Publications by authors named "Chigusa Morizane"

144 Publications

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer.

Int J Clin Oncol 2021 Aug 8. Epub 2021 Aug 8.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background: Although FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.

Methods: FOLFIRINOX (intravenous oxaliplatin 85 mg/m, irinotecan 180 mg/m, levofolinate 200 mg/m, 5-fluorouracil (5-FU) bolus 400 mg/m and 5-FU 46 h infusion 2400 mg/m) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.

Results: At the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5-40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7-74.9) and 15.7 months (95% CI 7.9-18.8), respectively.

Conclusions: This phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.

Trial Registration: http://www.umin.ac.jp/ctr/index-j.htm , UMIN000017538. Date of registration: May/13/2015.
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http://dx.doi.org/10.1007/s10147-021-02001-yDOI Listing
August 2021

Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113.

Sci Rep 2021 Jun 18;11(1):12885. Epub 2021 Jun 18.

Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504-0.937) in the low CCr group. Although the total number of incidences of all Grade 3-4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
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http://dx.doi.org/10.1038/s41598-021-92166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213853PMC
June 2021

Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives.

Jpn J Clin Oncol 2021 Aug;51(8):1185-1196

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors. In this review, we summarize the results of various clinical trials that have been conducted to investigate the efficacy and safety of various therapeutic options for NENs. Based on the encouraging results obtained from these trials, various therapeutic options have been established for the treatment of NENs, including somatostatin analogs (SSAs), molecularly targeted drugs and cytotoxic agents. In addition, peptide receptor radionucleotide therapy has recently been evaluated for the treatment of various NENs. We also discuss the approach for selecting the appropriate drugs and sequence of treatment with the various drug classes, as recommended by different treatment guidelines. Finally, we discuss the scope for future research in this field, especially into the merits of combination therapy with molecularly targeted drugs plus SSAs, along with ongoing studies.
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http://dx.doi.org/10.1093/jjco/hyab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326384PMC
August 2021

Survey of surgical resections for neuroendocrine liver metastases: A project study of the Japan Neuroendocrine Tumor Society (JNETS).

J Hepatobiliary Pancreat Sci 2021 Jun 20;28(6):489-497. Epub 2021 Apr 20.

Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan.

Background/purpose: Hepatic resection is considered the treatment of choice for neuroendocrine liver metastases (NELM). However, the safety and efficacy of resection have not been fully evaluated using a large cohort. The aim of the present study was to collect real-world data regarding hepatic resections for NELM.

Methods: A retrospective, multicenter survey was conducted. The background characteristics of patients undergoing an initial hepatic resection for NELM, the operative details, pathological findings, and patient outcomes were investigated.

Results: A total of 222 patients were enrolled from 30 institutions. The primary tumor site was the pancreas in 58.6%, and the presentation of NELM was synchronous in 63.1% of the cases. Concomitant resection of the primary tumor and liver metastases was performed for 66.4% of the synchronous metastases, and the 90-day morbidity and mortality rates were 12.6% and 0.9%, respectively. The operations resulted in R2 resections in 26.1% of the cases, and 83.4% of the patients experienced recurrence after R0/1 resections. However, the patients were treated using multiple modalities after R2 resection or recurrence, and the overall survival rate was relatively favorable, with 5-year and 10-year survival rates of 70.2%, and 43.4%, respectively. Univariable and multivariable analyses identified the tumor grading (G3) of the primary tumor as a significant prognostic factor for both the recurrence-free and overall survivals.

Conclusions: The present data confirmed the safety of the surgical resection of NELM. Although recurrences were frequent, the survival outcomes after resection were favorable when a multi-disciplinary treatment approach was used.
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http://dx.doi.org/10.1002/jhbp.956DOI Listing
June 2021

Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases: A Proposal of Risk Stratification and Identification of a Synaptophysin-positive Aggressive Subset.

Am J Surg Pathol 2021 05;45(5):616-626

Departments of Diagnostic Pathology.

Epithelioid hemangioendothelioma (EHE) is a rare vascular endothelial neoplasm with characteristic histology and distinctive fusion genes. Its clinical presentation and outcome are heterogeneous, and the determinants of survival are controversial. In this study, we aimed to identify clinicopathologic prognostic factors of EHE in a retrospective cohort of 62 cases with CAMTA1/TFE3/WWTR1 alterations. The tumors were of the CAMTA1 subtype for 59 cases, TFE3 subtype for 2 cases, and variant WWTR1 subtype (WWTR1-ACTL6A) for 1 case. Twenty-two tumors (35.5%) demonstrated atypical histology, defined by having at least 2 of the following 3 findings: high mitotic activity (>1/2 mm2), high nuclear grade, and coagulative necrosis. During a median follow-up of 34 months, 11 patients (18%) died, and the 5-year overall survival rate was 78.8%. Survival did not correlate with such clinical parameters as age, sex, tumor sites, multifocality, and multiorgan involvement. Conversely, based on both univariate and multivariate analyses, large tumor size (>30 mm) and histologic atypia were significantly associated with a shorter survival. A proposed 3-tiered risk assessment system using these 2 parameters significantly stratified the patients into low-risk, intermediate-risk, and high-risk groups with 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively (P<0.001). Four tumors (6.4%) expressed synaptophysin, which all belonged to the high-risk group and pursued an aggressive course. The present study demonstrated the independent prognostic significance of large tumor size and atypical histology in EHE, as well as the value of risk stratification using these 2 factors. Moreover, we revealed a small EHE subset with aberrant synaptophysin expression, which may have potential prognostic and diagnostic implications.
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http://dx.doi.org/10.1097/PAS.0000000000001660DOI Listing
May 2021

A randomized, double-blind, phase II study of oral histone deacetylase inhibitor resminostat plus S-1 versus placebo plus S-1 in biliary tract cancers previously treated with gemcitabine plus platinum-based chemotherapy.

Cancer Med 2021 03 26;10(6):2088-2099. Epub 2021 Feb 26.

Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan.

Purpose: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs.

Methods: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety.

Results: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%).

Conclusions: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883).
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http://dx.doi.org/10.1002/cam4.3813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957161PMC
March 2021

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

Pancreatology 2021 Jun 14;21(4):738-745. Epub 2021 Feb 14.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Background: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC.

Methods: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed.

Results: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the β coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001).

Conclusions: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.
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http://dx.doi.org/10.1016/j.pan.2021.02.008DOI Listing
June 2021

Phase I studies of peptide vaccine cocktails derived from GPC3, WDRPUH and NEIL3 for advanced hepatocellular carcinoma.

Immunotherapy 2021 Apr 2;13(5):371-385. Epub 2021 Feb 2.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1-3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1-6 (HLA-A24 or A02-restricted). Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933; JapicCTI-142477.
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http://dx.doi.org/10.2217/imt-2020-0278DOI Listing
April 2021

FOLFIRINOX in advanced pancreatic cancer patients with the double-variant type of UGT1A1 *28 and *6 polymorphism: a multicenter, retrospective study.

Cancer Chemother Pharmacol 2021 03 2;87(3):397-404. Epub 2021 Jan 2.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Background: UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV.

Patients And Methods: Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV.

Results: A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of  ≥ 150 mg/m than in those who had received the drug at an initial dose of  ≤ 120 mg/m (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of  ≤ 120 mg/m were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV.

Conclusion: Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of  ≤ 120 mg/m.
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http://dx.doi.org/10.1007/s00280-020-04206-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889544PMC
March 2021

Multicenter Retrospective Analysis of Chemotherapy for Advanced Pancreatic Acinar Cell Carcinoma: Potential Efficacy of Platinum- and Irinotecan-Containing Regimens.

Pancreas 2021 01;50(1):77-82

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo.

Objectives: The aim of this multicenter retrospective study was to identify the optimal chemotherapeutic regimen for advanced pancreatic acinar cell carcinoma (PACC).

Methods: Fifty-eight patients with histopathologically confirmed advanced PACC who had received chemotherapy between 1996 and 2013 were enrolled. The clinical characteristics of the patients and the treatment efficacy data were collected from the medical records at 16 Japanese institutions, using standardized data collection instrument.

Results: The most commonly selected treatment regimens were gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens. The overall response rate in the patients who received first-line chemotherapy were 7% and 38%, respectively, and the median overall survival was 13.2 months. When the data for all the treatment lines were aggregated, the response rates to gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens were 7%, 18%, 40%, and 29%, respectively. The overall survival tended to be better in patients who had received a platinum-containing regimen (hazard ratio, 0.50; 95% confidence interval, 0.23-1.11; P = 0.08) or irinotecan-containing regimen (hazard ratio, 0.42; 95% confidence interval, 0.15-1.19; P = 0.09) at least once in the treatment course as compared with those who had not.

Conclusions: Our findings suggested that platinum- and irinotecan-containing regimens exhibited some potential efficacy in patients with advanced PACC.
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http://dx.doi.org/10.1097/MPA.0000000000001718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748047PMC
January 2021

Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results.

BMC Cancer 2020 Nov 16;20(1):1105. Epub 2020 Nov 16.

National Cancer Centre Hospital, Tokyo, Japan.

Background: Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1-3, FGFRs 1-4, and PDGFR-α) was evaluated for second-line treatment of BTC.

Methods: In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles.

Results: Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2-27.2). Median PFS was 3.19 months (95% CI: 2.79-7.23) per investigator assessment and 1.64 months (95% CI: 1.41-3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50-11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related.

Conclusions: Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population.

Trial Registration: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.
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http://dx.doi.org/10.1186/s12885-020-07365-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667859PMC
November 2020

Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study).

J Gastroenterol 2021 03 26;56(3):250-260. Epub 2020 Oct 26.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics.

Methods: Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients.

Results: A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression).

Conclusions: FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.
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http://dx.doi.org/10.1007/s00535-020-01735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932978PMC
March 2021

Hydrocolloid dressing as a prophylactic use for hand-foot skin reaction induced by multitargeted kinase inhibitors: protocol of a phase 3 randomised self-controlled study.

BMJ Open 2020 10 6;10(10):e038276. Epub 2020 Oct 6.

Department of Nursing, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Introduction: Although topical use of moisturisers is slightly effective for the prevention and avoiding the aggravation of hand-foot syndrome induced by multikinase inhibitors, there is still room for improvement. Hydrocolloid dressing is a type of wound dressing often used for wounds such as decubitus ulcers. The purpose of this study is to verify the usefulness of application of hydrocolloid dressings as prophylaxis against development of hand-foot syndrome induced by multikinase inhibitors by comparing the effects of this dressing and standard supportive care (moisturising care alone) within the same individuals.

Methods: This study is a phase 3 randomised, self-controlled study to compare prophylactic moisturising care with or without hydrocolloid dressing for hand-foot syndrome induced by multikinase inhibitors. Patients with radically unresectable advanced or recurrent colorectal carcinoma, gastrointestinal stromal tumour and hepatocellular carcinoma who scheduled to receive regorafenib or sorafenib therapy are eligible for enrolment.Supportive care for hand-foot syndrome will consist of basic moisturising care with or without hydrocolloid dressing. If hand-foot syndrome occurs, a steroid ointment will be applied two times per day at the affected sites. The primary endpoint is an incidence rate of grade 2 or more severe hand-foot syndrome (soles of the feet only) assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events V.4.0. Grading of hand-foot syndrome will be performed by central review using photographs taken weekly by blinded trained physicians. The ethical approval was obtained from National Cancer Center Hospital. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conference.

Discussion: If the positive results are found in this study, it is shown that hydrocolloid dressing is effective not only as a symptom management but also as a prevention in hand-foot syndrome induced by multikinase.

Trial Status: The enrolment was started in January 2019, and planned to closed in January 2021. As of February 2020, 26 patients enrolled in this study.

Trial Registration Number: UMIN Clinical Trial Registry (UMIN000034853).

Protocol Version: V.1.4, 9 January 2020.
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http://dx.doi.org/10.1136/bmjopen-2020-038276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539604PMC
October 2020

Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies.

Nat Med 2020 12 5;26(12):1859-1864. Epub 2020 Oct 5.

Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan.

Comprehensive genomic profiling enables genomic biomarker detection in advanced solid tumors. Here, to evaluate the utility of circulating tumor DNA (ctDNA) genotyping, we compare trial enrollment using ctDNA sequencing in 1,687 patients with advanced gastrointestinal (GI) cancer in SCRUM-Japan GOZILA (no. UMIN000016343), an observational ctDNA-based screening study, to enrollment using tumor tissue sequencing in the same centers and network (GI-SCREEN, 5,621 patients). ctDNA genotyping significantly shortened the screening duration (11 versus 33 days, P < 0.0001) and improved the trial enrollment rate (9.5 versus 4.1%, P < 0.0001) without compromising treatment efficacy compared to tissue genotyping. We also describe the clonal architecture of ctDNA profiles in ~2,000 patients with advanced GI cancer, which reinforces the relevance of many targetable oncogenic drivers and highlights multiple new drivers as candidates for clinical development. ctDNA genotyping has the potential to accelerate innovation in precision medicine and its delivery to individual patients.
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http://dx.doi.org/10.1038/s41591-020-1063-5DOI Listing
December 2020

Multicenter Phase II Trial of Axitinib Monotherapy for Gemcitabine-Based Chemotherapy Refractory Advanced Biliary Tract Cancer (AX-BC Study).

Oncologist 2021 02 17;26(2):97-e201. Epub 2020 Oct 17.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Lessons Learned: Axitinib exhibited marginal activity against gemcitabine-refractory unselected biliary tract cancer. Pretreated soluble vascular endothelial growth factor receptor-2 may be a useful biomarker for axitinib treatment outcome. Ascites should be carefully monitored in patients receiving anti-vascular endothelial growth factor receptor therapy including axitinib in advanced biliary tract cancer.

Background: There are no clear options for second-line treatment in patients with gemcitabine (GEM)-refractory biliary tract cancer (BTC). We conducted a multicenter, single-arm, phase II trial to confirm the efficacy and safety of axitinib, a potent selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3, in patients with GEM-refractory BTC.

Methods: Patients refractory or intolerant to GEM-based chemotherapy were enrolled. Axitinib was administered orally at an initial dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS), and the threshold and expected values were set at 2 and 3 months, respectively. The target sample size was 32 patients.

Results: Nineteen patients were enrolled. The trial was interrupted for a total of 13 months for the evaluation of adverse events. Thirteen patients were previously treated with ≥2 regimens. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1-4.1). The median overall survival was 5.8 months (95% CI: 3.3-9.7). The response rate was 5.3% (95% CI: 0.0-15.3). Grade 3 ascites occurred in two patients. Baseline soluble VEGFR-2 levels were significantly associated with PFS.

Conclusion: Axitinib exhibited marginal activity against GEM-refractory BTC. Ascites should be carefully monitored in axitinib-treated patients with advanced BTC.
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http://dx.doi.org/10.1002/onco.13547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873316PMC
February 2021

Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: a retrospective multicenter cohort study.

BMC Cancer 2020 Oct 1;20(1):946. Epub 2020 Oct 1.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Background: Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer. Although UC has been considered a highly aggressive malignancy, no clinical studies have addressed the efficacy of chemotherapy for unresectable UC. Therefore, we conducted multicenter retrospective study to investigate the efficacy of chemotherapy in patients with UC of the pancreas.

Methods: This multicenter retrospective cohort study was conducted at 17 institutions in Japan between January 2007 and December 2017. A total of 50 patients treated with chemotherapy were analyzed.

Results: The median overall survival (OS) in UC patients treated with chemotherapy was 4.08 months. The details of first-line chemotherapy were as follows: gemcitabine (n = 24), S-1 (n = 12), gemcitabine plus nab-paclitaxel (n = 6), and other treatment (n = 8). The median progression-free survival (PFS) was 1.61 months in the gemcitabine group, 2.96 months in the S-1 group, and 4.60 months in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel significantly improved PFS compared with gemcitabine (p = 0.014). The objective response rate (ORR) was 4.2% in the gemcitabine group, 0.0% in the S-1 group, and 33.3% in the gemcitabine plus nab-paclitaxel group. Gemcitabine plus nab-paclitaxel also showed a significantly higher ORR compared with both gemcitabine and S-1 (gemcitabine plus nab-paclitaxel vs. gemcitabine: p = 0.033; gemcitabine plus nab-paclitaxel vs. S-1: p = 0.034). A paclitaxel-containing first-line regimen significantly improved OS compared with a non-paclitaxel-containing regimen (6.94 months vs. 3.75 months, respectively; p = 0.041). After adjustment, use of a paclitaxel-containing regimen in any line was still an independent predictor of OS (hazard ratio for OS, 0.221; 95% confidence interval, 0.076-0.647; p = 0.006) in multiple imputation by chained equation.

Conclusions: The results of the present study indicate that a paclitaxel-containing regimen would offer relatively longer survival, and it is considered a reasonable option for treating patients with unresectable UC.
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http://dx.doi.org/10.1186/s12885-020-07462-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529509PMC
October 2020

Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer.

Hum Pathol 2020 11 3;105:9-19. Epub 2020 Sep 3.

Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, 104-0045, Japan.

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has improved clinical outcomes in patients with HER2-positive breast and gastric cancers, although ineffective or recurrent cases are present. One reason for this is the heterogeneity of HER2 expression in cancer cells. The aim of this study was to investigate the clinicopathological characteristics and HER2 status of patients with biliary tract cancers (BTCs). We examined HER2 protein expression by immunohistochemistry, HER2 gene amplification by fluorescence in situ hybridization, and both HER2 protein and gene levels simultaneously by gene-protein assay. Samples were collected from 454 patients who underwent surgical resection for BTCs (110 intrahepatic cholangiocarcinomas [ICC], 67 perihilar extrahepatic cholangiocarcinomas [ECC-Bp], 119 distal extrahepatic cholangiocarcinomas [ECC-Bd], 80 gallbladder carcinomas [GBC], and 79 ampullary carcinomas [AVC]). HER2 status was assessed according to the guidelines for HER2 testing in gastroesophageal adenocarcinoma. HER2-positive status was detected in 14.5% of BTCs (3.7% of ICC, 3.0% of ECC-Bp, 18.5% of ECC-Bd, 31.3% of GBC, and 16.4% of AVC). Furthermore, HER2-positivity tended to correlate with low histological grade, tumor histology, and macroscopic features in certain tumors. HER2 heterogeneity was common and highly frequent (83%) in BTC cases. Reduced HER2 protein expression in the deeper invasive areas with simultaneous dedifferentiation was frequently observed in HER2-positive cancer cells. The findings of this study suggest that a large subgroup of HER2-positive BTC cases can be considered for HER2-targeted therapy. Moreover, the HER2 status in BTCs should be determined carefully using a sensitive approach toward larger cancer tissues.
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http://dx.doi.org/10.1016/j.humpath.2020.08.006DOI Listing
November 2020

Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups.

Pancreatology 2020 Oct 8;20(7):1421-1427. Epub 2020 Aug 8.

Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.

Background/objectives: Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3.

Methods: We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3.

Results: The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26-67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92-4.86, P = 0.077).

Conclusions: Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.
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http://dx.doi.org/10.1016/j.pan.2020.07.400DOI Listing
October 2020

-Glycan-Altered Extracellular Vesicles: A Specific Serum Marker Elevated in Pancreatic Cancer.

Cancers (Basel) 2020 Aug 31;12(9). Epub 2020 Aug 31.

Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by -glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with -glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening.
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http://dx.doi.org/10.3390/cancers12092469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563872PMC
August 2020

Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer.

Ann Surg 2020 Aug 18. Epub 2020 Aug 18.

Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Objective: The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC.

Summary Of Background Data: Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified.

Methods: We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis.

Results: Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis.

Conclusions: Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.
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http://dx.doi.org/10.1097/SLA.0000000000004213DOI Listing
August 2020

Optimal strategy of systemic treatment for unresectable pancreatic neuroendocrine tumors based upon opinion of Japanese experts.

Pancreatology 2020 Jul 9;20(5):944-950. Epub 2020 Jun 9.

Department of Surgery, Otsu Red Cross Hospital, Otsu, Japan.

Background/objectives: A number of therapeutic agents have been reported to be clinically useful for the management of the patients with unresectable pancreatic neuroendocrine tumors (PanNETs) including somatostatin analogues, molecular-targeted agents and cytotoxic agents. However, the optimal strategy for selection among those treatment modalities above in these patients has remained unexplored.

Methods: Japanese experts for PanNET discussed and determined the optimal treatment strategies according to the results of previously reported studies.

Results: The tumor volume of liver metastases and the Ki-67 labeling index were unanimously accepted as indicators of the tumor burden and tumor aggressiveness, respectively, which are two most clinically pivotal factors for determining the strategy of systemic treatment for unresectable PanNETs. In addition, for those with a relatively small tumor burden and slow disease progression, somatostatin analogues were selected as the first-line treatment agents. For those with a relatively large tumor burden and rapid tumor progression, cytotoxic agents were selected, possibly aiming at tumor shrinkage. For those of intermediate tumor volume and/or growth rate, molecular-targeted agents were selected as the first choice. Based on this strategy discussed among the experts, we tentatively prepared a MAP for proposing optimal treatment strategy and examined its validity in some patients with unresectable PanNETs. Results validated the usefulness of this MAP proposed for patients harbouring unresectable PanNETs.

Conclusion: We herein propose a tentative MAP for optimal treatment selection for the patients harbouring unresectable PanNETs. Further large scale studies are, however, warranted to validate the usefulness of this MAP proposed in this study.
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http://dx.doi.org/10.1016/j.pan.2020.06.002DOI Listing
July 2020

Phase II clinical trial of gemcitabine plus oxaliplatin in patients with metastatic pancreatic adenocarcinoma with a family history of pancreatic/breast/ovarian/prostate cancer or personal history of breast/ovarian/prostate cancer (FABRIC study).

Int J Clin Oncol 2020 Oct 13;25(10):1835-1843. Epub 2020 Jun 13.

Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.

Background: A family/personal history of breast, ovarian, or pancreatic cancer is a useful predictive marker for response to platinum-based chemotherapy in treating patients with pancreatic cancer. These cancers, and prostate cancer, are known as BRCA-related malignancies. We evaluated the efficacy of gemcitabine plus oxaliplatin (GEMOX) in patients with metastatic pancreatic cancer with a family/personal history of these cancers.

Methods: Chemotherapy-naïve patients with metastatic pancreatic cancer with a family history of pancreatic/breast/ovarian/prostate cancer or a personal history of breast/ovarian/prostate cancer were included. Patients received fixed dose-rate gemcitabine (1000 mg/m) and oxaliplatin (100 mg/m) every 2 weeks. The primary endpoint was 1-year survival, and the threshold and expected values were set at 30 and 50%, respectively. The target sample size was determined to be 43, with a one-sided alpha value of 5% and power of 80%. A total of 45 patients were enrolled.

Results: Among the first 43 enrolled patients, the 1-year survival rate was 27.9% [90% confidence interval (CI) 17.0-41.3], which did not meet the primary endpoint. Median overall survival, progression-free survival, and response rates were 7.6 months (95% CI 6.0-10.7), 4.0 months (95% CI 2.0-4.6), and 26.7% (95% CI 14.6-41.9), respectively, in all registered patients. The GEMOX regimen was generally tolerated; the most common grade three or higher adverse events were hematological toxicities.

Conclusion: GEMOX did not show the expected efficacy in patients with metastatic pancreatic cancer with a family or personal history of pancreatic/breast/ovarian/prostate cancer. Selection of GEMOX based on family/personal history is not recommended.

Trial Registration Number: UMIN000017894.
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http://dx.doi.org/10.1007/s10147-020-01721-xDOI Listing
October 2020

Broadening the therapeutic horizon of advanced biliary tract cancer through molecular characterisation.

Cancer Treat Rev 2020 Jun 12;86:101998. Epub 2020 Mar 12.

The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United Kingdom. Electronic address:

Biliary tract cancers (BTC) comprise a group of rare and heterogeneous poor-prognosis tumours with the incidence of intrahepatic cholangiocarcinoma increasing over recent years. Combination chemotherapy with gemcitabine and cisplatin is the established first-line treatment for advanced BTC with a significant but modest survival advantage over monotherapy. There remains no accepted standard treatment in the second-line setting, although recent results from a randomised study have shown a survival benefit with 5-fluorouracil and oxaliplatin chemotherapy. Historically, clinical trials investigating targeted therapies in unselected BTC have failed to demonstrate significant clinical benefit. More recently, advancement in molecular exploration of BTC has shed light on the complex biological heterogeneity within these tumours and has also identified actionable genomic aberrations, such as fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) and BRAF mutations, which offer promise with the anticipation of increased responses and durable clinical benefit in selected patients. Several targeted drugs have now entered clinical development with some encouraging results being seen. Here we review the current and rapidly evolving therapeutic landscape of advanced BTC, including targeted therapies and immunotherapy. We also discuss how recent efforts and successes in BTC are overcoming the obstacles typically associated with precision medicine in rare cancers. Ultimately, the management of advanced BTC is likely to become molecularly selected in the near future with the hope of finally improving the bleak prognosis of patients with this disease.
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http://dx.doi.org/10.1016/j.ctrv.2020.101998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222858PMC
June 2020

Novel endoscopic technique for trisegment drainage in patients with unresectable hilar malignant biliary strictures (with video).

Gastrointest Endosc 2020 Sep 10;92(3):763-769. Epub 2020 Mar 10.

Department of Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.

Background And Aims: Three or more stents may be needed in patients with extensive stricturing in Bismuth type IIIa/IV hilar malignant strictures. Partial stent-in-stent (PSIS) deployment has been the primary intervention for hilar malignant biliary stricture (MBS). However, simultaneous side-by-side (SBS) stent placement has become feasible with the development of the <6F diameter stent delivery system. Our aim was to assess the efficacy and safety of a new hybrid method combining PSIS and SBS stent placement for trisegment biliary drainage.

Methods: This study included 17 consecutive patients with Bismuth IIIa or IV malignant strictures who underwent endoscopic drainage using the hybrid method. Diameters of the delivery stents were 5.4F (n = 10) and 5.7F (n = 7).

Results: The technical success rate was 82% (14/17), and the median length of procedures was 54 minutes. Two patients required predilatation for deployment of the third self-expandable metallic stent through the mesh of the first deployed stent. Two patients (12%) developed cholecystitis as early adverse events, and 1 patient (6%) developed liver abscess as a late adverse event. The time to recurrent biliary obstruction among those with successful initial trisegmental drainage was 189 days (95% confidence interval, 124-254).

Conclusions: The hybrid method for unresectable hilar MBS is an effective endoscopic drainage method, and the ease of these procedures is partly attributed to the thinner stent delivery system.
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http://dx.doi.org/10.1016/j.gie.2020.03.003DOI Listing
September 2020

A review of changes to and clinical implications of the eighth TNM classification of hepatobiliary and pancreatic cancers.

Jpn J Clin Oncol 2019 Dec;49(12):1073-1082

Department of Medical Oncology, Kyorin University Faculty of Medicine, Japan.

Hepatobiliary and pancreatic cancers have poor outcomes. Clinical staging is useful for predicting survival and selecting treatment options. The 8th edition of tumor-node metastasis (TNM) was published in 2016 and came into effect from 2018. Regarding liver cancer (hepatocellular carcinoma), tumour size and vascular invasion were more emphasized adding numbers. Tumour size was included for intrahepatic cholangiocarcinoma. T2 for gallbladder cancer was divided into two categories based on the side of invasion, and lymph node metastasis was classified according to the number of lymph nodes, not the site. The N category for perihilar cholangiocarcinoma was changed to the same as that for gallbladder cancer (total number of regional lymph nodes). The depth of tumour invasion using cut-off values of 5 and 12 mm was adopted as the T category for distal cholangiocarcinoma. The N category was also changed (the total number of regional lymph nodes). Regarding cancer of the ampulla of Vater, the T category was classified in more detail and the N category was also changed to the total number of regional lymph nodes. T1 for pancreatic cancer was separated into T1 subcategories (T1a, T1b and T1c) based on cut-off values of 5 and 10 mm. T1-T3 were classified with cut-off values of ≤2 cm, >2 to 4 cm and >4 cm. Furthermore, the N category was changed to the total number of regional lymph nodes. Although there are limitations due to treatment decisions only being based on imaging interpretation, this classification predicts the prognosis of patients more accurately than the previous edition.
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http://dx.doi.org/10.1093/jjco/hyz150DOI Listing
December 2019

Germline mutations in cancer-predisposition genes in patients with biliary tract cancer.

Oncotarget 2019 Oct 15;10(57):5949-5957. Epub 2019 Oct 15.

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.

The prevalence of germline mutations in patients with biliary tract carcinoma (BTC) remains unclear. Here, we investigated the prevalence and types of germline mutations in patients with BTC. We reviewed 269 patients with pathologically proven BTC and collected clinical characteristics, including medical and family histories. Additionally, we evaluated germline variants in 21 genes associated with hereditary predisposition for cancer by targeted sequencing in patients meeting ≥1 of the following criteria: 1) hereditary breast and/or ovarian cancer (HBOC) testing criteria modified for BTC, 2) Revised Bethesda Guidelines (RBGs) modified for BTC (modified RBG), 3) familial BTC criteria, or 4) young BTC criteria. Among the 269 patients, 80 met at least one criterion. Three pathogenic mutations in three patients were identified: two in and one in . Among the 16 patients meeting modified HBOC testing criteria, 2 harbored germline mutations, and 1 harbored a germline mutation. However, no mutation in mismatch-repair genes were detected, despite 63 patients meeting modified RBG screening criteria and 18 qualifying as young BTC patients. We detected high prevalence of pathogenic germline mutations in and none in mismatch-repair genes in BTC patients following enrichment according to family or medical history in this study.
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http://dx.doi.org/10.18632/oncotarget.27224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800267PMC
October 2019

Genomic Profiles and Current Therapeutic Agents in Neuroendocrine Neoplasms.

Curr Drug Targets 2020 ;21(4):389-405

Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan.

Neuroendocrine neoplasms (NENs) are rare tumors that mainly occur in the gastroenteropancreatic (GEP) tract and lungs. According to the current World Health Organization classification for GEP-NENs and lung NENs, treatment strategies differ for well-differentiated and poorly differentiated subtypes. For well-differentiated GEP-NENs, somatostatin analogues (SSA), peptide receptor radionuclide therapy, and molecular-targeted agents are approved as the standards of care based on phase III clinical trial data. Promising data regarding the use of everolimus and the novel SSA pasireotide for lung NENs are emerging, though additional studies are required to confirm these effects. For poorly differentiated tumors from the GEP tract and lung, a platinum-based cytotoxic regimen is widely used. Genomic analysis has recently revealed a diverse pattern of primary organ-dependent mutations, and the use of traditional treatment strategies versus organ-specific strategies is currently under discussion. In addition, clinical trials for several molecular-targeted agents and immune checkpoint inhibitors for the treatment of NENs are currently underway. Accumulating genomic information is expected to contribute to the development of novel therapies for other organ-derived NENs or poorly differentiated neuroendocrine carcinomas (NECs). Here, we provide an updated overview of the current knowledge regarding genomic profiles and representative agents for NENs and highlight the prospects for future investigations.
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http://dx.doi.org/10.2174/1389450119666191014105211DOI Listing
February 2021

Correction: Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma.

Oncotarget 2019 Sep 10;10(52):5494. Epub 2019 Sep 10.

Laboratory of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.

[This corrects the article DOI: 10.18632/oncotarget.24930.].
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http://dx.doi.org/10.18632/oncotarget.27199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739219PMC
September 2019
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