T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

Extramural venous invasion is an independent predictor of poor outcome in colorectal cancer, whereas the significance of the intramural component of venous and lymphatic and perineural invasion is unclear. To evaluate the prognostic impact of intramural components for venous, lymphatic, and perineural invasions and the relation of these invasion patterns with clinicopathological features in patients with colon cancer. A retrospective cross-sectional study. The analysis included 626 patients with colon cancer in stages II and III. All patients were divided into four categories (no invasion, intramural invasion only, extramural invasion only, or both intramural and extramural invasions) for vascular invasion, lymphatic invasion and perineural invasion. The primary outcomes were 5-year disease-free and overall survival. Right-sided (for vascular invasion, 24.7% vs. 33.9%, p = 0.007; for perineural invasion, 34.5% vs. 41.5%, p = 0.034) and dMMR tumors (for vascular invasion, 13.5% vs. 33.5, p < 0.001; for perineural invasion, 25% vs. 41.4%, p = 0.004) exhibited less venous and perineural invasion. Compared with no invasion, presence of intramural invasion only, did not exert any effect on disease-free or overall survival for vascular invasion, lymphatic invasion, and perineural invasion. Multivariate analyses revealed that the presence of both intramural and extramural invasion was independently associated with poor disease-free and overall survival for venous (hazard ratios: 2.39, p = 0.001; hazard ratios: 2.46, p = 0.001), lymphatic (hazard ratios: 2.456, p < 0.001; hazard ratios: 2.13, p = 0.02) and perineural invasion (hazard ratios: 2.99, p < 0.001; hazard ratios: 2.68, p < 0.001), respectively. Our data strongly advocates the importance of reporting intramural and extramural components of invasion since the presence of intramural invasion alone may not be considered as a high-risk factor for systemic recurrence.

We present the case of a 39-year-old woman with a biliocutaneous fistula and a history of surgery for colon cancer. Metastasis to the left lobe of the liver had been detected 3 months before her referral to us and she had been treated with endoscopic retrograde cholangiopancreatography (ERCP)-guided insertion of an uncovered self-expandable metal stent (SEMS; 8-cm long) for obstructive jaundice caused by the metastasis. Post-procedural swelling appeared in the upper abdominal region and subsequently a fistula developed with bilious discharge from the skin over the right upper quadrant, which persisted for 3 months. She was referred to our clinic with fever; jaundice, abdominal distension, and tenderness were the notable findings on her physical examination. A computed tomography (CT) scan revealed a fistula tract from the left lobe of the liver to the skin, passing through the anterior abdominal wall, with inflammatory changes in the surrounding tissue. After clinical and radiological evaluation, ERCP was performed for the evaluation of the stent but was unsuccessful owing to migration of the SEMS into the common bile duct. After she had completed 3 months of ciprofloxacin therapy, an endoscopic ultrasound (EUS)-guided hepatogastrostomy was performed. A puncture was performed from the stomach to the left intrahepatic bile duct using a 19-gauge needle. The tract was dilated with a bougie, and then a drainage catheter to the stomach (7-Fr, 7-cm biliary plastic stent; Boston Scientific, Marlborough, Massachusetts, USA) was placed ([Video 1]). The fistula in the upper abdomen was noted to have healed 3 days after performance of the hepatogastrostomy. Video 1 Endoscopic ultrasound-guided hepatogastrostomy in a patient with a biliocutaneous fistula. Endoscopy_UCTN_Code_CPL_1AK_2AC Publication Date: 27 February 2020 (online) © Georg Thieme Verlag KG Stuttgart · New York