Background:Activating mutation of KRAS and BRAF are focused on as potential prognostic and predictive biomarkers in patients with colorectal cancer (CRC) treated with anti-EGFR therapies. This study investigated the clinicopathological features and prognostic impact of KRAS/BRAF mutation in advanced and recurrent CRC patients.Method:Patients with advanced and recurrent CRC treated with systemic chemotherapy (n=229) were analysed for KRAS/BRAF genotypes by cycleave PCR. Prognostic factors associated with survival were identified by univariate and multivariate analyses using the Cox proportional hazards model.Results:KRAS and BRAF mutations were present in 34.5% and 6.5% of patients, respectively. BRAF mutated tumours were more likely to develop on the right of the colon, and to be of the poorly differentiated adenocarcinoma or mucinous carcinoma, and peritoneal metastasis. The median overall survival (OS) for BRAF mutation-positive and KRAS 13 mutation-positive patients was 11.0 and 27.7 months, respectively, which was significantly worse than that for patients with wild-type (wt) KRAS and BRAF (40.6 months) (BRAF; HR=4.25, P<0.001, KRAS13; HR=2.03, P=0.024). After adjustment for significant features by multivariate Cox regression analysis, BRAF mutation was associated with poor OS (HR=4.23, P=0.019).Conclusion:Presence of mutated BRAF is one of the most powerful prognostic factors for advanced and recurrent CRC. The KRAS13 mutation showed a trend towards poor OS in patients with advanced and recurrent CRC.

IMPORTANCE Immunotherapy using immune checkpoint inhibitors has been remarkably effective for treating multiple cancer types, and the gut microbiome is a possible factor affecting immune checkpoint inhibitor efficacy. However, the association between the gut microbiome and immune status of the tumor microenvironment remains unclear. Short-chain fatty acids (SCFAs) are major end product metabolites produced by the gut microbiota and have wide-ranging impacts on host physiology. OBJECTIVE To evaluate fecal and plasma SCFAs in patients with solid cancer tumors treated with programmed cell death-1 inhibitors (PD-1i).

Background Blocking the PD-1 pathway induces immune-related adverse events (irAEs) which often involve the thyroid gland (thyroid irAEs). Clinical features of a thyroid irAE including its predictability and relationship to prognosis remain to be elucidated. Methods Two hundred consecutive patients treated with nivolumab at Kyoto University Hospital between September 1, 2014 and August 31, 2017 were included in a retrospective cohort study. We systematically determined and classified subclinical and overt thyroid irAEs based on data collected of serum free T4 and TSH levels. Baseline characteristics and detailed clinical data were analyzed, and analyses of overall survival (OS) excluded patients censored within 1 month from the first administration of nivolumab. Results Sixty-seven patients (33.5%) developed thyroid irAEs and these were divided into a subclinical thyroid irAE group ( n = 40, 20.0%) and an overt thyroid irAE group ( n = 27, 13.5%). Patients with thyroid uptake of FDG-PET before treatment showed high incidences of overt thyroid irAE (adjusted odds ratio 14.48; 95% confidence interval [CI] 3.12–67.19), while the same relationship was not seen with subclinical thyroid irAE. Regarding the total cohort, the thyroid irAE (+) group had a significantly longer median OS than the thyroid irAE (−) group (16.1 versus 13.6 months, hazard ratio [HR] 0.61; 95% CI 0.39–0.93). In 112 non-excluded patients with lung cancer, the thyroid irAE (+) group similarly had a longer median OS than the thyroid irAE (−) group (not reached versus 14.2 months, HR 0.51; 95% CI 0.27–0.92). However, this observation was not seen in 41 non-excluded patients with malignant melanoma (12.0 versus 18.3 months, HR 1.54; 95% CI 0.67–3.43). Conclusions By thyroid uptake of FDG-PET, overt thyroid irAEs could be predicted before nivolumab therapy. Thyroid irAEs related to good prognosis in lung cancer but might be inconclusive in malignant melanoma.

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Our results indicate that neutropenia or leukopenia experienced during chemotherapy is associated with improved survival in patients with advanced cancer or hematological malignancies undergoing chemotherapy. Future prospective analyses designed to investigate the potential impact of chemotherapy dose adjustment coupled with monitoring of neutropenia or leukopenia on survival are warranted.