A multicenter, prospective, phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to an anti-EGFR antibody: HGCSG1801.

Aflibercept (AFL) plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a prospective open-label phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese patients with mCRC failing a prior oxaliplatin-based chemotherapy plus an anti-EGFR agent. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months. Forty three patients were enrolled between November 2019 and October 2022. The primary endpoint was met: 6-month PFS rate was 58.8% (90% confidence interval [CI], 45.7%-72.0%). Median PFS and OS were 7.3 months (95% CI, 5.5-11.0 months) and 18.8 months (95% CI, 12.9-26.6 months), respectively. The overall response rate was 20.9% (95% CI, 10.0-36.0%) and disease control rate was 88.4% (95% CI, 74.9-96.1%). The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%), and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. This study suggests that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese patients with mCRC who failed prior oxaliplatin-based chemotherapy plus an anti-EGFR agent.

Phase II Study of Continued Trastuzumab Plus Irinotecan in Patients with HER2-positive Gastric Cancer Previously Treated with Trastuzumab (HGCSG 1201).

BACKGROUND: The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported. METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status. RESULTS: Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%). CONCLUSION: With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier: UMIN000007636.

Multicenter, prospective, observational study of chemotherapy-induced dysgeusia in gastrointestinal cancer.

PURPOSE: Dysgeusia is an adverse event caused by chemotherapy. Although retrospective studies have shown zinc administration improves dysgeusia, there have been no prospective studies. The present study examined effects of zinc therapy on dysgeusia in patients with gastrointestinal cancer. METHODS: This multicenter, prospective, observational study enrolled patients with dysgeusia during chemotherapy treatment. Patients received no intervention (control), polaprezinc p.o., or zinc acetate hydrate p.o., and serum zinc levels were measured at 0 (baseline), 6, and 12 weeks. Dysgeusia was assessed using CTCAE v5.0 and subjective total taste acuity (STTA) criteria using questionnaires at baseline and 12 weeks. RESULTS: From February 2020 to June 2021, 180 patients were enrolled from 17 institutes. There were no differences in mean baseline serum zinc levels among the groups (67.3, 66.6, and 67.5 µg/dL in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. P = 0.846). The changes in mean serum zinc levels after 12 weeks were - 3.8, + 14.3, and + 46.6 µg/dL, and the efficacy rates of dysgeusia were 33.3%, 36.8%, and 34.6% using CTCAE and 33.3%, 52.6%, 32.7% using STTA in the no intervention, polaprezinc, and zinc acetate hydrate groups, respectively. The STTA scores improved in all groups, with significant improvement observed in the polaprezinc group compared with the no intervention group (P = 0.045). CONCLUSION: There was no significant correlation between the degree of serum zinc elevation and improvement in dysgeusia, suggesting that polaprezinc, but not zinc acetate hydrate, was effective in improving chemotherapy-induced dysgeusia. TRIAL REGISTRATION: UMIN000039653. Date of registration: March 2, 2020.

Very urgent endoscopic retrograde cholangiopancreatography is associated with early discharge in patients with non-severe acute cholangitis.

BACKGROUND: endoscopic retrograde cholangiopancreatography (ERCP) is a first-line procedure for biliary drainage in patients with acute cholangitis, and there are no studies focused on very urgent ERCP within several hours of hospital arrival. This study aimed to elucidate the use of very urgent ERCP for non-severe acute cholangitis. METHODS: this retrospective observational study included patients with non-severe acute cholangitis who underwent ERCP between April 2011 and June 2020 in our institution. Patients were stratified into three groups based on time to ERCP after hospital arrival: very urgent (≤ 3 hours), urgent (3-24 hours) and elective (> 24 hours). The primary outcome was length of hospital stay (LOS). RESULTS: the study cohort included 291 patients, 168 males (57.7 %), with a median age of 76 (interquartile range, 70-83) years. In all, 47, 196 and 48 patients underwent very urgent, urgent and elective ERCP, respectively. Median LOS in the very urgent, urgent, and elective groups was 12, 14, and 15 days, respectively (Kaplan-Meier method). A shorter LOS was associated with earlier ERCP (log-rank trend test, p = 0.04). The rates of readmission within 30 days of discharge and of adverse events were not significantly different among the three groups. By multivariate analysis, very urgent ERCP was associated with a significantly earlier discharge than urgent and elective ERCP (HR, 0.71, p = 0.04 and HR, 0.47, p < 0.01, respectively). In addition, age ≥ 75 years, pancreatitis, albumin ≤ 2.8 g/dL and two or more ERCP procedures were associated with a significantly longer LOS (HRs < 1, p < 0.05). CONCLUSIONS: very urgent ERCP for non-severe acute cholangitis was associated with early discharge.

Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan.

BACKGROUND: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. METHODS: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. RESULTS: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. CONCLUSIONS: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.

Multicenter Cohort Study to Assess the Association between Changes on Imaging and Outcome after Regorafenib Treatment (KSCC1603).

BACKGROUND: Molecular targeted drugs having angiogenesis-inhibiting properties allow the induction of necrosis inside tumors. We retrospectively investigated the relationship between changes on imaging associated with regorafenib (REGO) and treatment outcomes using real-world data. PATIENTS AND METHODS: The eligibility criteria included an ECOG PS of 0-1, a starting dose of 120 or 160 mg/day of REGO, and a duration of treatment of at least 35 days. Regarding changes on imaging, cavitation in lung lesions (CLL), morphologic response of liver lesions (MRL), and change of liver metastasis density (CLD) were evaluated. RESULTS: We finally screened 671 cases, and 226 cases were eligible. In total, 172 and 145 patients had lung and liver metastases, respectively. Among the patients with lung metastasis, CLL was found in 69 patients (40.0%). The median progression-free survival (PFS) of the patients with and those without CLL was 3.2 and 2.4 months, respectively (hazard ratio [HR] = 0.758; 95% confidence interval [CI]: 0.529-1.087), and the median overall survival (OS) of these groups was 10.5 and 8.9 months, respectively (HR = 0.862; 95% CI: 0.579-1.285). MRL and CLD of liver metastasis were analyzed in 145 and 90 patients, respectively. The median OS with and without MRL was 8.9 and 8.2 months, respectively, whereas the median OS with and without CLD was 11.6 and 7.7 months, respectively (HR = 0.523; 95% CI: 0.275-0.992). CONCLUSION: CLL may predict PFS but not OS among patients with lung metastasis. CLD was predictive of favorable outcomes for REGO in patients with liver metastasis.

Impact of single-heterozygous UGT1A1 on the clinical outcomes of irinotecan monotherapy after fluoropyrimidine and platinum-based combination therapy for gastric cancer: a multicenter retrospective study.

BACKGROUND: It is unclear whether the UGT1A1 status, single heterozygous (SH) or wild type (WT), is associated with the efficacy and toxicity of irinotecan monotherapy in advanced gastric cancer (AGC). We investigated the association between clinical outcomes (efficacy and safety) and UGT1A1 status in patients who received irinotecan monotherapy. METHODS: We evaluated AGC patients who received irinotecan monotherapy between January 2011 and December 2017. Efficacy was assessed according to overall survival (OS) and progression-free survival (PFS). Toxicity was graded using the Common Toxicity Criteria for Adverse Events (version 4.0). RESULTS: A total of 100 patients were evaluated (62 and 38 patients with UGT1A1 WT and SH, respectively). In the WT and SH groups, the irinotecan dose was reduced in 19 (30.6%) and 18 (47.2%) patients (p = 0.135), respectively; treatment was delayed due to adverse events (AEs) in 19 (30.6%) and 13 (34.2%) patients (p = 0.826), respectively; the median PFS was 3.15 and 3.25 months (HR, 0.734; 95% CI 0.465-1.158; p = 0.184), respectively; and the median OS was 10.4 and 7.26 months (HR, 1.137; 95% CI 0.752-1.721; p = 0.543), respectively. Severe hematological AEs (Grade ≥ 3) were significantly more frequent in the SH group than in the WT group (63% vs. 36%; p = 0.008), while severe non-hematological AEs was not significantly different (16.0% vs. 6.5%; p = 0.173). CONCLUSION: There was no significant difference in the efficacy of irinotecan monotherapy between UGT1A1 WT and UGT1A1 SH, but UGT1A1 SH was associated with a high frequency of severe hematological toxicity.

[A Case of Unknown Primary Carcinoma with Dermatomyositis].

A 50-year-old woman was diagnosed with dermatomyositis at the department of neurology in our hospital; she then received steroid pulse therapy. A positron emission computed tomography(PET-CT)revealed swollen lymph nodes near the aorta and in the left inguinal region. She presented at our institution for examination to determine the cause of her lymphadenopathy, but the primary site of the carcinoma was unknown. A histopathological examination of the lymph node specimen obtained using endoscopic ultrasonography-guided fine-needle aspiration(EUS-FNA)revealed a moderately to poorly differentiated adenocarcinoma. The patient underwent lymphadenectomy. After the surgery, a new lymph node metastasis appeared in the lower abdomen. We initiated a combination treatment with chemotherapy and radiotherapy. The patient died because of disease progression 31 months after her first visit.

[A case of mixed adenoneuroendocrine carcinoma of the distal bile duct].

We diagnosed distal cholangiocarcinoma in a 76-year-old woman who was then treated by subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed a well-differentiated tubular adenocarcinoma on the side of the bile duct, and a neuroendocrine carcinoma in an area outside the bile duct where the tumor had infiltrated. Immunohistochemical staining identified homology between cytokeratins and MUC, indicating a similar origin. This report discusses problems associated with diagnosis and treatment by summarizing 22 patients who underwent curative resection and subsequently had a confirmed prognosis.

Study protocol of HGCSG1404 SNOW study: a phase I/II trial of combined chemotherapy of S-1, nab-paclitaxel and oxaliplatin administered biweekly to patients with advanced gastric cancer.

BACKGROUND: In Japan, S-1 plus cisplatin (SP) regimen has become a standard therapy for patients with advanced gastric cancer. Moreover, the S-1 plus oxaliplatin regimen is now a standard treatment. Nab-paclitaxel was developed for chemotherapy of gastric cancer in Japanese clinical practice. Nab-paclitaxel, created with albumin-bound paclitaxel particles, has high transferability to tumour tissues and does not cause hypersensitivity reactions because of a different chemical composition compared with docetaxel and paclitaxel. A combination of S-1, nab-paclitaxel and oxaliplatin (which we named 'SNOW regimen') can be a promising triplet therapy for advanced gastric cancer. Although we have to pay attention to chemotherapy-induced neuropathy, we aim to investigate the recommended dose of this regimen in a phase I study. Furthermore, we will investigate its efficacy and toxicity in a phase II study. METHODS: The phase I study is a dose-escalation study using a standard 3 plus 3 design, followed by expansion cohorts. The SNOW regimen involves 28-day cycles with escalated doses of nab-paclitaxel (100-175 mg/m2 on days 1 and 15) and fixed doses of oxaliplatin (65 mg/ m2 on days 1 and 15) and S-1 (80 mg/m2/day on day 1 to 14). The primary endpoints are assessment of dose limiting toxicities and determination of maximum tolerated dose to investigate the recommended dose in the subsequent phase II study. In the phase II study, the primary endpoint is objective response rate. Secondary endpoints are assessment of safety, progression-free survival, disease control rate, overall survival and time to treatment failure. Adverse events were monitored and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. DISCUSSION: Triplet therapies for advanced gastric cancer patients have been evaluated in clinical trials. The SNOW regimen can be a promising new triplet therapy. TRIAL REGISTRATION: This study is performed at institutes that participate in Hokkaido Gastrointestinal Cancer Study Group (HGCSG) and registered as UMIN000016788 . Registrated 16 March 2015.

Autopsy of invasive ductal pancreatic carcinoma that transformed into a tumor producing granulocyte colony-stimulating factor.

A 64-year-old woman was diagnosed with unresectable pancreatic cancer and underwent chemotherapy. However, the number of leukocytes significantly increased as the disease progressed. Serum G-CSF values also increased, and she eventually died on day 511 after diagnosis. Immediately after autopsy, immunohistochemical staining with an anti-G-CSF monoclonal antibody was positive in the poorly differentiated adenocarcinoma area of the primary pancreatic cancer and liver metastatic foci, but negative in the well-differentiated tubular adenocarcinoma part of the primary pancreatic cancer. During de-differentiation, invasive pancreatic ductal carcinoma appeared to have changed to a tumor that produced G-CSF.

Multi-organ disseminated mucosa-associated lymphoid tissue lymphoma.

A 61-year-old man was admitted to our hospital with extreme weight loss. Abdominal ultrasonography revealed an 8-cm tumor of the pancreatic head. Further investigation revealed orbital, pulmonary, pancreatic, colonic, and bone marrow lesions. A histopathological examination of the pancreatic tumor specimen obtained using endoscopic ultrasound-guided fine-needle aspiration revealed mucosa-associated lymphoid tissue (MALT) lymphoma. Monoclonal rearrangement of immunoglobulin heavy chain was found in the pulmonary, pancreatic, colonic, and bone marrow lesions. We diagnosed multi-organ disseminated MALT lymphoma, with the largest lesion located in the pancreatic head. Chemo-radiation therapy resulted in complete remission.

Non-islet cell tumor hypoglycemia caused by a big insulin-like growth factor II- producing hepatocellular carcinoma:an autopsy case report.

A 73-year-old man with a hepatocellular carcinoma was admitted to our hospital. He suffered from recurrent severe hypoglycemia. An autopsy was performed after his death. Anti-insulin-like growth factor II (IGF-II) monoclonal antibody immunostaining of the hepatocellular carcinoma was positive. Western immunoblot analysis of the serum revealed highly elevated IGF-II. Therefore, we diagnosed this case as a non-islet cell tumor hypoglycemia caused by a big IGF-II-producing hepatocellular carcinoma.