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BackgroundSafety and effectiveness of aflibercept with 5‐fluorouracil/levofolinate/irinotecan have not been reported in Japanese patients with metastatic colorectal cancer (mCRC) in a real-world clinical setting.MethodsThis post-marketing surveillance enrolled patients with un-resectable advanced or recurrent mCRC who were prescribed aflibercept from December 2017 to June 2019 in Japan. Data, collected up to 1 year from starting treatment, included patient background, safety, and effectiveness assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or physician’s evaluation.ResultsOf 261 patients registered from 64 centers, 235 [53.2% male with a median age of 67 years (range 28–84)] received treatment and were included in the safety analysis. Aflibercept was received at 1st, 2nd, and ≥ 3rd line in 1.3%, 48.1%, and 50.2% of patients, respectively. Median number of treatment cycles was 6 (range 1–22) and relative dose intensity was 75.4% (range 14.3–101.8%). Adverse events (all grades) were reported in 88.5% of patients, including neutropenia (34.5%), proteinuria (24.7%), hypertension (17.0%), diarrhea (17.0%), and decreased appetite (15.3%). Three treatment-related deaths occurred by perforation of the digestive tract, pneumonia and gastrointestinal bleeding, and sudden death. The effectiveness analysis included 198 patients. Overall response rate was 6.1% (1st line, 0%; 2nd line, 10.1%; ≥ 3rd line, 2.1%) and disease control rate was 47.5% (1st line, 100%; 2nd line, 58.6%; ≥ 3rd line, 34.4%).ConclusionNo new risks of aflibercept were identified in real clinical practice. Effectiveness in patients at the 2nd line was consistent with previous reports.

Background Large type 3 and type 4 gastric cancers have extremely poor prognoses. To address this, neoadjuvant chemotherapy may be a promising approach. The phase III JCOG0501 study, conducted to confirm the superiority of neoadjuvant S-1 plus cisplatin followed by D2 gastrectomy over upfront surgery, showed no survival benefit for neoadjuvant S-1 plus cisplatin. In Korea, the PRODIGY study, which was a phase III study of neoadjuvant docetaxel plus oxaliplatin plus S-1 (DOS) followed by surgery and adjuvant S-1 versus surgery and adjuvant S-1 for gastric cancer of T2-3N+ or T4Nany, showed that progression-free survival (PFS) was significantly superior in the neoadjuvant DOS arm. Therefore, DOS therapy may be a promising candidate for preoperative chemotherapy for large type 3 or type 4 gastric cancer. Methods Preoperative docetaxel 40 mg/m 2 and oxaliplatin 100 mg/m 2 will be intravenously administered on day1 every three weeks. S-1 will be orally administered 80 mg/m 2 on days 1–14 of a 21-day cycle. Patients will receive three courses of treatment and gastrectomy with ≥D2 lymph node dissection. Postoperative S-1 plus docetaxel therapy (DS) will be administered according to the JACCRO GC-07 (START-2) study. The primary endpoint is the 3-year PFS rate. Secondary endpoints include PFS time, overall survival time, pathological response rate, response rate according to RECIST version1.1, proportion of completion of neoadjuvant chemotherapy, R0 resection rate, proportion of completion of surgery, proportion of completion of protocol treatment, proportion of negative conversion of CY, adverse event occurrence rate, and nutritional evaluation. The null hypothesis for the 3-year PFS rate is 45% and the expected value is 60%. The total sample size is 46 considering that the registration period and follow-up period are two and three years, respectively. Discussion This is a prospective, multicenter, single-arm, open-label, phase II trial assessing the efficacy and safety of preoperative DOS and postoperative DS for large type 3 or type 4 gastric cancer. The results will inform future phase III trials and are expected to lead to new treatment strategies for large type 3 or type 4 gastric cancer. Trial registration Registered with Japan Registry of Clinical Trials on October 11, 2019 ( jRCTs051190060 ).

Background and Aim: Fluoropyrimidines (FPs) are key drugs in many chemotherapy regimens; however, recipients are often prone to diarrhea due to gastrointestinal toxicity. Disruption of the intestinal epithelial barrier function by FPs leads to dysbiosis, which may exacerbate intestinal epithelial cell damage as a secondary effect and trigger diarrhea. However, despite studies on chemotherapy-induced changes in the intestinal microbiome of humans, the relationship between dysbiosis and diarrhea is unclear. In this study, we aimed to investigate the relationship between chemotherapy-induced diarrhea and the intestinal microbiome. Methods: We conducted a single-center prospective observational study. Twenty-three patients who received chemotherapy, including FPs as first-line chemotherapy for colorectal cancer, were included. Stool samples were collected before the start of chemotherapy and after one cycle of treatment to analyze intestinal microbiome composition and perform PICRUSt predictive metagenomic analysis. Results: Gastrointestinal toxicity was observed in 7 of 23 patients (30.4%), diarrhea was observed in 4 (17.4%), and nausea and anorexia were observed in 3 (13.0%). In 19 patients treated with oral FPs, the α diversity of the microbial community decreased significantly following chemotherapy only in the diarrheal group. At the phylum level, the diarrheal group showed a significant decrease in the abundance of Firmicutes and a significant increase in the abundance of Bacteroidetes with chemotherapy (p = 0.013 and 0.011, respectively). In the same groups, at the genus level, Bifidobacterium abundance was significantly decreased (p = 0.019). In contrast, in the non-diarrheal group, Actinobacteria abundance increased significantly with chemotherapy at the phylum level (p = 0.011). Further, Bifidobacterium, Fusicatenibacter, and Dorea abundance significantly increased at the genus level (p = 0.006, 0.019, and 0.011, respectively). The PICRUSt predictive metagenomic analysis revealed that chemotherapy caused significant differences in membrane transport in KEGG pathway level 2 and in 8 KEGG pathway level 3, including transporters and oxidative phosphorylation in the diarrhea group. Conclusion: Organic-acid-producing bacteria seem to be involved in diarrhea associated with chemotherapy, including FPs.

BackgroundAlthough 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. MethodsFOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) 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.ResultsAt 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.ConclusionsThis 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 registrationhttp://www.umin.ac.jp/ctr/index-j.htm, UMIN000017538. Date of registration: May/13/2015

BackgroundThe TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC).ObjectiveThis exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC.Patients and MethodsThe disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed.ResultsBaseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25–84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12–2.98]) and IL-8-high (1.70 [1.02–2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14–0.79]), IL-8-low (0.31 [0.14–0.70]), IL-6-low (0.19 [0.07–0.50]), osteopontin-low (0.39 [0.17–0.88]), thrombospondin-2-low (0.42 [0.18–0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10–0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS.ConclusionLow baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted.Clinical Trial Registration NumberjRCTs031180122.

Background Hepatectomy has a high risk of perioperative bleeding due to the underlying disease. Here, we investigated the postoperative impact of allogeneic blood transfusion during hepatectomy. Methods The surgical outcomes in 385 patients who underwent hepatic resection for hepatocellular carcinoma were retrospectively reviewed. The association of allogeneic blood transfusion with surgical outcomes and remnant liver regeneration data was analyzed. Results Eighty-six patients (24.0%) received an allogeneic blood transfusion and 272 patients (76.0%) did not. After propensity score matching, the incidence rates of postoperative complication (Clavien-Dindo grade >IIIA), posthepatectomy liver failure, and massive ascites were significantly higher for the group that received a blood transfusion than for the group that did not receive blood transfusion (P < .001, P = .001, and <.001, respectively). Postoperative measures of total bilirubin, albumin, platelet count, prothrombin time, aspartate aminotransferase, and alanine aminotransferase were significantly more favorable in patients without blood transfusion until day 7 after surgery. There were no correlations in the remnant liver regeneration at 7 days, and 1, 2, 5, and 12 months postoperatively between the 2 groups (P = .585, .383, .507, .261, and .430, respectively). Regarding prognosis, there was no significant difference in overall and recurrence-free survival between the 2 groups (P = .065 and .166, respectively). Conclusion Allogeneic transfusion during hepatectomy strongly affected remnant liver function in the early postoperative period; however, this was not related to the remnant liver regeneration volume. Despite that the allogeneic transfusion resulted in poorer postoperative laboratory test results and increased postoperative complication and mortality rates, it had no effect on the long-term prognosis.

Background A cytotoxic chemotherapeutic regimen is not routinely recommended for frail elderly patients with unresectable colorectal cancer (CRC) because of susceptibility to treatment. Panitumumab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Use of panitumumab as first-line therapy is expected to be well tolerated and to improve survival rates, even in patients who are not eligible for intensive chemotherapy. However, the efficacy and safety of panitumumab as the first-line therapy for the frail elderly patients with unresectable CRC have not been yet studied. Methods We plan to conduct a prospective multi-center phase II study. Patients with wild-type RAS unresectable CRC aged ≥76 years or ≥ 65 who are not considered eligible for intensive chemotherapy will be included in the study. A total of 36 patients will be enrolled from Osaka Gastrointestinal Cancer Chemotherapy Study Group for over 2 years. Panitumumab 6 mg/kg IV infusion will be administered every 2 weeks. The purpose of this trial is to assess the efficacy of panitumumab as first-line therapy for patients with unresectable CRC. The primary endpoint is to determine the disease control rate. Secondary endpoints include progression-free survival, overall survival, response rate, time to treatment failure, and the incidence of grade 3/4 toxicities. Discussion This is a prospective phase II trial assessing the efficacy of panitumumab monotherapy in the elderly patients with wild-type RAS unresectable CRC. Trial registration The ethics committee of the Osaka Medical College approved this study on November 7, 2016. The trial registration number of the government was UMIN000024528 on December 1, 2016. It was registered prospectively (the day of enrollment of the first participant was February 9, 2017).

Laparoscopic hepatectomy (LH) is very difficult to perform in patients with cirrhosis because of the haemorrhagic and fibrotic nature of the liver, although there are various advantages to laparoscopic surgery. To investigate the surgical outcomes, and efficacy and safety of LH versus open hepatectomy (OH) for hepatocellular carcinoma (HCC) resection. A total of 112 patients with cirrhosis, who underwent hepatectomy, were analysed retrospectively. We investigated the safety and efficacy of LH for HCC with cirrhosis. Student's and χ tests, Mann-Whitney's test, Wilcoxon's signed-rank test, and Fisher's exact test were used in the statistical analysis. Seventy-one patients underwent LH, and 41 underwent OH. The conversion rate from LH to OH was 12.7%. After propensity score matching, the estimated blood loss was significantly lower in the LH group than in the OH group (25 vs. 310 ml; < 0.001), and there was a significant difference between the groups in the operative time ( = 0.091). The LH group had complication rates of 3.6% and 0% for refractory ascites and pleural effusion, respectively, while those were 17.9% and 10.7%, respectively, in the OH group ( = 0.019 and = 0.005, respectively). The LH group had no mortality, whereas the OH group had a mortality rate of 10.7% ( = 0.038). The postoperative length of stay was significantly longer in the LH group than in the OH group (9 days vs. 14 days) ( = 0.002). LH can be performed safely for HCC with cirrhosis. More favourable results are achieved with LH than with OH in terms of surgical outcomes.

BackgroundThis open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC).MethodsPatients were randomised (1:1) to receive FTD/TPI (35 mg/m2 twice daily, days 1–5 and days 8–12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33.ResultsOverall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99–1.93; Pnoninferiority = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55–1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%).ConclusionsFTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC.Clinical trial registrationJapicCTI-173618, jRCTs031180122.