RNA expression profiling of peritoneal metastasis from pancreatic cancer treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Objectives: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Methods: Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Results: Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). Conclusions: In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer? A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Methods: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline. Results: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients. Conclusions: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.

Importance of biopsy site selection for peritoneal regression grading score (PRGS) in peritoneal metastasis treated with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: The four-tiered peritoneal regression grading score (PRGS) is used for histological response evaluation in patients with peritoneal metastasis (PM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Four quadrant biopsies (QBs) from the parietal peritoneum should be assessed by PRGS, but consensus on biopsy site strategy for follow-up biopsies during repeated PIPACs is lacking. We aimed to evaluate whether there is a difference between PRGS in QBs from clips marked PM (QB-CM) compared to biopsies from PM with the visually most malignant features (worst biopsy, WB). Methods: Prospective, descriptive study. During the first PIPAC, index QBs sites were marked with metal clips. During the second PIPAC, an independent surgical oncologist selected biopsy site for WB and biopsies were taken from QB-CM and WB. One blinded pathologist evaluated all biopsies according to PRGS. From each biopsy, three step sections were stained H&E, followed by an immunostained section, and another three step sections stained H&E. Results: Thirty-four patients were included from March 2020 to May 2021. Median age 64 years. Maximum mean PRGS in QB-CM at PIPAC 1 was 3.3 (SD 1.2). Maximum mean PRGS in QB-CM at PIPAC 2 was 2.6 (SD 1.2), whereas mean PRGS in WB at PIPAC 2 was 2.4 (SD 1.3). At PIPAC 2, there was agreement between maximum PRGS from QB-CM and PRGS from WB in 21 patients. Maximum PRGS from QB-CM was higher in nine and lower in four patients, compared to PRGS from WB. Conclusions: Biopsies from QB-CM did not overestimate treatment response compared to biopsies from WB.

Learning Curves of Ivor Lewis Totally Minimally Invasive Esophagectomy by Hospital and Surgeon Characteristics: A Retrospective Multinational Cohort Study.

OBJECTIVE: To describe the pooled learning curves of Ivor Lewis totally minimally invasive esophagectomy (TMIE) in hospitals stratified by predefined hospital- and surgeon-related factors. BACKGROUND: Ivor Lewis (TMIE is known to have a long learning curve which is associated with considerable learning associated morbidity. It is unknown whether hospital and surgeon characteristics are associated with more efficient learning. METHODS: A retrospective analysis of prospectively collected data of consecutive Ivor Lewis TMIE patients in 14 European hospitals was performed. Outcome parameters used as proxy for efficient learning were learning curve length, learning associated morbidity, and the plateau level regarding anastomotic leakage and textbook outcome. Pooled incidences were plotted for the factor-based subgroups using generalized additive models and 2-phase models. Casemix predicted outcomes were plotted and compared with observed outcomes. The investigated factors included annual volume, TMIE experience, clinic visits, courses and fellowships followed, and proctor supervision. RESULTS: This study included 2121 patients. The length of the learning curve was shorter for centers with an annual volume >50 compared to centers with an annual volume <50. Analysis with an annual volume cut-off of 30 cases showed similar but less pronounced results. No outcomes suggesting more efficient learning were found for longer experience as consultant, visiting an expert clinic, completing a minimally invasive esophagectomy fellowship or implementation under proctor supervision. CONCLUSIONS: More efficient learning was observed in centers with higher annual volume. Visiting an expert clinic, completing a fellowship, or implementation under a proctor's supervision were not associated with more efficient learning.

Surgery for acute cholecystitis in Denmark.

OBJECTIVE: Despite laparoscopic cholecystectomy being the preferred treatment for elective cholecystectomy, surgery for acute cholecystitis is often performed using the open method. The aim of the study was to assess the incidence of cholecystectomy for acute cholecystitis and to determine the proportion of laparoscopically completed procedures compared with all cholecystectomies for acute cholecystitis. MATERIAL AND METHODS: Data from the Danish National Patient Registry were analysed. The annual numbers of all cholecystectomies and of cholecystectomies performed for acute cholecystitis from 1996 to 2004 were registered. Separate data for open and laparoscopic operations were obtained. RESULTS: An increase in the number of cholecystectomies for acute cholecystitis from 13.6 in 1996 to 17.2/100,000 in 2004 was observed (p<0.05). In 1996, 41% of cholecystectomies performed for acute cholecystitis were completed laparoscopically as compared with 64% in 2004 (p<0.05). For laparoscopic cholecystectomies performed for reasons other than acute cholecystitis, the corresponding rates were 78% and 87%, respectively (p<0.05). CONCLUSIONS: The total number of patients having cholecystectomy for acute cholecystitis has increased as has the rate of laparoscopically completed procedures. It is not known whether it is possible to obtain a further reduction in the number of open cholecystectomies.