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Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

BackgroundCancer-associated fibroblasts (CAFs) reportedly enhance the progression of gastrointestinal surgery; however, the role of CAFs in ampullary carcinomas remains poorly examined. This study aimed to investigate the effect of CAFs on the survival of patients with ampullary carcinoma.Materials and methodsA retrospective analysis of 67 patients who underwent pancreatoduodenectomy between January 2000 and December 2021 was performed. CAFs were defined as spindle-shaped cells that expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP). The impact of CAFs on survival, including recurrence-free (RFS) and disease-specific survival (DSS), as well as prognostic factors associated with survival, was analyzed.ResultsThe high-α-SMA group had significantly worse 5-year RFS (47.6% vs. 82.2%, p = 0.003) and 5-year DSS (67.5% vs. 93.3%, p = 0.01) than the low-α-SMA group. RFS (p = 0.04) and DSS (p = 0.02) in the high-FAP group were significantly worse than those in the low-FAP group. Multivariable analyses found that high α-SMA expression was an independent predictor of RFS [hazard ratio (HR): 3.68; 95% confidence intervals (CI): 1.21–12.4; p = 0.02] and DSS (HR: 8.54; 95% CI: 1.21–170; p = 0.03).ConclusionsCAFs, particularly α-SMA, can be useful predictors of survival in patients undergoing radical resection for ampullary carcinomas.

Aim The aim of this study is to clarify whether radical surgery for advanced esophageal hiatal hernia contribute to the improvement of cardiac load. Background & Methods In Japan, endoscopic surgery for esophageal hiatal hernia is increasing. In many cases, patients with mixed type hernia have the main symptom of meal passage disorder due to gastric torsion. On the other hand, there are cases in which the contents of hernia squeeze the heart and lung and the symptoms of respiratory and circulatory system get worse. And there are cases where cardiac load is exacerbated and QOL is got worse. Therefore, in addition to conventional surgical adaptation criteria such as vomiting and food loss, cardiac load aggravation may be added to the new surgical adaptation criteria. In this study, we measured BNP before and after surgery in the case of mixed type hiatal hernia who underwent surgery at our hospital, and examined changes in cardiac load. Our surgical procedure of laparoscopic fundoplication is basically toupet fundplication. In the elderly patients, the formation of toupet fundplication is about half a cycle, which is slightly looser than usual, in order to avoid passage obstruction of the wrap. If the esophageal hiatus is too large and it is difficult to suture closure, try to reduce the air pressure of laparoscopic surgery as much as possible to reduce the resistance to the suture closure. And we try not to damage the diaphragm leg. Results We experienced 70 esophageal hiatal hernia surgeries in 2012-2018 and 45 patient had mixed type hiatal hernia. In mixed type hiatal hernia case, 18 cases (40.0%) had chest symptoms such as fatigue and dyspnea on exertion. And there were 12 cases in which BNP could be measured before and after surgery as an evaluation for the presence of cardiac load. Postoperative BNP decreased in 11 of 12 cases from preoperative values. Almost all cases chest symptoms improved. In the above 45 cases, there have been no cases of reoperation and very few cases have taken proton pump inhibitors after surgery. Conclusion Surgical cases of giant hiatal hernia may increase in the future, especially in the elderly. Surgery for giant hiatal hernia can contribute to the improvement of cardiac load.

Anterior cervical plate fixation is a common surgical treatment for cervical spine trauma, disc herniation, or cervical spondylosis. Esophageal perforation following anterior cervical plate fixation is a rare but serious complication. Management of esophageal perforation is controversial; however, we suggest treating most cases surgically because this condition is slow to heal and often fatal. We managed 2 cases of esophageal perforation following anterior cervical plate fixation by flap reconstruction with the pectoralis major muscle in one case and a jejunal free flap in the other. Here, we report our experience and review the surgical indications.

Thoracoscopic esophagectomy in the prone position (TEPP) might enable solo-surgery in cases requiring resection of the esophagus and the surrounding lymph nodes due to the associated advantages of good exposure of the surgical field and ergonomic considerations for the surgeon. However, no one approach can be for all patients requiring extensive lymphadenectomy. We recently developed an assistant-based procedure to standardize exposure of the surgical field. Patients were divided into 1 of 2 groups:a pre-standardization group (n=37) and a post-standardization group (n=28). The thoracoscopic operative time was significantly shorter (p=0.0037) in the post-standardization group (n=28; 267 ± 31 min) than in the pre-standardization group (n=37;301 ± 53 min). Further, learning curve analysis using the moving average method showed stabilization of the thoracoscopic operative time after the standardization. No significant differences were found in the number of mediastinal lymph nodes dissected or intraoperative blood loss between the 2 groups. There were also no significant differences in the complication rate. Assistant-based surgery and standardization of the procedure resulted in a well-exposed and safe surgical field. TEPP decreased the operative time, even in patients requiring extensive lymphadenectomy.