Details of a Researcher - Hirata, Kenro

Papers - Hirata, Kenro

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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

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

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

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

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

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

ISSN 03850684

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<sup>V600E</sup> 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

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

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

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

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

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

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

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

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

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

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

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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