Radiation enteropathy-related depression: A neglectable course of disease by gut bacterial dysbiosis.

Radiation enteropathy (RE) is common in patients treated with radiotherapy for pelvic-abdominal cancers. Accumulating data indicate that gut commensal bacteria determine intestinal radiosensitivity. Radiotherapy can result in gut bacterial dysbiosis. Gut bacterial dysbiosis contributes to the pathogenesis of RE. Mild to moderate depressive symptoms can be observed in patients with RE in clinical settings; however, the rate of these symptoms has not been reported. Studies have demonstrated that gut bacterial dysbiosis induces depression. In the state of comorbidity, RE and depression may be understood as local and abscopal manifestations of gut bacterial disorders. The ability of comorbid depression to worsen inflammatory bowel disease (IBD) has long been demonstrated and is associated with dysfunction of cholinergic neural anti-inflammatory pathways. There is a lack of direct evidence for RE comorbid with depression. It is widely accepted that RE shares similar pathophysiologic mechanisms with IBD. Therefore, we may be able to draw on the findings of the relationship between IBD and depression. This review will explore the relationship between gut bacteria, RE, and depression in light of the available evidence and indicate a method for investigating the mechanisms of RE combined with depression. We will also describe new developments in the treatment of RE with probiotics, prebiotics, and fecal microbial transplantation.

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas.

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas.

Lung adenocarcinomas exhibit various patterns of genomic alterations. During the development of this cancer, KRAS serves as a driver oncogene with a relatively high mutational frequency. Emerging data suggest that lung adenocarcinomas with KRAS mutations can show enhanced PD-L1 expression and additional somatic mutations, thus linking the prospect of applying immune checkpoint blockade therapy to this disease. However, the responses of KRAS-mutant lung adenocarcinomas to this therapy are distinct, which is largely attributed to the heterogeneity in the tumoral immune milieus. Recently, it was revealed that KRAS-mutant lung adenocarcinomas simultaneously expressing either a LKB1 or TP53 mutation typically have different immune profiles of their tumours: tumours with a KRAS/TP53 co-mutation generally present with a significant upregulation of PD-L1 expression and tumoricidal T-cell accumulation, and those with a KRAS/LKB1 co-mutation are frequently negative for PD-L1 expression and have few tumoricidal immune infiltrates. In this regard, interrogating TP53 or LKB1 mutation in addition to PD-L1 expression will be promising in guiding clinical use of immune checkpoint blockade therapy for KRAS-mutant lung adenocarcinomas.