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Background/Aims: Clinically relevant postoperative pancreatic fistula (CR-POPF) after distal pancreatectomy (DP) occurs in 20%–40% of patients and remains a leading cause of morbidity and increased healthcare cost in this patient group. Recently, several studies suggested decreased risk of CR-POPF with the use of peri-firing compression (PFC) technique. The aim of this report was to conduct a systematic review to get an overview of the current knowledge on the use of PFC in DP. In addition, our experience with PFC was presented.Methods: The systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Also, 19 patients undergoing DP with the use of PFC at Oslo University Hospital were studied. The primary endpoint was incidence of CR-POPF.Results: Seven articles reporting a total of 771 patients were ultimately included in the systematic review. Only two of these were case–control studies examining outcomes in patients with and without PFC, while the rest were case series. These were heterogeneous in terms of staplers used, cartridge selection policy, and PFC technique. Both case–control studies reported significantly reduced CR- POPF incidence with PFC. Eight (21%) of our patients developed CR-POPF after DP with PFC. Only one patient developed CR-POPF among those with pancreatic transection site thickness ⩽1.5 cm.Conclusion: Evidence on potential benefits of PFC in DP is limited in quantity and quality. Our findings suggest that the use of PFC does not lead to reduction in the incidence of CR-POPF. Yet, there might be a benefit from PFC when dealing with a thin pancreas.

In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.

Background and objective: Bariatric surgery with Roux-en-Y gastric bypass (RYGB) is widely used to treat morbid obesity and present diagnostic and therapeutic challenges in patients with pancreatic and periampullary tumors. The aim of this study was to describe diagnostic tools and challenges in performing pancreatoduodenectomy (PD) on patients with altered anatomy after RYGB.Methods: Patients undergoing PD after RYGB from April 2015 to June 2022 at a tertiary referral center were identified. Preoperative workup, operative techniques, and outcomes were reviewed. A literature search was performed to identify articles reporting PD in post-RYGB patients.Results: Of a total of 788 PDs, six patients had previous RYGB. The majority were women (n = 5), and median age was 59 years. The patients most commonly presented with pain (50%) and jaundice (50%) with a median of 5.5 years after RYGB. The gastric remnant was resected in all cases, and reconstruction of the pancreatobiliary drainage was achieved using the distal part of the pre-existing pancreatobiliary limb in all patients. Median follow-up was 60 months. The Clavien–Dindo grade ⩾3 complications occurred in two patients (33.3%), and 90 days mortality occurred in one patient (16.6%). The literature search revealed 9 articles reporting a total of 122 cases, specifically addressing PD after RYGB.Conclusions: Reconstruction after PD in post-RYGB patients may be challenging. Resection of the gastric remnant and use of the pre-existing biliopancreatic limb may be a safe strategy, but surgeons should be prepared for other reconstruction options for creation of a new pancreatobiliary limb.

Background and objective: An association between body mass index (BMI) and pancreatic cancer is suggested in observational studies. However, further studies are required to substantiate available evidence. The aim of this study was to explore the association between BMI and pancreatic ductal adenocarcinoma (PDAC) risk, treatment, and mortality.Methods: A registry-based cohort study was performed by combining data from four registries in Norway. Baseline data were collected between 1963 and 1975 with follow-up data collected until 2018. Kaplan–Meier curves and multivariable Cox regressions were estimated. Chi-square tests were used to analyze differences between groups.Results: The study cohort consisted of 1,723,692 individuals. A total of 8973 PDAC cases were identified during 55,744,749 person-years of follow-up. A 5 kg/m2increase in BMI was associated with an increased risk of PDAC if high BMI at young age (16–29 years) (hazard ratio (HR): 1.21, 95% confidence interval (CI): 1.13–1.31), both for men (HR: 1.30, 95% CI: 1.15–1.46) and women (HR: 1.16, 95% CI: 1.05–1.28). In men, there was a 52% increase in risk of early-onset PDAC (

Background: Traditionally, patients with large liver tumors (≥ 50 mm) have been considered for anatomic major hepatectomy. Laparoscopic resection of large liver lesions is technically challenging and often performed by surgeons with extensive experience. The current study aimed to evaluate the surgical and oncologic safety of laparoscopic parenchyma-sparing liver resection in patients with large colorectal metastases. Methods: Patients who primarily underwent laparoscopic parenchyma-sparing liver resection (less than 3 consecutive liver segments) for colorectal liver metastases between 1999 and 2019 at Oslo University Hospital were analyzed. In some recent cases, a computer-assisted surgical planning system was used to better visualize and understand the patients’ liver anatomy, as well as a tool to further improve the resection strategy. The surgical and oncologic outcomes of patients with large (≥ 50 mm) and small (< 50 mm) tumors were compared. Multivariable Cox-regression analysis was performed to identify risk factors for survival. Results: In total 587 patients met the inclusion criteria (large tumor group, n= 59; and small tumor group, n= 528). Median tumor size was 60 mm (range, 50–110) in the large tumor group and 21 mm (3–48) in the small tumor group (p< 0.001). Patient age and CEA level were higher in the large tumor group (8.4 μg/L vs. 4.6 μg/L, p< 0.001). Operation time and conversion rate were similar, while median blood loss was higher in the large tumor group (500 ml vs. 200 ml, p< 0.001). Patients in the large tumor group had shorter 5 year overall survival (34% vs 49%, p= 0.027). However, in the multivariable Cox-regression analysis tumor size did not impact survival, unlike parameters such as age, ASA score, CEA level, extrahepatic disease at liver surgery, and positive lymph nodes in the primary tumor. Conclusion: Laparoscopic parenchyma-sparing resections for large colorectal liver metastases provide satisfactory short and long-term outcomes. Graphical abstract:

Minimally invasive pancreatoduodenectomy has gained popularity throughout the last decade. For laparoscopic pancreatoduodenectomy, some high-level evidence exists, but with conflicting results. There are currently no published randomized controlled trials comparing robotic and open pancreatoduodenectomy. Comparative long-term data for patients with pancreatic ductal adenocarcinoma is lacking to date. Based on the existing evidence, current observed benefits of minimally invasive pancreatoduodenectomy over open pancreatoduodenectomy seem scarce, but retrospective data indicate the safety of these procedures in selected patients. As familiarity with the robotic platform increases, studies have shown an expansion in indications, also including patients with vascular involvement and even indicating favorable results in patients with obesity and high-risk morphometric features. Several ongoing randomized controlled trials aim to investigate potential differences in short- and long-term outcomes between minimally invasive and open pancreatoduodenectomy. Their results are much awaited.

IMPORTANCE: Portal vein embolization (PVE) has been implemented in patients with extensive colorectal liver metastases to increase the number of patients able to undergo liver resection. Liver transplant could be an alternative in selected patients with extensive liver-only disease, and we have recently shown promising survival outcomes. OBJECTIVE: To compare overall survival (OS) among patients with colorectal cancer and high liver metastasis tumor load who were treated with liver transplant or with PVE and liver resection. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study assessed 50 patients with colorectal cancer liver metastases who were previously enrolled in liver transplant studies between November 2006 and August 2019 at Oslo University Hospital in Norway. Those patients were compared with a retrospective cohort of 53 patients in the Oslo University Hospital PVE database from March 2006 through November 2015 with similar selection criteria who underwent PVE and liver resection. MAIN OUTCOMES AND MEASURES: The OS among patients with high tumor load after liver transplant was compared with that among patients with high tumor load who underwent PVE and liver resection. High tumor load was defined as 9 or more metastatic tumors or a diameter of 5.5 cm or longer for the largest liver lesion. RESULTS: In the PVE cohort of 53 patients, the median age was 61.8 years (range, 34.3-71.3 years), and 36 patients (68%) were men. The 5-year OS rate among 38 patients who underwent liver resection after PVE was 44.6%. The 5-year OS rate for patients with high tumor load was 33.4% for those who underwent liver transplant and 6.7% for those who underwent PVE. Among patients with high tumor load and left-sided primary tumors, the 5-year OS rate was 45.3% for those receiving a liver allograft and 12.5% for those treated with PVE and liver resection. CONCLUSIONS AND RELEVANCE: Patients with nonresectable disease, an extensive liver tumor load, and left-sided primary tumors had long OS after liver transplant, exceeding the survival outcome for those patients treated with PVE and liver resection.

Studies in mice and humans have shown that CD8+T cell immunosurveillance in non-lymphoid tissues is dominated by resident populations. Whether CD4+T cells use the same strategies to survey peripheral tissues is less clear. Here, examining the turnover of CD4+T cells in transplanted duodenum in humans, we demonstrate that the majority of CD4+T cells were still donor-derived one year after transplantation. In contrast to memory CD4+T cells in peripheral blood, intestinal CD4+TRMcells expressed CD69 and CD161, but only a minor fraction expressed CD103. Functionally, intestinal CD4+TRMcells were very potent cytokine producers; the vast majority being polyfunctional TH1 cells, whereas a minor fraction produced IL-17. Interestingly, a fraction of intestinal CD4+T cells produced granzyme-B and perforin after activation. Together, we show that the intestinal CD4+T-cell compartment is dominated by resident populations that survive for more than 1 year. This finding is of high relevance for the development of oral vaccines and therapies for diseases in the gut.

Studies in mice and humans have shown that CD8+T cell immunosurveillance in non-lymphoid tissues is dominated by resident populations. Whether CD4+T cells use the same strategies to survey peripheral tissues is less clear. Here, examining the turnover of CD4+T cells in transplanted duodenum in humans, we demonstrate that the majority of CD4+T cells were still donor-derived one year after transplantation. In contrast to memory CD4+T cells in peripheral blood, intestinal CD4+TRMcells expressed CD69 and CD161, but only a minor fraction expressed CD103. Functionally, intestinal CD4+TRMcells were very potent cytokine producers; the vast majority being polyfunctional TH1 cells, whereas a minor fraction produced IL-17. Interestingly, a fraction of intestinal CD4+T cells produced granzyme-B and perforin after activation. Together, we show that the intestinal CD4+T-cell compartment is dominated by resident populations that survive for more than 1 year. This finding is of high relevance for the development of oral vaccines and therapies for diseases in the gut.

IMPORTANCE: Perforated colonic diverticulitis usually requires surgical resection, with significant morbidity. Short-term results from randomized clinical trials have indicated that laparoscopic lavage is a feasible alternative to resection. However, it appears that no long-term results are available. OBJECTIVE: To compare long-term (5-year) outcomes of laparoscopic peritoneal lavage and primary resection as treatments of perforated purulent diverticulitis. DESIGN, SETTING, AND PARTICIPANTS: This international multicenter randomized clinical trial was conducted in 21 hospitals in Sweden and Norway, which enrolled patients between February 2010 and June 2014. Long-term follow-up was conducted between March 2018 and November 2019. Patients with symptoms of left-sided acute perforated diverticulitis, indicating urgent surgical need and computed tomography–verified free air, were eligible. Those available for trial intervention (Hinchey stages <IV) were included in the long-term follow-up. INTERVENTIONS: Patients were assigned to undergo laparoscopic peritoneal lavage or colon resection based on computer-generated, center-stratified block randomization. MAIN OUTCOMES AND MEASURES: The primary outcome was severe complications within 5 years. Secondary outcomes included mortality, secondary operations, recurrences, stomas, functional outcomes, and quality of life. RESULTS: Of 199 randomized patients, 101 were assigned to undergo laparoscopic peritoneal lavage and 98 were assigned to colon resection. At the time of surgery, perforated purulent diverticulitis was confirmed in 145 patients randomized to lavage (n = 74) and resection (n = 71). The median follow-up was 59 (interquartile range, 51-78; full range, 0-110) months, and 3 patients were lost to follow-up, leaving a final analysis of 73 patients who had had laparoscopic lavage (mean [SD] age, 66.4 [13] years; 39 men [53%]) and 69 who had received a resection (mean [SD] age, 63.5 [14] years; 36 men [52%]). Severe complications occurred in 36% (n = 26) in the laparoscopic lavage group and 35% (n = 24) in the resection group (P = .92). Overall mortality was 32% (n = 23) in the laparoscopic lavage group and 25% (n = 17) in the resection group (P = .36). The stoma prevalence was 8% (n = 4) in the laparoscopic lavage group vs 33% (n = 17; P = .002) in the resection group among patients who remained alive, and secondary operations, including stoma reversal, were performed in 36% (n = 26) vs 35% (n = 24; P = .92), respectively. Recurrence of diverticulitis was higher following laparoscopic lavage (21% [n = 15] vs 4% [n = 3]; P = .004). In the laparoscopic lavage group, 30% (n = 21) underwent a sigmoid resection. There were no significant differences in the EuroQoL-5D questionnaire or Cleveland Global Quality of Life scores between the groups. CONCLUSIONS AND RELEVANCE: Long-term follow-up showed no differences in severe complications. Recurrence of diverticulitis after laparoscopic lavage was more common, often leading to sigmoid resection. This must be weighed against the lower stoma prevalence in this group. Shared decision-making considering both short-term and long-term consequences is encouraged. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01047462

ABSTRACTPatients with colorectal liver metastases (CLM) commonly receive neoadjuvant chemotherapy (NACT) prior to surgical resection. NACT may induce immunogenic cell death with subsequent recruitment of T-cells to the tumor microenvironment, which could be exploited by immune checkpoint inhibition (ICI). In theory, this could expand the use of ICI to obtain responses also in microsatellite stable colorectal cancer, but evidence to suggest optimal treatment schedules are lacking. In this study, densities of total-, cytotoxic-, helper- and regulatory T-cells were quantified by immunohistochemistry in resected CLM from 92 patients included in the OSLO-COMET trial (NCT01516710). All but one patient had microsatellite stable tumors (91/92). Associations between T-cell densities and clinicopathological parameters were analyzed. Fluoropyrimidine-based NACT (in most cases with addition of oxaliplatin or irinotecan) was administered to 45 patients completed median 8 weeks prior to surgical resection. No overall association was found between NACT administration and intratumoral T-cell densities. However, within the NACT group, a short time interval (<9.5 weeks) between NACT completion and CLM resection was strongly associated with high intratumoral T-cell densities compared to the long-interval and no NACT groups (medians 491, 236, and 292 cells/mm2, respectively; P< .0001). The results from this study suggest that the observed increase in intratumoral T-cells after NACT administration may be transient. The significance of this finding should be further explored to ensure that optimal treatment schedules are chosen for studies combining cytotoxic chemotherapy and ICI.

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for >1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

Macrophages (Mfs) are instrumental in maintaining immune homeostasis in the intestine, yet studies on the origin and heterogeneity of human intestinal Mfs are scarce. Here, we identified four distinct Mf subpopulations in human small intestine (SI). Assessment of their turnover in duodenal transplants revealed that all Mf subsets were completely replaced over time; Mf1 and Mf2, phenotypically similar to peripheral blood monocytes (PBMos), were largely replaced within 3 wk, whereas two subsets with features of mature Mfs, Mf3 and Mf4, exhibited significantly slower replacement. Mf3 and Mf4 localized differently in SI; Mf3 formed a dense network in mucosal lamina propria, whereas Mf4 was enriched in submucosa. Transcriptional analysis showed that all Mf subsets were markedly distinct from PBMos and dendritic cells. Compared with PBMos, Mf subpopulations showed reduced responsiveness to proinflammatory stimuli but were proficient at endocytosis of particulate and soluble material. These data provide a comprehensive analysis of human SI Mf population and suggest a precursor-progeny relationship with PBMos.

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Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19+ PC subset was dynamically exchanged, whereas of two CD19− PC subsets, CD45+ PCs exhibited little and CD45− PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45− PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19− PC subsets support selection and maintenance of protective PCs for life in human intestine.

Macrophages are a heterogeneous population of cells involved in tissue homeostasis, inflammation, and cancer. Although macrophages are densely distributed throughout the human intestine, our understanding of how gut macrophages maintain tissue homeostasis is limited. Here we show that colonic lamina propria macrophages (LpMs) and muscularis macrophages (MMs) consist of monocyte-like cells that differentiate into multiple transcriptionally distinct subsets. LpMs comprise subsets with proinflammatory properties and subsets with high antigen-presenting and phagocytic capacity. The latter are strategically positioned close to the surface epithelium. Most MMs differentiate along two trajectories: one that upregulates genes associated with immune activation and angiogenesis, and one that upregulates genes associated with neuronal homeostasis. Importantly, MMs are located adjacent to neurons and vessels. Cell–cell interaction and gene network analysis indicated that survival, migration, transcriptional reprogramming, and niche-specific localization of LpMs and MMs are controlled by an extensive interaction with tissue-resident cells and a few key transcription factors.

Lower urinary tract symptoms caused by benign prostatic obstruction is a common disorder and the incidence is increasing with higher life expectancy. The present article focuses on recently published methods to diagnose bladder outlet obstruction and differ between benign obstruction and prostate cancer in lower urinary tract symptoms patients.

Throughout the last century, the incidence of diverticular disease of the colon has increased tremendously in industrialized countries; nevertheless, the management of this condition is still controversial. Although several international guidelines for the management of diverticular disease are based on the same evidence, the recommendations differ greatly, emphasizing the lack of high-quality prospective studies. In Scandinavia, official guidelines for the management of diverticular disease exist only in Denmark. However, the treatment policies are quite similar in all Scandinavian countries. Computed tomography is the first choice for imaging of acute diverticulitis and its complications. Furthermore, the use of antibiotics in uncomplicated diverticulitis is nearly abandoned in Scandinavia, whereas several international guidelines still recommend their use. There is a broad consensus that abscesses secondary to acute diverticulitis can safely be managed with percutaneous drainage, which is in line with international recommendations. The surgical management of perforated diverticulitis with peritonitis is still as controversial in Scandinavia as elsewhere. Common surgical options are laparoscopic peritoneal lavage, primary resection with anastomosis, and primary resection with terminal colostomy (Hartmann’s procedure). Elective sigmoid resection in patients with diverticular disease seems to be performed less frequently in Scandinavia than in other European countries; the right indications are a current matter of debate. Symptomatic uncomplicated diverticular disease in the absence of diverticulitis has not gained great attention in Scandinavia.

Biliary adenofibroma is a rare benign liver tumor with potential for malignant transition. It has a bile duct origin characterized by a complex tubulocystic biliary epithelium with fibrous stroma. MRI features may suggest this uncommon entity, and histological findings can be diagnostic. We report a case of biliary adenofibroma with transformation to an intrahepatic cholangiocarcinoma.

Human CD4+CD25+ regulatory T (TR) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring TRcells develop in the thymus, adaptive TRcells develop in the periphery from naive CD4+ T cells. Adaptive TRcells may express cyclooxygenase type 2 (COX‐2) and suppress effector T cells by a PGE2‐dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive TRcells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25– T cells, the cells expressed FOXP3 and COX‐2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time‐points from Day 2, although suppression was merely present at Day 7. The adaptive TRcells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF‐β, IL‐10, and PGE2. However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.

In the present study, we investigate the mechanism for the protein kinase A (PKA)-mediated activation of C-terminal Src kinase (Csk). Although isolated Csk kinase domain was phosphorylated at Ser364 by PKA to the same stoichiometry as wild-type Csk, significant activation of the isolated Csk kinase domain by PKA was observed only in the presence of the purified Src homology 3 domain (SH3 domain). Furthermore, the interaction between the SH3 and kinase domains was facilitated by PKA-mediated phosphorylation of the kinase domain, as evaluated by surface plasmon resonance. This suggests that an overall structural domain organization and interaction between the kinase and SH3 domains are important for the activity of Csk and its regulation by PKA.