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.

Objectives The primary aim of this study was to evaluate the histological adequacy of the liver tissue specimens obtained with a 20-gauge fine-needle biopsy needle and the secondary aim was to test the safety endoscopic ultrasound-guided liver biopsy with a 20-gauge fine-needle biopsy needle with the wet-heparinized suction technique. Methods Forty patients who underwent endoscopic ultrasound-guided liver biopsy were included in the study. A 20-gauge fine-needle biopsy needle was used with the wet-heparinized suction technique to make one pass each from the left and the right lobe. Histologic characteristics of the specimens were evaluated, and patients were observed after the procedure in order to intervene in case of an adverse event. Results The median longest core fragment was 22 mm from the left lobe [first quartile–third quartile 20–25 mm, interquartile range (IQR) 5 mm], and 20 mm (first quartile–third quartile 17–22 mm, IQR 5 mm) from the right lobe. The median cumulative core length per patient was 103 mm (91–108 mm, IQR 17 mm). The median cumulative number of complete portal triads per patient was 69.50 (52.25–82.25, IQR 30). The rate of diagnostic yield was 100%. Post-biopsy self-limiting abdominal pain was reported in two patients (5%). The most common histologic diagnosis was fatty liver disease (25%). Conclusion Endoscopic ultrasound-guided liver biopsy with the wet-heparinized suction technique using a 20-gauge fine-needle biopsy needle is a safe alternative method in clinical practice.

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. Postprocedural 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.