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：ESMO Open  

Background: Pembrolizumab, an immune checkpoint inhibitor (ICI), shows significant survival benefits in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but its efficacy in microsatellite-stable (MSS) mCRC is limited. Although ICIs are effective in tumor mutational burden-high (TMB-H) solid tumors, the impact on MSS-TMB-H mCRC, a rare subset within MSS mCRC, remains unclear. Materials and methods: We conducted a retrospective analysis using clinical and genomic data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository in Japan. Patients with MSS-TMB-H mCRC who underwent tissue-based comprehensive genomic profiling and were treated with pembrolizumab or other later-line therapies were included. Pembrolizumab's efficacy was compared with that of trifluridine/tipiracil (FTD/TPI) and regorafenib. Genomic profiles of MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-low (TMB-L) CRCs were analyzed across 71 cancer-related genes. Results: Among 127 TMB-H mCRC cases treated with pembrolizumab in the C-CAT repository, 77 were MSS and 50 were MSI-H. Pembrolizumab showed significantly shorter time to treatment failure (TTF) and overall survival (OS) in patients with MSS-TMB-H mCRC compared with those with MSI-H-TMB-H mCRC [median TTF 2.0 versus 10.6 months; hazard ratio (HR) 4.79, 95% confidence interval (CI) 2.65-8.64, median OS 4.5 versus 33.6 months; HR 9.86, 95% CI 3.93-24.77, both P < 0.0001]. Among MSS-TMB-H mCRC patients, 19 received pembrolizumab, 73 received FTD/TPI (±bevacizumab), and 18 received regorafenib as their first later-line therapy. Pembrolizumab showed significantly shorter TTF and OS compared with FTD/TPI (median TTF 1.6 versus 4.1 months; HR 2.66, 95% CI 1.41-5.02, P = 0.0017, median OS 5.4 versus 13.8 months; HR 2.42, 95% CI, 1.09-5.38, P = 0.025). Genomic analysis of 6737 CRCs revealed that MSS-TMB-H CRCs harbored fewer pathogenic alterations than MSI-H-TMB-H CRCs but had a profile similar to MSS-TMB-L CRCs. Conclusions: Pembrolizumab may be less effective than FTD/TPI in later-line treatment of MSS-TMB-H mCRC, potentially due to genomic similarities between MSS-TMB-H and MSS-TMB-L CRC, suggesting the need for alternative therapeutic strategies in this subgroup.

DOI： 10.1016/j.esmoop.2024.104108

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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：Nature Communications  

Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39⁺PD-1⁺CD8⁺ T cells, specifically the TCF1⁺ subset, precursor exhausted T (CD39⁺ Tpex) cells, which positively correlate with ICB benefit. CD39⁺ Tpex cells are predominantly in the stroma, while differentiated CD39⁺ exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39⁺ Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39⁺ Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39⁺PD-1⁺CD8⁺ T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors.

DOI： 10.1038/s41467-024-53262-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：Japanese Journal of Clinical Oncology  

Background: Malignant primary cardiac tumors require multimodal approaches including surgery, chemotherapy and radiotherapy, but these treatments can be associated with cardiovascular complications. However, few reports have described the cardiovascular complications related to primary cardiac tumor treatment because of their rarity. Methods: Clinical records of patients with primary cardiac tumors treated at Kyushu University Hospital from January 2010 to August 2021 were retrospectively examined. Results: Of the 47 primary cardiac tumor patients, 13 (28%) were diagnosed with malignancy, including 5 angiosarcomas, 3 intimal sarcomas, 3 diffuse large B-cell lymphomas, 1 Ewing’s sarcoma and 1 fibrosarcoma. Cardiovascular events were observed in 10 patients (77%), including cardiac dysfunction in 6 patients, arrhythmias in 5 patients, right heart failure in 2 patients, and excessively prolonged prothrombin time due to the combination of warfarin and chemotherapy in 1 patient. Two patients who showed notable cardiac complications are described. Case A involved a 69-year-old woman who underwent surgery for a left atrial intimal sarcoma, followed by postoperative chemotherapy with doxorubicin plus ifosfamide and radiotherapy. After three cycles of chemotherapy and sequential radiotherapy, her left ventricular ejection fraction decreased to 34%, and ongoing heart failure therapy was required. Case B involved a 66-year-old man who received chemotherapy for primary cardiac lymphoma, resulting in tumor shrinkage. However, due to tumor involvement of the intraventricular septum, atrioventricular block developed, requiring cardiac pacemaker implantation. Conclusion: High incidences of cardiac failure and arrhythmias were observed during multimodal treatments for malignant primary cardiac tumors. Proper management of complications may lead to a favorable prognosis in patients with malignant primary cardiac tumors.

DOI： 10.1093/jjco/hyae138

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記述言語：その他   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   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 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   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   掲載種別：研究論文（学術雑誌）   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）  

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： doi: 10.1007/s00262-023-03505-4.

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

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

DOI： 10.3389/fonc.2023.1260818

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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：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%CI: 6.0 – 25.8 months): 17.1 months (95%CI: 6.0 – not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 – 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months–NR): 40.8 months (95%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% 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：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：(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）  

Background/aim: The immune system has a pivotal role in modulating the response to chemotherapy in breast cancer (BC). However, the immune status during chemotherapy remains unclear. We evaluated the sequential changes in peripheral systemic immunity markers in BC patients treated with various chemotherapeutic agents.

Materials and methods: We examined the correlation between the peripheral systemic immunity markers, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC) and the local cytolytic activity (CYT) score obtained by quantitative reverse-transcription polymerase chain reaction of 84 preoperative BC patients. Next, we observed the sequential changes in the peripheral systemic immunity markers during treatment with four anticancer drugs: oral 5-fluorouracil derivative; S-1, epirubicin plus cyclophosphamide; paclitaxel plus the anti-vascular endothelial growth factor antibody bevacizumab, and eribulin in 172 HER2-negative advanced BC patients. Finally, we examined the correlation between the changes in the peripheral systemic immunity markers, time to treatment failure (TTF) and progression-free survival (PFS).

Results: A negative correlation was found between ALC and NLR. ALC-low and NLR-high cases were positively associated with CYT score-low cases. The ratio of ALC-increase and NLR-decrease varies depending on the anticancer drugs used. The responder group (TTF ≥3 months) had a higher NLR-decrease ratio than the nonresponder group (TTF <3 months). Patients with a high NLR-decrease ratio showed higher PFS.

Conclusion: The change in ALC or NLR varies according to the anticancer drugs, suggesting differential immunomodulatory effects of the drugs. Furthermore, the change in NLR reflects the therapeutic efficacy of chemotherapy in advanced BC.

DOI： doi: 10.21873/cgp.20373.

記述言語：英語   出版者・発行元：Cancer Genomics and Proteomics  

Background/Aim: The immune system has a pivotal role in modulating the response to chemotherapy in breast cancer (BC). However, the immune status during chemotherapy remains unclear. We evaluated the sequential changes in peripheral systemic immunity markers in BC patients treated with various chemotherapeutic agents. Materials and Methods: We examined the correlation between the peripheral systemic immunity markers, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC) and the local cytolytic activity (CYT) score obtained by quantitative reverse-transcription polymerase chain reaction of 84 preoperative BC patients. Next, we observed the sequential changes in the peripheral systemic immunity markers during treatment with four anticancer drugs: oral 5-fluorouracil derivative; S-1, epirubicin plus cyclophosphamide; paclitaxel plus the anti-vascular endothelial growth factor antibody bevacizumab, and eribulin in 172 HER2-negative advanced BC patients. Finally, we examined the correlation between the changes in the peripheral systemic immunity markers, time to treatment failure (TTF) and progression-free survival (PFS). Results: A negative correlation was found between ALC and NLR. ALC-low and NLR-high cases were positively associated with CYT score-low cases. The ratio of ALC-increase and NLR-decrease varies depending on the anticancer drugs used. The responder group (TTF .3 months) had a higher NLR-decrease ratio than the nonresponder group (TTF <3 months). Patients with a high NLR-decrease ratio showed higher PFS. Conclusion: The change in ALC or NLR varies according to the anticancer drugs, suggesting differential immunomodulatory effects of the drugs. Furthermore, the change in NLR reflects the therapeutic efficacy of chemotherapy in advanced BC.

DOI： 10.21873/cgp.20373

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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/s13691-022-00572-9

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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。

出版者・発行元：Journal of the Society of Powder Technology Japan  

It is important to consider the equipment wear in bead mills to maintain quality and control operational costs. In the conventional wear simulation, mesh deformation is applied using wear laws. There is a problem that the mesh is broken when large mesh deformations occur. We propose the wear simulation model which represents shape deformation by the interface capturing method in this study. The proposed model is robust because the model deforms equipment shape without requiring mesh deformation. Moreover, proposed model reduces computational costs by coupling with IB-DEM (Impulse-Based Discrete Element Method) which allows for a larger time step size than conventional DEM. We demonstrate the wear results when significant shape deformations occur due to collision with beads. We verify the proposed model by comparing the numerical results with actual worn parts by applying to the dry bead mill.

DOI： 10.4164/sptj.60.470

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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：日本語   出版者・発行元：日本メディカルセンター  

DOI： 10.19020/cg.0000002384

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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  

<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title>Background</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>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.</jats:p>
</jats:sec>

DOI： 10.1093/jjco/hyac103

Web of Science

Scopus

PubMed

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Web of Science

出版者・発行元：Journal of the Society of Powder Technology Japan  

While the Discrete Element Method (DEM) is expected to evaluate wet grinding performance of bead mills, the conventional DEM requires high computational cost because it has the limitation of the time step size for stable computation. In addition, the simulation of wet grinding process requires additional cost to consider the interaction between beads and fluids by using such as CFD-DEM coupling techniques. This study proposes an analysis system for evaluating wet grinding performance of bead mills with less computational cost. Our proposed system adopts the Impulse-Based DEM (IB-DEM) which can use large time step size, the wall model by using the Sign Distance Function (SDF) which flexibly represents complicated shape walls, and the simple modeling of fluid force which can reduce computational cost. We verify our proposed system by comparing the numerical results with experimental results of bead mills with different shapes of rotors.

DOI： 10.4164/sptj.59.488

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE: Anti-PD-1 antibody is the standard therapy for treatment-resistant gastric cancer, but only a limited number of patients respond. Additionally, cases of hyper-progressive disease (HPD) in which tumor growth accelerates after anti-PD-1 antibody administration have been reported; however, the biological mechanism has not been elucidated. PATIENT CONCERNS: In the present case, metastatic gastric cancer was treated with the anti-PD-1 antibody, nivolumab, as third-line treatment. DIAGNOSIS: After the initiation of nivolumab therapy, a rapidly enlarging para-aortic lymph nodes were observed leading to the diagnosis of HPD. INTERVENTIONS: Multiplex immunohistochemistry was used to examine immune cells infiltrating in the primary tumor and in liver metastasis which were obtained before nivolumab treatment, and in lymph node metastasis which presented with HPD after nivolumab therapy. OUTCOMES: In the primary tumor, helper T (Th) cells, cytotoxic T lymphocytes (CTLs), regulatory T (Treg) cells, and PD-L1-negative macrophages were observed. On the other hand, in metastatic lymph nodes presenting with HPD, PD-L1-positive macrophages prominently increased, while Treg cells, CTLs, and Th cells decreased. PD-L1 expression was not observed in gastric cancer cells among the three specimens. LESSONS: The findings suggest the possibility that PD-L1-positive M2 macrophage might contribute to acceleration of tumor growth with anti-PD-1 therapy in the present case.

DOI： 10.1097/md.0000000000025773

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1038/s41598-021-82448-1

記述言語：その他   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1038/s41598-020-77898-y

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1016/j.bbrc.2020.06.153

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified.

Methods: Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated.

Results: After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank p = 0.0008, 0.0003, 0.0035 and 0.0040).

Conclusions: Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.

DOI： 10.1038/s41416-020-0810-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1080/2162402x.2020.1724763

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.1002/2211-5463.12765

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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）  

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）  

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% had prior platinum therapy. The median age was 66 (range 27-81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1-62). Forty-six patients (31.5%) required initial dose reduction at the physician's discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30-4.08 months], and the median OS was 6.61 months (95% CI 5.94-7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% 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：その他   掲載種別：研究論文（学術雑誌）  

Background: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear.

Patients and methods: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined.

Results: The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m2 of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m2, the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m2 A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months.

Conclusion: An initial oxaliplatin dose of 130 mg/m2 resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance.

DOI： 10.21873/anticanres.11614

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

DOI： 10.3892/mco.2017.1205

記述言語：英語   掲載種別：研究論文（学術雑誌）  

<jats:title>ABSTRACT</jats:title>
<jats:p>Live attenuated vaccines against measles have been developed through adaptation of clinical isolates of measles virus (MV) in various cultured cells. Analyses using recombinant MVs with chimeric genomes between wild-type and Edmonston vaccine strains indicated that viruses possessing the polymerase protein genes of the Edmonston strain exhibited attenuated viral gene expression and growth in cultured cells as well as in mice expressing an MV receptor, signaling lymphocyte activation molecule, regardless of whether the virus genome had the wild-type or vaccine-type promoter sequence. These data demonstrate that the polymerase protein genes of the Edmonston strain contribute to its attenuated phenotype.</jats:p>

DOI： 10.1128/jvi.00867-08

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：日本語   出版者・発行元：医学図書出版(株)  

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記述言語：英語  

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

記述言語：日本語  

記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本乳癌学会  

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記述言語：日本語   出版者・発行元：大道学館出版部  

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記述言語：日本語   出版者・発行元：大道学館出版部  

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.

DOI： 10.19020/cg.0000002384

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.

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本消化器病学会-九州支部  

J-GLOBAL

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記述言語：英語  

記述言語：その他  

35

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances anti-tumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 and has shown efficacy for platinum-refractory recurrent or advanced head and neck cancer (HNC). However, subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for HNC and specifically associated with the prognosis have not been clarified. Methods: Peripheral blood mononuclear cells of 15 HNC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). We performed comprehensive analysis of the proportion of immune cell subsets by flow cytometry, including the expression of coinhibitory and costimulatory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), B and T lymphocyte attenuator (BTLA), CD28, OX40, inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were also analyzed. Results: Median progression free survival (PFS) of the whole patients was 96 days (95&#37; CI 70–308). After a single course of nivolumab, patients showed a significant increase in activated central memory and effector subsets of CD4+/CD8+ T cells and activated helper T1 cells (p = 0.0039, 0.0078, 0.0273, 0.0391, 0.0391). A trend of increase of activated effector memory CD4+/CD8+ T cell was observed (p = 0.4961, 0.3594). At the time of PD, effector regulatory T cells, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells and BTLA positive CD4+/CD8+ T cells significantly increased. Significant positive correlations were found between PFS and the proportion of OX40 positive CD4+/CD8+ T cells before nivolumab therapy (p = 0.0239, 0.0134). Conclusions: Nivolumab therapy enhances activation of central memory and effector subsets of CD4+/CD8+ T cells. The expression level of OX40 on T cells was correlated with efficacy of nivolumab therapy in HNC patients.

DOI： 10.1200/jco.2020.38.5_suppl.35

記述言語：その他  

54

Background: Anti-programmed death-1 (PD-1) monoclonal antibody, nivolumab, enhances antitumor activity by inhibiting the interaction of PD-1 and programmed death-1 ligand 1 (PD-L1) and has shown efficacy for advanced gastric cancer (AGC) in the salvage line. However, specific subsets of immune cells predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified. Methods: Peripheral blood mononuclear cells of 20 AGC patients treated with nivolumab were prospectively obtained before the initial and second administrations of nivolumab, and at the time of progressive disease (PD). The proportion of immune cell subsets were systematically analyzed by flow cytometry, including the expression of costimulatory and coinhibitory molecules such as T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T cell antigen-4 (CTLA-4), CD28, OX40, and inducible T cell costimulator (ICOS). Association between changes in the proportion of the subsets and therapeutic effect were analyzed. Results: Median progression free survival (PFS) of the whole patients was 51 days (95&#37; CI 35–83). After a single course of nivolumab, patients showed a significant increase in activated effector memory and activated effector subsets of CD4+/CD8+ T cells (p = 0.018, 0.018, 0.032, 0.024). At the time of PD, proportions of myeloid dendritic cell, IgM memory B cell and Tfh-Th1/17 cell subsets decreased (p = 0.024, 0.013, 0.0039). On the other hand, LAG3 positive CD4+/CD8+ T cells, TIM-3 positive CD4+/CD8 T cells increased at the time of PD (p = 0.013, 0.032, 0.042, 0.042). Significant positive correlations were found between PFS and the proportion of LAG3 positive CD4+/CD8+ T cells (p = 0.0056, 0.0054), OX 40 positive CD4+/CD8+ T cells (p = 0.0034, 0.0006) prior to the initial nivolumab therapy. Conclusions: Nivolumab therapy enhances activation of effector memory and effector subsets of CD4+/CD8+ T cells. The expression level of LAG3 and OX40 on T cells might be correlated with efficacy of nivolumab therapy.

DOI： 10.1200/jco.2019.37.4_suppl.54