A spatial expression atlas of the adult human proximal small intestine.

The mouse small intestine shows profound variability in gene expression along the crypt-villus axis1,2. Whether similar spatial heterogeneity exists in the adult human gut remains unclear. Here we use spatial transcriptomics, spatial proteomics and single-molecule fluorescence in situ hybridization to reconstruct a comprehensive spatial expression atlas of the adult human proximal small intestine. We describe zonated expression and cell type representation for epithelial, mesenchymal and immune cell types. We find that migrating enterocytes switch from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip. Villus tip cells are pro-immunogenic, recruiting γδ T cells and macrophages to the tip, in contrast to their immunosuppressive roles in mouse. We also show that the human small intestine contains abundant serrated and branched villi that are enriched at the tops of circular folds. Our study presents a detailed resource for understanding the biology of the adult human small intestine.

Highly complex liver resections: Exploring the boundaries of feasibility and safety.

INTRODUCTION: In select clinical scenarios, advanced techniques for volume manipulation and vascular reconstruction are needed for complete hepatic tumor removal. These highly complex liver resections (HCLRs) entail a heightened risk of severe complications. Here, we describe the results of HCLR performed in a 3-year time period. MATERIALS AND METHODS: We conducted a retrospective analysis encompassing patients who underwent hepatic resections between June 15, 2020, and June 15, 2023. HCLR was defined according to previously established criteria, and included associating liver partition and portal vein ligation for staged hepatectomy. The outcomes of HCLR were compared to all non-HCLR performed within the same time frame. RESULTS: Among 167 hepatic resections, 26 were considered HCLR, and all were major resections. Five utilized total vascular exclusion, with venovenous bypass in three, and hypothermic liver perfusion in three. Five resections included vascular reconstructions, and one included hypothermic circulatory arrest for extraction of a tumor extending to the right atrium. Of the non-HCLR, 38 (26.9%) were major, and 49 (34.7%) were performed laparoscopically. The rates of overall major postoperative complications were comparable between those who underwent HCLR versus non-HCLR. HCLR was associated with increased rates of biliary complications, readmissions, and reoperation. However, no postoperative 90-day mortality was documented within patients that underwent HCLR compared to two in the non-HCLR group. CONCLUSIONS: In expert hands, HCLR can be performed with acceptable complication profile, akin to that of major non-HCLR. Those with questionable resectability should be referred to tertiary hepato-pancreato-biliary centers.

Long-term overall survival in patients undergoing liver resection for metastatic anal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: There is limited research on management of metastatic anal canal squamous cell carcinoma (SCC) to the liver. This study aimed to describe outcomes for patients undergoing liver resection of anal SCC metastases. METHODS: A multicenter, retrospective cohort study was conducted by three tertiary-referral centers. Patients undergoing liver surgery between 2008 and 2022 were included. Cox regression analysis was performed to evaluate predictors of recurrence and survival and Kaplan-Meier analysis was performed for 1-, 3-, and 5-year survival. RESULTS: Twenty-one patients underwent liver resection and/or ablation. None were HIV positive and 24% had known HPV infection. 20/21(95%) patients had undergone Nigro protocol for management of the primary tumor with 12/21 (57%) patients experiencing complete response. 4/21 (19%) patients had synchronous liver metastases at time of diagnosis. Median tumor size was 5.0 cm and median tumor number was one. At analysis, 52% remained alive. Median overall survival was 32.2 months. 5-year overall survival was 50%. Median recurrence-free survival was 7.7 months and 5-year recurrence-free survival was 30%. Need for salvage abdominoperineal resection was negatively associated with recurrence-free survival. The most common site of recurrence was the liver. CONCLUSIONS: Liver resection for metastatic anal SCC can be beneficial for appropriately selected patients.

Laparoscopic versus open liver resections for intrahepatic cholangiocarcinoma and gallbladder cancer: the Mayo clinic experience.

BACKGROUND: Data regarding laparoscopic liver resections(LLRs) for Gallbladder cancer(GBC) and Intrahepatic Cholangiocarcinoma(iCCA) are sparse. This study compared LLRs with open liver resections(OLRs) in a high-volume center. METHODS: Data of patients who underwent LLR or OLR for GBC or iCCA at Mayo-Clinic between 01/2016 and 04/2021 were retrospectively compared. Proportional hazards models were used to compare the approach on survival. RESULTS: 32 and 52 patients underwent LLR and OLR during the study period, respectively. 64 and 20 patients had iCCA and GBC, respectively. LLR had lower median blood loss (250 mL vs. 475 mL, p = 0.001) and shorter median length of stay compared to OLR (3.0 days vs. 6.0 days, p = 0.001). LLR and OLR did not differ in post-operative major complication (25% vs. 32.7%, p = 0.62), negative margin (100% vs. 90.4%, p = 0.15) and completeness of lymphadenectomy rates (36.8% vs. 45.5%, p = 0.59). The median number of harvested lymph node was 4.0 and 5.0 for LLR and OLR, respectively (p = 0.347). There were no associations between approach and 3-year overall and disease-free survival between LLR and OLR (49.8% vs. 63.2% and 39.6% vs. 21.5%, p = 0.66 and p = 0.69). DISCUSSION: With appropriate patient selection and when compared to OLRs, LLRs for GBC and iCCA are feasible, safe and offer potential short-term benefits without compromising on oncological resection principals and long-term outcomes.

Safety and Outcomes of Combined Pancreatic and Hepatic Resections for Metastatic Pancreatic Neuroendocrine Tumors.

BACKGROUND: Approximately 40-50% of patients with pancreatic neuroendocrine tumors (pNETs) initially present with distant metastases. Little is known about the outcomes of patients undergoing combined pancreatic and hepatic resections for this indication. METHODS: Patients who underwent hepatectomy for metastatic pNETs at Mayo Clinic Rochester from 2000 to 2020 were retrospectively reviewed. Major pancreatectomy was defined as pancreaticoduodenectomy or total pancreatectomy, and major hepatectomy as right hepatectomy or trisegmentectomy. Characteristics and outcomes of patients who underwent pancreatectomy with simultaneous hepatectomy were compared with those of patients who underwent isolated hepatectomy (with or without prior history of pancreatectomy). RESULTS: 205 patients who underwent hepatectomy for metastatic pNETs were identified: 131 underwent pancreatectomy with simultaneous hepatectomy and 74 underwent isolated hepatectomy. Among patients undergoing simultaneous hepatectomy, 89 patients underwent minor pancreatectomy with minor hepatectomy, 11 patients underwent major pancreatectomy with minor hepatectomy, 30 patients underwent minor pancreatectomy with major hepatectomy, and 1 patient underwent major pancreatectomy with major hepatectomy. Patients undergoing simultaneous hepatectomy had more numerous liver lesions (10 or more lesions in 54% vs. 34%, p = 0.008), but the groups were otherwise similar. Rates of any major complications (31% versus 24%, p = 0.43), hepatectomy-specific complications such as bile leak, hemorrhage, and liver failure (0.8-7.6% vs. 1.4-12%, p = 0.30-0.99), and 90-day mortality (1.5% vs. 2.7%, p = 0.62) were similar between the two groups. 5-year overall survival was 64% after combined resections and 65% after isolated hepatectomy (p = 0.93). CONCLUSION: For patients with metastatic pNETs, combined pancreatic and hepatic resections can be performed with acceptable morbidity and mortality in selected patients at high-volume institutions.

Artificial intelligence for identification of focal lesions in intraoperative liver ultrasonography.

PURPOSE: Intraoperative ultrasonography (IOUS) of the liver is a crucial adjunct in every liver resection and may significantly impact intraoperative surgical decisions. However, IOUS is highly operator dependent and has a steep learning curve. We describe the design and assessment of an artificial intelligence (AI) system to identify focal liver lesions in IOUS. METHODS: IOUS images were collected during liver resections performed between November 2020 and November 2021. The images were labeled by radiologists and surgeons as normal liver tissue versus images that contain liver lesions. A convolutional neural network (CNN) was trained and tested to classify images based on the labeling. Algorithm performance was tested in terms of area under the curves (AUCs), accuracy, sensitivity, specificity, F1 score, positive predictive value, and negative predictive value. RESULTS: Overall, the dataset included 5043 IOUS images from 16 patients. Of these, 2576 were labeled as normal liver tissue and 2467 as containing focal liver lesions. Training and testing image sets were taken from different patients. Network performance area under the curve (AUC) was 80.2 ± 2.9%, and the overall classification accuracy was 74.6% ± 3.1%. For maximal sensitivity of 99%, the classification specificity is 36.4 ± 9.4%. CONCLUSIONS: This study provides for the first time a proof of concept for the use of AI in IOUS and show that high accuracy can be achieved. Further studies using high volume data are warranted to increase accuracy and differentiate between lesion types.

Hepatocellular carcinoma as predominant cancer subgroup accounting for sex differences in post-hepatectomy liver failure, morbidity and mortality.

BACKGROUND: Experimental evidence suggests sex dependent differences in liver regeneration. Limited evidence is available examining sex differences in post-hepatectomy liver failure (PHLF) and postoperative outcomes. Our aim was to assess the influence of sex on the outcomes after liver resection. METHODS: The hepatectomy targeted National Surgical Quality Improvement Program (NSQIP) database was assessed for associations between sex and outcomes. RESULTS: A total of 13,401 patients underwent elective hepatic resection between 2014-2017. PHLF was highest among male patients with hepatocellular carcinoma (HCC) (OR = 2.81,95%CI:1.40-5.62). Male sex was independently associated with increased PHLF (OR = 1.47,95%CI:1.15-1.88), major complications (OR = 1.25,95%CI:1.08-1.45), mortality (OR = 1.61,95%CI:1.03-2.50), and if only major resections were assessed (OR = 1.38,95%CI:1.03-1.84). Diagnosis specific subgroup analyses revealed that effects of sex were predominantly HCC associated. CONCLUSIONS: This is the largest series investigating the effects of gender on outcomes after hepatic resection. We documented that women undergoing liver resection have significantly lower risk of PHLF. This difference seemed influenced by the striking increase of PHLF in male HCC patients. These hypothesis suggest that sex might play a role in preoperative risk stratification.

Laparoscopic Subtotal Cholecystectomy for the Difficult Gallbladder: A Safe Alternative.

BACKGROUND: The safe completion of cholecystectomy is dependent on proper identification and secure closure of the cystic duct. Effecting this closure poses a great challenge when inflammatory changes obscure the anatomy. Subtotal cholecystectomy allows for near complete removal of the gallbladder and complete evacuation of the stones while avoiding dissection in the hazardous area. OBJECTIVES: To describe experience with laparoscopic subtotal cholecystectomy. METHODS: Subtotal cholecystectomy was performed when the critical view of safety could not be achieved. Surgical technique was similar in all cases and included opening the Hartmann's pouch, removing stones obstructing the gallbladder outlet, and identifying the opening of the cystic duct, as well as circumferential transection of the gallbladder neck, closure of the gallbladder stump, and excision of the gallbladder fundus. Data retrieved from patient charts included demographics, pre-operative history, operative and postoperative course, and late complications. No bile duct injuries were observed in this series. RESULTS: A total of 53 patients underwent laparoscopic subtotal cholecystectomy (2010-2018). Ten patients were operated during the acute course of the disease and 43 electively. Acute cholecystitis was the leading cause for gallbladder removal. Cholecystostomy tube was placed in 18 patients during acute hospitalization. The gallbladder remnant was closed and a drain was placed in most patients. Of the 53 patients, 42 had an uneventful postoperative course. CONCLUSIONS: Laparoscopic subtotal cholecystectomy is an effective surgical technique to avoid bile duct injury when the cystic duct cannot safely be identified. Subtotal cholecystectomy has acceptable morbidity and obviates the need for conversion in these difficult cases.

Volvulus and bowel obstruction in ATR-X syndrome-clinical report and review of literature.

Alpha thalassemia-mental retardation, X-linked (ATR-X) syndrome is a rare genetic disorder with a variety of clinical manifestations. Gastrointestinal symptoms described in this syndrome include difficulties in feeding, regurgitation and vomiting which may lead to aspiration pneumonia, abdominal pain, distention, and constipation. We present a 19-year-old male diagnosed with ATR-X syndrome, who suffered from recurrent colonic volvulus that ultimately led to bowel necrosis with severe septic shock requiring emergent surgical intervention. During 1 year, the patient was readmitted four times due to poor oral intake, dehydration and abdominal distention. Investigation revealed partial small bowel volvulus which resolved with non-operative treatment. Small and large bowel volvulus are uncommon and life-threatening gastrointestinal manifestations of ATR-X patients, which may contribute to the common phenomenon of prolonged food refusal in these patients.

Linking factors to incisional hernia following pancreatic surgery: a 14-year retrospective analysis.

BACKGROUND: Incisional hernias (IH) are a significant postoperative complication with profound implications for patient morbidity and healthcare costs. The relationship between IH and perioperative factors in pancreatic surgery, with particular attention to preoperative biliary stents and pancreatic fistulas requires further exploration. METHODS: This retrospective observational study examined adult patients who underwent open pancreatic surgeries via midline incision at a high-volume tertiary hepatopancreatobiliary center from January 2008 to December 2021. The study focused on IH incidence and associated risk factors, with particular attention to preoperative biliary stents and pancreatic fistulas. RESULTS: In a cohort of 620 individuals undergoing pancreatic surgery, 351 had open surgery with at least one-year follow-up. Within a median follow-up of 794 days (IQR 1694-537), the overall incidence of IH was 17.38%. The highest frequency of IH was observed among patients who had a Pancreaticoduodenectomy (PD). Significant predictors for the development of IH within the entire study population in a multivariable analysis included perioperative biliary stenting (OR 2.05; 95% CI 1.06-3.96; p = 0.03), increased age at diagnosis (OR 2.05; 95% CI 1.06-3.96; p = 0.01), and BMI (OR 1.08; 95% CI 1.01-1.15; p = 0.01). In the subset of patients who underwent Pancreaticoduodenectomy (PD), although the presence of biliary stents was associated with a heightened occurrence of SSIs, it did not demonstrate a direct correlation with an increased incidence of incisional hernias (IH). The development of pancreatic fistulas did not show a significant correlation with IH in either the Distal Pancreatectomy with Splenectomy (DPS) or the PD patient groups. CONCLUSIONS: The study underscores a notable association between biliary stent placement and increased IH risk after PD, mediated by elevated SSI incidence. Pancreatic fistulas were not directly correlated with IH in the studied cohorts. Further research is necessary to validate these findings and guide clinical practice.

Perioperative Platelet Count Ratio Predicts Long-Term Survival after Left Pancreatectomy and Splenectomy for Pancreatic Adenocarcinoma.

BACKGROUND: The value of platelet characteristics as a prognostic factor in patients with pancreatic adenocarcinoma (PDAC) remains unclear. METHODS: We assessed the prognostic ability of post-splenectomy thrombocytosis in patients who underwent left pancreatectomy for PDAC. Perioperative platelet count ratio (PPR), defined as the ratio between the maximum platelet count during the first five days following surgery and the preoperative level, was assessed in relation to long-term outcomes in patients who underwent left pancreatectomy for PDAC between November 2008 and October 2022. RESULTS: A comparative cohort of 245 patients who underwent pancreaticoduodenectomy for PDAC was also evaluated. The median PPR among 106 patients who underwent left pancreatectomy was 1.4 (IQR1.1, 1.8). Forty-six had a PPR ≥ 1.5 (median 1.9, IQR1.7, 2.4) and 60 had a PPR < 1.5 (median 1.2, IQR1.0, 1.3). Patients with a PPR ≥ 1.5 had increased median overall survival (OS) compared to patients with a PPR < 1.5 (40 months vs. 20 months, p < 0.001). In multivariate analysis, PPR < 1.5 remained a strong predictor of worse OS (HR 2.24, p = 0.008). Among patients who underwent pancreaticoduodenectomy, the median PPR was 1.1 (IQR1.0, 1.3), which was significantly lower compared to patients who underwent left pancreatectomy (p > 0.001) and did not predict OS. CONCLUSION: PPR is a biomarker for OS after left pancreatectomy for PDAC. Further studies are warranted to consolidate these findings.

A Synchronous Robotic Resection of Colorectal Cancer and Liver Metastases-Our Initial Experience.

INTRODUCTION: Synchronous robotic colorectal and liver resection for metastatic colorectal cancer (mCRC) is gaining popularity. This case series describes our initial institutional experience. METHODS: A retrospective study of synchronous robotic colorectal and liver resections for metastatic colorectal cancer (March 2020 to December 2021). RESULTS: Eight patients underwent synchronous robotic resections. The median age was 59 (45-72), and the median body mass index was 29 (20-33). Seven received neoadjuvant chemotherapy, and five rectal cancers received neoadjuvant radiotherapy. One patient had a low anterior resection with major hepatectomy, two had low anterior resection with minor hepatectomy, and one had abdominoperineal resection with major hepatectomy. One patient had a left colectomy with minor hepatectomy, and two had right colectomies with minor hepatectomy. We used five robotic 8/12 mm ports in all cases. Extraction incisions were Pfannenstiel in four patients, colostomy site in two patients, one perineal incision, and one supra-umbilical incision. The median estimated blood loss was 200 mL (25-500), and the median operative time was 448 min (374-576). There were no intra-operative complications or conversions. Five patients had the liver resection first, and two of six anastomoses were performed before the liver resection. The Median length of stay was 4 days (3-14). There were two post-operative complications, prolonged ileus and DVT, with a Clavien-Dindo complication grade of I and II, respectively. There were no readmissions or reoperations. All colorectal and liver resection margins were negative. CONCLUSIONS: Synchronous robotic colorectal and liver resection can be performed effectively utilizing one port configuration with acceptable short-term outcomes and quality of oncologic resection.

Extracellular Vesicular Transmission of miR-423-5p from HepG2 Cells Inhibits the Differentiation of Hepatic Stellate Cells.

Liver fibrosis (LF) is a major cause of morbidity and mortality worldwide. Hepatic stellate cells (HSCs) are the primary source of extracellular matrix in the liver and their activation is a central event in LF development. Extracellular vesicles (EVs) are intercellular communication agents, which play important roles in physiological processes in chronic liver diseases. The aim of this study was to examine the crosstalk between hepatocytes and HSCs mediated by hepatocyte-secreted EVs. EVs were purified from primary mouse hepatocytes, HepG2 cell lines, under normal or stressed conditions. The effect of EVs on primary HSCs (pHSCs) differentiation was evaluated by measuring of differentiation markers. In addition, their impact on the carbon tetrachloride (CCl4)-induced fibrosis mouse model was evaluated. The results demonstrated that HepG2-EVs regulate HSC differentiation and that under stress conditions, promoted pHSCs differentiation into the myofibroblast phenotype. The evaluation of miRNA sequences in the HepG2 secreted EVs demonstrated high levels of miR-423-5p. The examination of EV cargo following stress conditions identified a significant reduction of miR-423-5p in HepG2-EVs relative to HepG2-EVs under normal conditions. In addition, pHSCs transfected with miR-423-5p mimic and exhibit lower mRNA levels of alpha smooth muscle actin and Collagen type 1 alpha, and the mRNA expression level of genes targeted the family with sequence-similarity-3 (FAM3) and Monoacylglycerol lipase (Mgll). This study strengthened the hypothesis that EVs are involved in LF and that their cargo changes in stress conditions. In addition, miR-423-5p was shown to be involved in HSCs differentiation and hence, fibrosis development.

The Impact of Establishing a Dedicated Liver Surgery Program at a University-affiliated Hospital on Workforce, Workload, Surgical Outcomes, and Trainee Surgical Autonomy and Academic Output.

Objective: To detail the implementation of a dedicated liver surgery program at a university-affiliated hospital and to analyze its impact on the community, workforce, workload, complexity of cases, the short-term outcomes, and residents and young faculties progression toward technical autonomy and academic production. Background: Due to the increased burden of liver tumors worldwide, there is an increased need for liver centers to better serve the community and facilitate the education of trainees in this field. Methods: The implementation of the program is described. The 3 domains of workload, research, and teaching were compared between 2-year periods before and after the implementation of the new program. The severity of disease, complexity of procedures, and subsequent morbidity and mortality were compared. Results: Compared with the 2-year period before the implementation of the new program, the number of liver resections increased by 36% within 2 years. The number of highly complex resections, the number of liver resections performed by residents and young faculties, and the number of publications increased 5.5-, 40-, and 6-fold, respectively. This was achieved by operating on more severe patients and performing more complex procedures, at the cost of a significant increase in morbidity but not mortality. Nevertheless, operations during the second period did not emerge as an independent predictor of severe morbidity. Conclusions: A new liver surgery program can fill the gap between the demand for and supply of liver surgeries, benefiting the community and the development of the next generation of liver surgeons.