Explore the vast range of titles available.

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1 + CXCL10 + macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3 + CD8 + effector-memory T cells (CD8 T EM ) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 T EM preferentially differentiate into clonally-expanded PD1 -  CD45RA + effector-memory CD8 + T cells (CD8 T EMRA ) with pronounced cytotoxicity. In contrast, in non-responders, CD8 T EM remain frozen in their effector-memory state. Finally, in responders, CD8 T EMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC. Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses.

BackgroundMinimally invasive pancreaticoduodenectomy with synchronous vein resection for pancreatic cancer is controversial. The aim of this study was to evaluate outcomes and describe the surgical technique of 3d-laparoscopic pylorus-resecting pancreaticoduodenectomy (3dLPD) with venous resection for pancreatic cancer.MethodsA retrospective cohort analysis was performed with 26 patients [male/female 11/15; median age 68 (range 45–83) years] who underwent 3dLPD with stented pancreaticogastrostomy and superior mesenteric or portal vein resection for pancreatic adenocarcinoma between November 2016 and June 2019. Median follow-up time after surgery was 12 months (range 3–32).ResultsMedian operating time was 340 min (range 240–420) and intra-operative blood loss was 100 mL (range 0–1000). Type of venous resection and reconstruction was wedge-resection with primary closure (n = 22), wedge-resection with reconstruction using a peritoneal patch (n = 3), and segmental resection with primary end-to-end reconstruction (n = 1). Laparoscopy was converted to open surgery in 4 (15%) patients. Postoperative complications occurred in 10 (38%) patients including severe complications (Clavien–Dindo grade > 2) in 4 (15%). Postoperative mortality was zero. R0 resection was achieved in 21 (81%) patients. Median number of lymph nodes retrieved was 25 (range 10–45). Venous patency was observed in 23 (88%) patients with a median patency duration of 11 months (range 0–31).Conclusions3dLPD with simultaneous venous resection for pancreatic cancer results in acceptable reconstruction patency and adequacy of surgical oncology without compromising clinical outcomes.

A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology. The development of cancer is typically accompanied by changes in the tumor microenvironment that support tumor growth and affect therapy response. Here, the authors show that increased intratumoral temperature is an inherent feature of human pancreatic cancer and contributes to therapy resistance by altering the lipid content of the tumor.

Background Minimally invasive liver resection (MILR) for colorectal liver metastases (CRLM) is gaining widespread acceptance. However, data are still lacking on the feasibility, long- and short-term outcomes of laparoscopic major hepatectomy (i.e., three or more liver segments). Methods Between October 2002 and December 2008, prospectively collected data of 117 patients who underwent major liver resection [97 open (OMLR) and 20 laparoscopic (LMLR) procedures] for CRLM were analyzed. Twenty patients in the LMLR group were matched with 20 patients of the OMLR based on 13 parameters. We compared the long- and short-term outcomes between these two groups. Results Median duration of surgery was 257.5 (range 75–360) min in LMLR versus 232.5 (range 120–400) min in OMLR ( P  = 0.228). Median blood loss during surgery was 550 ml in each group (range 100–4,000 vs. 100–2,500 ml, P  = 0.884). There was no statistically significant difference in the rate of postoperative complications (both severity and location). Median magnitude of tumor-free resection margin was 7.5 versus 5.5 mm in the laparoscopy versus open group, respectively ( P  = 0.651). Median disease-free survival (DFS) of the entire study population was 18.4 months [95% confidence interval (CI) 11.9–50.0 months]. Median overall survival (OS) was 50.7 months (95% CI 36.2 months to undetermined). The estimated DFS and OS rates at 1, 2, and 5 years were comparable in the two groups ( P  = 0.637 and 0.872, respectively). Conclusion Laparoscopic MLR for selected CRLM is feasible and might result in comparable oncologic outcomes as in open liver resection.

Background Despite significant advancements in cancer immunotherapy, survival outcomes remain poor in patients with pancreatic ductal adenocarcinoma. Methods In this early phase II clinical trial, we evaluated the combined effects of immunotherapy with dual immune checkpoint inhibitors durvalumab and tremelimumab, local tumor ablation with microwave energy, and gemcitabine on progression-free survival in twelve patients with non-metastatic unresectable locally advanced pancreatic adenocarcinoma. Single-cell transcriptomics and T cell receptor profiling were used to characterize the tumor microenvironment and peripheral blood immune cell repertoire. Results Here we show that from these twelve patients (median progression-free survival = 8.9 months, 95% confidence interval 3.2–18.4), eight patients received the combination therapy (median progression-free survival of 11.2 months, 95% confidence interval 4.0–18.4). One of these eight patients experiences grade 5 toxicity. Using single-cell transcriptomics and T cell receptor profiling, we characterize the tumor microenvironment and peripheral blood immune cell repertoire of six patients, of which three patients contain paired samples before and after the start of immunotherapy. We find substantial overlap in T cell receptors and CD8-Temra cells in the tumor microenvironment and in peripheral blood. Integration of the single-cell dataset with an independent bulk transcriptome cohort reveals that a high CD8-Temra gene signature is associated with improved overall survival. While there are interesting trends, T cell receptor-related metrics do not show statistically significant correlations with progression-free survival in this dataset. Conclusions These findings suggest that CD8-Temra cells may serve as potential biomarkers and therapeutic targets for immunotherapy efficacy in pancreatic ductal adenocarcinoma, pending validation in larger cohorts. We hypothesize that local tumor ablation may enhance tumor immunogenicity and systemic anti-tumor responses, supporting their integration into future treatment strategies. Future studies with larger cohorts are needed to validate these findings and optimize treatment protocols for wider clinical applicability. Plain Language Summary Pancreatic cancer is one of the deadliest forms of cancer, and current treatments have only limited success. This study aimed to explore whether combining immunotherapy with local tumor ablation and chemotherapy could improve outcomes for patients with advanced pancreatic cancer that cannot be surgically removed. Local tumor ablation is a treatment that destroy cancer cells inside the body by applying heat without surgery. We treated twelve patients and studied how their immune systems responded, using advanced techniques to analyze cancer and blood samples. We found that certain immune cells, called CD8-Temra cells, were linked to better survival, suggesting they could help guide future treatments. Our findings suggest that combining local tumor ablation with immunotherapy may improve the body’s ability to fight cancer, but larger studies are needed to confirm these results. Topal et al. evaluate a novel combination of local ablation, checkpoint inhibition, and chemotherapy in advanced pancreatic cancer, indicating a potential role for CD8-Temra cells in predicting immunotherapy benefit.

Background Several clinicopathological predictors of survival after curative surgery for perihilar cholangiocarcinoma (pCCA) have been identified; however, conflicting reports remain. The aim was to analyse clinical and oncological outcomes after curative resection of pCCA and to determine prognostic factors. Methods Eighty-eight consecutive patients with pCCA underwent surgery with curative intent between 1998 and 2017. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Twenty-one prognostic factors were evaluated using multivariate Cox regression models. Results Postoperative complications were observed in 73 (83%) patients of which 41 (47%) were severe complications (therapy-oriented severity grading system (TOSGS) grade > 2), including a 90-day mortality of 9% ( n = 8). Overall survival (OS) and disease-free survival (DFS) rates at 5 and 10 years after surgery were 33% and 19%, and 37% and 30%, respectively. Independent predictors of OS were locoregional lymph node metastasis (LNM) (risk ratio (RR) 2.12, confidence interval (CI) 1.19–3.81, p = 0.011), patient American Society of Anesthesiologists (ASA) physical status classification system > 2 (RR 2.10, CI 1.03–4.26, p = 0.043), and depth of tumour penetration (pT) > 2 (RR 2.58, CI 1.03–6.30, p = 0.043). The presence of locoregional LNM (RR 2.95, CI 1.51–5.90, p = 0.002) and caudate lobe resection (RR 2.19, CI 1.01–5.14, p = 0.048) were found as independent predictors of DFS. Conclusions Curative surgery for pCCA carries high risks with poor long-term survival. Locoregional LNM was the only predictor for both OS and DFS.

Background C ytoreductive surgery (CRS) plus hyperthermic intra-operative peritoneal chemotherapy (HIPC) for gastric peritoneal carcinomatosis (PC) is controversial, and selection criteria for this treatment modality are lacking. Methods Thirty-two patients (F/M ratio 12/20; median (range) age 58 (32-75) years) underwent CRS + HIPC with cisplatin for PC from gastric adenocarcinoma in 2010-2014. This monocentric phase-2 nonrandomized prospective study with a power of 90% aimed to improve the 1-year overall survival (OS) rate with 40% (historical reference of 52% to 72%). Median PCI score was 8 (range 1-20), number of regions involved was 6 (range 1-11). The impact of 16 prognostic factors on survival was evaluated using univariable and multivariable Cox regression models. Follow-up was complete in all patients, and closed 2 years after patient inclusion. Results All patients had complete cytoreduction (CCR-0) and histopathological R0 resection. PCI