Purpose: Pancreatic ductal adenocarcinoma (PDAC) is considered a low-immunogenic (LI) tumor with a “cold” tumor microenvironment and is mostly unresponsive to immune checkpoint blockade therapies. In this study, we decipher the impact of intratumoral heterogeneity of immune determinants on antitumor responses. Experimental Design: We performed spatial proteomic and transcriptomic analyses and multiplex immunofluorescence on multiple tumor regions, including tumor center (TC) and invasive front (IF), from 220 patients with PDAC, classified according to their transcriptomic immune signaling into high-immunogenic PDAC (HI-PDAC, n = 54) and LI PDAC (LI-PDAC, n = 166). Spatial compartments (tumor: pancytokeratin+/CD45− and leukocytes: pancytokeratin−/CD45+) were defined by fluorescence imaging. Results: HI-PDAC exhibited higher densities of cytotoxic T lymphocytes with upregulation of T-cell priming–associated immune determinants, including CD40, ITGAM, glucocorticoid-induced TNF–related receptor, CXCL10, granzyme B, IFNG, and HLA-DR, which were significantly more prominent at the IF than at the TC. In contrast, LI-PDAC exhibited immune-evasive tumor microenvironments with downregulation of immune determinants and a negative gradient from TC to IF. Patients with HI-PDAC had significantly better outcomes but showed more frequently exhausted immune phenotypes. Conclusions: Our results indicate strategic differences in the regulation of immune determinants, leading to different levels of effectiveness of antitumor responses between HI and LI tumors and dynamic spatial changes, which affect the evolution of immune evasion and patient outcomes. This finding supports the coevolution of tumor and immune cells and may help define therapeutic vulnerabilities to improve antitumor immunity and harness the responsiveness to immune checkpoint inhibitors in patients with PDAC.

Objective: To assess the efficacy and safety of fully closed-loop (FCL) compared with usual care (UC) glucose control in patients experiencing major abdominal surgery-related stress hyperglycemia. Background: Major abdominal surgery-related stress and periprocedural interventions predispose to perioperative hyperglycemia, both in diabetes and non-diabetes patients. Insulin corrects hyperglycemia effectively, but its safe use remains challenging. Methods: In this two-centre randomized controlled trial, we contrasted subcutaneous FCL with UC glucose management in patients undergoing major abdominal surgery anticipated to experience prolonged hyperglycemia. FCL (CamAPS HX, Dexcom G6, mylife YpsoPump 1.5x) or UC treatment was used from hospital admission to discharge (max 20 d). Glucose control was assessed using continuous glucose monitoring (masked in the UC group). The primary outcome was the proportion of time with sensor glucose values in a target range of 5.6 to 10.0 mmol/L. Results: Thirty-seven surgical patients (54% pancreas, 22% liver, 19% upper gastrointestinal, 5% lower gastrointestinal), of whom 18 received FCL and 19 UC glucose management, were included in the analysis. The mean ± SD percentage time with sensor glucose in the target range was 80.1% ± 10.0% in the FCL and 53.7% ± 19.7% in the UC group (P < 0.001). Mean glucose was 7.5 ± 0.5 mmol/L in the FCL and 9.1 ± 2.4 mmol/L in the UC group (P = 0.015). Time in hypoglycemia (<3.0 mmol/L) was low in either group. No study-related serious adverse events occurred. Conclusions: The FCL approach resulted in significantly better glycemic control compared with UC management, without increasing the risk of hypoglycemia. Automated glucose-responsive insulin delivery is a safe and effective strategy to minimize hyperglycemia in complex surgical populations.

Insulinomas are rare tumors, in the majority of cases best treated by surgical resection. Preoperative localization of insulinoma is challenging. The more precise the preoperative localization the less invasive and safer is the resection. The purpose of the study is to check the impact of a new technique to localize insulinoma on the surgical strategy. We present exact preoperative localization with Glucagon-like peptide-1 receptor (GLP-1R) imaging. This allows a more precise resection thereby reducing surgical access trauma, loss of healthy pancreatic tissue and increasing safety and quality of the surgical intervention. With the help of precise preoperative localization of insulinoma with GLP-1R imaging the surgeon is able to minimize the amount of resected healthy pancreatic tissue. We hypothesize that GLP-1R imaging will become a preoperative diagnostic tool to be used for many patients scheduled for open or laparoscopic insulinoma resection.

Background: Partial pancreaticoduodenectomy (PD) followed by adjuvant chemotherapy (AC) is standard treatment for resectable pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head. Total pancreatectomy (TP) has historically been reserved for extensive tumors or salvage procedures due to concerns about morbidity and quality of life (QoL). However, recent evidence shows comparable perioperative outcomes and QoL between TP and PD. The authors hypothesized that avoiding postoperative pancreatic fistula TP would achieve AC initiation and completion rates similar to those for PD, even in more complex patients. Methods: This study retrospectively analysed all patients who underwent TP or PD for PDAC at the authors’ center between 2014 and 2021. Rates, timing, and completion of AC were compared. The decision for TP versus PD was based on patient and intraoperative factors at the discretion of the surgeon. Results: Of 263 included patients, 74 underwent TP and 189 underwent PD. Total pancreatectomy was performed mainly for repetitive positive resection margins or splenic vessel involvement (59 %). The TP patients had more comorbidities (liver disease, 16.2 % vs 5.8 % p = 0.013; diabetes, 40.5 % vs 24.9 % p = 0.016), longer surgeries (7.2 vs 6 h; p = 0.001), more vascular reconstructions (77 % vs 50.8 %; p = 0.001), and greater blood loss (1200 vs 600 ml; p = 0.001). Despite these factors, morbidity and mortality were comparable. The two groups did not differ in rates of AC initiation (66 % vs 76 %; p = 0.156), completion (69.4 % vs 74.1 %; p = 0.578), and timing (median, 7 weeks in both groups; p = 0.533). Conclusion: Despite higher surgical complexity, AC initiation and completion rates after TP were comparable with those after PD. With modern diabetes management, TP represents a valid surgical option for selected high-risk patients without compromising oncologic treatment.

Background: According to current guidelines, preoperative endoscopic retrograde cholangiopancreatography (ERCP) with biliary stenting (ERCP/stenting) is often necessary in patients with obstructive jaundice due to pancreatic ductal adenocarcinoma (PDAC), including severe jaundice (bilirubin > 250 umol/l), pruritus, cholangitis, cholestatic liver dysfunction, renal failure, severe malnutrition, or delayed surgery for tumors requiring neoadjuvant chemotherapy. We aimed to investigate the impact of preoperative ERCP/stenting on postoperative and long-term outcomes following pancreaticoduodenectomy (PD) for PDAC. Methods: Clinicopathological data of patients who underwent partial/total PD for PDAC between 2012 and 2019 in two hepato-pancreato-biliary centers in Germany and Switzerland were assessed. We compared patients treated with preoperative ERCP/stenting with those directly undergoing surgery according to postoperative morbidity, postoperative mortality, overall survival (OS) and disease-free survival (DFS). Results: During the study period, 192 patients underwent partial/total PD for PDAC. ERCP/stenting was performed in 105 patients, and 87 patients underwent resection without prior intervention. Postoperative 90-day overall morbidity rate (71% vs. 56%, p = 0.029) and superficial surgical site infection (SSI) rate (39% vs. 17%, p < 0.001) were significantly worse following preoperative ERCP/stenting. Major postoperative morbidity rate (18% vs. 21%, p = 0.650), organ/space SSI rate (7% vs. 14%, p = 0.100), and 90-day postoperative mortality rate (4% vs. 2%, p = 0.549) did not significantly differ between the two groups. After excluding 44 patients for whom the indication for ERCP/stenting was not consistent with current guidelines, ERCP/stenting was associated with a higher superficial SSI rate (36% vs. 17%, p = 0.009) and shorter length of stay (12 vs. 16 days, p = 0.004). Median OS (ERCP/stenting: 18 months vs. no ERCP/stenting: 23 months, p = 0.490) and median DFS (ERCP/stenting: 14 months vs. no ERCP/stenting: 18 months, p = 0.645) were independent from the utilization of ERCP/stenting. Conclusions: Preoperative ERCP/stenting in patients with PDAC can be performed without increasing organ/space SSI, major perioperative morbidity, and mortality rates and without worsening oncologic outcomes. However, it is associated with higher superficial SSI rates. If ERCP/stenting is not performed routinely but according to current guidelines, it is also associated with a shorter length of hospital stay. Further refinement of the indications for preoperative ERCP/stenting may reduce superficial SSI rates.

Zusammenfassung Das Pankreaskarzinom stellt sowohl eine therapeutische Herausforderung dar: für den Chirurgen auf Grund der anatomischen Nähe zu vitalen Arterien und Venen, welche eine onkologische Resektion mit weitem Sicherheitsabstand oft nicht zulassen, für den Onkologen aufgrund der im Vergleich zu anderen Malignomen des Gastrointestinaltrakts limitierten Wirksamkeit einer Systemtherapie. Viele klinische Studien, welche interessante therapeutische Ansätze prüften, verliefen bisher frustran. Im Gegensatz zu anderen soliden Tumoren, bei denen Immuncheckpoint-Inhibitoren (ICI) mit Erfolg eingesetzt werden, ist dieser Ansatz bisher lediglich Patienten mit Mikrosatelliten-instabilen Pankreaskarzinomen (< 1 %) vorbehalten. Präliminäre Daten deuten jedoch auf neue Behandlungsansätze mit ICI in Kombination mit Chemotherapeutika hin. Neue Chemotherapie-Ansätze zielen auf die verbesserte Verfügbarkeit der zytotoxischen Substanzen an der Tumorzelle ab. Ermutigende Ansätze zeichnen sich auch bei den treibermutationsgerichteten Behandlungen ab, deren Effektivität zurzeit in laufenden Studien geprüft wird. Für alle mittels Resektion behandelbaren Karzinome gilt, dass die Therapie durch eine Chemotherapie – sei es neoadjuvant oder adjuvant – ergänzt werden soll. Bei metastasierten, respektive nichtresezierbaren, Pankreaskarzinomen sollte bereits früh im diagnostischen Algorithmus ein NGS durchgeführt werden, um in der Subgruppe von KRAS–Wildtyp-Tumoren potenziell medikamentös angehbare Zielstrukturen zu identifizieren.