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Background

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an established treatment for peritoneal metastases (PM) of various origins. The spleen is frequently involved in advanced disease, making splenectomy a common procedure in CRS. This study aimed to evaluate postoperative complications and prognosis associated with splenectomy during CRS + HIPEC.

Patients and methods

Data from patients undergoing CRS + HIPEC from 2012 to 2022 were retrospectively collected from a prospectively maintained HIPEC registry. Postoperative complications according to Clavien-Dindo, overall survival (OS), and disease-free survival (DFS) were compared between patients undergoing splenectomy (n = 109) and the control group without splenectomy (n = 282). Cox proportional hazards models were used to identify independent prognostic factors.

Results

The splenectomy group had significantly higher PCI (median 25 vs. 8, p < 0.001) and more frequent diaphragmatic peritonectomy (83% vs. 70%, p < 0.001). High PCI was an independent predictor for splenectomy (adjusted OR 1.18, 95% CI 1.12-1.24). In univariable analysis, the likelihood of severe postoperative complications (Clavien-Dindo grade 3-4) was higher after splenectomy (OR 1.77, 95% CI 1.12-2.80), with increased rates of sepsis and kidney failure. In multivariable analysis, diaphragmatic resection (adjusted OR 4.81, 95% CI 1.99-11.61) was associated with severe complications, whereas splenectomy was not. Splenectomy was also not a predictor of OS and DFS after multivariable adjustment. In contrast, PCI >= 20 and synchronous liver resection were associated with worse OS.

Conclusion

The need for splenectomy during CRS + HIPEC reflects more advanced peritoneal disease; however, splenectomy is not an independent risk factor for postoperative complications. Likewise, it does not independently affect overall or disease-free survival.

Objective: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has improved outcomes in colorectal cancer (CRC) patients with peritoneal metastases (PM), yet evidence regarding perioperative risk and long-term survival in those 75 years or older remains uncertain. The aim of this study was to evaluate whether age ≥75 years impacts on overall survival (OS) and postoperative in-hospital morbidity, according to Clavien-Dindo classification (CD), compared with patients aged <75 years.

Method: This population-based study collected data from the National Swedish HIPEC Registry, including patients with colorectal PM operated with CRS-HIPEC. Patients were stratified by age (≤74 vs ≥75) with OS as primary outcome. Secondary outcomes were in-hospital mortality, postoperative morbidity and disease free survival (DFS). Potential variables assessed for association with OS were Complete Cytoreduction Score (CCS), Peritoneal Carcinomatosis Index (PCI) score, p/ypN stage of the primary tumor, postoperative morbidity and age.

Results: A total of 592 patients were operated between 2004 and 2021, of which 553 were ≤74 years and 39 were ≥75 years. OS did not differ between age groups (p = .951). Factors affecting OS negatively were high CCS (p = .004), PCI ≥21 (p = .009) and p/ypN2 (p = .041). No difference was observed in DFS (p = .525). The rate of CD grade III-IV was 27% in patients ≤74 years and 21% in patients ≥75 years (p = .495). The in-hospital mortality rate was 1.3% in patients ≤74 and none in patients ≥75 years. Reoperation rates were similar between groups.

Conclusion: These results indicate that age above 74 should not automatically exclude patients from undergoing CRS-HIPEC. Careful selection ensures favorable survival without an increase in postoperative morbidity.

Studying the pathogenesis of human-adapted microorganisms is challenging, since small animal models often fail to recapitulate human physiology. Hence, the comprehensive genetic and regulatory circuits driving the infection process of principal human pathogens such as Shigella flexneri remain to be defined. We combined large-scale Shigella infections of enteroids and colonoids with transposon-directed insertion sequencing and Bayesian statistical modeling to address infection bottlenecks, thereby establishing the comprehensive genome-wide map of Shigella genes required to infect human intestinal epithelium. This revealed the Shigella virulence effectors essential for epithelial cell colonization across geometries and intestinal segments, identified over 100 chromosomal genes involved in the process and uncovered a post-transcriptional mechanism whereby tRNA-modification enzymes and differential codon usage exert global control of a bacterial virulence program. Our findings provide a broadly applicable framework for combining advanced organotypic tissue culture with functional genomics and computational tools to map human–microorganism interactions at scale.

Introduction: Appendiceal adenocarcinoma represents a diagnostic and therapeutic challenge since it is prone to early lymphatic and peritoneal spread. We aimed to analyze the proportion of lymph node metastases in completion right hemicolectomy specimens, risk factors for peritoneal metastases (PM), and prognosis after definitive treatment.

Methods: Ninety-three patients with appendiceal adenocarcinoma scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) in Uppsala 2004-2020 were identified from a prospectively maintained registry. Risk factors for PM were assessed based on the presence (CT + group, n = 55) or absence (CT - group, n = 37) of visible PM at baseline CT scan. Prognostic factors were analyzed based on the actual presence (PM group, n = 66) or absence (no PM group, n = 27) of PM.

Results: The median age was 60 (26-78). Forty-eight patients were women. Resection of PM at initial surgery indicated an 80 % risk of finding PM at a follow-up exploration. R1 appendectomy and perforated appendix had a similar risk for PM (24 %,26 %) which increased to 38 % if both were present. Regional lymph node metastases occurred in 31 % in the CT + group vs. 14 % in the CT- group (p = 0.005) and was associated with poor survival HR 5.16 (1.49-17.81). The 5-year OS and DFS rates were 54 % and 29 % in the PM group.

Conclusions: Patients with certain risk factors have a high likelihood of PM despite a normal CT scan, which justifies selective exploration at a HIPEC center. Regional lymph node spread supports the current practice of completion right hemicolectomy and is a significant prognostic factor.

Despite their relatedness, Salmonella and Shigella enteropathogens differ in infectious dose, pathogenesis, and disease kinetics. The prototype strains Salmonella enterica serovar Typhimurium (Salmonella) and Shigella flexneri (Shigella) use Type-3-secretion-systems (T3SSs) to colonize intestinal epithelial cells (IECs). However, they have evolved unique sets of T3SS effectors and accessory virulence factors. A synthesis of how these differences impact the temporal progression of infection in non-transformed human epithelia is missing. Here, we followed Salmonella and Shigella infections of human enteroids and colonoids by time-lapse imaging to pinpoint virulence factor modules that shape the divergent epithelial colonization strategies. By an apical targeting module that integrates flagella and the SPI-4-encoded adhesin system with T3SS-1, Salmonella accomplishes appreciable numbers of apical IEC invasion events. These are promptly counteracted by IEC death, thus fostering a polyclonal iterative epithelial colonization strategy. The lack of a corresponding apical targeting module in Shigella makes this pathogen reliant on external factors, for example, preexisting damage, for rare apical access to the intraepithelial environment. However, Shigella compensates for this ineptness by an intraepithelial expansion module reliant on the tight coupling of OspC3-dependent temporal delay of cell death and IcsA-mediated mobility. This module enables intraepithelial Shigella to evade the IEC death response just long enough to expand laterally, thus fostering an essentially monoclonal colonization strategy. Taken together, the study reveals how a small set of virulence factors shapes divergent epithelial colonization strategies by related enterobacteria.

Pathogen invasion of intestinal epithelial cells (IECs) is a key gut infection event. The dynamics of this process in intact epithelia and the factors governing IEC susceptibility remain underexplored. We present a resource for live-cell infection imaging in human enteroid-/colonoid-derived IEC layers across maturation states and in the presence or absence of soluble mucus production. Utilization of this resource shows how human IEC maturation fortifies the apical surface against invasion by Salmonella Typhimurium (S.Tm). Immature IEC layers appear permissive to S.Tm invasion, but maturation toward an enterocyte/colonocyte phenotype reduces the susceptibility by up to 10-fold. This shift couples to downregulated expression of actin regulatory proteins exploited by the pathogen, an increased dependence on the S.Tm effector SipA, and the build-up of the apical IEC glycocalyx linked to surface-attached mucins like MUC13 and nullifiable by StcE-enzyme treatment. This underscores how the maturation state of human IECs governs susceptibility to bacterial invasion.

Background

Prediction of open–close and long-term outcome is challenging in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prognostic scores often include factors not known at baseline. Therefore, we aimed to analyze whether patterns of preoperative tumor markers could aid in prediction of open–close surgery and outcome in patients with pseudomyxoma peritonei (PMP) or colorectal peritoneal metastases (PM).

Patients and Methods

All patients accepted for CRS and HIPEC for PMP or colorectal PM at Uppsala University Hospital in 2013–2021 were included. The tumor markers CEA, CA19-9, CA125, CA72-4, and CA15-3 were clustered using the k-means algorithm; the average silhouette width determined the optimal numbers of clusters.

Results

Clustering of patients with PMP (n = 138) and colorectal PM (n = 213) resulted in two clusters each. PMPCluster-1 (n = 124) had a 5-year overall survival (OS) of 77% (95% CI 69−85%), 11 (9%) open–close surgeries, and a median peritoneal cancer index (PCI) of 17. PMPCluster-2 (n = 14) patients had poorer prognosis (36%, 95% CI 15–85%, p = 0.003), more often open–close (n = 6, 43%, p = 0.002), and higher PCI (median 36, p < 0.001). ColorectalCluster-1 (n = 191) had a 5-year OS of 28% (95% CI 21–37%), median PCI of 11, and 38 (20%) open–close surgeries. ColorectalCluster-2 (n = 22) had poorer prognosis (10%, 95% CI 3–36%, p = 0.02), higher PCI (median 26, p < 0.001), higher completeness of cytoreduction score (p = 0.005), but no difference in open–close surgery (n = 6, 27%, p = 0.411). PMPCluster-2 and ColorectalCluster-2 were characterized by markedly elevated tumor markers. Open–close surgery was unusual in cases of normal CA72-4.

Conclusions

Elevation of several preoperative tumor markers is associated with poor prognosis and increased risk of open–close. CA72-4 deserves increased attention.

Objectives: The effects of preoperative chemotherapy have been poorly studied in colorectal cancer with peritoneal metastases (CRC-PM). This study evaluated preoperative chemotherapy from the first multi-disciplinary team meeting (MDT) decision, focusing on the response rates, surgical outcomes, and survival. Methods: This retrospective cohort study analyzed consecutive patients with resectable or potentially resectable CRC-PM evaluated at Uppsala University Hospital's peritoneal-MDT between March 2019 and December 2023. Kaplan-Meier curves and Cox-regression analyses were used for survival analysis. Results: Of 179 patients, 81 underwent upfront surgery; 52 received doublet chemotherapy and 46 received doublet with targeted therapy. Targeted group showed a 52% overall response rate vs. 36% for doublet group (p=0.14), with patients selected for CRS and HIPEC at a 52% vs. 31% rate, respectively, p=0.086. The median overall survival was superior in the targeted group than in the doublet group (intention-to-treat with all patients included): 21 (95%CI: 18-35) vs. 17 (95%CI: 14-22) months (p=0.027). The VEGF-targeted therapy outperformed EGFR-targeted therapy: 32 (95%CI: 21-Not reached) vs. 15 (95%CI: 11-40) months (p=0.042). Conclusions: Preoperative chemotherapy with targeted antibodies improves overall survival in CRC-PM in patients that are not candidates for upfront CRS and HIPEC. Bevacizumab is associated with improvement over EGFR targeted treatment in a subgroup analysis. 

Purpose

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRSH) or liver resection have led to increased survival in patients with peritoneal or liver metastases of colorectal cancer. Selected patients undergo concomitant CRSH and liver resection. Differences in survival and morbidity between patients who underwent concomitant surgery, CRSH or liver resection for peritoneal and/or liver metastases were compared.

Methods

Patients who underwent liver resection and/or CRSH for colorectal liver and/or peritoneal metastases, 2006-2016, were included. Regression analysis was used to evaluate the associations between baseline characteristics and survival.

Results

Overall, 634 patients were studied. Twenty-eight patients had peritoneal and liver metastases, 121 patients had peritoneal metastases only, and 485 patients had isolated liver metastases. Median survival after concomitant treatment was 23.8 months (95% CI 12.8-43.8), after CRSH 34.5 months (95% CI 27.1-41.9), and after liver resection 54.2 months (95% CI 47.4-61.0) (p < 0.001). Increased hepatic tumor burden (HR 3.2, 95% CI 1.8-5.8) and high-volume peritoneal disease (HR 6.0, 95% CI 3.7-9.8) were associated with decreased survival in multivariate analysis. Postoperative complications according to a Clavien-Dindo score > 3a were observed in 11% in the liver resection group, 15% in the CRSH group, and 11% in the concomitant treatment group (p = 0.945).

Conclusions

Patients treated with concomitant surgery for liver and peritoneal metastases experienced a shorter median overall survival than patients treated for metastases at an isolated site but had a similar rate of severe postoperative complications. The extent of peritoneal spread seemed to impact survival more than the tumor burden in the liver.