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In a phase 1–2 trial involving patients with advanced pancreatic cancer, sotorasib (a KRAS G12C inhibitor) resulted in a response in 21% of the patients and a median progression-free survival of 4 months.

Four variants of the highly hemolytic antimicrobial peptide Pin2 were chemically synthesized with the aim to investigate the role of the proline residue in this peptide, by replacing it with the motif glycine-valine-glycine [GVG], which was found to confer low hemolytic activity in a spider antimicrobial peptide. The proline residue in position 14 of Pin2 was substituted by [V], [GV], [VG] and [GVG]. Only the peptide variant with the proline substituted for [GVG] was less hemolytic compared to that of all other variants. The peptide variant [GVG] kept its antimicrobial activity in Muller-Hilton agar diffusion assays, whereas the other three variants were less effective. However, all Pin2 antimicrobial peptide variants, were active when challenged against a Gram-positive bacteria in Muller-Hilton broth assays suggesting that chemical properties of the antimicrobial peptides such as hydrophobicity is an important indication for antimicrobial activity in semi-solid environments.

The value of automatic bolus tracking in late-arterial and portal-venous phase imaging of the liver with a multislice CT scanner as compared with fixed time-delay examination in patients without circulatory disturbances is evaluated. For the evaluation of known or suspected liver disease, 98 multiphase contrast-enhanced CT examinations including double late-arterial phase imaging were randomized into either scanning with a scan delay of 30 s from the beginning of contrast material injection or scanning with automatic bolus tracking. Contrast material was injected at 0.07 ml/kg body weight/s over 30 s. Contrast enhancement in each acquisition was measured in the aorta, portal vein, liver, pancreas and hepatocellular carcinomas. The density difference between hepatocellular carcinomas and the hepatic parenchyma was calculated. The mean time to the first-pass acquisition as determined by automatic bolus tracking was 29.6 s. No statistically significant difference was observed between the two groups either in any enhancement in any acquisition or in the lesion-to-liver density difference. The use of automatic bolus tracking in late-arterial and portal-venous phase hepatic CT does not significantly improve the degree of contrast enhancement in the aorta, portal vein, liver and pancreas or lesion-to-liver conspicuity in patients without circulatory disturbances.

We report the case of a patient with gastric and bone metastases arising from an invasive lobular carcinoma of the breast coexisting with ductal carcinoma at the same time. A 68-year-old woman with gastric and right costal tumors was referred to our hospital. Esophagogastroduodenoscopy (EGD) revealed irregular, slightly elevated lesions extending from the gastric body to the antrum, and biopsy specimens revealed a poorly differentiated adenocarcinoma. Furthermore, abdominal contrast-enhanced computed tomography (CT) revealed extensive wall thickening with homogeneous enhancement in the stomach. 18F-2-deoxy-2-fluoro-glucose positron emission tomography (FDG-PET) showed intense FDG uptake in the right mammary gland and right third rib. Moreover, fine-needle aspiration of the third right rib lump and the right breast mass lesion was performed, and subsequent pathological investigations revealed metastatic adenocarcinoma and invasive ductal carcinoma, respectively. Immunohistochemical examination revealed that estrogen receptor was strongly positive (>95%) in breast cancer and focally positive (<5%) in gastric cancer with bone metastasis. In addition, another right breast tumor was detected by breast magnetic resonance imaging (MRI), and biopsy revealed invasive lobular carcinoma that matched the histological findings of bone and gastric lesions, including immunohistochemical examination. The patient was treated with an aromatase inhibitor, a CDK4/6 inhibitor, and a receptor activator of nuclear factor-kappa B ligand (RANKL) monoclonal antibody. She showed no symptoms or disease progression at 9-month follow-up after the initiation of systemic drug treatment. Invasive lobular carcinoma can metastasize to the gastrointestinal tract, and new treatment developments are expected as more cases will accumulate in the future.

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Background First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m 2 ), irinotecan (IRI: 200 mg/m 2 ), and BEV (7.5 mg/m 2 )] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be “0.8 < HR < 1.25” under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4). Discussion Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN. Trial registration Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.

BackgroundA 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.MethodsChemotherapy-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/m2) and oxaliplatin (100 mg/m2) 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.ResultsAmong 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.ConclusionGEMOX 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 numberUMIN000017894.

Purpose Pembrolizumab demonstrated antitumor activity in programmed death ligand 1 positive (combined positive score (CPS) ≥ 1) gastric/gastroesophageal junction cancer in KEYNOTE-059 (third line or beyond), KEYNOTE-061 (second line), and KEYNOTE-062 (first line). We characterized efficacy and safety of pembrolizumab monotherapy in Japanese patients across several lines of therapy in these studies. Methods This analysis was conducted in 34 patients from KEYNOTE-059 cohort 1 (all pembrolizumab), including 13 patients with CPS ≥ 1, 65 patients with CPS ≥ 1 from KEYNOTE-061 (pembrolizumab, n  = 27; chemotherapy, n  = 38), and 70 patients with CPS ≥ 1 from KEYNOTE-062 (pembrolizumab, n  = 38; chemotherapy, n  = 32). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated. Results In KEYNOTE-059, ORR with pembrolizumab was 9%, median PFS was 2 months, and median OS was 10 months. In KEYNOTE-061, median OS was 12 months with pembrolizumab versus 10 months with chemotherapy (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.39–1.15). Median PFS (pembrolizumab vs. chemotherapy) was 2 months versus 4 months (HR, 1.21; 95% CI, 0.69–2.13); ORR was 7% versus 18%. In KEYNOTE-062, median OS was 20 months with pembrolizumab versus 18 months with chemotherapy (HR, 0.76; 95% CI, 0.43–1.33). Median PFS (pembrolizumab vs. chemotherapy) was 6 months versus 7 months (HR, 1.03; 95% CI, 0.61–1.74); ORR was 29% versus 34%. Conclusions The current analysis provides valuable information that anti–PD-1 therapies are worthy of further assessment for gastric cancer. Trial Registration ClinicalTrials.gov: NCT02335411 (KEYNOTE-059), NCT02370498 (KEYNOTE-061), and NCT02494583 (KEYNOTE-062).

In the Original publication of the article, the authors found an error in the “Results” section under the heading “Abstract”. The corrected text is given below.

The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group. This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥3 and OABSS question 3 score ≥2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit. Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered. Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.