characteristics of patients with lung cancer with EBs have remained incompletely defined, however. METHODS: A total of 488 patients with primary lung cancer with or without EBs as detected by computed tomography were studied retrospectively, and the regional relationship between EBs and the primary cancer was evaluated. RESULTS: EBs were detected in 45 of the 488 patients with lung cancer (9.2&#37;) (in 45 of 339 smokers [13.3&#37;] versus in 0 of 149 never-smokers [0&#37;]). The frequency of lung cancer in an upper lobe was significantly higher in smokers with EBs than in those without EBs (71.1&#37; versus 47.3&#37;, p = 0.0107). The lobar site of primary lung cancer in smokers with EBs was significantly associated with that of the EBs (p < 0.0001). Most primary lung cancers (86.7&#37;) in such patients were found in the area adjoining EBs. Smoking patients with lung cancer with EBs were significantly younger (63.6 versus 67.7 years, p = 0.0179) and had tumors with a lower frequency of epidermal growth factor gene (EGFR) mutations (3.8&#37; versus 24.2&#37;, p = 0.0184) compared with those without EBs. CONCLUSIONS: The clinical characteristics of smoking patients with lung cancer differ according to the absence or presence of EBs, with patients with EBs being potentially more susceptible to the carcinogenic effects of cigarette smoke. Further analysis of genetic alterations is warranted to elucidate the mechanism of carcinogenesis for lung cancer associated with EBs.

DOI： 10.1016/j.jtho.2016.04.024

記述言語：英語  

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95&#37; confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95&#37; CI 0.785-1.249). The best overall RRs were 64&#37; for FOLFIRI + Bev and 62&#37; for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11&#37; in FOLFIRI + Bev/5&#37; in mFOLFOX6 + Bev), neutropenia (46&#37;/35&#37;), diarrhea (9&#37;/5&#37;), febrile neutropenia (5&#37;/2&#37;), peripheral neuropathy (0&#37;/22&#37;), and venous thromboembolism (6&#37;/2&#37;). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

DOI： 10.1093/annonc/mdw206

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported.
Case presentation: A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab.
Conclusion: The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.

DOI： 10.1097/MD.0000000000004283

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan.
Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn's disease. Three ulcerative colitis and four Crohn's disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15&#37;, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78&#37;. Grade 3/4 adverse events (AEs) were observed in 16 patients (55&#37;). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23&#37;, respectively (P<0.01). Dose reduction was required in 11 patients (38&#37;), eight of whom required it for hematological AEs. Adjuvant chemotherapy for CAC exhibited sufficient efficacy, whereas modest efficacy was shown for palliative chemotherapy for CAC. AEs, particularly nonhematological AEs, were closely associated with disease activity of colitis.

DOI： 10.1097/CAD.0000000000000338

記述言語：英語  

We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4 days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4 weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2016.03.015

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function inhumanglioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface.

DOI： 10.1158/0008-5472.CAN-15-2121

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Efficacy and Safety of TAS-102 in Clinical Practice of Salvage Chemotherapy for Metastatic Colorectal Cancer.
BACKGROUND: TAS-102 is an anti-metabolite which demonstrated activity against multidrug-resistant advanced colorectal cancer. Its major toxicities are hematological disorders. PATIENTS AND METHODS: Background, TAS-102 efficacy, toxicities and outcomes for patients with multidrug-resistant advanced colorectal cancer from six Institutions of the Kyushu Medical Oncology Group were retrospectively surveyed. RESULTS: Forty-three patients, including fragile patients due to declining performance status and other comorbidities (37&#37;) were analyzed. Efficacy was reflected in an objective overall response of 3&#37;, median progression-free survival of 74 days (2.5 months) and median overall survival of 229 days (7.6 months). The most frequent Common Terminology Criteria for Adverse Events grade 3/4 adverse events were neutropenia (44&#37;), leukopenia (26&#37;) and anemia (23&#37;). Febrile neutropenia was found in 7&#37;. Sub-group analysis demonstrated an improved outcome on treatment with the sequence regorafenib-TAS-102. CONCLUSION: TAS-102 was safely administered to modestly fragile patients with equivalent efficacy to that for the non-fragile population. Further investigation of sequential treatment using regorafenib and TAS-102 is needed.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 75-year-old man diagnosed with ileal gastrointestinal tumor with peritoneal dissemination was subjected to salvage treatment with regorafenib at 120 mg/day. Following the initiation of the treatment, liver dysfunction appeared on day 28, and continued to worsen despite termination of the treatment. Since no increase in the levels of serum immunoglobulins of the patient was observed, and negative results were obtained for the analysis of viral markers and autoantibodies, a diagnosis of regorafenib-induced hepatitis was suggested. In consequence, the patient received steroid pulse therapy and continuous administration of prednisolone, without sufficient improvement. Liver biopsy revealed interface hepatitis with prominent plasma cell infiltration, suggesting regorafenib-induced autoimmune hepatitis. The patient was then administered azathioprine and prednisolone, which improved the hepatic injury. The present case represents the first report of successful treatment of regorafenib-induced severe hepatic injury by the use of an immunosuppressant.

DOI： 10.3892/ol.2015.3853

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. SubSequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.

DOI： 10.3892/ol.2015.3938

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 64-year-old male presented with increased abdominal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for a-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50&#37; was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.

DOI： 10.3892/ol.2015.3708

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. Patients and methods: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/ m2/day on days 1-14 and cisplatin 60 mg/m2 on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m2 on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). Results: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months
hazard ratio (HR) = 0.82
95&#37; confidence interval (CI) 0.68-0.99
P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months
HR = 0.99
95&#37; CI 0.81-1.21
P = 0.9068). In patients with measurable disease, the response rates were 60&#37; in the SP3 arm and 50&#37; in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19&#37; versus 9&#37;) and neutropenia (39&#37; versus 9&#37;) were more frequent in SP3. Conclusions: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.

DOI： 10.1093/annonc/mdv316

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mutation of T790M in EGFR is a major mechanism of resistance to treatment with EGFR-TKIs. Only qualitative detection (presence or absence) of T790M has been described to date, however. Digital PCR (dPCR) analysis has recently been applied to the quantitative detection of target molecules in cancer with high sensitivity. In the present study, 25 tumor samples (13 obtained before and 12 after EGFR-TKI treatment) from 18 NSCLC patients with activating EGFR mutations were evaluated for T790M with dPCR. The ratio of the number of T790M alleles to that of activating mutation alleles (T/A) was determined. dPCR detected T790M in all 25 samples. Although T790M was present in all pre-TKI samples from 13 patients, 10 of these patients had a low T/A ratio and manifested substantial tumor shrinkage during treatment with EGFR-TKIs. In six of seven patients for whom both pre-and post-TKI samples were available, the T/A ratio increased markedly during EGFR-TKI treatment. Highly sensitive dPCR thus detected T790M in all NSCLC patients harboring activating EGFR mutations whether or not they had received EGFR-TKI treatment. Not only highly sensitive but also quantitative detection of T790M is important for evaluation of the contribution of T790M to EGFR-TKI resistance.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Metastatic renal cell carcinoma (mRCC) had been a chemo-refractory disease, but recent advances in multiple kinase inhibitors such as sunitinib have dramatically changed the clinical course of mRCC. Sunitinib is used for mRCC chemotherapy based on the favorable results of a recent clinical trial, but specific biomarkers predicting efficacy and safety are not yet available. Locally advanced bile duct carcinoma (BDC) has generally been treated with single agent gemcitabine or as doublet therapy with cisplatin. Concomitant occurrence of mRCC and BDC is extremely rare, and a standard therapeutic strategy has not been established.
Case presentation: A 65-year-old woman was diagnosed as having multiple mRCC and intercurrent, locally advanced BDC. A single course of combination therapy with sunitinib (25 mg/day, day2-15) and gemcitabine (750 mg/m(2), days 1, 8) was administered, and this showed obvious effects, with partial response for mRCC and stable disease for BDC. However, the patient also experienced severe adverse events, including hematological and various non-hematological toxicities; the combination therapy was then terminated on day 13 after its initiation. She recovered on day 28 and is alive 3.5 years after the diagnosis. The plasma trough levels of sunitinib and its active metabolite SU12662 on day 13 were 91.5 ng/mL and 19.2 ng/mL, respectively, which were relatively higher than in previous reports. Analysis of her single nucleotide polymorphisms (SNPs) detected TC in ABCB1 3435C/T, TC in 1236C/T and TT in 2677G/T, suggesting a possible TTT haplotype.
Conclusion: A rare case of double cancer of mRCC and BDC was treated by combination chemotherapy. Although unknown synergistic mechanisms of these agents may be involved, severe toxicities might be possibly associated with high sunitinib exposure. Further exploration of combination therapy with sunitinib and gemcitabine is required.

DOI： 10.1186/s12885-015-1443-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stem cell is defined as the cell having the ability of self-renew and differentiation. Due to the development of flow cytometric analysis and immunodeficient mouse model, stem cell research had dramatically progressed. Based on the knowledge of normal stem cell, concept of cancer stem cell, which have self-renewal ability and tumorigenic potential in immunodeficient mouse, have been established. Cancer stem cell population in various cancers has been identified using cell surface markers, such as CD44, and therapeutic strategies have been developing. Moreover, as accumulating the knowledge of cancer stem cell, it has revealed that cancer stem cell has high plasticity. We introduce here the evolving cancer stem cell concept.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amrubicin monotherapy for patients with extrapulmonary neuroendocrine carcinoma after platinum-based chemotherapy.
Purpose: Extrapulmonary neuroendocrine carcinomas (EPNEC) are rarely observed and are associated with poor outcomes. Based on the clinicopathological similarity, treatment used for small cell lung carcinoma has also been employed for EPNEC, but the response to such therapy has not been well examined. The goal of this study was to investigate amrubicin (AMR) monotherapy as a salvage therapy for EPNEC arising from digestive organs. Methods: Patients with EPNEC of the digestive organs who had prior platinum-based chemotherapy and were subsequently treated with AMR between July 2005 and December 2013 at any one of four institutions were retrospectively examined to characterize the safety and efficacy of AMR. Results: Thirteen patients (ten males, three females; median age 64 years) were examined. Primary cancer sites included stomach (n = 6), rectum (n = 3), esophagus (n = 2), liver (n = 1) and pancreas (n = 1). Prior irinotecan- and etoposide-containing chemotherapies were used in ten and six patients, respectively. Median initial dose of AMR was 40 mg/m²/day for three consecutive days, and median of treatment cycles was 4 (range 1-9). The objective response rate (ORR) was 38.5 &#37;. Median progression-free survival (PFS) and overall survival (OS) were 107 (range 22-275) and 215 days (range 71-535), respectively. Common severe adverse events (grade 3/4) were neutropenia (84.6 &#37;) and febrile neutropenia (30.8 &#37;). Patient with longer platinum-free interval (>90 days) exhibited longer PFS and OS than those with shorter platinum-free interval (190 vs. 63 days and 348 vs. 145 days, respectively). Conclusions: AMR showed evidence of clinical activity and safety when used for the treatment of EPNEC. It might be especially useful for populations with sensitive relapse.

DOI： 10.1007/s00280-015-2706-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients.
The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti-epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti-EGFR antibody therapy may be ineffective: First, anti-EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti-EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele-specific PCR-based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin-fixed, paraffin-embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices.

DOI： 10.1111/cas.12595

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reduced dose of salvage-line regorafenib monotherapy for metastatic colorectal cancer in Japan.
BACKGROUND: Salvage-line regorafenib monotherapy exhibited a marked survival benefit for metastatic colorectal cancer (mCRC). However, the toxicity of this regimen has resulted in the clinical use of a reduced dose of regorafenib. PATIENTS AND METHODS: Thirty-two Japanese mCRC patients (median age=61 years) who had been treated with regorafenib were retrospectively examined. RESULTS: Best objective response rate was 0&#37; and stable disease (SD) was 31&#37;. Median progression-free survival was 81 days and median overall survival was 233 days. Adverse events of any grade were observed in all patients: 17 (53&#37;) patients suffered grade 3 or 4 adverse events including fatigue (13&#37;), anorexia (13&#37;), hand-foot skin reaction (22&#37;) and elevations of alanine aminotransferase/aspartate aminotransferase (19&#37;/16&#37;). One patient with grade 5 liver dysfunction was identified (3&#37;). Twenty-nine (91&#37;) patients required treatment dose reduction or a delay in treatment. The relative dose intensity was 59&#37;. Regorafenib treatments were terminated because of disease progression (59&#37;) or adverse events (34&#37;). CONCLUSION: Despite a decrease in the intensity of regorafenib treatment, because of severe adverse events, a fairly favorable efficacy was achieved in Japanese patients.

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

DOI： 10.1158/1538-7445.AM2014-4967

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

DOI： 10.1158/1538-7445.AM2014-1947

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

DOI： 10.1093/annonc/mdu435.18

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

DOI： 10.1093/annonc/mdu435.121

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background:Severe hypocalcennia sometimes develops during denosumab treatment for bone metastases from cancer and is, therefore, an important issue. However, limited information is available on the risk factors for hypocalcemia and the appropriate interval for monitoring serum calcium concentration. Objective: The present study aimed to identify the risk factors for grade >= 2 hypocalcennia and to investigate the time course of serum calcium concentrations in patients receiving denosumab for bone metastases from cancer. Method: The medical records of 66 cancer patients treated with denosumab between April 2012 and August 2013 were retrospectively reviewed. Result: Of the 66 enrolled patients, 11, 5, and 1 developed grade 1, 2, and 3 hypocalcemia, respectively. All 4 patients with a baseline estimated glomerular filtration rate (eGFR) of <30 mL/min developed hypocalcemia. Hypocalcemia occurred in only 20&#37;, 24&#37;, and 15&#37; of patients with an eGFR of 30 to 59, 60 to 89, and >= 90 mL/min, respectively. Multivariate logistic regression analysis revealed that lower eGFR values (odds ratio, 1.72 per 10 mL/min decrease, P = 0.02) were significantly associated with grade >= 2 hypocalcemia. In 11 patients who developed hypocalcemia during the first treatment course, the mean calcium concentrations decreased from 9.8 mg/dL at baseline to 8.4 mg/dL during the first week and reached a nadir of 8.1 mg/dL during the second week. Conclusion: Our results support more frequent monitoring of serum calcium concentrations at baseline and during the first 2 weeks of treatment in patients receiving denosumab, especially those with an eGFR <30 mL/min.

DOI： 10.1177/1060028014539919

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy. Case presentation. A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief. Conclusions: Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control. © 2014 Sagara et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1756-0500-7-377

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Japanese guidelines for the proper use of granulocyte-colony stimulating factor (G-CSF) have been revised on the basis of the current international guidelines and latest evidence. The guidelines for primary and secondary prophylactic administration of G-CSF are clearly defined in the revised version. Primary prophylactic administration is recommended as per the incidence of febrile neutropenia (FN): it is highly recommended for patients with an FN rate > 20%, but selectively recommended for patients with an FN rate < 20%. Secondary prophylactic administration is recommended only for patients who should be maintained on a constant dose of G-CSF for curative purposes. The revised version aims to improve, not limit, the clinical use of G-CSF based on both patient- and evidence-oriented decisions in clinical practice.

記述言語：英語  

DOI： 10.1200/jco.2014.32.15_suppl.3534

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Bevacizumab (BV) is widely used in chemotherapy for metastatic colorectal cancer (mCRC). Although specific adverse events have been observed, their risk factors have not been clarified. Patients and Methods: 178 mCRC patients who underwent chemotherapy were retrospectively examined and correlations between possible risk factors and adverse events were analyzed. Results: 87 out of 178 patients were treated with BV-containing chemotherapy. Possible risk factors for BV-related adverse events were: remaining primary tumor, current bleeding, history of arterial thromboembolism (ATE), hypertension, and proteinuria, and these were observed in 22&#37;, 2&#37;, 7&#37;, 16&#37;, and 8&#37; of patients, respectively. Patients with hypertension prior to chemotherapy developed significantly worse hypertension (p=0.018). Gastrointestinal bleeding occurred in 3 out of 18 patients with residual primary tumor (16.7&#37;) and 6 out of 63 patients with no primary tumor (8.7&#37;) (p=0.385). Conclusion: Pre-existing hypertension appears to be a risk factor for BV-related deterioration of hypertension.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Undifferentiated malignant neoplasms, which occur primarily in the pulmonary artery, are extremely rare and associated with poor outcomes as there is no effective therapy. A 67-year-old woman visited our hospital with complaints of dry cough and dyspnea on exertion. A contrast-enhanced chest computed tomography revealed an intravascular tumor obstructing the left pulmonary artery and a pedunculated lesion extending to the main and right pulmonary artery. Multiple metastases in the lung, bones and bilateral adrenal glands were identified by fluorodeoxyglucose-positron emission tomography. A small sample was obtained by catheter aspiration biopsy of the intravascular tumor, and examination revealed undifferentiated small atypical cells. The tumor was diagnosed as an undifferentiated neoplasm arising from the pulmonary artery based on immunohistochemical findings, including the absence of expressions of organ-specific markers. Systemic chemotherapy (paclitaxel and carboplatin) and concurrent radiation were performed as treatment for the primary tumor. Marked shrinkage of the intravascular tumor was achieved, and no serious adverse events were observed during therapy. Chemotherapy was continued for 5 months, but the patient died because of tumor progression 9 months after the initial diagnosis. Chemoradiotherapy has efficacy against undifferentiated neoplasm of the pulmonary artery.

DOI： 10.1159/000365387

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

肺癌は小細胞肺癌と非小細胞肺癌の大きく二つに分けられる．非小細胞肺癌は肺癌の約85&#37;を占め，腺癌，扁平上皮癌，大細胞癌に分けられる．非小細胞肺癌に対する治療は手術，放射線，化学療法の大きく三つに分けられるが，近年における化学療法の進歩は目覚ましく，その大きな要因は個別化治療の進歩にあると考えられる．本稿では非小細胞肺癌における化学療法の進歩について個別化治療を中心に概説する．

DOI： 10.15017/1446200

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Bevacizumab is a widely used agent for treatment for colorectal cancer. Though it relates to several adverse events, a few cases have been reported of drug-induced interstitial lung damage in bevacizumab-based chemotherapy for advanced colorectal cancer. In this study, we retrospectively reviewed a consecutive series of 72 patients with advanced colorectal cancer who received bevacizumab-based chemotherapy and identified five cases (6.9 &#37;) who developed interstitial pneumonia (IP). The median age was 68 years, all five were male, and four of five patients were smokers. Three cases were asymptomatic, and they immediately recovered by withdrawal of chemotherapeutic drugs. On the other hand, two severe cases were required high-dose infusion of corticosteroid. It is suggested that early diagnosis of IP contributes to prevent exacerbation of the event and results in better outcomes. IP may have been associated with systemic chemotherapy, suggesting that a caution should be raised for pulmonary damage by bevacizumab-based chemotherapy.

DOI： 10.1007/s12032-014-0856-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Antiemetic triplet therapy including dexamethasone (DEX) is widely used for patients receiving highly emetogenic chemotherapy (HEC). In Japan, the appropriate dose of DEX has not been established for this combination. Materials and Methods: To assess the efficacy and safety of increased-dose DEX, we retrospectively examined patients receiving HEC with antiemetic triplet therapy. Results: Twenty-four patients (fosaprepitant group) were given an increased-dose of DEX (average total dose: 45.8mg), fosaprepitant, and 5-HT3 antagonist. A lower-dose of DEX (33.6mg), oral aprepitant, and 5-HT3 antagonist were administered to the other 48 patients (aprepitant group). The vomiting control rates in the fosaprepitant and aprepitant groups were 100% and 85.4% in the acute phase, and were 75.0% and 64.6% in the delayed phase. The incidences of toxicity were similar comparing the two groups. Conclusions: Triplet therapy using an increased-dose of DEX is suggested to be safe and effective for patients receiving HEC.

DOI： 10.7314/APJCP.2014.15.1.461

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Malignant peritoneal mesothelioma (PM) is an extremely rare disease. Pemetrexed and platinum have been used for advanced PM following malignant pleural mesothelioma (PLM). Because PM differs considerably from PLM in clinical features, the efficacy and safety of these therapies have yet to be established. Patients and Methods: Six Japanese patients with PM who had been treated with pemetrexed-based chemotherapy in four Institutions were retrospectively identified. Treatment response, progression-free survival, and overall survival were examined. Toxicities of therapy were also evaluated. Results: Three patients with mild ascites achieved clinical benefits (one with partial response and two with stable disease). Treatments with reduced cisplatin or carboplatin for patients with massive ascites were safely performed. Median PFS and OS were 7.2 and 13.1 months, respectively. Grade 3 hematological toxicities appeared in two patients with massive ascites. Conclusion: Selection of chemotherapy based on the patient's condition, such as ascites, might be important for advanced PM.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Efficacy and safety of capecitabine plus cisplatin in Japanese patients with advanced or metastatic gastric cancer: subset analyses of the AVAGAST study and the ToGA study.
BACKGROUND: Capecitabine plus cisplatin (XP) is recognized as one of the global standard first-line chemotherapy regimens for patients with metastatic gastric cancer (mGC). Recent multinational phase III trials in mGC have been conducted with XP as the control arm, although no data on XP in Japanese patients with mGC have been published to date. The AVAGAST (XP ± bevacizumab in mGC) and ToGA (XP ± trastuzumab in human epidermal growth factor receptor 2 [HER2]-positive mGC) studies were the first two global studies including Japanese mGC patients. The aim of this analysis was to investigate the efficacy and safety of XP in Japanese mGC patients, using AVAGAST and ToGA subgroup data. METHODS: Efficacy and safety analyses were carried out in Japanese patients with mGC receiving XP alone, based on results from the AVAGAST and ToGA studies. There were differences in the target populations between the two studies; for example, the ToGA study limited patients to those with HER2-positive tumors; therefore, efficacy was evaluated separately. RESULTS: Ninety-four Japanese patients in the AVAGAST study and 50 in the ToGA study received XP alone. Median overall and progression-free survivals were 14.2 and 5.7 months, respectively, in the AVAGAST study, and 17.7 and 5.6 months, respectively, in the ToGA study. Overall response rates were 49.2 &#37; in the AVAGAST and 58.5 &#37; in the ToGA study. Adverse events were generally mild; the most common grade 3/4 events were neutropenia, anemia, anorexia, and nausea. CONCLUSIONS: XP is effective and well tolerated in Japanese patients with mGC, and could be one of the standard regimens for the first-line treatment in this cohort.

DOI： 10.1007/s10120-012-0167-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10120-012-0205-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase I study of bevacizumab combined with irinotecan and S-1 as second-line chemotherapy in patients with advanced colorectal cancer.
PURPOSE: The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan has been reported to be a promising regimen for advanced colorectal cancer. However, the safety and efficacy of bevacizumab (BV) to combine with irinotecan and S-1 has not been determined. The aim of the study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of BV combined with irinotecan plus S-1, and to observe the safety and efficacy of this regimen as second-line chemotherapy in patients with advanced colorectal cancer. METHODS: This study initially had been planned as a phase I/II study. Eighty mg/m(2) of irinotecan on days 1 and 8, 80 mg/m(2) of S-1 for 14 consecutive days, and two doses of BV (Level 1; 10 mg/kg, Level -1; 7.5 mg/kg) were administered on day 1 every 3 weeks. RESULTS: Fourteen patients were enrolled in phase I of the study between January 2008 and September 2010. Dose-limiting toxicities were diarrhea, abdominal pain, and infection. The MTD and RD of BV were determined to be 10 mg/kg and 7.5 mg/kg, respectively. The main adverse events were leukopenia, anorexia, and diarrhea. There were no treatment-related deaths. An independent review committee was scheduled to evaluate safety in phase I, but this trial closed early due to toxicity. CONCLUSIONS: This study identified the risk of gastrointestinal toxicity with the combination of irinotecan, S-1 and BV as second-line chemotherapy in patients with advanced colorectal cancer.

DOI： 10.1007/s00280-012-2023-7

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s13691-012-0060-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95&#37; confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95&#37; CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95&#37; CI, 17.6-25.6) and 16.5 months (95&#37; CI, 11.8-21.2), respectively. Overall response rates were 25 and 29&#37;, respectively. The most common grade a parts per thousand yen3 bevacizumab-related adverse events were hypertension (5.0&#37;) and bleeding (3.8&#37;). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU.

DOI： 10.1007/s12032-011-0151-2

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

[Development trends for therapeutic antibody].
Recent developments for therapeutic antibody have provided new options for cancer treatments. Modification of antibody molecules pursuing improvement of binding efficacy for Fcgamma receptors and enabling efficient recycling of antibody have been performed. Novel constructs of antibody possessing multivalent specificity and conjugated agents have also been developed. Based on exploration of new class of target molecules for therapeutic antibody, antibodies enhancing anti-tumor immunity such as anti-CTLA-4 antibody have appeared. These advancements would achieve more effective and safer therapy for various kinds of cancers.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A multicenter phase II study of the stop-and-go modified FOLFOX6 with bevacizumab for first-line treatment of patients with metastatic colorectal cancer
Currently, no prospective data exists to support a "stop-and-go" modified FOLFOX6 regimen with bevacizumab in metastatic colorectal cancer (mCRC) patients. This study aimed to evaluate the efficacy and safety of this regimen in first-line mCRC patients. Eligible patients (age ≥20 years) had previously untreated mCRC; Eastern Cooperative Oncology Group performance status of 0-2; and adequate hematologic, hepatic, and renal function. The modified FOLFOX6 regimen and bevacizumab (5 mg/kg) was administered intravenously every 2 weeks. After 8 cycles, patients received maintenance therapy with simplified LV5FU2 and bevacizumab until completion of 8 cycles or disease progression. After maintenance therapy, patients received another 8 cycles of modified FOLFOX6 with bevacizumab until completion of 8 cycles or disease progression. We recruited 50 patients between August 2007 and January 2009. The overall response rate was 48&#37; (80&#37; confidence interval [CI]; 38.2-58) with outcomes as follows: complete response, n = 1; partial response, n = 23; stable disease, n = 21; progression, n = 1; and not evaluated, n = 4. Median time to treatment failure was 7.7 months (80&#37; CI: 6.2-8.0), and median progression-free survival was 12.8 months (80&#37; CI: 10.8-14). Grade 3/4 toxicities included neutropenia (40&#37;), nausea (4&#37;), diarrhea (14&#37;), thrombosis (4&#37;), and hypertension (4&#37;) et al. Grade 1, 2, or 3 peripheral neuropathy was reported in 38&#37;, 40&#37;, and 10&#37; of patients, respectively. The stop-and-go modified FOLFOX6 and bevacizumab regimen is effective and well tolerated as first-line chemotherapy for mCRC patients.

DOI： 10.1007/s10637-011-9779-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

There is emerging evidence that human solid tumor cells originate from cancer stem cells (CSCs). In cancer cell lines, tumor-initiating CSCs are mainly found in the side population (SP) that has the capacity to extrude dyes such as Hoechst 33342. We found that Nanog is expressed specifically in SP cells of human gastrointestinal (GI) cancer cells. Nucleotide sequencing revealed that NanogP8 but not Nanog was expressed in GI cancer cells. Transfection of NanogP8 into GI cancer cell lines promoted cell proliferation, while its inhibition by anti-Nanog siRNA suppressed the proliferation. lmmunohistochemical staining of primary GI cancer tissues revealed NanogP8 protein to be strongly expressed in 3 out of 60 cases. In these cases, NanogP8 was found especially in an infiltrative part of the tumor, in proliferating cells with Ki67 expression. These data suggest that NanogP8 is involved in Cl cancer development in a fraction of patients, in whom it presumably acts by supporting CSC proliferation. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2012.04.011

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction. Advanced gastric carcinoma often decreases quality of life because of upper gastrointestinal tract stenosis. Self-expandable metal stents have been thought to be an effective, minimally invasive treatment for stenosis. However, the effectiveness of self-expandable metal stent placement for carcinomatous stenosis of the gastric body and antrum has not been clarified, and there have been few reports of such cases. Case presentation. A 74-year-old Japanese woman developed stenosis of the gastric body and antrum caused by advanced gastric cancer during first-line chemotherapy. She developed weight loss and poor nutrition due to inadequate intake. Self-expandable metal stent placement for stenosis of the gastric body and antrum ameliorated her symptoms rapidly and improved her general condition and quality of life. Eight days after self-expandable metal stent placement, second-line chemotherapy could be administered safely. Oral intake and nutritional status were maintained for 117 days after self-expandable metal stent placement, and she died of gastric cancer 176 days after self-expandable metal stent placement and initiation of second-line chemotherapy. Conclusions: Self-expandable metal stent placement for carcinomatous stenosis in the gastric body and antrum could be an effective therapeutic strategy for patients with inadequate oral uptake. It may provide rapid improvement of the patients general condition and oral intake with minimal complications, comparatively long-term symptom relief, and a survival benefit by allowing second-line chemotherapy.

DOI： 10.1186/1752-1947-6-315

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Trastuzumab for Gastric Cancer (ToGA) study is the first international trial to include Japanese patients with human epidermal growth factor 2 (HER2) positive advanced/metastatic gastric or gastroesophageal junction cancer. ToGA showed that trastuzumab plus chemotherapy (capecitabine/cisplatin or 5-fluorouracil/cisplatin) improved overall survival in the overall population (hazard ratio 0.74). Regional differences in outcome in favor of Japanese populations were observed in other studies; therefore, subgroup analyses of ToGA may contribute to the evaluation of the potential benefits of this regimen in Japanese patients.
We performed subgroup analyses on 101 Japanese patients enrolled into ToGA (trastuzumab plus chemotherapy, n = 51; chemotherapy, n = 50).
Median overall survival in the Japanese subgroup was 15.9 months (95&#37; confidence interval 12-25) for trastuzumab plus chemotherapy and 17.7 months (95&#37; confidence interval 12-24) for chemotherapy (hazard ratio 1.00; 95&#37; confidence interval 0.59-1.69). After adjusting for prespecified covariates, the estimated hazard ratio for overall survival was 0.68 (95&#37; confidence interval 0.36-1.27). Further post hoc and exploratory examinations supported the robustness of the adjusted hazard ratios.
After adjusting for imbalanced patient backgrounds between arms, overall survival of Japanese patients with human epidermal growth factor 2 positive advanced/metastatic gastric or gastroesophageal junction cancer who received trastuzumab plus chemotherapy was improved compared with patients who received chemotherapy alone.

DOI： 10.1007/s10120-011-0118-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLC gamma 2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation-associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells. (Blood. 2012;119(10): 2263-2273)

DOI： 10.1182/blood-2011-04-351965

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase 2 study of modified irinotecan and bolus 5-fluorouracil/l-leucovorin in Japanese metastatic colorectal cancer patients.
INTRODUCTION: Using the recommended doses obtained from our previous phase 1 trial of a modified Saltz chemotherapy regimen for metastatic colorectal cancer (weekly irinotecan and bolus 5-fluorouracil/l-leucovorin for 3 weeks every 28 days), we performed the present phase 2 trial to evaluate efficacy and toxicity. METHODS: A total of 29 patients with metastatic colorectal cancer were included. Our modified Saltz regimen was administered. The primary endpoint was overall response rate. RESULTS: Of the 29 patients, 11 had previous chemotherapy. A partial response occurred in 11 patients, stable disease in 16 patients, and progressive disease in two patients. Disease control rate was 93.1&#37;. Response rates with and without previous treatment were 18.2&#37; and 50&#37;, respectively. Median progression-free survival was 17.3 months. The main hematologic toxicities were leukopenia (22.6&#37;) and neutropenia (45.2&#37;). No treatment-related deaths occurred. CONCLUSION: Our modified Saltz regimen exhibited sufficient efficacy, feasibility, and manageable toxicity as a therapeutic option for selected colorectal cancer patients.

DOI： 10.1007/s12325-012-0002-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Iron is essential in cellular proliferation and survival based on its crucial roles in DNA and ATP synthesis. Tumor cells proliferate rapidly even in patients with low serum iron, although their actual mechanisms are not well known. To elucidate molecular mechanisms of efficient tumor progression under the hypoferric condition, we studied the roles of six-transmembrane epithelial antigen of the prostate family member 3 (STEAP3), which was reported to facilitate iron uptake. Using Raji cells with low STEAP3 mRNA expression, human STEAP3-overexpressing cells were established. The impact of STEAP3 expression was analyzed about the amount of iron storage, the survival under hypoferric conditions in vitro and the growth of tumor in vivo. STEAP3 overexpression increased ferritin, an indicator of iron storage, in STEAP3-overexpressing Raji cells. STEAP3 gave Raji cells the resistance to iron deprivation-induced apoptosis. These STEAP3-overexpressing Raji cells preserved efficient growth even in hypoferric mice, while parental Raji cells grew less rapidly. In addition, iron deficiency enhanced S7EAP3 mRNA expression in tumor cells. Furthermore, human colorectal cancer tissues exhibited more S7EAP3 mRNA expression and iron storage compared with normal colon mucosa. These findings indicate that STEAP3 maintains iron storage in human malignant cells and tumor proliferation under the hypoferric condition. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2011.07.022

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We performed continuous dendritic cells (DCs) vaccination to treat a patient with chemotherapy-resistant recurrent rectal carcinoma and lung and bone metastases. A patient has received a total of 66 DC vaccinations at 14-day intervals for 3 years until his death. Necrotic whole tumor. cells (WTC) were selected as the tumor-associated antigen source because they showed a greater capacity for DC maturation and interleukin-12 secretion than both necrotic tumor lysate alone and necrotic tumor cell fragment alone. After the sixth vaccination, both skin test and interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISPOT) response by peripheral blood T-cells to WTC-pulsed DCs were positive. Importantly, T-cell responses were positive towards DCs pulsed with several synthetic peptides including Carcinoembryonic antigen (CEA), Melanoma associated antigen (MAGE)1 and MAGE3. A biopsy specimen collected from the pelvic bone metastasis after the 6th vaccination showed marked necrotic change of the carcinoma cells, with many infiltrating mononuclear cells. The patient did not show any particular adverse reactions to vaccination such as autoimmune phenomena. Our experience of this case suggests that continuous long-term vaccination with autologous WTC-pulsed DCs can elicit in vivo T-cell response against multiple tumor-associated antigens and induce tumor regression in disease that has proven resistant to intensive chemo- or radiation therapy.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase II study of sequential treatment with S-1 and cisplatin for metastatic gastric cancer.
PURPOSE: This single-arm, phase II clinical study evaluated the efficacy and safety of sequential treatment with S-1 followed by cisplatin in patients with advanced or recurrent gastric cancer. METHODS: Fifty patients with histologically confirmed advanced or recurrent gastric cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who had measurable and/or assessable lesions and gave written informed consent were enrolled. S-1 (40 mg/m(2), bid) was administered on days 1-21, and cisplatin (70 mg/m(2)) was given as an intravenous infusion on day 22 of a 35-day cycle. Treatment was continued until disease progression or intolerable adverse events. Cisplatin was administered for 6 cycles. Adverse events were assessed according to Common Terminology Criteria of Adverse Events version 3.0, and efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.0 for patients with measurable lesions and by the criteria of the Japanese Research Society for Gastric Cancer for all patients. RESULTS: Efficacy could be evaluated in 49 of the 50 enrolled patients. The median age was 62 years. Lesions were measurable in 38 patients and assessable in 11. The response rate was 44.7&#37; in patients with measurable lesions and 40.8&#37; overall. The progression-free survival and overall survival were, respectively, 233 days (7.8 months) and 574 days (19.0 months) in patients with measurable lesions and 192 days (6.4 months) and 402 days (13.4 months) overall. Serious adverse events (grade 3 or higher) included neutropenia (24.5&#37;), anemia (20.4&#37;), and anorexia (20.4&#37;) and were safely managed. CONCLUSION: The safety and effectiveness of sequential treatment with S-1 followed by cisplatin every 35 days is equivalent to that reported for conventional chemotherapeutic regimens in patients with advanced or recurrent gastric cancer.

DOI： 10.1007/s00280-010-1529-0

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase I/II study of a 3-week cycle of irinotecan and S-1 in patients with advanced colorectal cancer.
The combination of an oral fluoropyrimidine derivative, S-1, and irinotecan is expected to be a promising regimen for advanced colorectal cancer. This study was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with S-1 in a 3-week cycle regimen and to observe the safety and efficacy for patients with previously untreated advanced colorectal cancer. Eighty milligrams per m(2) of S-1 was given orally for 14 consecutive days and escalated doses of irinotecan were administered on days 1 and 8 every 3 weeks in the phase I trial. Forty patients were treated at the RD during the phase II trial. Forty-three patients were enrolled between February 2005 and March 2007. The dose-limiting toxicity was diarrhea and abdominal pain. The MTD of irinotecan was 100 mg/m(2) and the RD was determined to be 80 mg/m(2) of irinotecan combined with 80 mg/m(2) of S-1. The phase II trial showed that 22 of 40 patients achieved a complete or partial response and eight had stable disease. The overall response rate was 55.0&#37;. The median progression-free survival time and median survival time were 6.7 and 21 months, respectively. There were no treatment-related deaths. The main toxicities were leukopenia, neutropenia, anorexia and diarrhea. This study suggests the combination of irinotecan and S-1 repeated every 3 weeks is tolerable and effective for patients with previously untreated advanced colorectal cancer.

DOI： 10.1111/j.1349-7006.2010.01728.x

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Irinotecan-based combination chemotherapy for metastatic small intestinal adenocarcinoma.
Metastatic small intestinal adenocarcinoma (SIA) is rare among digestive tract malignancies, and a standard therapy has yet to be established. The present study described a patient who was treated with irinotecan-based chemotherapy. A 67-year-old woman with a long history of anemia was diagnosed as having SIA using small bowel endoscopy. Tumor invasion of the mesentery and multiple metastases to the lungs and peritoneal lymph nodes were detected. Nine courses of chemotherapy, each consisting of bolus infusion of 5-fluorouracil at 500 mg/m(2), plus infusion of irinotecan at 100 mg/m(2) with l-leucovorin at 20 mg/m(2) on days 1, 8 and 15, were administered at 4-weekly intervals postoperatively. After two courses, the metastatic nodules in the lungs showed a decrease in number and size, and this response continued for over 6 months. Adverse events were manageable during this period. The patient succumbed to the disease 12 months after the initial diagnosis. The present results therefore suggest that irinotecan-based chemotherapy is a potential treatment for metastatic SIA.

DOI： 10.3892/ol_00000074

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cetuximab is a monoclonal antibody that inhibits human epidermal growth factor receptor, and was approved for metastatic advanced colorectal cancer (mCRC) in 2008 in Japan. Evidences confirming the efficacy of cetuximab have been accumulated in western countries. As the first- and second-line therapy, cetuximab plus chemotherapy showed longer survival compared with chemotherapy alone. As a third-line chemotherapy, among various anti-cancer agents for mCRC, only cetuximab could exhibit survival benefits in monotherapy or combination therapy with irinotecan. Recent studies suggest that the status of KRAS mutation is a predictive marker in colorectal cancer patients treated with cetuximab, and these findings lead to personalized cancer treatment.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Advanced unresectable pancreatic cancer has an extremely poor prognosis despite intensive chemotherapy. As a new therapeutic modality, we investigated nonmyeloablative allogeneic hematopoietic stem cell transplantation from a related donor.
Methods: Five patients with chemotherapy-resistant pancreatic cancer received allogeneic peripheral blood stem cell transplantation after a conditioning regimen consisting of low-dose total body irradiation and fludarabine. The prophylaxis for graft-versus-host disease consisted of mycophenolate mofetil and cyclosporine.
Results: The median age of the 5 patients was 54 years, and the median duration from diagnosis to nonmyeloablative allogeneic hematopoietic stem cell transplantation was 10 months. Three of the 5 patients achieved complete donor chimerism of peripheral T cells, at a median time of day 42. Acute graft-versus-host disease developed in 3 patients: grade 2 in 2 patients and grade 1 in 1. Tumor reduction was observed in 2 patients: 1 patient showed disappearance of the pancreatic tumor, and the other patient showed approximately 20&#37; reduction of the tumor. Marked elevation of tumor necrosis factor alpha was observed as the tumor regressed.
Conclusions: Although advanced pancreatic cancer progresses rapidly, some graft-versus-tumor effects and pivotal role of tumor necrosis factor alpha were suggested. To obtain the durable response, patient selection and new strategies become important.

DOI： 10.1097/MPA.0b013e3181b576ee

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Oxaliplatin-induced allergic reaction in patients with colorectal cancer in Japan.
BACKGROUND: Oxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities. METHODS: In order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies. RESULTS: One hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17&#37;) were found to have developed allergic reactions. Sixteen patients (13&#37;) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4&#37;) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2-15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients' background characteristics such as sex, history of allergy, and profile of other adverse events. CONCLUSION: Allergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions.

DOI： 10.1007/s10147-009-0883-6

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase I study of the sequential administration of S-1 and cisplatin for metastatic gastric cancer.
The combination of 5-fluorouracil (5-FU) and cisplatin (CDDP) has been reported to be active against metastatic gastric cancer (MGC) and great synergy has been shown in vivo and in vitro when 5-FU precedes CDDP. The sequential combination of S-1 (tegafur, oxonic acid, 5-chloro-2,4-dihydroxypyridine) followed by CDDP for MGC was investigated. A phase I trial applying increasing doses of oral administration of S-1 (65-80 mg/m(2)) for 21 days and increasing doses of CDDP (60-80 mg/m(2)) on day 22 every 35 days was conducted in order to determine the maximum tolerated dose (MTD) and recommended phase II dose. Patients with metastatic or recurrent gastric cancer, no prior chemotherapy, measurable disease, ECOG performance status less than 3 and adequate organ functions were eligible for the study. Three patients were treated at each dose level with escalation based on toxicity. Fifteen patients were included and evaluated for dose-limiting toxicity (DLT) and MTD. DLT included NCICTC grade 3 anorexia and fatigue in patients treated at S-1 80 mg/m(2) and CDDP 80 mg/m(2) (dose level 5). The other toxicities, grade 3 or higher, included neutropenia (grade 3) and nausea/vomiting (grade 3). Non-hematological toxicities were grade 1/2 and included diarrhea, nausea and stomatitis. There was no treatment-related mortality. Therefore, the recommended dose was a combination of S-1 at 80 mg/m(2) and CDDP at 70 mg/m(2). This sequential administration of S-1 and CDDP every 35 days is tolerable and warrants a phase II trial. A multicenter phase II study is currently under way.

記述言語：英語   掲載種別：研究論文（その他学術会議資料等）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

[A case of bone marrow carcinosis from gastric cancer that presented hypocalcemia caused by zoledronic acid during the treatment of methotrexate/5-fluorouracil sequential therapy].
The case was a 64-year-old man. He was diagnosed as gastric cancer, lymph node metastases, brain metastases, bone marrow carcinomas, and disseminated intravascular coagulation(DIC). He was started on methotrexate(MTX)/5- fluorouracil(5-FU)sequential therapy(weekly administration of MTX(100 mg/m(2), iv bolus)followed by 5-FU(600 mg/m(2), iv bolus)with a 3 h interval). DIC was resolved, and the tumor marker decreased remarkably. Four weeks later, he received zoledronic acid 4 mg to prevent skeletal complication. Next day, fatigue and anorexia onset. Six days later, laboratory data showed severe hypocalcemia. He was started on calcium gluconate 3.4 g/day. The calcium level was normalized in twelve days, and the symptoms were improved. MTX /5-FU therapy was resumed, and his condition remained stable. However, after the ninth dosage, he developed fatigue and low back pain, and the DIC relapsed. We started paclitaxel therapy. But it was not effective and he died ten days later. It was considered that careful attention to hypocalcemia is necessary when we use zoledronic acid for the bone marrow carcinomas treated with chemotherapy.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Schedule-dependent synergistic interaction between gemcitabine and oxaliplatin in human gallbladder adenocarcinoma cell lines.
To define the most effective combination schedule of gemcitabine and oxaliplatin (L-OHP), we investigated the in-vitro interaction between these drugs in a panel of four human gallbladder adenocarcinoma cell lines (HAG-1, GB-d1, NOZ, and G-415). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of gemcitabine followed by L-OHP exhibited synergistic effects in all four cell lines, whereas the reverse sequence largely showed an antagonism. Gemcitabine exclusively arrested cells at the G0/G1 phase, and L-OHP at the G2/M phase, as measured by flow cytometric analyses. Apoptosis was most prominent when cells were treated simultaneously or in a sequence gemcitabine followed by L-OHP, producing apoptosis in treated cells (27-30&#37;). In contrast, the reverse sequence yielded only 6-7&#37; induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment, which compared the number of HAG-1 cells 7 days after these combination schedules. These findings suggest that the interaction of gemcitabine and L-OHP is highly schedule dependent, with the most efficacious interaction observed in either simultaneous combination or in a sequence combination of gemcitabine followed by L-OHP.

DOI： 10.1097/CAD.0b013e3283218080

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM(+) memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-x(L) and Mcl-1, whereas it rather accelerated apoptosis of IgM(+) memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM(+) memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tell), an Akt coactivator, was found in naive B cells, and enforced expression of Tell induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM(+) memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tell and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM(+) memory B cells. The Journal of Immunology, 2009, 182: 1490-1499.

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pancreatic cancer is a frequent cause of cancer-related mortality and has an extremely poor prognosis. To evaluate the efficacy of allogeneic hematopoietic SCT with reduced-intensity conditioning (RICT) against pancreatic cancer, we analyzed the clinical data of 22 patients. After a fludarabine-based conditioning regimen followed by the infusion of PBSCs, all but two achieved engraftment. Complete, partial and minor response was observed in 1, 2 and 2 patients, respectively, with an overall response rate of 23&#37;. Median survival was only 139 days and the major cause of death was tumor progression. Poor performance status before RICT and a lower number of infused CD34-positive cells were associated with shorter survival after RICT. Patients who developed chronic GVHD tended to survive longer than those who did not. These findings support the investigation of a novel treatment strategy to enhance the immunological effect against pancreatic cancer.

DOI： 10.1038/bmt.2008.94

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 59-year-old man complaining of dyspnea, anterior chest oppression, and hypotension was diagnosed to have cardiac tamponade due to massive pericardial effusion. A cytological analysis of the pericardial effusion disclosed adenocarcinoma. An endoscopic study revealed gastric cancer in the lesser curvature wall of the middle body of the stomach, and signet-ring cell carcinoma was confirmed histologically. The gastric cancer was complicated by malignant pericardial effusion, and metastasis to the mediastinal lymph nodes. The patient was treated with pericardiocentesis followed by systemic chemotherapy consisting of TS-1 and cisplatin (CDDP). After 5 months, pericardial effusion disappeared and the primary gastric tumor decreased in size. Our experience suggests that the systemic chemotherapy of TS-1 and CDDP may be effective for controlling advanced gastric signet-cell carcinoma accompanied by malignant pericardial effusion.

DOI： 10.1007/s12032-007-9010-6

記述言語：英語  

Exosomes are nanovesicles produced constitutively and inducibly by several types of cells. They are generated as intraluminal vesicles of multivesicular bodies and express MHC and several endosomal/lysosomal proteins. In spite of their potential role in cellular immunity, the regulatory mechanisms of exosome production are largely unknown. In this study, we have established a novel ELISA system to quantify exosomal HLA using a combination of anti-HLA class I and anti-HLA-DR mAb. We found that exosomal HLA production of B cells was enhanced by contact with CD4(+) T cells. Neutralizing anti-CD154 (CD40L) mAb inhibited this effect, and a soluble CD40L significantly increased production of exosomal HLA in B cells. In addition, B cell stimulation via BCR and TLR9 enhanced their production while IL-4 stimulation alone failed to do so. Strikingly, an inhibitor of the classical NF-kappa B pathway drastically inhibited exosomal HLA production in stimulated B cells, indicating that the classical NF-kappa B pathway is critical for exosomal HLA production in B cells. Together, these findings suggest a pivotal role of B cell activation in exosomal HLA production in vivo.

DOI： 10.1002/eji.200737694

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serosal inflammation. FMF gene (MEFV) mutations have been identified primarily in patients from Mediterranean populations. Although several clinical cases have been reported in Japan, there have been few reports to date on mutation analysis. We studied FMF patients and their relatives to examine the clinical and genetic features of this disease in the Japanese population. Methods: Twelve Japanese FMF patients who met the Tel Hashomer criteria and a total of 17 relatives from 5 of 10 families underwent molecular genetic studies to detect MEFV mutations. The characteristics of these Japanese FMF patients and geno-phenotypical correlations were examined. Results: Almost all of our patients had been suffering for a long time from fever of unknown origin and one patient also had systemic amyloidosis. In our 12 FMF patients, we detected the substitutions E84K, L110P, E148Q, R761H and M694I. We also newly diagnosed 2 relatives as having FMF based on clinical symptoms and the existence of FMF mutations. One patient was homozygous for E148Q, the patient with systemic amyloidosis was a homozygote for M694I and 4 patients from 3 families were compound heterozygotes for E148Q and M694I. Three patients in one family were compound heterozygotes for E148Q, L110P and M694I. There were 3 patients who were heterozygous for E84K, L110P-E148Q or M694I and had no other nucleotide changes in the exons of MEFV. On the other hand, 2 relatives who had never experienced symptoms of FMF were homozygous for L110P-E148Q as well as compound heterozygous for E148Q/ E148Q-R761H. E148Q and M694I were the most frequently detected substitutions in our study. Conclusions: MEFV mutations occur in Japanese FMF patients though FMF is rare in Japan. The identification of MEFV mutations could be a reliable diagnostic test for FMF. The results of genetic analyses on 14 Japanese FMF patients in this study revealed that E148Q and M694I are frequent alleles. © Copyright Clinical and Experimental Rheumatology 2008.

記述言語：英語  

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Metastatic basaloid-squamous cell carcinoma of the esophagus treated by 5-fluorouracil and cisplatin.
Basaloid squamous cell carcinoma (BSC) of the esophagus is a rare malignant disease. We report here a patient with recurrent esophageal BSC, who was successfully treated by systemic chemotherapy containing 5-fluorouracil (5-FU) and cisplatin (CDDP). A 57-year-old woman was diagnosed as having squamous cell carcinoma of the esophagus upon endoscopic examination. Curative esophagectomy with lymph node dissection was performed under the thoracoscope. The pathological diagnosis of the surgical specimen was BSC. Five months after operation, the patient was diagnosed as having a recurrence of the BSC with metastases to the liver and spleen, and a right paraclavicular lymph node. She was given systemic chemotherapy consisting of continuous infusion of 800 mg/d of 5-FU and 3 h infusion of 20 mg/d of CDDP for 5 consecutive days every 4 wk. The metastatic lesions in the spleen and right paraclavicular lymph node disappeared, and the liver metastasis was apparently reduced in size after 2 courses of chemotherapy. The tumor regression was seen over 6 courses, with progression afterwards. Although subsequent treatment with CPT-11 and CDDP was not effective, docetaxel and vinorelbine temporarily controlled the tumor growth for 2 mo. 5-FU and CDDP combination may be useful for the patients with advanced BSC.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP) has demonstrated activities in various malignancies, including head and neck, lung, esophageal, gastric, and pancreatic cancers. We reviewed our experience of 11 patients diagnosed as carcinoma of unknown primary site (CUPS), who were treated with infusional 5-FU and CDDP between January 1998 and December 2005. The median number of cycles administered was three (range: 1-12). All patients had measurable disease. Six partial responses were obtained (response rate: 54.5%, 95% confidence interval: 23.4-83.3%). The median survival time for all patients was 10 mo (range, 2-37 mo). The median time to disease progression was 3 mo (range, 1-6 mo). This regimen was well tolerated, with grade 3-4 neutropenia (two patients), febrile neutropenia (one patient), grade 3 nausea/vomiting (one patient), and grade 3 stomatitis (two patients). Grade 2 leukoencephalopathy was observed in one patient. No treatment-related death was observed. The combination chemotherapy of infusional 5-FU and CDDP was feasible and tolerated with promising activity for CUPS.

DOI： 10.1007/BF02698049

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells.
PURPOSE: Although gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been demonstrated to exhibit its antitumor activity by the blockade of EGF receptor, the role of signaling pathways downstream of EGFR in gefitinib sensitivity remains unknown. In this study, we investigated the mechanistic role of Src and Ras, major oncogene products implicated in the pathogenesis of many human cancers in gefitinib sensitivity. METHODS: Using parental and v-src- or c-H-ras-transfected HAG-1 human gallbladder adenocarcinoma cell lines, effects of gefitinib on cytotoxicity, cell cycle purtubation and apoptosis, and tyrosine phosphorylation of EGFR, Akt, and Erk were determined by WST-1 assay, flow cytometry, and Western blots, respectively. RESULTS: Activated Ras and Src conferred a strong resistance to gefitinib by nearly 30-fold and 200-fold, respectively. Gefitinib induced accumulation of cells in the G0/G1 phase of the cell cycle at 24-h, with progressive expansion of apoptotic cell population in parental HAG-1 cells, but these effects were completely abolished in v-src- or c-H-ras-transfected cell line. Upon gefitinib treatment, EGFR activation and subsequent downstream activation through Erk and Akt were significantly inhibited in HAG-1 cells. By contrast, gefinitib failed to inhibit the activation of both Akt and Erk in v-src-transfected cells and Erk, but not Akt in c-H-ras-transfected cells, despite the blockade of EGFR activation in these respective cell lines. Treatment of v-src-transfected cells with herbimycin A, a Src tyrosine kinase inhibitor, partially reversed the gefitinib resistance, with concomitant inhibition of Akt and Erk. CONCLUSION: Our results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways, thus providing a strategic rationale for assessment of these specific signaling molecules downstream of EGFR to customize treatment.

DOI： 10.1007/s00280-006-0219-4

記述言語：日本語  

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background & Aims: Autoreactive T cells that proliferate in response to autoantigens are found in both autoimmune disease and controls but have important qualitative differences in relative activation states, costimulation signal requirements, and pathogenetic significance. Understanding the mechanism for activation of autoreactive T cells will be critical in the treatment of autoimmune diseases. Methods: To understand the differences between autoreactive T cells in primary biliary cirrhosis (PBC) versus controls, we have developed autoreactive T-cell clones (TCCs) from patients with PBC and healthy controls and have used a peptide corresponding to the CD4 major auto-epitope to define the relative proliferative and cytokine response. Results: Using an enzyme-linked immunosorbent spot assay, peripheral blood mononuclear cells (PBMCs) from PBC, but not from controls, produce interferon (IFN)-gamma regardless of whether costimulation-competent or -incompetent antigen-presenting cells (APC) were used. In contrast, a significant number of IFN-gamma-producing cells were found in PBMCs from controls but only if costimulation-competent PBMCs presented an autoantigenic peptide. In addition, costimulation-dependent autoreactive TCCs became anergic after a single round of stimulation in the presence of APC that did not provide a costimulatory signal, whereas some costimulation-independent autoreactive TCCs required repeated stimulation to become anergic and the others did not become anergic. Finally, anergic TCCs produced interleukin-10, but no IFN-gamma, and exhibited regulatory functions in an antigen-dependent, cell contact-independent, and partially interleukin-10-mediated manner. Conclusions: These data relate specifically to the functional characteristics of autoreactive T cells in PBC but are also generically important for understanding the mechanisms for generating pathogenetic autoreactive T cells.

DOI： 10.1053/j.gastro.2006.05.056

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In-vitro differential metabolism and activity of 5-fluorouracil between short-term, high-dose and long-term, low-dose treatments in human squamous carcinoma cells.
Although continuous infusion of 5-fluorouracil (5-FU) has been clinically demonstrated to be superior to bolus administration, the mechanistic difference between the treatments still remains unclear. Here, we investigated in vitro whether there were any differences in the metabolism and activity of 5-FU between these schedules. To simulate bolus and infusional treatments of 5-FU, HST-1 human squamous carcinoma cells were treated with short-term, high-doses and long-term, low-doses so that the area under the curve (AUC) of 5-FU became equivalent between both schedules, and compared the cytotoxicity, fluorinated RNA (F-RNA) levels, 5-fluorodeoxyuridine monophosphate (FdUMP) content and thymidylate synthase (TS) activity. F-RNA and FdUMP were measured by capillary gas chromatography-mass spectrometry and competitive ligand-binding assay, respectively. The [H]FdUMP binding site in TS was determined as an index of the amount of TS using the radio-binding assay. Long-term, low-dose treatment of 5-FU was found to be 1.3-1.7 times more cytotoxic than the short-term, high-dose treatment. F-RNA content increased as the AUC of 5-FU was increased and was 2-4 times significantly higher in the cells treated with the long-term, low-dose than those with the short-term, high-dose schedule, indicating that the levels of F-RNA are AUC and schedule dependent. In contrast, there were no significant differences in FdUMP levels, TS activity and TS inhibition rate between the schedules. These data suggest that the superior activity of 5-FU administered long-term, low-dose over short-term, high-dose could be explained by more 5-FU incorporated into RNA during a long-term, low-dose exposure, thus providing a strategic rationale for the clinical advantage of continuous infusion over bolus administration.

DOI： 10.1097/01.cad.0000203380.22361.6c

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In-vitro schedule-dependent interaction between oxaliplatin and 5-fluorouracil in human gastric cancer cell lines.
In order to define the most effective combination schedule of oxaliplatin (L-OHP) and 5-fluorouracil (5-FU), we investigated the in vitro interaction between these drugs in a panel of four human gastric adenocarcinoma cell lines (MKN-1, NUGC-3, NUGC-5 and AZ-521). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of L-OHP followed by 5-FU exhibited synergistic effects in all four cell lines, whereas the reverse sequence yielded a clear antagonism. 5-FU exclusively arrested cells at the G0/G1 phase, and L-OHP at the G0/G1 and G2/M phases. Apoptosis was most prominent when cells were treated simultaneously or in a sequence of L-OHP followed by 5-FU, producing apoptosis in the majority of treated cells (55.5-61.5&#37;). In contrast, the reverse sequence yielded only 20&#37; induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment which compared the total number of NUGC-3 cells 7 days after these combination schedules. These findings suggest that the interaction of 5-FU and L-OHP could be highly schedule dependent, with the most efficacious interaction observed in simultaneous combination and that 5-FU followed by L-OHP would not be recommended in clinical trials for patients with advanced gastric cancer.

DOI： 10.1097/01.cad.0000198912.98442.cd

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells.
Although gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been clinically demonstrated to be effective for certain cancer cell types, the molecular mechanisms of the anti-tumor activity have not been fully elucidated. In this study, we investigated the mechanism of gefitinib-induced growth inhibition and apoptosis in HAG-1 human gallbladder adenocarcinoma cells. Treatment of gefitinib at a dose of 1 microM resulted in a significant growth inhibition, and the cell number irreversibly declined after 72-h incubation, with a progressive expansion of apoptotic cell population over 120-h. Following 2-h treatment, gefitinib significantly inhibited EGFR autophosphorylation and subsequent downstream signaling pathway through Erk and Akt, and induced accumulation of cells in the G0/G1 phase of the cell cycle at 24-h, accompanied by a concomitant increase in p21 transcript and increased expression of p27. Gefitinib did not affect the amount of total and phosphorylated p53 at serine 15, but upregulated the expression of total Bax, with subsequent increase in p18 Bax, an active form of Bax. The expression of Bcl-2 and Bad was unchanged. An increase in gefitinib-induced expression of total Bax might be due to the decreased degradation of Bax, because the level of Bax mRNA has not been altered by gefitinib treatment. Gefitinib promoted the cleavage of full-length p21 Bax into p18 Bax in mitochondrial-enriched fraction, a characteristic feature of Bax activation toward apoptosis. Moreover, blockade of Bax by using anti-Bax small interfering double stranded RNA (siRNA) significantly reduced gefitinib-induced apoptosis. Taken together, these data suggest a critical role of p18 Bax in gefitinib-induced apoptosis.

DOI： 10.1002/jcb.20678

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Feasibility study of ambulatory continuous infusion of 5-fluorouracil followed by cisplatin through hepatic artery for metastatic colorectal cancer.
PURPOSE: A great synergy has been reported in a number of preclinical studies when 5-fluorouracil (5-FU) precedes cisplatin (CDDP). The objective of this study was to determine the feasibility of ambulatory continuous infusion of 5-FU followed by CDDP through hepatic artery for metastatic colorectal cancer. PATIENTS AND METHODS: Seventeen patients with unresectable liver metastases, who underwent primary tumor resection, were treated with 5-FU (450 mg/m2/day) for seven consecutive days followed by CDDP (100 mg/body/week) for seven consecutive days, each administered continuously by using a balloon pump via Infuse-A-Port catheter inserted into common hepatic artery. The doses of drugs were reduced 20&#37; in patients older than 70 years. The treatment was repeated every 4-6 weeks until disease progression. RESULTS: Of 17 assessable patients, nine patients showed PR (53&#37;; 95&#37; CI, 29.3-76.7&#37;) and eight patients had SD (47&#37;; 95&#37; CI, 23.3-70.7&#37;), with disease control rate of 100&#37;. The median overall survival was 26 months (95&#37; CI: 17.5-41 months) and TTP 14 months (95&#37; CI: 11-20.3 months). Two patients (11.8&#37;), who showed progression due to collateral feeding arteries, responded to HAI again after occlusion. Grade 3 toxicity included leukopenia (12&#37;) and anemia (24&#37;). Grade 4 toxicity was absent. Four patients (23.5&#37;) progressed at extrahepatic sites. CONCLUSIONS: This sequential combination of 5-FU followed by CDDP through hepatic artery is active and safe in an outpatient setting, and warrants further multi-institutional study, although prevention of micrometastasis would be mandatory to further prolong overall survival.

DOI： 10.1007/s00280-005-0021-8

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood monocytes of 12 healthy volunteers (hMo-DCs) and 11 patients (pMo-DCs) with malignancies by culture for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4. In this study, we focused on the cytogram pattern by FACS analysis. A gate (R1) was set up by which more than 95&#37; of hMo-DCs were contained. Mo-DCs having lower side scatter than the R1 (R2) comprised 4.5&#37; of hMo-DCs and 24.2&#37; of pMo-DCs. Expressions of antigen presentation-related molecules and phagocytic ability in the R2 of pMo-DCs were lower than those in the R1 population. The R2, but not R1, in pMo-DCs decreased in number between days 7 and 14, and expression levels of antigen presentation-related molecules in the living pMo-DCs on day 14 increased. The 11 patients received dendritic cell vaccine therapy with autologous, tumor-pulsed mature Mo-DCs (day 7). The low R2 group (R2&lt
10&#37;, 3 patients) had a significantly higher positive delayed-type hypersensitivity reaction against autologous tumor-pulsed Mo-DCs than that of the high R2 group (R2&gt
10&#37;, 8 patients) (p&lt
0.001). These results indicate that the R2 of pMo-DCs may be a dysfunctional and short-lived subset.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Synergistic interaction between oxaliplatin and SN-38 in human gastric cancer cell lines in vitro.
The interaction between CPT-11 and oxaliplatin, a new platinum derivative that has a great antitumor activity against colon cancer, has not been determined in gastric cancer cells. In this study, we investigated in vitro cytotoxic activity of oxaliplatin alone or in combination with SN-38, an active metabolite of CPT-11, using different exposure schedules in three human gastric cancer cell lines (AZ-521, MKN-45, and NUGC-4). Cytotoxicity was determined by WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation was evaluated by flow cytometry. In 24-h exposure, simultaneous administration of oxaliplatin and SN-38 showed a synergistic effect in AZ-521 and NUGC-4 cells, and an additive effect in MKN-45 cells. Greater than additive effects were observed in all of the cell lines when cells were treated with oxaliplatin followed by SN-38, whereas such effects were observed only in NUGC-4 cells in the reverse sequence. Flow cytometric analyses at IC(50) indicated that apoptosis was most prominent in simultaneous exposures with accumulation of cells in both G(0)/G(1) and S phases. These results suggest that SN-38 may kill the cells recovering from the G(1) block produced by oxaliplatin as they progress into the S phase. Simultaneous administration appears most active in gastric cancer cell lines. These results may provide important information for a clinical trial of oxaliplatin and CPT-11 combination for patients with gastric cancer.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In vitro sequence-dependent interaction between nedaplatin and paclitaxel in human cancer cell lines.
PURPOSE: To define the most effective combination schedule of paclitaxel and nedaplatin, a new platinum derivative, we investigated the in vitro interaction between these drugs in AZ-521 and NUGC-4 gastric adenocarcinoma and KSE-1 esophageal squamous carcinoma cell lines. MATERIALS AND METHODS: Cytotoxic activity was determined by the WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism using a quantitative method based on the median-effect principle of Chou and Talalay. Cell-cycle perturbation and apoptosis were evaluated by means of flow cytometry. RESULTS: Upon 24-h sequential exposure, the sequence paclitaxel followed by nedaplatin induced greater than additive effects in all of the cell lines, with synergistic interactions in NUGC-4 and KSE-1 cells. By contrast, antagonistic effects were observed with the reverse sequence. Simultaneous treatment resulted in either a synergistic or antagonistic effect, depending on the cell line. Therefore, the sequence paclitaxel followed by nedaplatin appears most active, at least in these three cell lines. Flow cytometric analyses at IC50 indicated that paclitaxel induced G2/M arrest with subsequent induction of apoptosis (56&#37;) in the sub-G1 phase. When paclitaxel preceded nedaplatin, apoptosis was most prominent (70&#37;) with pronounced G2/M arrest. By contrast, the reverse sequence yielded only 28&#37; induction of apoptotic cells, with almost identical cell-cycle distribution patterns to those observed with nedaplatin alone, indicating that the activity of paclitaxel is abolished by pretreatment with nedaplatin. CONCLUSIONS: Our findings suggest that the interaction of nedaplatin and paclitaxel is highly schedule dependent and that the sequential administration of paclitaxel followed by nedaplatin should be thus incorporated into the design of a clinical trial.

DOI： 10.1007/s00280-004-0991-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/S1470-2045(05)70285-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In vitro schedule-dependent interaction between paclitaxel and oxaliplatin in human cancer cell lines.
PURPOSE: In order to define the most effective administration schedule of the combination of paclitaxel and oxaliplatin, we investigated the in vitro interaction between these drugs in a panel of three human cancer cell lines (AZ-521 gastric adenocarcinoma cell line, HST-1 tongue squamous carcinoma cell line, and KSE-1 esophageal squamous carcinoma cell line). MATERIALS AND METHODS: Cytotoxic activity was determined by the WST-1 assay. Different administration schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. RESULTS: Simultaneous treatment of cells with paclitaxel and oxaliplatin showed greater than additive effects. Upon 24-h sequential exposure, the sequence of paclitaxel followed by oxaliplatin showed synergistic effects in AZ-521 and HST-1 cells, and greater than additive effects in KSE-1 cells, while the opposite sequence yielded marked antagonistic effects in all three cell lines. Flow cytometric analysis indicated that paclitaxel induced G(2)/M arrest with subsequent induction of apoptosis in the sub-G(1) phase. Apoptosis was most prominent when paclitaxel preceded oxaliplatin, which produced apoptosis in the majority of treated cells (75&#37;). By contrast, the reverse sequence yielded only 39&#37; induction of apoptotic cells, the rate being not different from those induced by each drug singly. CONCLUSIONS: Our findings suggest that the interaction of paclitaxel and oxaliplatin is highly schedule-dependent and that the sequential administration of paclitaxel followed by oxaliplatin should thus be incorporated into the design of a clinical trial.

DOI： 10.1007/s00280-004-0966-z

記述言語：英語  

Efficient engraftment of primary adult T-cell leukemia cells in newborn NOD/SCID/β2-microglobulin^null mice
Adult T-cell leukemia (ATL) develops via multiple oncogenic steps in human T-cell leukemia virus type I (HTLV-I) carriers. To better understand pathogenesis of ATL, we developed a novel xenogeneic engraftment model in which primary ATL cells are intravenously transplanted into neonatal nonobese diabetic (NOD)/severe-combined immunodeficiency (SCID)/β2-microglobulin^null (NOD/SCID/β2m^null) mice. Acute-type ATL cells engrafted in the peripheral blood and in the lymph nodes of recipients at a high efficiency. Engrafted ATL cells were dually positive for human CD4 and CD25, and displayed patterns of HTLV-I integration identical to those of donors by Southern blot analysis. These cells infiltrated into recipients' liver, and formed nodular lesions, recapitulating the clinical feature of each patient. In contrast, in smoldering-type ATL cases, multiple clones of ATL cells engrafted efficiently in NOD/SCID/β2m^null mice. When smoldering-type ATL cells were retransplanted into secondary NOD/SCID/β2m^null recipients, single HTLV-I-infected clones became predominant, suggesting that clones with dominant proliferative activity can be competitively selected in this xenogeneic system. Taken together, the NOD/SCID/β2m^null newborn system is useful to understand kinetics, metastasis, and disease progression of ATL in vivo.

DOI： 10.1038/sj.leu.2403829

記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study focused on the question of how monocyte-derived dendritic cells (Mo-DCs) that capture dead tumor cells (Mo-DCs-Tum) secrete interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α). Mo-DCs-Tum showed higher secretions of IL-12 and TNF-α than were shown by Mo-DCs. Enhanced nuclear factor-kappa B (NF-κB) activation was also induced in MoDCs-Tum within 6 h. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed both IL-12 and TNF-α secretions from Mo-DCs-Tum. Administration of recombinant TNF-α or IL-12 enhanced IL-12 or TNF-α secretion respectively in Mo-DCs-Tum. Addition of anti-TNF-α or anti-IL-12 neutralizing antibody decreased NF-κB activation and IL-12 or TNF-α secretion in Mo-DCs-Tum. These results suggest that TNF-α or IL-12 secretion induces NF-κB activation, and it stimulates further TNF-α and IL-12 secretions, i.e., an IL-12/TNF-α/NF-κB autocrine loop, in Mo-DCs-Tum. Thus, Mo-DCs-Tum secrete a large amount of IL-12 and TNF-α through accelerated NF-κB activation induced by the IL-12/TNF-α/NF- κB autocrine loop. © Springer-Verlag 2004.

DOI： 10.1007/s00262-004-0568-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the effect of exosomes secreted from human monocyte-derived dendritic cells (Mo-DCs), which are generated from PBMCs in response to treatment with GM-CSF and IL-4, on naive CD4+ T cell survival in vitro. Exosomes isolated from culture supernatants of Mo-DCs (&gt
90&#37; purity) were purified with anti-HLA-DP, -DQ, -DR-coated paramagnetic beads. Purified exosomes prolonged the survival of naive CD4+ T cells (&gt
98&#37; purity) in vitro. Treatment with neutralizing mAb against HLA-DR significantly decreased the supportive effect of purified exosomes on CD4+ T cell survival. Exosomes increased nuclear translocation of NF-κB in naive CD4+ T cells, and NF-κB activation was significantly suppressed by anti-HLA-DR mAb or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). In addition, PDTC inhibited the effect of exosomes on naive CD4+ T cell survival. Thus, exosomes secreted by Mo-DCs appear to support naive CD4+ T cell survival via NF-κB activation induced by interaction of HLA-DR and TCRs. © 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cellimm.2004.11.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Protection against methotrexate toxicity by a soybean protein- and omega-3 fatty acid-containing diet: comparative study with a casein-containing diet.
Effects of two clinically used liquid diets on toxicity and antitumor activity of methotrexate (MTX) were investigated in Sprague-Dawley (SD) rats and tumor-bearing mice, respectively. Diets tested were commercially available formulas enriched either with soybean and omega-3 fatty acids or with casein. The soybean-containing diet offered significant protection against MTX toxicity in rats compared with the casein-containing diet, completely alleviating MTX-induced anorexia, diarrhea, and weight loss, when ingested as the sole diet and fed 7 days prior to and 7 days following intraperitoneal MTX injection. As a result, 90&#37; of rats were alive on soybean-containing diet while all rats were dead on casein-containing diet. Histologic examination of the small intestine of MTX-treated rats revealed that the soybean-containing diet significantly prevented loss of mucosal villus tips compared to the casein-containing diet. Pharmocokinetic examination indicated that plasma MTX concentrations were similar for rats in the two diet-defined groups. No significant differences were observed between diets in survival of mice injected with L1210 mouse leukemia cells and subsequently with MTX. Thus the soybean-containing diet appeared to be superior to the casein-containing diet in preventing gastrointestinal toxicity while preserving antitumor activity. A soybean diet enriched in omega-3 fatty acids may be a useful adjunct to MTX treatment of human cancers.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Phase I study of CPT-11 and bolus 5-FU/ l-leucovorin in patients with metastatic colorectal cancer.
BACKGROUND: Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. METHODS: We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled. RESULTS: At dose level 2 (CPT-11, 100 mg/m(2); 5-FU, 400 mg/m(2); and l-LV, 25 mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100 mg/m(2); 5-FU, 500 mg/m(2); and l-LV, 25 mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3-4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39&#37;), and 8 patients (44&#37;) experienced stable disease. CONCLUSION: This CPT-11/5-FU/ l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway. Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.

DOI： 10.1007/s10147-003-0371-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dendritic cell-like cells (Mo-DCs) generated from peripheral blood monocytes with interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used as tools to treat cancer patients (DC-vaccines). Because Mo-DCs have multiple antigen presentation-related functions, including phagocytosis, migration, cytokine production, and T cell stimulation, establishment of a method for simultaneously evaluating the various functions of Mo-DCs is important. We developed a new in vitro three-dimensional two-layer collagen matrix culture model that consists of a collagen gel containing Mo-DCs as the lower layer and a collagen gel containing necrotic GCTM-1 tumor cells and/or T cells as the upper layer. We used this system to observe simultaneously multiple functions of Mo-DCs by phase-contrast or fluorescence microscopy and to assess IL-12 secretion during more than 2 weeks of culture. We also observed interactions between Mo-DCs and necrotic GCTM-1 or T cells on an individual cell basis by time-lapse videomicroscopy. In addition, we collected Mo-DCs from the collagen gels by collagenase treatment and analyzed the expression of antigen presentation-related molecules such as HLA-DR, CD80, CD83, and CD86 on Mo-DCs. This model may be a useful tool for evaluation of the various functions of Mo-DCs used as DC vaccines and for studies of the complex behaviors of Mo-DCs in vivo. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jim.2004.01.014

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Effective adoptive cancer immunotherapy depends on an ability to generate tumor-antigen-presenting cells and tumor-reactive effector lymphocytes and to deliver these effector cells to the tumor. Dendritic cells (DCs) are the most potent antigen-presenting cells, capable of sensitizing T cells to new and recall antigens. Many studies have shown that tumors express unique proteins that can be loaded on DCs to trigger an immune response. The current experimental and clinical statuses of adoptive transfer of tumor antigen-pulsed DCs and vaccine-primed activated T cells are summarized herein. Clinical trials of antigen-pulsed DCs have been conducted in patients with various types of cancer, including non-Hodgkin lymphoma, multiple myeloma, prostate cancer, renal cell carcinoma, malignant melanoma, colorectal cancer, and non-small cell lung cancer. These studies have shown that antigen-loaded DC vaccination is safe and promising for the treatment of cancer. In addition, tumor vaccine-primed T cells have been shown to induce antitumor activity in vivo. Several clinical studies are being conducted on the use of vaccine-primed T cells such as tumor-drainage lymph node. It is reasonable to consider using both tumor antigen-pulsed DCs and vaccine-primed lymphocytes as adjuvants. We are now investigating the use of autologous whole tumor antigen-pulsed DCs and the DC vaccine-primed activated lymphocytes in patients with multiple metastasis of solid tumors.

DOI： 10.1111/j.1749-0774.2003.tb00151.x

記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

Clinical use of Herceptin (trastuzumab), which is a humanized monoclonal antibody against HER2, started for patients with HER2-overexpressing breast cancer. To potentiate the efficacy of the Herceptin therapy, this study focused on the combination of Herceptin with activated immune lymphocytes. We used peripheral blood mononuclear cells (PBMCs) as effector cells and used HER2-unexpressing K562 cells, HER2-weakly-expressing breast carcinoma cells (Breast-M), or HER2-strongly-expressing breast carcinoma cells (BT-474) as target cells. Interleukin-2 (IL-2)-activated PBMCs, IL-2/OKT-3-activated PBMCs and a streptococcal preparation OK-432-activated PBMCs were generated and used as effector cells. Cytotoxic activity was determined with 4-hour 51Cr release assay. Both fresh PBMCs and activated PBMCs exhibited Herceptin-dependent cytotoxicity. Importantly, Herceptin-dependent cytotoxicity was found even at a lower effector to target cell ratio (E/T ratio) than that of Herceptin-independent cytotoxicity. In addition, Herceptin-dependent cytotoxicity by these activated PBMCs was observed even in HER2-weakly-expressing Breast-M cells. Since γ-globulin or anti-CD16 antibody abrogated Herceptin-dependent cytotoxicity, it seems likely that antibody-dependent cellular cytotoxicity (ADCC) plays an important role in the Herceptin-dependent cytotoxicity. We present a recurrent breast cancer patient with malignant pleural effusion, in which HER2-strongly-expressing tumor cells were present, who was undergoing Herceptin therapy. Cluster formation between tumor cells and intrapleural mononuclear cells was induced 24 hours after intravenous injection of Herceptin (4 mg/kg). Mononuclear cells bound specifically to HER2-strongly-expressing tumor cells but not to other cells, such as mesothelial cells, suggested a Herceptin-mediated binding like ADCC in vivo. Taken together, these findings suggest that the combination of Herceptin with various types of activated lymphocytes may be a new therapeutic strategy, not only for HER2-strongly-expressing breast cancer but also for HER2-weakly-expressing cancer.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Purpose: We sought to determine whether cyclosporin-A (CsA) enhances docetaxel [Taxotere (TXT)]-induced apoptosis in human gastric carcinoma cells, and, if so, to determine the relation between this apoptosis and nuclear factor-κB (NF-κB) activation. Experimental Design: Two human gastric carcinoma cell lines (GCTM-1 and MK-1), a human embryonic pulmonary fibroblast cell line, and human umbilical vein endothelial cells were used as drug targets. Apoptotic cell death was verified morphologically by nuclear fragmentation assay with Hoechst staining. Electrophoretic mobility shift assays were performed to check for nuclear translocation of NF-κB. The therapeutic effects of a combination of TXT and CsA were assessed in a mouse peritoneal dissemination model. Results: A combination of CsA (5 μM) and TXT (10 nM) significantly enhanced apoptotic cell death in both carcinoma cell lines but not in nonmalignant cell lines in comparison with the single-agent treatment alone. This effect was not related to drug uptake, efflux, or MDR1 expression. These effects were also observed in freshly obtained TXT-resistant gastric carcinoma cells isolated from a patient with malignant ascites. TXT alone induced NF-κB activation in both carcinoma cell types, and this activation was suppressed by CsA. A combination of TXT and NF-κB decoy, a well-known NF-κB inhibitor, also enhanced apoptotic cell death in the carcinoma cells. A combination of CsA and TXT significantly suppressed peritoneal dissemination in vivo relative to the single-agent effect. Conclusions: Treatment with CsA and TXT in combination may be an effective therapeutic strategy for patients with gastric carcinoma.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have conducted a pilot study with combined immunotherapy using autologous lymphocytes activated ex vivo and monocyte-derived dendritic cells in combination with low-dose OK-432, a streptococcal preparation, in five patients with peritoneal or pleural carcinomatosis who were resistant to standard chemotherapy. All patients were given 3 to 10 courses of the combined immunotherapy. No severe adverse reactions occurred. Effusion production was decreased in all of the patients. Significant decreases in tumor markers of both effusions and sera as well as effusion volume occurred in all of the patients. Cytological examinations revealed a marked decrease or disappearance of cancer cells in those effusions. Three patients showed increase in IFN-gamma levels in the effusions. The overall prognosis of the patients was acceptable and the mean survival time was more than 9 months. The locoregional immunotherapy seems to be encouraging in view of therapeutic modality in patients who are resistant to standard chemotherapy. Our study provides a new protocol for immunotherapy and warrants further phase I/II clinical study for chemo-resistant patients with malignant effusion.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

For vaccinations based on dendritic cells (DCs), maturation of DCs is critical to the induction of T-cell responses. We tested the efficacy of streptococcal preparation OK-432 as a Good Manufacturing Practice (GMP)-grade maturation agent. OK-432 is currently used in Japan as a cancer immunotherapy drug. Immature monocyte-derived dendritic cells (imMo-DCs) isolated from human peripheral blood monocytes stimulated with granulocyte-macrophage colony stimulating factor and interleukin-4 were exposed to maturation factors, i.e., lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) plus prostaglandin E2 (PGE2), and OK-432 for 2 days. OK-432 increased expression of activation- and maturation-related molecules such as HLA-DR, CD80, CD83, and CD86 in imMo-DCs at levels similar to that of TNF-α plus PGE2, and higher than that of LPS. All agents examined induced allogeneic T-cell proliferation at a similar level. Only OK-432 caused significant production of interleukin-12 (IL-12) p70 and interferon γ (IFN-γ) at both the mRNA and protein levels in imMo-DCs. Neutralizing antibody against IL-12 p70 blocked IFN-γ secretion from OK-432-stimulated Mo-DCs. IL-12 p70 produced by OK-432-stimulated imMo-DCs induced secretion of IFN-γ by CD4+ T cells. OK-432 and LPS activated nuclear factor κ B (NF-κB) in imMo-DCs. Both secretion of IL-12 p70 and IFN-γ and activation of NF-κB induced by OK-432 were suppressed when imMo-DCs were pretreated with cytochalasin B. These results indicate that uptake of OK-432 by imMo-DCs is an early critical event for IL-12 p70 production and that NF-κB activation induced by OK-432 also contributes partially to IL-12 p70 production. In conclusion, OK-432 is a GMP-grade maturation agent and may be a potential tool for DC-based vaccine therapies.

DOI： 10.1007/s00262-003-0394-7

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background & Aims: Previous work has suggested that CD4⁺ CD28^- or costimulation-independent T cells are increased in autoimmune diseases. In this study, we compared frequency and qualitative characteristics of autoreactive costimulation-independent or CD4⁺ CD28^- T cells in primary biliary cirrhosis (PBC) by taking advantage of the well-defined immunodominant autoepitope of the E2 component of pyruvate dehydrogenase (PDC-E2). Methods: We determined the frequency of costimulation-independent autoreactive T cells that respond to PDC-E2 163-176 and the frequency of CD4⁺ CD28^- T cells. Finally, we determined the role of biliary epithelial cells (BEC) as both an antigen-presenting cell or, alternatively, as a target cell for T-cell-mediated cytotoxicity. Results: The precursor frequency of costimulation-independent CD4⁺ T cells that respond to PDC-E2 163-176 and the frequency of CD4⁺ CD28^- T cells were dramatically elevated in PBC. Furthermore, 2 types of T-cell clones that respond to PDC-E2 163-176 emerged from this study. One type was costimulation dependent and the other costimulation independent. Both types of clones lyse BEC in a similar effector target (E/T) ratio distribution. However, BEC did not help the proliferation of any T-cell clones. Furthermore, costimulation-independent T-cell clones do not become anergic by BEC. Conclusions: In PBC, costimulation-independent autoreactive T cells, which do not become anergic, increase and maintain the autoimmune response. In controls, although autoantigens are expressed on BEC and autoantigen-reactive T cells exist around BEC, autoantigen-reactive T cells are costimulation dependent and will become anergic and maintain peripheral tolerance.

DOI： 10.1016/j.gastro.2003.07.013

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dendritic cells (DCs) are antigen-presenting cells specialized for the induction of the primary T-cell response. Tumor immunotherapy using DCs loaded with tumor antigens is under way for patients with several types of advanced malignancies. In this study, DC-like cells (Mo-DCs) were generated from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor and interleukin-4. The antigen-presenting abilities, including capture of apoptotic tumor cells, IL-12 secretion, expression of antigen-presentation-related molecules (HLA-ABC, HLA-DR, and CD80), and mixed leukocyte reaction, of Mo-DCs from 37 patients with advanced cancer (pMo-DCs) were compared to those of 20 healthy volunteers (hMo-DCs). Seven days after the initial culture, no significant difference was found in either the number or the size of Mo-DC-forming colonies between the two groups. However, most of the antigen-presenting abilities of pMo-DCs were weaker than those of hMo-DCs on day 7. On day 14, both number and size of colonies were significantly decreased in pMo-DCs but not in hMo-DCs. Interestingly, the antigen-presenting abilities of the remaining pMo-DCs gradually strengthened with time and by day 14 no significant difference was observed between pMo-DCs and hMo-DCs. These results indicate that pMo-DCs contain dysfunctional and short-lived Mo-DC subsets. © 2002 Elsevier Science (USA).

DOI： 10.1006/clim.2002.5293

記述言語：英語   掲載種別：研究論文（学術雑誌）  

An in vitro organotypic culture model is needed to understand the complexities of carcinoma tissue consisting of carcinoma cells, stromal cells, and extracellular matrices. We developed a new in vitro model of carcinoma tissue using a rotary cell culture system with four disposable vessels (RCCS™-4D) that provides a simulated microgravity condition. Solid collagen gels containing human pancreatic carcinoma NOR-P1 cells and fibroblasts or minced human pancreatic carcinoma tissue were cultured under a simulated microgravity condition or a static 1g condition for seven days. NOR-P1 cultures subjected to the simulated microgravity condition showed greater numbers of mitotic, cycling (Ki-67-positive), nuclear factor-κ B-activating cells, and a lower number of apoptotic cells than were shown by cultures subjected to the static 1g condition. In addition, human pancreatic carcinoma specimens cultured under the simulated microgravity condition maintained the heterogeneous composition and cellular activity (determined by the cycling cell ratio and mitotic index) of the original carcinoma tissue better than static culture conditions. This new 3-D rotary cell culture system with four disposal vessels may be useful for in vitro studies of complex pancreatic carcinoma tissue.

記述言語：英語  

OX40/OX40 ligand (OX40L) proteins play critical roles in the T cell-B cell and T cell-dendritic cell interactions. Here we describe the intercellular transfer of OX40L molecules by a non-Ag specific manner. After 2-h coculture of activated CD4(+) T cell (OX40L(-), OX40(+)) with FLAG peptide-tagged OX40L (OX40L-flag) protein-expressing COS-1 cells, the OX40L-flag protein was detected on the cell surface of the CD4(+) T cells by both anti-OX40L and anti-FLAG mAbs. The intercellular OX40L transfer was specifically abrogated by pretreatment of the COS-1 cells with anti-OX40L mAb, 5A8. The OX40L transfer to OX40-negative cells was also observed, indicating an OX40-independent pathway of OX40L transfer. HUVECs, allostimulated monocytes, and human T cell leukemia virus type I-infected T cells, which all express OX40L, can potentially act as the donor cells of OX40L. The entire molecule of OX40L was transferred and stabilized on the recipient cell membrane with discrete punctate formation. The transferred OX40L on normal CD4(+) T cells was functionally active as they stimulated latent HIV-1-infected cells to produce viral proteins via OX40 signaling. Therefore, these findings suggest that the intercellular molecular transfer of functional OX40L may be involved in modifying the immune responses.

記述言語：英語  

The possible role of carbohydrate in the interaction of HLA-C with a human inhibitory natural Killer cell Immunoglobulin-like Receptor with two Ib domains, KIR2DL1, was investigated. Transfectants of 721.221 (a class I MHC-negative human B cell line) expressing only HLA-Cw4 or -Cw6 or their respective non-glycosylated mutants (N86Q, S88A) were made. The binding of a KIR2DL1-Ig fusion protein to the non-glycosylated mutant HLA-Cw4- or -Cw6-expressing cells was markedly decreased compared to the wild type-expressing cells. The ability to induce an inhibitory signal in the NK tumor line YTS transfected with KIR2DL1 was also impaired in the nonglycosylated mutant expressing cells. Furthermore, in a second functional assay, mutant HLA-Cw I and -Cw6 molecules had impaired ability to induce signal transduction in BW cells expressing a KIR2DL1-CD3 zeta chain chimeric protein. Thus, the deletion of the N-linked glycosylation signal in HLA-Cw4 and -Cw6 greatly reduced recognition by KIR2DL1. Alternative interpretations of the data are discussed. (C) American Society for Histocompatibility and Immunogenetics, 2000. Published by Elsevier Science Inc.

DOI： 10.1016/S0198-8859(00)00184-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

W6/32 is one of the most common monoclonal antibodies (mAb) used to characterize human class I major histocompatibility complex (MHC) molecules. It recognizes a conformational epitope on the intact MWC molecule containing both beta(2)-microglobulin (beta(2)-m) and the heavy chain. Labelling proteins by biotinylation is a very useful technique of for their detection, purification and analysis A common method for biotinylating proteins is through the use of N-hydroxysuccinimide (NHS) biotin or Sulfo-NHS-biotin where the free amino groups on the protein are used for coupling the biotin moiety. However, W6/32 was unable to effectively immunoprecipitate biotinylated human class I MHC molecules including the human non-classical HLA-G molecule. FACScan analysis confirmed that biotinylating human class I MHC and HLA-G molecules prevents the recognition of these molecule by W6/32. In contrast, the recognition by another conformation-dependent monoclonal antibody, ME1, specific to HLA-B27 molecules, remained totally unaffected.

記述言語：英語  

Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-tenninal portion of HLA-G. Assays using transfectants expressing a variety of HLA-Cw6 mutants identified the transmembrane sequence and, in particular, cysteine at position 309 as necessary for inhibition of 68&#37; (25/37) of NK cell lines and 23&#37; (33/145) of NK clones tested. Moreover, these NK clones inhibited by target cell expression of HLA-Cw6 and dependent upon the transmembrane sequence were found not to express or to only dimly express NK inhibitory receptors (NKIR1) that are EB6/HP3E4-positive. Furthermore, assays using monoclonal antibody blocking suggest that an NK receptor other than NKIR1 or CD94 is responsible for recognition dependent upon the transmembrane sequence of HLA-Cw6.

DOI： 10.1084/jem.189.8.1265

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The efficacy of long-term, high dose interferon-α (IFN-α) therapy was studied in seven patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). IFN-α was administered at a dose of 6 x 106 international units daily for the initial 2 weeks and thereafter 3 times a week for the following 22 weeks. Five patients showed a sustained improvement in motor performance during and up to 6 months after the completion of IFN-a. The other patient who responded to IFN-α initially dropped out at 3 months because of depression, while another patient first deteriorated and thereafter dropped out. In the six responders,the absolute number of peripheral blood lymphocytes (PBL) harboring the HTLV-I genome as evaluated by the quantitative polymerase chain reaction method decreased significantly during the therapy period (28.6 ± 16.6&#37; reduction, P=0.0083), whereas the one deteriorated patient showed a 2.5-fold increase in HTLV-I-infected cells. The autoproliferation of CD4+ T clone cells from a single cell culture was markedly depressed even after the cessation of IFN-α in the responders who completed long-term IFN-α therapy. In addition, the CD8+DR+ T cells in the peripheral blood and soluble IL-2 receptor levels in the sera increased significantly during the therapy in all patients (P=0.0431 and P=0.0041, respectively). Therefore, the results of our study suggested that both the reduction of HTLV-I proviral DNA load and immunomodulation by long-term IFN-α therapy contributed to its sustained clinical benefits.

DOI： 10.1016/S0022-510X(96)05319-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Antibodies specific for the products of the human T cell lymphotropic virus type 1 (HTLV-I) pX frame-shift mutants were studied by ELISA. The serum IgG antibodies to the synthetic peptide corresponding to one nucleotide insertion at position 7784 were significantly more common in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in HTLV-I carriers who had neither HAM/TSP nor adult T cell leukemia (39% vs. 5%). The seropositivities to the other synthetic peptides, which corresponded to the one nucleotide deletion at position 7475 and the internal deletion of nt 7754-7819 and nt 7853-7936, were rare. A genetic study confirmed the presence of the responsible mutation of the pX gene in peripheral blood mononuclear cells and central nervous system tissue from HTLV-I-infected subjects with and without HAM/TSP. These results suggest that HTLV-I pX frame-shift mutants are expressed in vivo in HTLV-I carriers; they also induce antibodies, especially in those with HAM/TSP.

DOI： 10.1093/infdis/173.5.1115

記述言語：その他  

Sequence-dependent modulation of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 human squamous carcinoma cell line.

記述言語：英語  

We have recently identified the principal linear neutralizing B cell epitopes of human T cell leukemia virus type (HTLV-I) on the envelope protein gp46, amino acids (aa) 187-199, by using a number of human mAbs. We therefore propose that this region would be a good candidate for a peptide-based HTLV-I vaccine. To develop a peptide-based vaccine that can induce a high titer of neutralizing Abs against HTLV-I, we first synthesized peptides of various lengths containing aa187-199. Because the addition of gp46 aa181-186 or aa200-210 to either the N-terminus or C-terminus of SP187-199 did not alter the antigenicity of the principal neutralizing determinant, we prepared two peptide-based vaccines, MAP181-203 and MAP181-210, by conjugating SP181-203 and SP181-210 with a branched polylysine oligomer. In rabbits, x4 to x8 and x8 to x64 titers of the neutralizing Abs were induced by immunization with MAP181-203 and MAP181-210, respectively. Furthermore, high titers of neutralizing Abs (x40 to x320) were elicited in five different strains of rats by immunization with MAP181-210. We also identified the major T cell epitope on gp46 aa194-210 in various Strains of rats immunized with MAP181-210. Furthermore, the peripheral T lymphocytes obtained from the majority of HTLV-I-infected patients including HTLV-1-associated myelopathy/tropical spastic paraparesis, adult T cell leukemia/lymphoma, and healthy carriers, proliferated in response to the peptides containing aa194-210. These results indicated that MAP181-210 contains a T cell helper epitope on aa194-210 not only in rats and rabbits, but also in humans with various HLA haplotypes. It is therefore possible that MAP181-210 could become one of the candidates for a peptide-based HTLV-I vaccine for human use.

記述言語：その他  

Characterization of a newly established human gallbladder carcinoma cell line.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

In order to define neutralization regions on the envelope antigen of human T-cell leukemia virus type I (HTLV-I), we have generated a number of new anti-envelope gp46 monoclonal antibodies from rats and mice. Epitopes recognized by new monoclonal antibodies which could neutralize HTLV-I in syncytium and transformation inhibition assays were localized to sequences in gp46 from amino acids 186 to 193, 190 to 195, 191 to 195, 191 to 196, and 194 to 199. Ovalbumin-conjugated synthetic gp46 peptides containing these neutralization epitopes, pep190-199 (a synthetic gp46 peptide containing amino acids 190 to 199) and pep180-204, but not pep185-194 or pep194-203, could give rise to HTLV-I-neutralizing antibody responses in rabbits. These immune or nonimmune rabbits were then challenged with HTLV-I by intravenous inoculation with 5 x 107 live HTLV-I-producing ILT-8M2 cells. By a PCR assay, it was revealed that HTLV-I provirus was detected in peripheral blood lymphocytes from nonimmune and pep288-312-immunized rabbits, whereas the provirus was not detected in peripheral blood lymphocytes from pep190-199- and pep180-204-immunized rabbits over an extended period. These results suggest that the induction of anti-gp46 neutralizing antibody responses by immunization with synthetic peptides has the potential to protect animals against HTLV-I infection in vivo.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The nucleotide sequence of human T‐lymphotropic virus type I (HTLV‐I) in central nervous system tissue was determined in 3 autopsy cases with HTLV‐I–associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 1 seropositive carrier without HAM/TSP but with multiple sclerosis. All HAM/TSP samples (3 spinal cords and 2 brains) and the sample from the seropositive carrier without HAM/TSP (brain) were positive for HTLV‐I env (5146–6681), pX5′ (6549–7494), and pX3′ (7354–8276) regions by the two‐step polymerase chain reaction method. A nucleotide sequence analysis of the pX5′ and pX3′ polymerase chain reaction products from nucleotides 6631 to 8259 revealed heterogeneity of the HTLV‐I genome in all cases. It is notable that 13 of 50 clones derived from the pX3′ polymerase chain reaction products were defective in the tax open reading frame while 7 were defective in the rex open reading frame in the HAM/TSP samples. All 17 clones from 1 HAM/TSP case were defective in the pX open reading frame II. One nucleotide insertion at 7784 creating a frame shift in both tax and rex was seen in all 3 HAM/TSP cases but not in the HTLV‐I carrier without HAM/TSP. The pX‐defective mutants found frequently in the central nervous system may contribute to the neural damage, since the pX gene products are essential for the transactivation of various cellular genes as well as for viral replication.

DOI： 10.1002/ana.410360206

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have generated 153 human mAb reacting with natural envelope glycoprotein-gp46 of human T-cell leukemia virus type-1 (HTLV-1) by the EBV- transformation of B lymphocytes obtained from patients with HTLV-1-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). Twenty-four of these mAb had neutralizing activity of HTLV-1 as determined by an HTLV-1-induced syncytium formation inhibition assay in vitro. The reactivity of these neutralizing mAb was studied by using 9 different synthetic peptides covering immunodominant regions of the gp46. Thirteen out of these 24 neutralizing mAb reacted with gp46 peptide 175-199, whereas one mAb reacted with gp46 213-236 and another one with gp46 288-317. The other 9 neutralizing mAb did not react with any of these peptides. Fine epitope mapping of the mAb reacting with gp46 peptide 175-199 revealed the presence of 4 distinct neutralizing B-cell epitopes on this region; (1) 187-193, (2) 191-196, (3) 193-199, and (4) continuous conformational B-cell epitope. The competitive antibody-binding inhibition experiments by soluble phase synthetic peptides showed that the binding activity of these neutralizing mAb to the corresponding synthetic peptides is equal to or a little lower than that to native gp46 protein, suggesting that synthetic peptides can form structure very similar to the neutralizing epitopes on native gp46 protein. The present study is the first systematic demonstration of multiple neutralizing B-cell epitopes of HTLV-1 in human HTLV-1 infection. It would be possible to prepare a synthetic peptide vaccine against HTLV-1 based on these newly identified multiple linear neutralizing B-cell epitopes of HTLV-1.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have generated a number of EBV-transformed B cell lines producing human mAb against human T cell leukemia virus type 1 (HTLV-1) from the peripheral blood B lymphocytes obtained from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis. Various synthetic peptides corresponding to antigenic regions of HTLV-1 gag and env proteins were used for the screening of antibodies in ELISA. In our study, four IgG mAb to the gag p19 amino acids 100 to 130, and 5 IgG mAb to the env p46 amino acids 175 to 199 were characterized. An immunofluorescence assay showed that all of these mAb specifically bound to the surface of HTLV-1-bearing cell lines. Among these mAb, one anti-gp46 mAb, designated KE36-11, neutralized the infectivity of HTLV-1 as determined by both the inhibition of HTLV-1-induced syncytium formation and transformation assays in vitro. An antibody-binding assay using overlapping oligopeptides revealed that KE36-11 recognized a new epitope locating between the gp46 amino acid sequence 187-193 (Ala-Pro-Pro- Leu-Leu-Pro-His). Another anti-gp46 mAb, designated KE36-7, showed antibody- dependent cellular cytotoxicity against HTLV-1-bearing cell line. KE36-7 bound strongly to the 10-mer peptide-gp46 187-196, and weakly to peptides containing the gp46 amino acid sequence 191-196 (Leu-Pro-His-Ser-Asn-Leu). These two epitopes, which are associated with HTLV-1 neutralization and antibody-dependent cellular cytotoxicity, are thus the first epitopes identified in human HTLV-1 infection. It is possible that passive immunization of humans with these two human mAb are effective on the protection of HTLV-1 infection in vivo.

開催年月日： 2010年7月

記述言語：その他   会議種別：口頭発表（一般）  

開催地：東京   国名：日本国  

開催年月日： 2009年10月

記述言語：その他  

開催地：横浜   国名：日本国  

開催年月日： 2008年6月

記述言語：その他  

開催地：chicago   国名：アメリカ合衆国  

開催年月日： 2021年5月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：web 講演会   国名：日本国  

開催年月日： 2011年7月

記述言語：その他   会議種別：シンポジウム・ワークショップ パネル（公募）  

国名：日本国  

開催年月日： 2011年5月

記述言語：その他   会議種別：口頭発表（一般）  

開催地：大阪市立大学   国名：日本国  

開催年月日： 2010年9月

記述言語：その他   会議種別：口頭発表（招待・特別）  

開催地：国立病院機構長崎医療センター   国名：日本国