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

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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）  

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

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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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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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

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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）  

DOI： 10.1007/s10147-024-02504-4

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: 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

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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

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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

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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

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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

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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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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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

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DOI： 10.1200/JCO.2024.42.3_suppl.TPS423

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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：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

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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

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DOI： 10.1016/j.annonc.2023.09.141

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DOI： 10.1016/j.annonc.2023.09.205

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DOI： 10.1016/j.annonc.2023.09.197

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DOI： 10.1016/j.annonc.2023.09.209

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DOI： 10.1016/j.annonc.2023.09.212

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DOI： 10.1016/j.annonc.2023.09.323

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DOI： 10.1016/j.annonc.2023.09.349

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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

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)

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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

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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

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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

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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。

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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.

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

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DOI： 10.1016/j.annonc.2023.04.136

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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

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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

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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

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記述言語：英語  

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

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DOI： 10.1007/s10120-022-01331-8

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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。

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：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

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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：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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   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   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  

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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

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記述言語：英語  

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。

記述言語：英語   出版者・発行元：(一社)日本癌治療学会  

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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）   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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jjco/hyac143

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。

DOI： 10.1016/j.annonc.2022.07.527

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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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.

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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

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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  

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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.

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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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語  

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

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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.

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記述言語：日本語  

PubMed

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  

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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

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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

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DOI： 10.1200/JCO.2022.40.4_suppl.280

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DOI： 10.1200/JCO.2022.40.4_suppl.258

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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

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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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jcm10214972

記述言語：英語  

DOI： 10.3892/mco.2021.2379

記述言語：英語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

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）  

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）  

DOI： 10.1002/cam4.3619

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

DOI： 10.3892/mco.2019.1894

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.1634/theoncologist.2018-0119

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.1093/annonc/mdy498

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.13826

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

DOI： 10.3892/or.2018.6464

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD.0000000000011042

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD.0000000000010378

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/esmoopen-2017-000301

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

DOI： 10.1634/theoncologist.2017-0275

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.analchem.7b03893

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD.0000000000008987

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.12101

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/CAD.0000000000000562

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/MD.0000000000008470

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.3892/ol.2017.6299

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.3892/mco.2017.1240

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.11614

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/mco.2017.1205

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

DOI： 10.1080/01635581.2017.1267774

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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  

DOI： 10.1093/annonc/mdw206

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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  

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）  

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）  

DOI： 10.3892/ol.2015.3853

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ol.2015.3938

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ol.2015.3708

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

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）  

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）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

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）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.1038/bmt.2008.94

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12032-007-9010-6

記述言語：英語  

DOI： 10.1002/eji.200737694

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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）  

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  

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）  

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）  

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）  

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）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

DOI： 10.1006/clim.2002.5293

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語  

記述言語：英語  

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）  

記述言語：英語  

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）  

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）  

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  

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）  

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）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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開催年月日： 2010年5月

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開催地：九州大学   国名：日本国  

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開催地：東京   国名：日本国  

開催年月日： 2010年3月

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国名：日本国  

開催年月日： 2009年11月

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国名：中華人民共和国  

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国名：ドイツ連邦共和国  

開催年月日： 2009年9月

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開催年月日： 2009年8月

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開催地：大分   国名：日本国  

開催年月日： 2009年6月

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開催地：福岡   国名：日本国  

開催年月日： 2009年6月

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開催地：大阪   国名：日本国