Papers - Hirata, Kenro

Appetite, coping strategies, and morale in older adults with advanced gastrointestinal cancer: a longitudinal observational study

Yagasaki K., Arahata T., Ishida N., Hirata K., Funato M., Hamamoto Y.

BMC Geriatrics 26 ( 1 )  2026.12

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Background: Older adults with advanced gastrointestinal cancer face diverse physical challenges associated with the disease, treatments, and aging. Maintaining morale is crucial for these patients, as it enables them to sustain psychological well-being and a sense of fulfillment. We aimed to assess the relationships between appetite, coping strategies, and changes in morale after three months of follow-up in older adults with advanced gastrointestinal cancer. Methods: A three-month longitudinal observational study was conducted among 79 older adults (aged 70 and over) with advanced gastrointestinal cancer receiving chemotherapy as outpatients at a hospital in Japan between 2022 and 2024. We assessed morale using the Philadelphia Geriatric Center Morale Scale, appetite using the Simplified Nutritional Appetite Questionnaire, coping strategies using the Brief Coping Orientation to Problems Experienced Inventory, frailty using the Geriatric 8 scale, and symptoms using the MD Anderson Symptom Inventory. A linear mixed-effects model was used to estimate the difference in change in morale from baseline to three months later between high- and low-appetite groups. Results: Data from 66 participants who completed the follow-up were analyzed. The participants (mean age = 76.8 years) had a mean nutritional appetite score of 14.3, morale score of 12.0, and frailty score of 11.7. Acceptance was the most frequently used coping strategy. At three months from baseline, morale was lower in the low-appetite group than in the high-appetite group. While the change in morale over three months did not differ significantly between the two appetite groups, the use of substances as a coping strategy was significantly associated with lower morale after three months (p = 0.01). Conclusions: While low baseline appetite was associated with lower morale, it was not significantly associated with changes in morale over three months. Instead, reliance on substance use as a coping strategy appeared more important. Therefore, monitoring substance use may be useful for identifying patients who need greater psychological support. Additionally, considering support methods that enable older adults to enjoy eating aligned with their values might be beneficial. These results serve as a foundation for future research aimed at understanding and supporting the morale of older adults with gastrointestinal cancer.

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Randomized phase II study of FOLFIRI plus ramucirumab versus FOLFOXIRI plus ramucirumab as first-line treatment for metastatic colorectal cancer: WJOG9216G (RECAST)

Kito Y., Yamazaki K., Shoji H., Yamada T., Tsushima T., Mitani S., Shiraishi K., Yasui H., Hara H., Hirata K., Esaki T., Shinohara Y., Tsuzuki T., Kajiura S., Masuishi T., Izawa N., Baba E., Murata K., Akazawa N., Suzuki Y., Satake H., Boku N., Hyodo I., Yoshimura K., Kawakami H., Hironaka S., Muro K.

European Journal of Cancer 238   116688 2026.05

ISSN  09598049

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Background FOLFOXIRI plus bevacizumab improved efficacies and increased some adverse events in untreated metastatic colorectal cancer (mCRC), compared with the doublet plus bevacizumab. The clinical outcomes of ramucirumab (RAM) in combination with FOLFIRI or FOLFOXIRI as a first-line treatment are unknown. In this randomized phase II study (WJOG9216G), we compared the efficacy and safety of these regimens to determine which is more promising. Methods Patients with untreated mCRC were randomly assigned to the FOLFIRI-RAM or FOLFOXIRI-RAM arms. The primary endpoint was a confirmed objective response rate (ORR), and secondary endpoints included early tumor shrinkage (ETS), progression-free survival (PFS), overall survival (OS), and safety. Results In total, 122 patients were randomized. The confirmed ORR was 59.3% and 60.3% in the FOLFIRI-RAM and FOLFOXIRI-RAM arms, respectively (odds ratio 1.04; P = 0.91). With a median follow-up period of 42.1 and 40.4 months, PFS was comparable between the FOLFIRI-RAM and FOLFOXIRI-RAM arms (median, 11.5 and 10.5 months). ETS rate (71.2% and 52.4%) and OS (median, 32.6 and 28.2 months) were significantly better in the FOLFIRI-RAM arm than in the FOLFOXIRI-RAM arm. The major grade ≥ 3 adverse events in the FOLFIRI-RAM and FOLFOXIRI-RAM arms were neutropenia (44.1% and 72.6%), anorexia (3.4% and 14.5%), and febrile neutropenia (3.4% and 11.3%). Conclusions FOLFOXIRI plus RAM was not superior to FOLFIRI plus RAM in terms of efficacy, including ORR, in patients with untreated mCRC. Instead, first-line FOLFIRI plus RAM showed clinical efficacy and safety profiles comparable to those of doublet chemotherapy plus bevacizumab.

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A pragmatic phase II trial evaluating treatment strategies using immune checkpoint inhibitors for metastatic esophageal cancer patients with severe dysphagia.

Nagata Y, Arai H, Izawa N, Inagaki C, Sugaya A, Hirata K, Tsushima T, Moriwaki T, Masuishi T, Nagatani Y, Harada K, Taguri M, Sunakawa Y

ESMO gastrointestinal oncology 11   100310 2026.03

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Real-world clinical utility of comprehensive genomic profiling in advanced solid tumors

Saito Y., Horie S., Kogure Y., Mizuno K., Ito Y., Mizukami Y., Kim H., Tamura Z., Koya J., Funakoshi T., Hirata K., Kataoka K.

Nature Medicine 32 ( 2 ) 690 - 701 2026.02

ISSN  10788956

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Comprehensive genomic profiling (CGP) is crucial in precision oncology, yet its real-world utility remains unclear. Here we analyzed data from the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics database, including clinical and genetic data from 54,185 patients with advanced solid tumors (consisting of 81 common and rare tumor types) who received CGP with a targeted sequencing panel covering 324 genes as part of their clinical care. We assessed the prognostic value of CGP-guided clinical evidence-level classification, showing that alterations predicting response to Pharmaceuticals and Medical Devices Agency-approved or Food and Drug Administration-approved therapies and to therapies supported by well-powered studies with expert consensus are detected in 16.6% and 8.1% of patients, respectively, and are associated with better prognosis than those with lower clinical evidence levels. Only 8% of patients receive CGP-guided approved–experimental genomic biomarker-linked therapies, although the proportion has improved over time. Substantial differences were observed across tumor types, with the proportions exceeding 20% in thyroid and lung cancers but remaining below 2% in pancreatic and liver cancers. Tumor-agnostic biomarker analyses reveal that tumor mutational burden (TMB) ≥20 mutations per megabase predicts better outcome across tumor types, regardless of microsatellite instability status, in TMB-high patients receiving pembrolizumab. Conversely, extramammary Pagetʼs disease is exceptionally resistant to pembrolizumab. The large-scale nationwide database allows evaluating inter-tumor type differences and investigating evidence-scarce situations, delineating where CGP offers greater benefit. These real-world findings complement those from clinical trials and prospective sequencing projects regarding CGP, providing valuable information for individualized treatment.

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Solvent-based or nab-paclitaxel plus ramucirumab for pretreated gastric cancer with peritoneal dissemination and prespecified biomarker analysis (P-SELECT/WJOG10617G): a randomised phase 2 trial in Japan

Hirata K., Hamamoto Y., Shoji H., Hara H., Kondoh C., Yasui H., Kajiwara T., Baba E., Ando T., Sugimoto N., Kawakami H., Katsuya H., Nagase M., Yamamoto Y., Yoshimura K., Ando M., Imamura C.K., Yamazaki K., Hironaka S., Muro K.

Eclinicalmedicine 92   103768 2026.02

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SummaryBackgroundGastric cancer (GC) with peritoneal dissemination remains a challenge with poor prognosis and limited treatment options. We aimed to compare solvent-based paclitaxel (sb-PTX) + ramucirumab (RAM) vs. nanoparticle-albumin-bound paclitaxel (nab-PTX) + RAM as second-line therapy for unresectable or recurrent GC with peritoneal dissemination.MethodsThis prospective, randomised, open-label, multicentre phase 2 trial was conducted at 58 centres within the West Japan Oncology Group (WJOG) in Japan. Eligible participants were patients with histologically-confirmed GC with peritoneal dissemination refractory or intolerant to first-line therapy. Patients were randomised 1:1 to receive sb-PTX + RAM or nab-PTX + RAM. Primary endpoint was overall survival (OS); key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), safety, and protocol-specified biomarker analyses including the assessment of stromal caveolin-1 (Cav-1) expression by immunohistochemistry on archival tumour specimens. The data cutoff for the analysis presented herein was January 27, 2021. This trial was registered in the Japan Registry of Clinical Trials (jRCTs031180022).FindingsBetween Oct 1, 2018, and Jan 27, 2020, 105 patients were assigned to sb-PTX + RAM (n = 53) or nab-PTX + RAM (n = 52). Median follow-up was 18.1 months. Median OS was 8.1 months with sb-PTX + RAM and 7.2 months with nab-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.960; 95% CI, 0.621–1.484; P = 0.631). Median PFS was 5.1 vs. 3.9 months (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.965; 95% CI, 0.642–1.450; P = 0.893). ORR was 20.7% vs. 20.0% (P = 0.993), and DCR was 77.4% vs. 63.5% (P = 0.150), with sb-PTX + RAM and nab-PTX + RAM. Grade≥3 neuropathy occurred in 7.5% with sb-PTX + RAM and 17.6% with nab-PTX + RAM, and febrile neutropenia in 11.3% vs. 5.9%. In biomarker analysis, OS and PFS improved stepwise with increasing Cav-1 expression in patients receiving nab-PTX + RAM (P = 0.007, P = 0.012); no such association was observed with sb-PTX + RAM. Among patients with high stromal Cav-1 expression (IHC score 3+), nab-PTX + RAM showed some evidence of improved OS compared with sb-PTX + RAM (HR [nab-PTX + RAM vs. sb-PTX + RAM], 0.371; 95% CI, 0.130–1.060; P = 0.055). The interaction between Cav-1 expression and treatment arm showed a non-significant trend (HR for interaction, 0.364; 95% CI, 0.115–1.152; P = 0.086), consistent with this finding.InterpretationTreatment with nab-PTX + RAM did not meet the prespecified threshold (HR < 0.90) for promising efficacy in patients with GC and peritoneal dissemination. High stromal Cav-1 expression was associated with improved efficacy of nab-PTX + RAM. Future studies should prospectively validate the predictive value of stromal Cav-1 in patients receiving nab-PTX + RAM.FundingTaiho Pharmaceutical Co. Ltd.

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Comment on "Proton Pump Inhibitors Attenuate the Effectiveness of Nivolumab Monotherapy in Patients with Advanced Gastric Cancer: a Retrospective Study".

Kawazoe H, Hirata K, Ohtani H

Journal of gastrointestinal cancer 57 ( 1 ) 18 2026.01

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The efficacy and safety of FOLFOX therapy for advanced esophageal squamous cell carcinoma

Shiraishi K., Okada M., Yamamoto S., Matsubara Y., Masuishi T., Shimozaki K., Yamamoto Y., Hirose S., Sugiyama K., Furuta M., Machida N., Takahashi N., Yoshii T., Kito Y., Tsuzuki T., Boku S., Tsuchihashi K., Sugaya A., Takayama T., Komori A., Mitani S., Matsumoto T., Nishimura T., Hirata K.

Scientific Reports 15 ( 1 ) 8031 2025.12

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Cisplatin-based chemotherapy is the standard advanced esophageal squamous cell carcinoma (ESCC) treatment. However, the 5-fluorouracil plus L-leucovorin and oxaliplatin (FOLFOX) regimen is available in Japan as an alternative to cisplatin-based chemotherapy, but its efficacy and safety remain unclear. Hence, we aimed to evaluate patients with advanced ESCC who received FOLFOX therapy retrospectively. Patients with advanced ESCC who received FOLFOX therapy at 18 institutions between April 2019 and October 2020 were included. Fifty-two patients received first-line FOLFOX treatment, while 39 received later-line FOLFOX treatment. The median progression-free survival, median overall survival, and objective response rate were 3.8 months (95% confidence interval [CI]: 3.0–5.0), 13.9 months (95% CI: 10.3–17.9 months), and 35% in the first-line group and 2.4 months (95% CI: 2.1–3.8 months), 7.2 months (95% CI: 5.3–9.8 months), and 4% in the later-line group, respectively. The most frequent grade 3 or 4 adverse events were neutropenia (23%) and anemia (12%) in the first-line group and neutropenia (18%), anorexia (13%), anemia (10%), and nausea (10%) in the later-line group. First-line FOLFOX treatment is suitable for patients with advanced ESCC. However, FOLFOX has shown limited efficacy as a later-line treatment.

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Site-specific prevalence of the NFE2L2 mutation in esophageal squamous cell carcinoma

Chida A., Hayashi H., Ishida N., So E., Kishimoto S., Horie S., Tsugaru K., Matsuda S., Kawakubo H., Nishihara H., Hamamoto Y., Kanai T., Kitagawa Y., Hirata K.

International Journal of Clinical Oncology 30 ( 12 ) 2576 - 2586 2025.12

ISSN  13419625

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Background: Precision medicine for esophageal squamous cell carcinoma (ESCC) has not been implemented owing to a lack of site-specific therapeutic markers and biomarkers. We hypothesized that the genomic background of each subsite of the esophagus might be different, allowing us to develop site-specific treatment strategies (cervical, upper thoracic, middle thoracic and lower thoracic). Methods: This was a single-center retrospective cohort study. Patients diagnosed with ESCC who underwent comprehensive genomic profiling (CGP) at Keio University Hospital between April 2017 and March 2024 were recruited. Genomic profiles were analyzed and compared across esophageal subsites. Results: Among the 107 patients with ESCC who underwent CGP, 6 were cervical, 16 were upper thoracic, 54 were middle thoracic, and 31 were lower thoracic. The most frequently altered genes were TP53, followed by CDKN2A and NFE2L2. The frequency of NFE2L2 mutations was significantly higher in the middle thoracic region (P = 0.041). The mutation rate increased from Stage I to IV (P = 0.0046). NFE2L2 mutations were rarely observed in early-stage cancers, suggesting that they may subsequently be acquired during growth and metastasis. Furthermore, a significant association was observed between a history of heavy alcohol consumption and NFE2L2 mutations. The overall survival of patients with unresectable or metastatic ESCC harboring NFE2L2 mutations was 12.0 months, compared to 29.7 months in patients without the mutations (HR: 2.37, P = 0.047). Conclusion: NFE2L2 mutations were more common in the middle thoracic esophagus, appeared to be associated with tumor progression, and were linked to poor prognosis.

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Proton Pump Inhibitors Attenuate the Effectiveness of Nivolumab Monotherapy in Patients with Advanced Gastric Cancer: A Retrospective Study.

Yamaguchi M, Kawazoe H, Kasai Y, Hirata K, Ohtani H

Journal of gastrointestinal cancer 56 ( 1 ) 226 2025.11

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Efficacy of Vonoprazan-Based Triple Therapy with Sitafloxacin and Amoxicillin for Third-Line Helicobacter pylori Eradication:. Multicenter Prospective Analysis on Drug Resistance and gyrA Mutations

Wasaki S., Mori H., Matsuzaki J., Suzuki H., Hirata K., Imaeda H., Yoshioka M., Nakazawa A., Okazawa A., Kanai T., Masaoka T.

Digestive Diseases 43 ( 5 ) 498 - 505 2025.10

ISSN  02572753

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WJOG18524G: a single-arm phase II study evaluating bemarituzumab combined with ramucirumab and paclitaxel in fibroblast growth factor receptor 2b (FGFR2b)-positive advanced gastric or gastroesophageal junction cancer (RAINBIRD).

Shimozaki K, Hirata K, Hayashi H, Sato Y, Komatsu Y, Taniguchi S, Takahashi N, Yamaguchi K, Furuta M, Kawakami T, Narita Y, Ando T, Makiyama A, Mitani S, Ogata T, Takegawa N, Okamoto W, Nishina T, Komoda M, Hosokawa A, Boku N, Kawakami H, Yamazaki K, Muro K

ESMO gastrointestinal oncology 9   100189 2025.09

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Phase II Study (NO LIMIT, WJOG13320G) of First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability-High Advanced Gastric or Esophagogastric Junction Cancer

Kawakami H., Kadowaki S., Makiyama A., Tsuda M., Hirata K., Sugimoto N., MacHida N., Hara H., Hirano H., Esaki T., Komatsu Y., Hironaka S., Kobayashi Y., Kakimi K., Chiba Y., Boku N., Hyodo I., Muro K.

Journal of Clinical Oncology 43 ( 19 ) 2184 - 2195 2025.07

ISSN  0732183X

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PURPOSEMicrosatellite instability-high (MSI-H) advanced gastric or esophagogastric junction cancer (AGC), accounting for 5%-6% of all AGC cases, has shown an enhanced responsiveness to immunotherapy. We performed a single-arm phase II study to evaluate the combination of nivolumab (NIVO) and low-dose (LD) ipilimumab (IPI) for first-line treatment of MSI-H AGC.PATIENTS AND METHODSPatients with MSI-H AGC received NIVO (240 mg once every 2 weeks) and IPI (1 mg/kg once every 6 weeks). The primary end point was overall response rate (ORR) assessed by blinded independent central review. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis. MSI-H status was confirmed with an MSI-IVD Kit (Falco).RESULTSTwenty-nine patients were enrolled. The ORR was 62.1% (95% CI, 42.3 to 79.3), with a complete response rate of 10.3%. The DCR was 79.3% (95% CI, 60.3 to 92.0). Treatment-related adverse events (TRAEs) of any grade occurred in 93.1% of patients, with those of grade ≥3 manifesting in 37.9% of patients. At the data cutoff (median follow-up of 9.0 months), treatment had been discontinued in 21 patients, with such discontinuation being due to TRAEs in 12 (41.4%) patients. However, after exclusion of one patient with progressive disease, the remaining 11 patients showed long-term antitumor efficacy after treatment discontinuation (range of response duration, 0.9+ to 15.6+ months). The median PFS was 13.8 months (95% CI, 13.7 months to not reached [NR]) and the median OS was NR (95% CI, 13.7 months to NR), with a 12-month OS rate of 79.5%.CONCLUSIONNIVO plus LD-IPI showed robust and durable antitumor efficacy as a first-line treatment for MSI-H AGC. Although TRAEs often led to treatment discontinuation, treatment efficacy was subsequently sustained in most patients.

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A rare case of ALK-positive histiocytosis with neurological involvement in a 70-year-old woman successfully managed with partial resection and alectinib.

So E, Ishida N, Chida A, Horie S, Kishimoto S, Tsugaru K, Hayashi H, Koda Y, Ozaki M, Okita H, Kanai T, Hirata K

International cancer conference journal 14 ( 3 ) 327 - 334 2025.07

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Investigating the Synergistic Effects of Pembrolizumab and Chemotherapy in Gastric and Gastroesophageal Junction Cancer

Okui J., Nagashima K., Matsuda S., Sato Y., Kawakubo H., Takeuchi M., Hirata K., Tsugaru K., Yamamoto S., Nomura M., Tsushima T., Takeuchi H., Kato K., Kitagawa Y.

Journal of Gastric Cancer 25 ( 3 ) 455 - 465 2025.07

ISSN  2093582X

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Purpose: Although immune checkpoint inhibitors (ICIs) and chemotherapy combinations have been approved for the treatment of gastric and gastroesophageal junction cancer (GC/ GEJC), whether immunochemotherapy (ICT) offers advantages over the simple addition of individual monotherapies remains unclear. This study aimed to investigate whether ICT has a synergistic effect in patients with advanced GC/GEJC. Materials and Methods: Reconstructed individual patient data were electronically extracted from the Kaplan-Meier curves of 3 randomized controlled trials comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062, and KEYNOTE-859). The observed progression-free survival (PFS) curve for each monotherapy was used to estimate the simulated PFS curve expected under an independent drug action model. If the observed curve demonstrated significantly better PFS than the simulated curve, combined ICI and chemotherapy was determined to have a synergistic effect, implying a superior outcome compared to adding-component monotherapy. Results: In patients with programmed cell death ligand 1 combined positive scores of ≥1 (n=2,194), the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9% and 6.89 months vs. 6.88 months, respectively. The one-sample log-rank test revealed no significant differences between the observed and simulated curves (P=0.107). Conclusions: The observed PFS with ICT was comparable to the predicted PFS based on the data for each monotherapy. Our findings do not provide direct evidence of synergistic effects, but they suggest that combining ICI and chemotherapy does not compromise efficacy. These results may support the continued clinical use of ICT in patients with advanced GC/GEJC.

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Prognostic factors for overall survival in advanced digestive neuroendocrine carcinoma treated with first-line cisplatin-based chemotherapy: a post hoc analysis of JCOG1213

Hirano H., Hirata K., Honma Y., Morizane C., Machida N., Kato K., Okusaka T., Boku N., Sekine S., Hiraoka N., Mizusawa J., Sano Y., Shibuya Y., Takahashi M., Fujimori N., Nomura M., Doki Y., Ueno M., Yoshikawa T., Takeuchi H.

ESMO Gastrointestinal Oncology 8   100178 2025.06

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Background: There is no consensus on prognostic factors for advanced digestive neuroendocrine carcinoma (ADNEC). JCOG1213 was a phase III randomized trial that demonstrated equivalent overall survival (OS) between cisplatin plus etoposide and cisplatin plus irinotecan as first-line chemotherapy for ADNEC. We aimed to retrospectively explore prognostic factors for OS in patients with ADNEC using data from JCOG1213. Patients and methods: The patients included in this post hoc analysis had ADNEC (2019 World Health Organization classification system) that was histologically confirmed by a central pathological review whose records included all clinical data required for multivariable analysis using a Cox proportional hazards model. Results: Among 170 patients enrolled in JCOG1213, a total of 129 patients with ADNEC were included in this analysis. Multivariable analysis identified elevated serum lactate dehydrogenase (LDH; >222 IU/l) as a significantly unfavorable prognostic factor for OS [hazard ratio (HR) 1.721, 95% confidence interval (CI) 1.144-2.589, P = 0.0092]. OS of patients with elevated serum LDH was shorter than that of patients without elevated serum LDH [median 9.5 months (95% CI 8.1-10.7 months) versus 15.6 months (95% CI 11.4-19.7 months); HR 1.799, 95% CI 1.242-2.604, P = 0.0019]. There were no distinct differences either in objective response rates or progression-free survival between patients with and without elevated serum LDH. Conclusion: Serum LDH may serve as a simple, non-invasive, and clinically informative biomarker for prognostic evaluation in patients with ADNEC undergoing first-line platinum-based chemotherapy.

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Investigating the synergistic effects of immunochemotherapy in esophageal squamous cell carcinoma.

Okui J, Nagashima K, Matsuda S, Sato Y, Kawakubo H, Takeuchi M, Hirata K, Yamamoto S, Nomura M, Tsushima T, Takeuchi H, Kato K, Kitagawa Y

Esophagus : official journal of the Japan Esophageal Society 22 ( 2 ) 188 - 197 2025.04

ISSN  1612-9059

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Clinical utility of comprehensive genomic profiling for advanced pancreatic cancer: insights from real-world data analysis

So E., Hayashi H., Shimozaki K., Horie S., Kishimoto S., Chida A., Saito Y., Tsugaru K., Hirata K., Tanishima S., Nishihara H., Kanai T., Hamamoto Y.

International Journal of Clinical Oncology 30 ( 4 ) 728 - 737 2025.04

ISSN  13419625

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Background: Precision medicine is a promising therapeutic strategy for pancreatic cancer. However, only a few patients are eligible for genotype-matched treatments because of the low detection rate of actionable genomic alterations, and the clinical application of comprehensive genomic profiling (CGP) in pancreatic cancer has not been completely investigated. CGP provides considerable information, including the prognosis and eligibility of patients for genotype-matched treatments, which can guide physicians’ treatment strategies. This study aimed to investigate the contribution of CGP to patient outcomes. Methods: This single-center retrospective cohort study enrolled patients with recurrent or metastatic pancreatic cancer with adenocarcinoma or adenosquamous carcinoma who underwent systemic chemotherapy between April 2018 and April 2022. We reviewed the medical records for patient characteristics, survival, and genomic information. We compared overall survival (OS) between patients who received CGP (CGP group) and those who did not (non-CGP group). Results: Of 111 eligible patients, 59 underwent CGP. Median OS was significantly longer in the CGP than the non-CGP group (25.2 vs. 11.8 months; hazard ratio, 0.49; P = 0.0013). Six patients (10.2%) underwent genotype-matched treatments, with a median OS of 35.5 months, compared to 17.0 months for those who did not. The CGP group demonstrated a higher transition rate to subsequent chemotherapy than did the non-CGP group (76.3% vs. 48.1%, P = 0.0030). Conclusions: OS was prolonged in patients with pancreatic cancer who underwent CGP, probably due to its influence on physicians’ treatment strategies. These findings highlight the importance of the proactive and timely implementation of CGP in patients with pancreatic cancer.

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Clinical characteristics of gastrointestinal stromal tumors with hypoglycemia

Chida A., Kawasaki K., Kuramoto J., Hayashi H., Kawahara T., Makiuchi S., So E., Shimizu S., Kishimoto S., Horie S., Saito Y., Shimozaki K., Tsugaru K., Togasaki K., Hirata K., Nishihara H., Kanai Y., Kanai T., Hamamoto Y.

Oncology Letters 28 ( 6 ) 568 2024.12

ISSN  17921074

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The development of tyrosine‑kinase inhibitors has improved survival rates for patients with gastrointestinal stromal tumors (GISTs). Despite the progress, not all the patients can universally receive the benefit from treatment due to the individual underlying conditions in a real‑world setting. The present study focused on the well‑known but under‑studied condition of GIST with hypoglycemia. Hypoglycemia in GIST is characterized by hypoglycemic symptoms such as dizziness, sweating and confusion. It is caused by several factors such as multiple liver metastases, drug adverse effects, postoperative complications and paraneoplastic syndrome [non‑islet cell tumor hypoglycemia (NICTH)]. Comprehensive analysis of this condition has been hindered due to its rarity, and has been mostly limited to case reports. In the present study, a single‑institution retrospective analysis of GIST with hypoglycemia was conducted to investigate its prevalence and prognosis, and the cause of this condition. The present study identified that the prevalence of hypoglycemic episodes of GIST was 4.1% in all patients with GIST, and recurrent hypoglycemic cases had a poor prognosis. The present study identified 1 case with recurrent hypoglycemia due to NICTH. Since NICTH is a rare hypoglycemic cause and requires further evaluation, an autopsy and genetic sequencing were performed using the available clinical materials. Through this histological and genetic investigation, the histological diversity of NICTH‑GIST was revealed and insulin‑like growth factor II (IGF‑II) amplification was identified. Furthermore, a chronological analysis was performed using multiple resected archived samples from the same case, and revealed that diffuse IGF‑II expression may have occurred in the early phase of tumor development. The present study catalogued the characteristics of GIST with hypoglycemia with a focus on NICTH‑GIST.

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Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial

Hirata K., Yoshida K., Katada C., Watanabe A., Tsushima T., Yamaguchi T., Yamamoto S., Ishikawa H., Sato Y., Imamura C.K., Tanigawara Y., Ito Y., Kato K., Kitagawa Y., Hamamoto Y.

BMC Cancer 24 ( 1 ) 873 2024.12

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Background: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. Methods: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m² weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m² or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). Results: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m² groups, respectively. All adverse events, except death in the 60 mg/m² group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. Conclusions: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m² weekly. Phase II trials at this dose are underway.

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The Effectiveness and Feasibility of Palliative Care via Video Telemedicine for Patients with Advanced Cancer: A Nonrandomized Prospective Clinical Trial Comparing Combination of Telemedicine and in-Person Care with in-Person Care Alone

Chida A., Hamamoto Y., Hirata K., Sato Y., So E., Kishimoto S., Noguchi S., Horie S., Saito Y., Shimozaki K., Tsugaru K., Togasaki K., Kawasaki K., Hayashi H., Kanai T.

Palliative Medicine Reports 5 ( 1 ) 503 - 511 2024.11

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Background: Palliative care has been shown to be effective for patients with advanced cancer; however, the best approach to deliver palliative care needs to be considered. We hypothesized that a combination of palliative care via video telemedicine (TMD) and usual outpatient treatment would improve patients’ quality of life (QOL) and ameliorate depression and prognosis. Methods: Patients with advanced cancer who terminated treatment with chemotherapy were enrolled. Patients who could perform videoconferencing were assigned to the TMD group and those who could not perform were assigned to the (no TMD; control) group. The primary endpoint was QOL, which was evaluated using the difference in the Functional Assessment of Cancer Therapy-General (FACT-G) scores between baseline and one-month follow-up. Secondary endpoints included depression, measured using the Center for Epidemiological Studies Depression (CES-D) scale, overall survival, and patient satisfaction. Results: Fifty patients were included in this study (25 in each group). A comparison of measures of QOL at one month showed that the TMD group maintained a better QOL. FACT-G decreased by 0.21 and 5.96 points in the TMD and no TMD groups, respectively (p = 0.047). The TMD group maintained better QOL. There were trends suggesting improvements in depression and survival which did not reach significance. CES-D increased by 0.92 and 3.50 points in the TMD and no TMD groups, respectively (p = 0.26). Median survival time was 7.82 (3.30–14.59) and 6.37 (2.33–11.04) months in the TMD and no TMD groups, respectively. The results of the Patient Satisfaction Questionnaire suggest that video TMD could be a feasible tool in palliative care. Conclusion: Video TMD is effective in maintaining the QOL of patients with advanced cancer and is feasible based on patient satisfaction. It is desirable to further evaluate the usefulness of palliative care using video TMD and evaluate its clinical applications.

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A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G

Matsumoto T., Yamamoto Y., Kotaka M., Masuishi T., Tsuji Y., Shoji H., Hirata K., Tsuduki T., Makiyama A., Izawa N., Takahashi N., Tsuda M., Yasui H., Ohta T., Kito Y., Otsu S., Hironaka S., Yamazaki K., Boku N., Hyodo I., Yoshimura K., Muro K.

Targeted Oncology (Targeted Oncology)  19 ( 2 ) 181 - 190 2024.03

ISSN  17762596

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Background: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. Objective: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. Methods: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. Results: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month–not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). Conclusions: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. Clinical Trial Registration: jRCTs041190100.

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Pre-existing Interstitial Lung Abnormalities and Immune Checkpoint Inhibitor-Related Pneumonitis in Solid Tumors: A Retrospective Analysis

Horiuchi K., Ikemura S., Sato T., Shimozaki K., Okamori S., Yamada Y., Yokoyama Y., Hashimoto M., Jinzaki M., Hirai I., Funakoshi T., Mizuno R., Oya M., Hirata K., Hamamoto Y., Terai H., Yasuda H., Kawada I., Soejima K., Fukunaga K.

Oncologist (Oncologist)  29 ( 1 ) E108 - E117 2024.01

ISSN  10837159

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Background: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy over previous cytotoxic chemotherapies in clinical trials among various tumors. Despite their favorable outcomes, they are associated with a unique set of toxicities termed as immune-related adverse events (irAEs). Among the toxicities, ICI-related pneumonitis has poor outcomes with little understanding of its risk factors. This retrospective study aimed to investigate whether pre-existing interstitial lung abnormality (ILA) is a potential risk factor for ICI-related pneumonitis. Materials and Methods: Patients with non-small cell lung cancer, malignant melanoma, renal cell carcinoma, and gastric cancer, who was administered either nivolumab, pembrolizumab, or atezolizumab between September 2014 and January 2019 were retrospectively reviewed. Information on baseline characteristics, computed tomography findings before administration of ICIs, clinical outcomes, and irAEs were collected from their medical records. Pre-existing ILA was categorized based on previous studies. Results: Two-hundred-nine patients with a median age of 68 years were included and 23 (11.0%) developed ICI-related pneumonitis. While smoking history and ICI agents were associated with ICI-related pneumonitis (P = .005 and .044, respectively), the categories of ILA were not associated with ICI-related pneumonitis (P = .428). None of the features of lung abnormalities were also associated with ICI-related pneumonitis. Multivariate logistic analysis indicated that smoking history was the only significant predictor of ICI-related pneumonitis (P = .028). Conclusion: This retrospective study did not demonstrate statistically significant association between pre-existing ILA and ICI-related pneumonitis, nor an association between radiologic features of ILA and ICI-related pneumonitis. Smoking history was independently associated with ICI-related pneumonitis. Further research is warranted for further understanding of the risk factors of ICI-related pneumonitis.

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Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G)

Takahashi N., Hara H., Nagashima K., Hirata K., Masuishi T., Matsumoto T., Kawakami H., Yamazaki K., Hironaka S., Boku N., Muro K.

BMC Cancer (BMC Cancer)  23 ( 1 ) 726 2023.12

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Background: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. Methods: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. Discussion: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. Trial registration: jRCTs041220120.

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Real-world management and outcomes of older patients with locally advanced esophageal squamous cell carcinoma: a multicenter retrospective study

Saito Y., Hamamoto Y., Hirata K., Yamasaki M., Watanabe M., Abe T., Tsubosa Y., Hamai Y., Murakami K., Bamba T., Yoshii T., Tsuda M., Watanabe M., Ueno M., Kitagawa Y.

BMC Cancer (BMC Cancer)  23 ( 1 ) 283 2023.12

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Background: Neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). Chemoradiotherapy (CRT) is an alternative treatment approach. However, both treatments are associated with toxicity, and the optimal treatment for older patients with ESCC is unknown. This study aimed to evaluate the treatment strategies and prognosis of older patients with locally advanced ESCC in a real-world setting. Methods: We retrospectively evaluated 381 older patients (≥ 65 years) with locally advanced ESCC (stage IB/II/III, excluding T4) who received anticancer therapy at 22 medical centers in Japan. Based on age, performance status (PS), and organ function, the patients were classified into two groups: clinical trial eligible and ineligible groups. Patients aged ≤ 75 years with adequate organ function and a PS of 0–1 were categorized into the eligible group. We compared the treatments and prognoses between the two groups. Results: The ineligible group had significantly shorter overall survival (OS) than the eligible group (hazard ratio [HR] for death, 1.65; 95% confidence interval [CI], 1.22–2.25; P = 0.001). The proportion of patients receiving NAC followed by surgery was significantly higher in the eligible group than in the ineligible group (P = 1.07 × 10–11), whereas the proportion of patients receiving CRT was higher in the ineligible group than in the eligible group (P = 3.09 × 10–3). Patients receiving NAC followed by surgery in the ineligible group had comparable OS to those receiving the same treatment in the eligible group (HR, 1.02; 95% CI, 0.57–1.82; P = 0.939). In contrast, patients receiving CRT in the ineligible group had significantly shorter OS than those receiving CRT in the eligible group (HR, 1.85; 95% CI, 1.02–3.37; P = 0.044). In the ineligible group, patients receiving radiation alone had comparable OS to those receiving CRT (HR, 1.13; 95% CI, 0.58–2.22; P = 0.717). Conclusions: NAC followed by surgery is justified for select older patients who can tolerate radical treatment, even if they are old or vulnerable to enrollment in clinical trials. CRT did not provide survival benefits over radiation alone in patients ineligible for clinical trials, suggesting the need to develop less-toxic CRT.

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Sunitinib-induced hyperammonemic encephalopathy in metastatic gastrointestinal stromal tumors: A case report.

Hayakawa T, Funakoshi S, Hamamoto Y, Hirata K, Kanai T

World journal of clinical cases 11 ( 31 ) 7629 - 7634 2023.11

ISSN  2307-8960

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Severe lichenoid eruption due to concomitant medications following nivolumab administration

Kakuta R., Tanese K., Hirata K., Emoto K., Takeuchi S., Shiiya C., Amagai M., Kubo A.

JEADV Clinical Practice (JEADV Clinical Practice)  2 ( 3 ) 594 - 597 2023.09

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Recently, immune checkpoint inhibitors have been administered for several cancers and have shown great efficacy. However, they are associated with various immune-related adverse events. Here, we report a case with severe lichenoid eruption following nivolumab administration that improved after the withdrawal of concomitant medications and the patient could continue nivolumab therapy. While nivolumab has been reported to cause severe skin reactions, the current case suggests that severe cutaneous manifestations after nivolumab administration could also be caused by the acquisition of immunogenicity of concomitant medications, including the one that was safely administered before nivolumab treatment and discontinuation of them may enable the patient to continue nivolumab therapy.

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Specified Clinical Research

Hirata K.

Gan to kagaku ryoho. Cancer &amp; chemotherapy (Gan to kagaku ryoho. Cancer &amp; chemotherapy)  49 ( 12 ) 1291 - 1294 2022.12

ISSN  03850684

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A series of research frauds, including data manipulation in clinical trials of pharmaceuticals represented by the hypertension drugs Diovan and Blopress and the leukemia treatment Tasigna, as well as violation of conflict of interest disclosure in relation to pharmaceutical companies, were uncovered from 2013 to 2014. In response, the Clinical Trials Act(Act No. 16 of 2017)was enacted by the ordinary Diet session on April 7, 2017(promulgated on April 14 of the same year)to ensure confidence in clinical research. In addition to requiring researchers to comply with the Standards for Conducting Clinical Research and to conclude and disclose contracts related to funding to pharmaceutical companies and other parties, the act also stipulates that the quality of reviews should be ensured by establishing an accredited certified review board, thereby promoting high-quality social and academic clinical research that is transparent, safe, and the purpose of the Act is to promote high-quality, socially and academically significant clinical research that ensures transparency and safety. The Act came into effect on April 1, 2018, but when it first came into effect, there was atrophy in clinical research, which is essential for drug development, due to a lack of understanding among researchers, delays in response by medical institutions, and complicated procedures and high implementation costs as typified by the enormous amount of paperwork. Now, several years after the enactment of the Act, the number of specified clinical research projects stipulated in the Act is on the increase, thanks to the Q and A issued by the Ministry of Health, Labour and Welfare regarding the implementation of the Clinical Trials Act and other administrative information, as well as to the ingenious implementation of the Act. In addition, various advantages of conducting research under the Clinical Trials Act have also become apparent. This article outlines the operation and points to keep in mind regarding the specified clinical research stipulated in the Clinical Trials Act.

[Specified Clinical Research].

Hirata K

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 12 ) 1291 - 1294 2022.12

ISSN  0385-0684

WJOG13219G: The Efficacy and Safety of FOLFOXIRI or Doublet plus Anti-VEGF Therapy in Previously Untreated BRAF^V600E Mutant Metastatic Colorectal Cancer: A Multi-Institutional Registry-Based Study (BRACELET Study)

Shimozaki K., Hirata K., Sato T., Nakamura M., Kato K., Hirano H., Kumekawa Y., Hino K., Kawakami K., Kito Y., Matsumoto T., Kawakami T., Komoda M., Nagashima K., Sato Y., Yamazaki K., Hironaka S., Takaishi H., Hamamoto Y., Muro K.

Clinical Colorectal Cancer (Clinical Colorectal Cancer)  21 ( 4 ) 339 - 346 2022.12

ISSN  15330028

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Background: The real-world survival benefit of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus anti-VEGF therapy (Triplet) over doublet chemotherapy (Doublet) remains controversial in patients with BRAFV600E mutant metastatic colorectal cancer (mCRC). Patients and Methods: WJOG13219G was a multicenter, retrospective, registry-based study of patients with BRAFV600E mutant mCRC who received first-line triplet or doublet chemotherapy from January 2014 to December 2019 in Japan. Inverse probability of treatment weighting (IPTW) was used to adjust for patient background. Results: The analysis included 79 and 91 patients in the Triplet and Doublet groups, respectively. The Triplet group was significantly younger and had better performance status. No statistical difference was noted in progression-free survival (PFS; HR, 0.82; 95% CI, 0.60–1.13; P = .22) and overall survival (OS; HR, 0.88; 95% CI, 0.62–1.25; P = .48) between both groups. IPTW analysis also showed no difference between the 2 groups in PFS (HR, 0.86; 95% CI, 0.69–1.08; P = .20) and OS (HR, 0.93; 95% CI, 0.73–1.20; P = .59). The Triplet and Doublet groups had an objective response rate of 53% and 41%, respectively (P = .10). At least one grade 3 or 4 adverse event was seen in 51 (65%) and 43 (47%) patients in the Triplet and Doublet groups, respectively, with the incidence of neutropenia being significantly higher in the former. Conclusion: Triplet therapy had no survival benefit versus doublet therapy in the overall and IPTW cohorts or specific subgroups for real-world patients with BRAFV600E mutant mCRC.

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Distribution of Residual Disease and Recurrence Patterns in Pathological Responders after Neoadjuvant Chemotherapy for Esophageal Squamous Cell Carcinoma

Matsuda S., Kawakubo H., Okamura A., Takahashi K., Toihata T., Takemura R., Mayanagi S., Hirata K., Irino T., Hamamoto Y., Takeuchi H., Facs , Watanabe M., Kitagawa Y.

Annals of Surgery (Annals of Surgery)  276 ( 2 ) 298 - 304 2022.08

ISSN  00034932

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Objective: This study aimed to elucidate the residual disease distribution and recurrence patterns in patients with ESCC responding to NAC. Summary Background Data: To appropriately plan a prospective trial for the organ preservation approach which includes additional chemoradiotherapy in patients who responded to NAC, the distribution of residual disease needs to be elucidated. Given that the residual tumor is located in the regional field, chemoradiotherapy can be safely added to eliminate the residual disease. Methods: Overall, 483 patients with resectable ESCC who received NAC followed by transthoracic esophagectomy at 2 high-volume centers were reviewed. The recurrence-free survival, overall survival (OS), and residual and recurrent tumor patterns were compared among the pathological responses. Results: Compared with nonpathological responders, pathological responders exhibited significantly longer recurrence-free survival [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.25 (P < 0.001)/0.17 (P < 0.001)/0.16 (P = 0.003)] and OS [hazard ratio of Grade 1b/2/3 compared with Grade 0; 0.26 (P < 0.001)/0.12 (P < 0.001)/0.11 (P = 0.003)]. In terms of the distribution of recurrence, the percentages of solitary recurrence in the regional field out of all recurrence was significantly higher in patients with Grade 1b (60%)/2 (67%)/3 (67%) whereas less than 25% in Grade 0 or 1a. Conclusions: It was found that postoperative recurrence in responders occurred in the regional field mostly as a solitary lesion without the distant failure, indicating that the residual tumor cells can be eliminated by additional chemoradiotherapy.

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Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen

Inokuchi K., Mori H., Matsuzaki J., Hirata K., Harada Y., Saito Y., Suzuki H., Kanai T., Masaoka T.

Helicobacter (Helicobacter)  27 ( 4 ) e12900 2022.08

ISSN  10834389

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Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

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Concordance analysis of microsatellite instability status between polymerase chain reaction based testing and next generation sequencing for solid tumors

Shimozaki K., Hayashi H., Tanishima S., Horie S., Chida A., Tsugaru K., Togasaki K., Kawasaki K., Aimono E., Hirata K., Nishihara H., Kanai T., Hamamoto Y.

Scientific Reports (Scientific Reports)  11 ( 1 ) 20003 2021.12

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Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, a polymerase chain reaction (PCR)-based method, was the first tumor-agnostic companion diagnostic to detect MSI status in MSI-H solid tumors. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available; however, its real-world concordance with PCR-based testing of MSI-H/dMMR remains to be investigated. The co-primary end points included the positive and negative predictive values of MSI-H/dMMR. A retrospective analysis of 80 patients who had undergone both MSI testing and NGS between July 2015 and March 2021 was conducted. Five patients were confirmed to have MSI-H in both examinations. Among the 75 patients diagnosed as microsatellite stable (MSS) by PCR-based testing, one with pancreatic cancer was diagnosed as having MSI-H after NGS. One patient with pancreatic cancer was diagnosed as having MSS in both tests was found to have a mutation in MLH1 by NGS, which was confirmed as dMMR by IHC staining. NGS had positive and negative predictive values of 100% (5/5) and 98.7% (74/75), respectively, for MSI-H. The concordance between NGS and PCR-based testing was 98.8% (79/80). Thus, NGS can be useful for evaluating MSI/MMR status in clinical practice and can be an important alternative method for detecting MSI-H/dMMR in the future.

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Prospective feasibility study of indigo naturalis ointment for chemotherapy-induced oral mucositis

Hirata, K., Yamada, Y., Hamamoto, Y., Tsunoda, K., Muramatsu, H., Horie, S., Sukawa, Y., Naganuma, M., Nakagawa, T. and Kanai, T.

BMJ Support Palliat Care (BMJ Supportive and Palliative Care)  13 ( e3 ) E1001 - E1007 2021.10

ISSN  2045-435x

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OBJECTIVES: Indigo naturalis, a herbal medicine effective against ulcerative colitis, exhibits anti-inflammatory effects and induces interleukin-22-mediated antimicrobial peptide production. Anti-inflammatory activity and the prevention of secondary infection are essential for the management of chemotherapy-induced oral mucositis (CIOM); therefore, we developed an indigo naturalis ointment to be administered topically for CIOM and evaluated its feasibility. METHODS: We performed a single-centre, open-label, prospective feasibility study from March 2017 to December 2018. The key eligibility criteria for the subjects were as follows: (1) receiving chemotherapy for a malignant tumour; (2) grade 1 or 2 CIOM and (3) receiving continuous oral care. The treatment protocol comprised topical indigo naturalis ointment application three times a day for 7 days. The primary endpoint assessed was feasibility. The secondary endpoints assessed were the changes in oral findings, oral cavity pain and safety. RESULTS: Nineteen patients with CIOM were enrolled. The average feasibility (the proportion of prescribed applications that were carried out) observed in this study was 94.7%±8.9% (95% CI 90.5% to 99.0%), which was higher than the expected feasibility. The revised oral assessment guide scores of the mucous membrane domain and total scores were significantly improved. All patients reported a reduction in oral cavity pain, with a median pain resolution duration of 6 days. No serious adverse events were observed. CONCLUSIONS: The indigo naturalis ointment was feasible, and showed the potential for efficacy and safety. Larger randomised controlled trials are needed to further assess the efficacy and safety of indigo naturalis compared with a placebo. TRIAL REGISTRATION NUMBER: UMIN000024271.

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Analysis of risk factors for immune-related adverse events in various solid tumors using real-world data

Shimozaki K., Sukawa Y., Sato Y., Horie S., Chida A., Tsugaru K., Togasaki K., Kawasaki K., Hirata K., Hayashi H., Hamamoto Y., Kanai T.

Future Oncology (Future Oncology)  17 ( 20 ) 2593 - 2603 2021.07

ISSN  14796694

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The aim of this study was to determine the risk factors for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors. The authors conducted a retrospective study in which patients with malignant melanoma, non-small-cell lung cancer, gastric cancer or renal cell carcinoma who received anti-PD-1/PD-L1 antibodies were included. Of 247 patients, 118 developed a total of 182 irAEs. In the multivariate Fine-Gray regression analysis, serum albumin level ≥3.6 g/dl (hazard ratio: 1.62; 95% CI: 1.10-2.39; p = 0.015) and history of Type I hypersensitivity reactions (hazard ratio: 1.48; 95% CI: 1.02-2.14; p = 0.037) were significantly associated with the development of irAEs. High serum albumin levels and history of Type I hypersensitivity reactions are risk factors for irAEs.

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Clinical, Endoscopic, and Pathological Characteristics of Immune Checkpoint Inhibitor-Induced Gastroenterocolitis

Hayashi Y., Hosoe N., Takabayashi K., Limpias Kamiya K.J.L., Tsugaru K., Shimozaki K., Hirata K., Fukuhara K., Fukuhara S., Mutaguchi M., Sujino T., Sukawa Y., Hamamoto Y., Naganuma M., Takaishi H., Shimoda M., Ogata H., Kanai T.

Digestive Diseases and Sciences (Digestive Diseases and Sciences)  66 ( 6 ) 2129 - 2134 2021.06

ISSN  01632116

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The entire intestinal tract surveillance using capsule endoscopy after immune checkpoint inhibitor administration: A prospective observational study

Shimozaki K., Hirata K., Horie S., Chida A., Tsugaru K., Hayashi Y., Kawasaki K., Miyanaga R., Hayashi H., Mizuno R., Funakoshi T., Hosoe N., Hamamoto Y., Kanai T.

Diagnostics (Diagnostics)  11 ( 3 )  2021.03

ISSN  2075-4418

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Background: Despite the proven efficacy of immune checkpoint inhibitors (ICIs) against various types of malignancies, they have been found to induce immune-related adverse events, such as enterocolitis; however, the clinical features of ICI-induced enterocolitis remain to be sufficiently elucidated, which is significant, considering the importance of early detection in the appropriate management and treatment of ICI-induced enterocolitis. Therefore, the current study aimed to determine the utility of capsule endoscopy as a screening tool for ICI-induced enterocolitis. Methods: This single-center, prospective, observational study was conducted on patients with malignancy who received any ICI between April 2016 and July 2020 at Keio University Hospital. Next, second-generation capsule endoscopy (CCE-2) was performed on day 60 after ICI initiation to explore the entire gastrointestinal tract. Results: Among the 30 patients enrolled herein, 23 underwent CCE-2. Accordingly, a total of 23 findings were observed in 14 (60.8%) patients at any portion of the gastrointestinal tract (7 patients in the colon, 4 patients in the small intestine, 2 patients in both the colon and the small intestine, and 1 patient in the stomach). After capsule endoscopy, 2 patients (8.7%) developed ICI-induced enterocolitis: both had significantly higher Capsule Scoring of Ulcerative Colitis than those who had not developed ICI-induced enterocolitis (p = 0.0455). No adverse events related to CCE-2 were observed. Conclusions: CCE-2 might be a safe and useful entire intestinal tract screening method for the early detection of ICI-induced enterocolitis in patients with malignancies.

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An investigator-initiated phase 2 study of nivolumab plus low-dose ipilimumab as first-line therapy for microsatellite instability—high advanced gastric or esophagogastric junction cancer (No limit, wjog13320g/ca209-7w7)

Kawakami H., Hironaka S., Esaki T., Chayama K., Tsuda M., Sugimoto N., Kadowaki S., Makiyama A., Machida N., Hirano H., Hirata K., Hara H., Yabusaki H., Komatsu Y., Muro K.

Cancers (Cancers)  13 ( 4 ) 1 - 12 2021.02

ISSN  2072-6694

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Nivolumab (NIVO) plus low-dose ipilimumab (IPI) has shown a promising survival benefit in first-line treatment of microsatellite instability-high (MSI-H) colorectal cancer. We hypothesized that this regimen might also be beneficial for MSI-H gastric cancer (GC), which accounts for ~5% of all GC cases. NO LIMIT (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of NIVO plus low-dose IPI for MSI-H GC in the first-line setting. Eligibility criteria include unresectable advanced, recurrent, or metastatic gastric or esophagogastric junction cancer with a histologically confirmed diagnosis of adenocarcinoma; confirmed MSI-H status with the MSI-IVD Kit (FALCO); no prior systemic anticancer therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a measurable lesion per RECIST 1.1. The primary objective of the study is to determine the overall response rate (ORR) for the NIVO+IPI regimen as assessed by blinded independent central review. Secondary end points include progression-free survival, overall survival, duration of response, safety, tolerability, and biomarkers. The number of patients was set at 28 on the basis of the threshold and expected ORR values of 35 and 65%, respectively, with a one-sided alpha error of 0.025 and power of 0.80. Subjects will receive treatment with nivolumab (240 mg) biweekly in combination with ipilimumab (1 mg/kg) every 6 weeks. The results of this study should clarify the therapeutic potential of NIVO+IPI for MSI-H GC in the first-line setting.

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Ulcerative colitis exacerbation after the onset of immune checkpoint inhibitor related colitis

Kayashima A., Shimozaki K., Hirata K., Mutaguchi M., Takabayashi K., Hayashi Y., Hosoe N., Ogata H., Sujino T., Kanai T.

Clinical Journal of Gastroenterology (Clinical Journal of Gastroenterology)  14 ( 1 ) 152 - 158 2021.02

ISSN  18657257

　View Summary

Immune checkpoint inhibitors (ICPI) have been reported to be effective in various carcinomas. They excessively activate the immune system, resulting in frequent immune-related adverse events (irAEs). Colitis induced by ICPI is one of the most common and is known as immune-mediated colitis (IMC). Although IMC and inflammatory bowel disease (IBD) are similar in many respects, there are very few reports of IMC in patients with preexisting IBD such as ulcerative colitis (UC) and Crohn's disease (CD). Whether preexisting IBD is concerned with the development of the colitis is not well known. Here, we reported the case who developed severe ulcerative colitis which started from IMC. It is an important case to follow the time course of the colitis developed. Our conclusion indicated that frequent colonoscopy was important for the management of IMC in a patient who has suffered chronic inflammatory disease, such as UC.

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Weekly paclitaxel plus ramucirumab versus weekly nab-paclitaxel plus ramucirumab for unresectable advanced or recurrent gastric cancer with peritoneal dissemination refractory to first-line therapy-the P-SELECT trial (WJOG10617G)-a randomised phase II trial by the West Japan Oncology Group

Hirata K., Hamamoto Y., Ando M., Imamura C.K., Yoshimura K., Yamazaki K., Hironaka S., Muro K.

BMC cancer (BMC cancer)  20 ( 1 )  2020.06

　View Summary

BACKGROUND: Ramucirumab (RAM) with weekly paclitaxel (wPTX) is a standard second-line therapy for advanced or recurrent gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX), an albumin-bound form of PTX, was developed to improve the therapeutic index of taxane treatment. However, the ABSOLUTE trial showed the non-inferiority of weekly nab-PTX (w-nab-PTX) to wPTX with respect to overall survival (OS) as second-line therapy for advanced or recurrent gastric cancer, and subgroup analysis of patients with peritoneal dissemination showed favourable OS and progression-free survival (PFS) in the w-nab-PTX arm compared to those in the wPTX arm. This study evaluated whether w-nab-PTX plus RAM is more effective than wPTX plus RAM for patients with peritoneal dissemination. METHODS: The P-SELECT trial (WJOG10617G) is a prospective, open-label, multicentre, randomised phase II study evaluating wPTX plus RAM (arm A) versus w-nab-PTX plus RAM (arm B). Key eligibility criteria include the following: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, and 5) ECOG Performance Status (PS) 0-2. Patients are randomised to either arm at a 1:1 ratio stratified by institution, PS, and severity of ascites. PTX (80 mg/m2; days 1, 8, and 15) and RAM (8 mg/kg; days 1 and 15) are administered every 4 weeks in arm A, while nab-PTX (100 mg/m2; days 1, 8, and 15) instead of PTX is administered in arm B. The primary endpoint is OS, and the main secondary endpoints are PFS, objective response rate, safety, neuropathy-specific quality of life, and biomarkers. To maintain a probability of ≥70% to ensure the hazard ratio for OS in arm B is lower than 0.90, 105 subjects are required. The study was initiated in October 2018 and is being conducted in 58 centres of the West Japan Oncology Group. DISCUSSION: The results of this study will determine whether w-nab-PTX plus RAM has the potential to be a preferred therapeutic option for advanced and recurrent gastric cancer with peritoneal dissemination, compared to wPTX plus RAM. TRIAL REGISTRATION: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs031180022, October 1, 2018).

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Clinical and Endoscopic Characteristics of Pyogenic Granuloma in the Small Intestine: A Case Series with Literature Review

Hayashi Y., Hosoe N., Takabayashi K., Kamiya K.J.L., Mutaguchi M., Miyanaga R., Hirata K., Fukuhara S., Mikami Y., Sujino T., Masugi Y., Naganuma M., Ogata H., Kanai T.

Internal medicine (Tokyo, Japan) (Internal medicine (Tokyo, Japan))  59 ( 4 ) 501 - 505 2020.02

ISSN  09182918

　View Summary

Pyogenic granuloma (PG) generally appears in the skin or oral cavity, but rarely occurs in the small intestine, where it can cause bleeding. To date, only 35 cases of small intestinal PG have been reported in the English literature. We retrospectively collected information from the clinical records of seven cases of small intestinal PG that were managed in our hospital and summarized the characteristics. Further information on the clinical characteristics was obtained from the literature. Capsule endoscopy, useful for identifying the source of hemorrhage in obscure gastrointestinal bleeding, can detect PGs. Treatment can often be accomplished with endoscopic mucosal resection.

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Multiple immune-related adverse events and anti-tumor efficacy: Real-world data on various solid tumors

Shimozaki K., Sukawa Y., Beppu N., Kurihara I., Suzuki S., Mizuno R., Funakoshi T., Ikemura S., Tsugaru K., Togasaki K., Kawasaki K., Hirata K., Hayashi H., Hamamoto Y., Takaishi H., Kanai T.

Cancer Management and Research (Cancer Management and Research)  12   4585 - 4593 2020

　View Summary

Purpose: Immune checkpoint inhibitors (ICIs) have been approved for various types of cancer; however, they cause a broad spectrum of immune-related adverse events (irAEs). The association between the development of irAEs and the clinical benefit remains uncertain. We aimed to evaluate the association of irAEs and the treatment efficacy in real-world practice. Patients and Methods: We conducted a retrospective study on patients with recurrent or metastatic non-small-cell lung cancer, malignant melanoma, renal cell carcinoma, or gastric cancer who received anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab, or atezolizumab) at the Keio University Hospital between September 2014 and January 2019. We recorded treatment-related AEs from medical records and graded them using the Common Terminology Criteria for Adverse Events version 4. We performed an overall survival (OS) analysis using a Cox proportional hazards model and the shared frailty model. Results: Of 212 patients eligible for this study, 108 experienced irAEs and 42 developed multiple irAEs. The median OS was significantly longer in the irAEs than in the no-irAE group (28.1 months vs 12.7 months; hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.33–0.73; P = 0.0004). Moreover, the OS of patients with multiple irAEs was significantly longer than that of patients with a single irAE (42.3 months vs 18.8 months; HR, 0.473; 95% CI, 0.346–0.647; P < 0.0001). Conclusion: Our single-center retrospective study revealed a significant tendency associating the development of multiple irAEs with favorable prognoses.

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Pancreatic fat content may increase the risk of imaging progression in low-risk branch duct intraductal papillary mucinous neoplasm

Kashiwagi K., Minami K., Seino T., Hirata K., Iwasaki E., Inoue N., Iwao Y., Kanai T.

Journal of Digestive Diseases (Journal of Digestive Diseases)  20 ( 10 ) 557 - 562 2019.10

ISSN  17512972

　View Summary

© 2019 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd Objective: To identify risk factors of imaging progression (increase in cyst size or main pancreatic duct size, or a new mural nodule) in low-risk branch duct intraductal papillary mucinous neoplasm (BD-IPMN), including obesity-related factors such as pancreatic fat content. Methods: Our hospital databases were searched for patients who had completed health checkup, including upper abdominal magnetic resonance imaging (MRI) over 48 months (August 2012 to July 2016). Individuals with BD-IPMN without worrisome features and high-risk stigmata who underwent surveillance with at least one follow-up MRI, irrespective of the follow-up period, were included. Pancreatic computed tomography attenuation indexes were defined as the difference between the pancreas and spleen attenuation (P - S) and the pancreas to spleen attenuation ratio (P/S). Results: Among 75 patients diagnosed as having low-risk BD-IPMN, during a median follow-up of 36 months, 11 (15%) had imaging progression in cyst size, including two with worrisome features. A multivariate logistic analysis showed that the initial cyst size and both indexes (P - S, or P/S) were significantly associated with imaging progression in IPMN, respectively (Model 1: odds ratio [OR] 1.188, 95% confidence interval [CI] 1.060-1.331, P = 0.003; OR 0.871, 95% CI 0.776-0.977, P = 0.019; Model 2: OR 1.186, 95% CI 1.064-1.322, P = 0.002; OR 0.002, 95% CI 0.000-0.970, P = 0.049). Conclusions: Pancreatic fat content and initial cyst size were significantly associated with imaging progression in low-risk BD-IPMN. Revisions of international consensus Fukuoka guidelines might be customized based on initial cyst size and pancreatic fat content.

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Unmet needs of cancer patients with chemotherapy-related hand-foot syndrome and targeted therapy-related hand-foot skin reaction: A qualitative study

Komatsu H., Yagasaki K., Hirata K., Hamamoto Y.

European Journal of Oncology Nursing (European Journal of Oncology Nursing)  38   65 - 69 2019.02

ISSN  14623889

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© 2018 Purpose: The objective of this qualitative study was to understand the perceived needs of advanced-stage cancer patients with chemotherapy-related hand-foot syndrome (HFS) and/or targeted therapy-related hand-foot skin reaction (HFSR). Method: Face-to-face interviews were conducted with 20 outpatients with advanced/recurrent cancer and chemotherapy-related HFS and/or targeted therapy-related HFSR using a semi-structured interview guide at Keio University Hospital, Tokyo, Japan. Thematic analysis was used to analyse the data. Results: The unmet needs of cancer patients with chemotherapy-related HFS and/or targeted therapy-related HFSR was identified through four themes: a sense of helplessness with persistent symptoms, noticeable appearance as a barrier to social participation, decreased willingness to work and continue treatment, and need of individual coping strategies. Conclusion: This study revealed unmet needs of cancer patients with chemotherapy-related HFS and/or targeted therapy-related HFSR that are not often voiced. Health care providers should provide full information in advance and find the best coping strategy for individual patients.

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Early administration of systemic chemotherapy should be considered for scirrhous gastric cancer: A case report

Aoki Y, Hamamoto Y, Ugamura A, Togasaki K, Suzuki T, Kawasaki K, Hirata K, Kasuga A, Sukawa Y, Kanai T, Takaishi H.

Mol Clin Oncol 10 ( 1 ) 113 - 117 2019

Research paper (scientific journal), Joint Work, Accepted

集学的治療を要する頸部食道がん

平田　賢郎

内科 123 ( 4 ) 549 - 550 2019

Research paper (scientific journal), Single Work

Inhibiting xCT improves 5-fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression

Miyoshi S., Tsugawa H., Matsuzaki J., Hirata K., Mori H., Saya H., Kanai T., Suzuki H.

Anticancer Research (Anticancer Research)  38 ( 11 ) 6163 - 6170 2018.11

ISSN  02507005

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© 2018 International Institute of Anticancer Research.All right reserved. Background/Aim: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. Materials and Methods: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. Results: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. Conclusion: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer.

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Post-progression survival following second-line chemotherapy in patients with advanced pancreatic cancer previously treated with gemcitabine: a meta-analysis

Kasuga A., Hamamoto Y., Takeuchi A., Okano N., Togasaki K., Aoki Y., Suzuki T., Kawasaki K., Hirata K., Sukawa Y., Kanai T., Takaishi H.

Investigational New Drugs (Investigational New Drugs)  36 ( 5 ) 939 - 948 2018.10

ISSN  01676997

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© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. We evaluated relationships between OS and PFS, PPS, and other variables. Results Totally, 17 RCTs with 3253 patients were identified. Median OS was strongly and moderately associated with median PPS and PFS, respectively (r = 0.913; p < 0.001 and 0.780; p < 0.001, respectively). The proportion of patients with good performance status was significantly associated with both PPS and PFS (r = 0.574, p < 0.001 and 0.492, p < 0.001, respectively). The induction rate of subsequent chemotherapy was related to the duration of PPS and OS (r = 0.640, p < 0.001 and 0.647, p < 0.001, respectively). Median PPS and OS were significantly longer in recent trials than those in older trials (3.55 versus 2.78 months, p < 0.001 and 6.29 versus 5.02 months, p < 0.001). Conclusions Median PPS was strongly correlated with median OS. Given the recently increased opportunity for subsequent chemotherapy and supportive care, PPS may serve as an important element to clarify problems in this setting.

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免疫チェックポイント阻害薬の自己免疫疾患関連副作用(irAE)としての腸炎

下嵜啓太郎、平田賢郎

IBD Research 12 ( 4 ) 247 - 253 2018

Research paper (scientific journal), Joint Work

再発食道癌の治療　化学療法・化学放射線療法

下嵜啓太郎、平田賢郎、浜本康夫

日本臨床 76 ( 8 ) 417 - 423 2018

Research paper (scientific journal), Joint Work

【免疫チェックポイント療法の新潮流】消化器癌治療における位置付けと今後の展望

津軽開、平田賢郎、浜本康夫

医薬ジャーナル 54 ( 8 ) 1849 - 1852 2018

Research paper (scientific journal), Joint Work

Complications and outcomes of routine endoscopy in the very elderly

Miyanaga R, Hosoe N, Naganuma M, Hirata K, Fukuhara S, Nakazato Y, Ojiro K, Iwasaki E, Yahagi N, Ogata H, Kanai T.

Endosc Int Open 6 ( 2 ) E224 - E229 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2364-3722

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BACKGROUND AND STUDY AIMS:  In Japan, the elderly population has been increasing annually. The number of elderly patients for whom esophagogastroduodenoscopy (EGD) and colonoscopy (CS) is indicated also has been rising. The aim of this study was to evaluate the safety and efficacy of routine endoscopy in a cohort of octogenarians aged 85 years and older - defined by the World Health Organization as the very elderly. PATIENTS AND METHODS:  A total of 5,586 patients underwent EGDs, and 2,484 patients underwent CSs performed at the Keio University Hospital from January to September 2014. One hundred eighty-five EGDs and 70 of the CS were performed in the very elderly. Six hundred nine EGDs and 262 CS were performed on younger patients (aged forties). Statistical analysis was performed by univariate and multivariate analyses. RESULTS:  On univariate analysis, the rate of adverse events (AEs) in the very elderly was significantly higher compared to the younger group (6.3 % vs. 1.1 %; P  < 0.01). Moreover, the very elderly cohort received substantial therapeutic intervention as compared to the younger (16.9 % vs. 6.9 %; P  < 0.01). On multivariate analysis, independent risk factors of AEs included: very elderly patients (odds ratio (OR) 3.30, 95 % confidence interval (CI) 1.05 - 10.35), inpatients (OR 3.22, 95 % CI 1.34 - 7.74), and use of pethidine hydrochloride prescription (OR 3.44, 95 % CI 1.51 - 7.81). CONCLUSIONS:  Routine endoscopy in the very elderly incurs a significant risk of AEs, particularly when combined with pethidine hydrochloride prescription.

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C型慢性肝炎/代償性肝硬変患者に対するオムビタスビル/パリダプレビル/リトナビル併用療法およびソフォスブビル/レジパスビル併用療法における治療前因子、治療効果、副作用についての検討

済生会医学・福祉共同研究    62 - 66 2018

Research paper (bulletin of university, research institution), Joint Work

Inter‑evaluator heterogeneity of clinical diagnosis for locally advanced esophageal squamous cell carcinoma.

Kenro Hirata

Esophagus  2017

Research paper (scientific journal)

Benefit of rebiopsy for deciding treatment strategy in rectal cancer: A case report.

Kenro Hirata

Oncol Lett 14 ( 3 ) 3697 - 3700 2017

Research paper (scientific journal)

Positive relationship between subsequent chemotherapy and overall survival in pancreatic cancer: meta-analysis of postprogression survival for first-line chemotherapy.

Kenro Hirata

Cancer Chemother Pharmacol 79 ( 3 ) 595 - 602 2017

Research paper (scientific journal)

Soft palatal melanosis, a simple predictor for neoplasia in the upper aerodigestive tract in Japanese alcoholic men

Kenro Hirata

Cancer Sci 108 ( 5 ) 1058 - 1064 2017

Research paper (scientific journal), Joint Work

主な抗がん薬と使用上の注意点 血管新生阻害薬

平田賢郎、青木優、浜本康夫、高石官均

腎と透析 83 ( 5 ) 737 - 739 2017

Research paper (scientific journal), Joint Work

C型慢性肝炎患者(セログループI)に対するダクルインザ・スンベプラ併用療法における治療前因子及び治療効果の検討

済生会医学・福祉共同研究  2017

Research paper (bulletin of university, research institution), Joint Work

Presence of columnar-lined esophagus is negatively associated with the presence of esophageal varices in Japanese alcoholic men.

Yokoyama A, Hirata K, Nakamura R, Omori T, Mizukami T, Aida J, Maruyama K, Yokoyama T.

World J Gastroenterol 23 ( 39 ) 7150 - 7159 2017

Research paper (scientific journal), Joint Work, Accepted

Rifabutin-based 10-day and 14-day triple therapy as a third-line and fourth-line regimen for Helicobacter pylori eradication: A pilot study.

Kenro Hirata

United European Gastroenterology Journal 4 ( 3 ) 380 - 387 2016

Research paper (scientific journal)

Efficacy of 10-day Sitafloxacin-Containing Third-Line Rescue Therapies for Helicobacter pylori Strains Containing the gyrA Mutation.

Kenro Hirata

Helicobacter  2016

C型慢性肝炎患者(1型高ウイルス量)に対するペグインターフェロン・リバビリン・シメプレビル併用療法における治療前因子、薬剤アドヒアランスと治療効果の検討

  61 - 65 2016

Research paper (bulletin of university, research institution), Joint Work

Confocal Laser Endomicroscopyでの下部消化管観察

細江直樹, 宮永亮一, 平田賢郎, 中里圭宏, 尾城啓輔, 長沼誠, 金井隆典, 緒方晴彦

消化器内視鏡 28 ( 3 ) 501 - 503 2016

Research paper (scientific journal), Joint Work, Accepted

Helicobacter pylori除菌後ディスペプシアとは何ですか

Hirata Kenro

Helicobacter Research 19 ( 2 ) 214 - 216 2015

胃食道逆流症

Hirata Kenro

Guidelines for Practical Medicine 2015    136 - 143 2015

ABC検診・内視鏡検診・X線検診のメリット・デメリット比較

Hirata Kenro

胃炎をどうする (日本医事新報社)     143 - 146 2015

胃MALTリンパ腫、悪性リンパ腫

Hirata Kenro

Jmedbook 40   100 - 102 2015

腹痛（みぞおちの痛み・下腹部の痛み）

Hirata Kenro

Jmedbook 40   26 - 28 2015

Obscure gastrointestinal bleeding: resection of a pyogenic granuloma of the ileum via double-balloon enteroscopy

Hirata Kenro

Clin J Gastroenterol 7 ( 5 ) 397 - 401 2014

異所性再発マーカーとしてのCD44v9

Hirata Kenro

日本臨床 72   343 - 347 2014

H. pylori感染胃炎〜最適な除菌とその先を見据えて〜

Hirata Kenro

Medicament News 2151   1 - 3 2014

CD44v9発現と内視鏡切除後の異所性再発リスクについて

Hirata Kenro

Progress in Medicine 34 ( 3 ) 423 - 425 2014

ピロリ菌と胃がん

Hirata Kenro

臨床と研究 91 ( 2 ) 166 - 169 2014

ICAT publication award: CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence.

Hirata Kenro

G.I.research 22 ( 3 ) 298 2014

Helicobacter pylori感染症と酸化ストレス

Hirata Kenro

酸化ストレスの医学  2014

がん幹細胞マーカーCD44v9の臨床応用 Clinical Application of CD44 variant 9 as a marker for cancer stem cells.

Hirata Kenro

最新医学 69 ( 12 ) 2601 - 2605 2014

Helicobacter pylori除菌の適応疾患

Hirata Kenro

Helicobacter Research 18 ( 6 ) 530 - 534 2014

The tumor suppressor microRNA-29c is downregulated and restored by celecoxib in human gastric cancer cells.

Kenro Hirata

Int J Cancer 132 ( 8 ) 1751 - 1760 2013

Joint Work

Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy.

Hirata Kenro

J Clin Biochem Nutr 52 ( 2 ) 172 - 178 2013

CD44 variant 9 expression in primary early gastric cancer as a predictive marker for recurrence.

Hirata Kenro

Br J Cancer 109 ( 2 ) 379 - 386 2013

H. pyloriはFDの病因となりうるか

Hirata Kenro

分子消化器病 10 ( 3 ) 224 - 228 2013

Validation of the GerdQ questionnaire for the management of gastro-oesophageal reflux disease in Japan.

Kenro Hirata

United European Gastroenterol J 1 ( 3 ) 175 - 183 2013

Joint Work

Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells.

Kenro Hirata

Cell Host Microbe 12 ( 6 ) 764 - 777 2012

Joint Work

Biliary findings assist in predicting enlargement of intraductal papillary mucinous neoplasms of the pancreas.

Kenro Hirata

Clin Gastroenterol Hepatol 11 ( 5 ) 548 - 554 2012

Joint Work

Overexpression of miR-142-5p and miR-155 in gastric mucosa-associated lymphoid tissue (MALT) lymphoma resistant to Helicobacter pylori eradication.

Kenro Hirata

PLoS One 7 ( 11 ) e47396 2012

Joint Work

Development of a novel microRNA promoter microarray for ChIP-on-chip assay to identify epigenetically regulated microRNAs.

Kenro Hirata

Biochem Biophys Res Commun 426 ( 1 ) 33 - 37 2012

Joint Work

FecA1, a bacterial iron transporter, determines the survival of Helicobacter pylori in the stomach.

Kenro Hirata

Free Radic Biol Med 52 ( 6 ) 1003 - 1010 2012

Joint Work

Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failures of first- and second-line therapies.

Kenro Hirata

Antimicrob Agents Chemother 56 ( 3 ) 1643 - 1645 2012

Joint Work

High frequency of overlap between functional dyspepsia and overactive bladder.

Kenro Hirata

Neurogastroenterol Motil 24 ( 9 ) 821 - 827 2012

Joint Work

Helicobacter pylori除菌後の逆流症状とQOLの変化に対する検討

Hirata Kenro

Progress in Medicine 31 ( 3 ) 822 - 824 2011

ヘリコバクター・ピロリ

Hirata Kenro

食品・免疫アレルギーの事典 (朝倉書店)   2011

GERDの診断と治療

Hirata Kenro

Medicina 48 ( 7 ) 1292 - 1295 2011

下血・血便

Hirata Kenro

綜合臨床 60   1189 - 1191 2011

microRNAの発現異常と癌化シグナル

Hirata Kenro

潰瘍 38 ( 2 ) 121 - 124 2011

Helicobacter pylori resistance to rifabutin in the last 7 years.

Kenro Hirata

Antimicrob Agents Chemother 55 ( 11 ) 5347 - 5355 2011

Joint Work

Enhancement of amoxicillin resistance after unsuccessful Helicobacter pylori eradication.

Kenro Hirata

Antimicrob Agents Chemother 55 ( 6 ) 3012 - 3014 2011

Joint Work

Enhanced bacterial efflux system is the first step to the development of metronidazole resistance in Helicobacter pylori.

Kenro Hirata

Biochem Biophys Res Commun 404 ( 2 ) 656 - 660 2011

Joint Work

Etiological difference between ultrashort- and short-segment Barrett's esophagus.

Kenro Hirata

J Gastroenterol 46 ( 3 ) 332 - 338 2011

Joint Work

Dysfunctional gastric emptying with down-regulation of muscle-specific microRNAs in Helicobacter pylori-infected mice.

Kenro Hirata

Gastroenterology 140 ( 1 ) 189 - 198 2011

Joint Work

Two amino acids mutation of ferric uptake regulator determines Helicobacter pylori resistance to metronidazole.

Kenro Hirata

Antioxid Redox Signal 14 ( 1 ) 15 - 23 2011

Joint Work

Contribution of efflux pumps to clarithromycin resistance in Helicobacter pylori.

Hirata Kenro

J Gastroenterol Hepatol 25   75 - 79 2010

Helicobacter pylori除菌前後の内視鏡所見の変化

Hirata Kenro

Helicobacter Research 14 ( 6 ) 440 - 444 2010

機能性ディスペプシアの臨床上の問題点

Hirata Kenro

綜合臨床 59 ( 12 ) 2469 - 2470 2010

胃・食道逆流症(GERD)

Hirata Kenro

ビジュアルブック　消化器病棟ケア・マニュアル  2010

Gallstones increase the prevalence of Barrett's esophagus.

Kenro Hirata

J Gastroenterol 45 ( 2 ) 171 - 178 2010

Joint Work

ITPとヘリコバクター感染

Hirata Kenro

血液フロンティア 19 ( 6 ) 891 - 896 2009

Effective inhibition of cell growth and invasion of melanoma by combined suppression of BRAF (V599E) and Skp2 with lentiviral RNAi.

Kenro Hirata

Int J Cancer 118 ( 2 ) 472 - 476 2006

Joint Work