Genomic characterization between HER2-positive and negative gastric cancer patients in a prospective trial.

BACKGROUND: We aimed to clarify the genomic characteristics of HER2-positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. METHODS: We collected 80 formalin-fixed paraffin-embedded (FFPE) samples (49 HER2+ and 31 HER2-) from gastric cancer patients who participated in the TROX-A1 trial (UMIN000036865). We queried a 435-gene panel (CANCERPLEX-JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2- gastric cancer patients were analyzed. RESULTS: Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2-negative patients. The number of total mutations in HER2-negative patients with ARID1A mutation was remarkably higher than that in HER2-positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2-positive cases was significantly higher than that in HER2-negative cases. Moreover, PTEN deletion was more common in HER2-positive cases. Finally, we found that, compared with HER2-positive patients, HER2-negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune-related pathways in HER2-negative patients. CONCLUSIONS: According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

Oncological Impact of the Level of Inferior Mesenteric Artery Ligation in Low Rectal Cancer Surgery.

BACKGROUND/AIM: This study aimed to evaluate the clinical impact of the level of inferior mesenteric artery (IMA) ligation in patients with advanced low rectal cancer. PATIENTS AND METHODS: All enrolled patients (n=350) underwent curative resection of rectal cancer with D3 lymph node dissection, with either IMA (high-tie) or superior rectal artery (SRA) (low-tie) ligation. RESULTS: There were 27 and 65 patients in the high-tie and low-tie groups, respectively. There was no significant difference in the postoperative complication rate. Postoperative anastomotic leakage developed in five patients in the low-tie group and none in the high-tie group. The overall recurrence rates were 37.0% (n=10) and 40.0% (n=26) in the high-tie and low-tie groups, respectively, with no significant difference between the two groups (p=0.748). Local recurrences and lymph node metastases developed in five and no patients in the high-tie group and in 13 and one patient in the low-tie group, respectively. In the multivariate analysis, pathological T4 and pathological N2 and N3 were independent poor prognostic factors for overall survival (OS), whereas left colic artery (LCA) preservation was not significant. CONCLUSION: No significant difference in oncological outcomes was observed in advanced low rectal cancer surgery with respect to the level of the IMA ligation. Thus, the less complicated high-tie procedure should be adopted as a standard procedure.

The skill qualification system for portal hypertension in Japan.

Objectives: The diverse treatments available for portal hypertension require specialized knowledge of hemodynamics and include endoscopic treatments, interventional radiology (IVR), and surgery. The Japan Society for Portal Hypertension has developed the skill qualification system (SQS) for portal hypertension and began examination in 2014. Here, the status and validity of the judgment of the SQS examination were evaluated. Methods: From 2014 to 2020, 79 applicants were evaluated by the SQS for portal hypertension. Each unedited video submitted as a candidate procedure was evaluated by two judges, and a grade of greater than 70% for the scoring items assessed by the judges was required to pass the examination. Inter-rater agreement of success/failure between the two judges was investigated by the AC1 coefficient. Results: The results of two judges differed for 11 of the 79 videos (13.9%), and five applicants (6.3%) ultimately failed the examination. The percentages of total points received by the applicants with endoscopic treatments, IVR, and surgery were 87.3%, 79.4%, and 80.8%, respectively. There were significant differences in the percentages between endoscopic treatments and IVR (P = 0.0015). The AC1 coefficients were 0.84 for the applicants overall, 0.93 for endoscopic treatments, 0.66 for IVR, and 0.72 for surgery. Similarly, there were significant differences in the AC1 coefficient between endoscopic treatments and IVR (P = 0.021). Conclusions: The SQS for portal hypertension of the Japan Society for Portal Hypertension showed high reliability for video assessments by the judges. This system may contribute to the spread and further development of safe and effective treatments for portal hypertension in Japan.

A phase II multicenter trial assessing the efficacy and safety of first-line S-1 + ramucirumab in elderly patients with advanced/recurrent gastric cancer: KSCC1701.

BACKGROUND: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC. PATIENTS AND METHODS: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40-60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1-based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety. RESULTS: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia. CONCLUSION: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

Palonosetron versus Granisetron in Combination with Aprepitant and Dexamethasone for the Prevention of Chemotherapy-Induced Nausea and Vomiting after Moderately Emetogenic Chemotherapy: A Single-Institutional Retrospective Cohort Study.

The triplet antiemetic regimen is administered to prevent chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC). However, the superiority of palonosetron over first-generation 5-hydroxytryptamine-3 receptor antagonists in triplet antiemetic therapy remains unclear. In this study, we evaluated the efficacy of palonosetron (PALO) and granisetron (GRA) in triplet antiemetic therapy for CINV. This study included 267 patients who received MEC at our hospital between April 2017 and September 2020. Patients were pretreated with antiemetic therapy comprising PALO or GRA and dexamethasone on day 1 and aprepitant on days 1-3. We evaluated the rate of complete response (CR) (i.e., no vomiting and no use of rescue medication) in the acute phase (0-24 h), delayed phase (24-120 h), and overall phase (0-120 h) after first-cycle chemotherapy. Furthermore, multivariate analysis was conducted to identify risk factors for non-CR. The rate of CR in the overall and delayed phases was significantly higher in the PALO group (91.9 and 91.9%, respectively) than in the GRA group (74.1 and 75.5%, respectively). In the acute phase, the incidence was not different between the GRA and PALO groups (96.5 and 99.2%, respectively). Multivariate analysis revealed that female sex and the use of GRA were risk factors for non-CR. Subgroup analysis revealed the superiority of PALO over GRA in female patients, but not in male patients. In conclusion, PALO was more effective than GRA in triplet antiemetic therapy in preventing CINV during MEC, especially for female patients.

Safety and efficacy of S-1 plus oxaliplatin 130 mg/m2 combination therapy in patients with previously untreated HER2-negative unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: a phase II trial (KSCC1501A).

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): A multicenter phase II trial.

BACKGROUND: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. METHODS: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%). CONCLUSIONS: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil. CLINICAL TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000025241).

Histidine-Rich Glycoprotein Alleviates Liver Ischemia/Reperfusion Injury in Mice With Nonalcoholic Steatohepatitis.

Hepatic ischemia/reperfusion injury (IRI) is a major complication of liver surgery and transplantation, especially in patients with nonalcoholic steatohepatitis (NASH). The mechanism of NASH susceptibility to IRI has not been fully clarified. We investigated the role of liver-produced histidine-rich glycoprotein (HRG) in NASH IRI. A NASH mouse model was established using C57BL/6J mice fed a methionine-choline-deficient diet (MCDD) for 6 weeks. The MCDD and standard diet groups were exposed to 60 minutes of partial hepatic ischemia/reperfusion (I/R). We further evaluated the impact of HRG in this context using HRG knockdown (KD) mice. IRI increased HRG expression in the standard diet group, but not in the MCDD group after I/R. HRG expression was inversely correlated with neutrophil infiltration and the formation of neutrophil extracellular traps (NETs). HRG KD mice showed severe liver injury with neutrophil infiltration and the formation of NETs. Pretreatment with supplementary HRG protected against I/R with the inhibition of neutrophil infiltration and the formation of NETs. In vitro, hepatocytes showed that the expression of HRG was upregulated under hypoxia/reoxygenation conditions, but not in response to oleic acid-treated hepatocytes. The decrease in HRG expression in fatty hepatocytes was accompanied by decreased farnesoid X receptor and hypoxia inducible factor 2 alpha subunit expression. HRG is a hepatoprotective factor during hepatic IRI because it decreases neutrophil infiltration and the formation of NETs. The decrease in HRG is a cause of susceptibility to IRI in steatotic livers. Therefore, HRG is a new therapeutic target for minimizing liver damage in patients with NASH.

Successful hybrid surgery for ileal conduit stomal varices following oxaliplatin-based chemotherapy in a patient with advanced colorectal cancer.

BACKGROUND: Ectopic variceal bleeding is a rare but life-threatening complication of portal hypertension (PH). Oxaliplatin-based chemotherapy for colorectal cancer (CRC) is associated with sinusoidal obstruction syndrome of the liver, which can lead to PH. CASE PRESENTATION: Here, we report a successful hybrid surgery that included intraoperative obliteration of ileal conduit stomal varices (ICSVs) for a 66-year-old woman with CRC and liver metastasis that had been treated multimodally during the previous 4 years, including 17 courses of oxaliplatin-based chemotherapy. She was admitted to our hospital for massive hemorrhage from an ileal conduct stoma. Image findings showed ICSVs as a part of portosystemic shunt, which were afferently supplied from the superior mesenteric vein (SMV) and drained by the numerous cutaneous veins connected to the left femoral vein. Obliteration of the stomal varices by interventional radiologic techniques alone was inappropriate because of difficulties of cannulating the efferent cutaneous veins. We, therefore, performed hybrid surgery for the ICSV, which included cannulation into the SMV branch and antegrade obliteration of the varices with a 5% solution of ethanolamine oleate with iopamidol under blocking the SMV flow, using a vascular clip and ligation. Hemorrhage in her ileal conduit stoma disappeared completely. CONCLUSION: Customized treatment of ectopic varices should be based on their precise vascular anatomy; hybrid surgery with intraoperative angiography is an alternative treatment for ectopic varices such as ICSV.

A phase I/II study of S-1 and irinotecan (IRIS) combined with cetuximab in patients with RAS wild-type metastatic colorectal cancer (KSCC1401).

PURPOSE: This study was designed to assess the tolerability, efficacy, and safety of tri-weekly irinotecan plus S-1 (IRIS) and weekly cetuximab in patients with metastatic colorectal cancer (mCRC). METHODS: The main eligibility criteria were RAS wild-type mCRC with no prior chemotherapy. S-1 was given orally at a dose of 40 mg/m2 (40-60 mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan was given on day 1 of each cycle at a dose of 150 mg/m2. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2), and 15 (250 mg/m2), and then once weekly (250 mg/m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was used to determine the maximum tolerated dose and the recommended dose (RD) of irinotecan. The primary end point of the Phase II study was overall response rate (ORR). RESULTS: Between December 2014 and September 2017, 4 and 54 patients were enrolled in phase I and phase II studies, respectively. No dose-limiting toxicity was observed in the phase I study, and the RD of irinotecan was 150 mg/m2. In the phase II study, the ORR was 56.9% (90% confidence interval 44.4%-68.7%). The safety profile revealed that the most common grade 3/4 adverse events were neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%), and diarrhea (11.8%). Grade 3/4 hand-foot skin syndrome occurred in nine patients (9.8%). CONCLUSION: This study showed that the efficacy and safety of IRIS combined with cetuximab were comparable to those for other first-line treatments. This regimen is a good candidate for first-line treatment of RAS wild-type mCRC.