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.

Myeloid derived suppressor cells mediate hepatocyte proliferation and immune suppression during liver regeneration following resection.

Liver regeneration following resection is a complex process relying on coordinated pathways and cell types in the remnant organ. Myeloid-Derived Suppressor Cells (MDSCs) have a role in liver regeneration-related angiogenesis but other roles they may play in this process remain to be elucidated. In this study, we sought to examine the effect of G-MDSCs on hepatocytes proliferation and immune modulation during liver regeneration. Global gene expression profiling of regenerating hepatocytes in mice with CD11b+Ly6G+ MDSCs (G-MDSCs) depletion revealed disrupted transcriptional progression from day one to day two after major liver resection. Key genes and pathways related to hepatocyte proliferation and immune response were differentially expressed upon MDSC depletion. Hepatocytes cellularity increased when co-cultured with G-MDSCs, or treated with amphiregulin, which G-MDSCs upregulate during regeneration. Cytometry by time-of-flight (CyTOF) analysis of the intra-liver immune milieu upon MDSC depletion during regeneration demonstrated increased natural killer cell proportions, alongside changes in other immune cell populations. Taken together, these results provide evidence that MDSCs contribute to early liver regeneration by promoting hepatocyte proliferation and modulating the intra-liver immune response, and illuminate the multifaceted role of MDSCs in liver regeneration.

A Prospective, Single-Arm Study to Evaluate the Safety and Efficacy of an Autologous Blood Clot Product in the Treatment of Anal Fistula.

BACKGROUND: Surgical treatment of complex perianal fistula is technically challenging, associated with risk of failure, and may require multiple procedures. In recent years, several biologic agents have been developed for permanently eradicating anal fistulous disease with variable success. In this study, the treatment is an autologous whole-blood product created from the patients' blood. It forms a provisional matrix that was found to be safe and effective in healing acute and chronic cutaneous wounds. OBJECTIVE: The study aimed to assess the efficacy and safety of an autologous blood clot product as a treatment for transsphincteric perianal fistulas. DESIGN: A prospective single-arm study. SETTINGS: A single tertiary medical center. PATIENTS: Patients with simple or complex transsphincteric fistulas confirmed by MRI were included in the study. Cause was either cryptoglandular or Crohn's disease related (in the absence of active luminal bowel disease). INTERVENTION: The outpatient procedure was performed under general anesthesia and consisted of: 1) physical debridement and cleansing of the fistula tract; 2) suture closure of the internal opening; and 3) instillation of the autologous blood clot product into the entire tract. MAIN OUTCOME MEASURES: Safety and efficacy at 6- and 12-months after surgery. RESULTS: Fifty-three patients (77% men) with a median age of 42 (20-72) years were included in the study. Three patients withdrew consent, and 1 patient was lost to follow-up. At the time of this interim analysis, 49 and 33 patients completed the 6- and 12-month follow-up period. Thirty-four of the 49 patients achieved complete healing (69%) at 6 months, but 20 of the 33 patients (60%) achieved healing after 1 year. All patients who achieved healing at 6 months remained healed at the 1-year mark. In a subgroup analysis of patients with Crohn's disease, 7 of 9 patients completed 1-year follow-up, with 5 patients (71%) achieving clinical remission. No major side effects or postoperative complications were noted, but 2 adverse events occurred (admission for pain control and coronavirus 2019 infection). LIMITATIONS: Noncomparative single-arm pilot study. CONCLUSIONS: Treatment with an autologous blood clot product in perianal fistular disease was found to be feasible and safe, with an acceptable healing rate in both cryptoglandular and Crohn's disease fistula-in-ano. Further comparative assessment is required to determine its potential role in the treatment paradigm of fistula-in-ano. See Video Abstract . BRAZO PARA EVALUAR LA SEGURIDAD Y EFICACIA DE RDVER, UN COGULO DE SANGRE AUTLOGO, EN EL TRATAMIENTO DE LA FSTULA ANAL: ANTECEDENTES:El tratamiento quirúrgico de la fístula perianal compleja es técnicamente desafiante, se asocia con riesgo de fracaso y puede requerir múltiples procedimientos. En los últimos años, se han desarrollado varios agentes biológicos con el fin de erradicar permanentemente la enfermedad fistulosa anal con éxito variable. El tratamiento RD2-Ver.02 es un producto de sangre total autólogo creado a partir de la sangre de los pacientes, que forma una matriz provisional que resultó segura y eficaz para curar heridas cutáneas agudas y crónicas.OBJETIVO:Evaluar la eficacia y seguridad de RD2-Ver.02 como tratamiento para las fístulas perianales transesfinterianas.DISEÑO:Un estudio prospectivo de un solo brazo.LUGARES:Un único centro médico terciario.PACIENTES:Se incluyeron en el estudio pacientes con fístulas transesfinterianas simples o complejas confirmadas mediante resonancia magnética. La etiología fue criptoglandular o relacionada con la enfermedad de Crohn (en ausencia de enfermedad intestinal luminal activa).INTERVENCIÓN:El procedimiento ambulatorio se realizó bajo anestesia general y consistió en: 1) desbridamiento físico y limpieza del trayecto fistuloso; 2) cierre con sutura de la abertura interna; y 3) instilación de RD2-Ver.02 en todo el tracto.PRINCIPALES MEDIDAS DE VALORACIÓN:Seguridad y eficacia a los 6 y 12 meses después de la cirugía.RESULTADOS:Se incluyeron en el estudio 53 pacientes (77% varones) con una mediana de edad de 42 (20-72) años. Tres pacientes retiraron su consentimiento y un paciente se perdió durante el seguimiento. En el momento de este análisis intermedio, 49 y 33 pacientes completaron el período de seguimiento de 6 y 12 meses, respectivamente. Treinta y cuatro (34) pacientes lograron una curación completa (69%) a los 6 meses, mientras que 20 de 33 pacientes (60%) lograron una curación después de un año. Todos los pacientes que lograron la curación a los 6 meses permanecieron curados al año. En un análisis de subgrupos de pacientes con enfermedad de Crohn, 7/9 pacientes completaron un seguimiento de un año y 5 pacientes (71%) alcanzaron la remisión clínica. No se observaron efectos secundarios importantes ni complicaciones postoperatorias, mientras que ocurrieron 2 eventos adversos (ingreso para control del dolor e infección por COVID-19).LIMITACIONES:Estudio piloto no comparativo de un solo brazo.CONCLUSIONES:Se encontró que el tratamiento con RD2-Ver.02 en la enfermedad fístula perianal es factible y seguro, con una tasa de curación aceptable tanto en la fístula criptoglandular como en la de Crohn en el ano. Se requiere una evaluación comparativa adicional para determinar su papel potencial en el paradigma de tratamiento de la fístula anal. (Pre-proofed version ).

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.

Kidney Transplantation in a Patient with Scleroderma.

BACKGROUND: Kidney involvement in systemic sclerosis (SSc) is common with altered kidney function present in approximately half of the patients [1]. Scleroderma renal crisis (SRC), the most severe kidney manifestation, occurs in about 20% of patients with this autoimmune disorder [1]. SRC mainly affects patients with the diffuse cutaneous systemic sclerosis (dcSSc) subtype of the disease, and particularly in those who are seropositive to anti RNA polymerase III antibodies [2]. In recent years, the prevalence of SRC has decreased following the initiation of medication therapy with angiotensin-converting-enzyme inhibitors (ACE-i). Previously, SRC mortality rates were as high as 78%. Contemporary studies in the post-ACE-i era suggest lower rates, with mortality rate ranging from 30% to 36% [3]. Nevertheless, progression to end-stage renal disease (ESRD) is evident and may require renal replacement therapies (RRTs). While renal transplant rates in SSc have increased, they constitute a small proportion of SSc-SRC patients (3-8%) and SSc-ESRD patients (4-17%).

[THE MULTIDISCIPLINARY GERIATRIC SURGERY UNIT AT THE CHAIM SHEBA MEDICAL CENTER - FIRST YEAR OF ACTIVITY].

INTRODUCTION: Recently, a Geriatric Surgery Unit (GSU) was established in the Sheba Medical Center. The Unit's aims include: professional assessment of surgical candidates, approval of the surgical plan by a multidisciplinary team discussion (MTD), and meeting the specific needs of the geriatric patient undergoing surgery. METHODS: We describe the establishment of the GSU and preliminary results from the first year of its activity (January-December 2022). The GSU team consisted of a geriatric nurse practitioner (NP), a geriatric physician, surgeons, anesthesiologists and a physiotherapist. Inclusion criteria for GSU assessment/treatment were age>80 years or substantial baseline geriatric morbidity. RESULTS: In 2022, 276 patients were treated by the GSU: 110 underwent elective comprehensive preoperative assessment in the NP clinic and the rest were assessed urgently/semi-electively during their hospitalization. One hundred and fifteen cases (median age 86 (65-98) years) were brought to MTD and considered for elective cholecystectomy (46.1%), colorectal procedures (16.5%), hernia repair (13.9%), hepatobiliary procedures (9.6%) or other surgeries (13.9%); of those, 49 patients (median age 86 (72-98) years) eventually proceeded to surgery, following which the median length of hospital stay (LOS) was 3.5 (1-60) days and the rate of postoperative complications was 46.7%. After discharge, the median duration of follow-up was 2.5 (0-18) months during which 4 patients died. Compared with geriatric patients who underwent cholecystectomy during 2021-2023 without MTD (n=39), in the cases discussed by the MTD, patients (n=17) had a shorter LOS (2.0±0.9 vs. 2.4±2.1 days), less 30-day Emergency Department referrals (12.5% vs. 28.2%) and less 30-day re-admissions (6.2% vs. 15.4%; all p≥0.3). CONCLUSIONS: Geriatric surgical patients require a designated professional approach to meet their unique perioperative needs. The effect of GSUs on perioperative outcomes merits further prospective studies.

The value of CA125 in predicting acute complicated colonic diverticulitis.

BACKGROUND: CA125 is a widely used serum marker for epithelial ovarian cancer which levels may also rise in benign conditions involving peritoneal irritation. We aimed to determine if serum CA125 levels can predict disease severity in patients presenting with acute diverticulitis. METHODS: We conducted a single-center prospective observational study, analyzing CA125 serum levels in patients who presented to the emergency department with computerized tomography-proven acute left-sided colonic diverticulitis. Univariate, multivariate, and receiver operating characteristic (ROC) analyses were used to correlate CA125 serum levels at time of initial presentation with the primary outcome (complicated diverticulitis) and secondary clinical outcomes (need for urgent intervention, length of hospital stay (LOS) and readmission rates). RESULTS: One hundred and fifty-one patients were enrolled between January 2018 and July 2020 (66.9% females, median age 61 years). Twenty-five patients (16.5%) presented with complicated diverticulitis. CA125 levels were significantly higher among patients with complicated (median: 16 (7-159) u/ml) vs. uncomplicated (8 (3-39) u/ml) diverticulitis (p < 0.001) and also correlated with the Hinchey severity class (p < 0.001). Higher CA125 levels upon admission were associated with a longer LOS and a greater chance to undergo invasive procedure during the hospitalization. In patients with a measurable intra-abdominal abscess (n = 24), CA125 levels were correlated with the size of the abscess (Spearman's r = 0.46, p = 0.02). On ROC analysis to predict complicated diverticulitis, the area under the curve (AUC) for CA125 (AUC = 0.82) was bigger than for the leukocyte count (AUC = 0.53), body temperature (AUC = 0.59), and neutrophil-lymphocyte ratio (AUC = 0.70) - all p values < 0.05. On multivariate analysis of factors available at presentation, CA125 was found to be the only independent predictor of complicated diverticulitis (OR 1.12 (95% CI 1.06-1.19), p < 0.001). CONCLUSIONS: The results from this feasibility study suggest that CA125 may accurately discriminate between simple and complicated diverticulitis, meriting further prospective investigation.

Readmission with acute kidney injury following ileostomy: patterns and predictors of a common phenomenon.

PURPOSE: Ileostomy is associated with various complications, often necessitating rehospitalization. High-output ileostomy is common and may lead to acute kidney injury (AKI). Here we describe the temporal pattern of readmission with AKI following ileostomy formation and identify risk factors. METHODS: Patients that underwent formation of ileostomy between 2008 and 2021 were included in this study. Readmission with AKI with high output ileostomy was defined as readmission with serum creatinine > 1.5-fold compared to the level at discharge or latest baseline (at least stage-1 AKI according to Kidney Disease: Improving Global Outcome (KDIGO) criteria), accompanied by ileostomy output > 1000 ml in 24 h. Patient characteristics and perioperative course were assessed to identify predictors for readmission with AKI. RESULTS: Of 1191 patients who underwent ileostomy, 198 (16.6%) were readmitted with a high output stoma and AKI. The mean time to readmission with AKI was 98.97 ± 156.36 days. Eighty-six patients (43.4%) had early readmission (within 30 days), and 66 (33%) were readmitted after more than 90 days. Over 90% of patients had more than one readmission, and 110 patients (55%) had 5 or more. Patient-related predictors for readmission with AKI were age > 65, body mass index > 30 kg/m2, and hypertension. Factors related to the postoperative course were AKI with creatinine > 2 mg/dl, postoperative hemoglobin < 8 g/dl or blood transfusion, albumin < 20 g/dl, high output stoma and need for loperamide, and length of hospital stay > 20 days. Factors related to early versus late readmissions and multiple readmissions were also analyzed. CONCLUSIONS: Readmission with AKI following ileostomy formation is a consequential event with distinct risk factors. Acknowledging these risk factors is the foundation for designing interventions aiming to reduce frequency of AKI readmissions in predisposed patient populations.

Ultrasound-Tomographic Image Fusion - A Novel Tool for Follow up After Acute Complicated Appendicitis.

BACKGROUND: Computerized tomography (CT) is an integral part of the follow-up and decision-making process in complicated acute appendicitis (AA) treated non-operatively. However, repeated CT scans are costly and cause radiation exposure. Ultrasound-tomographic image fusion is a novel tool that integrates CT images to an Ultrasound (US) machine, thus allowing accurate assessment of the healing process compared to CT on presentation. In this study, we aimed to assess the feasibility of US-CT fusion as part of the management of appendicitis. MATERIALS AND METHODS: We retrospectively collected data of consecutive patients with complicated AA managed non-operatively and followed up with US Fusion for clinical decision-making. Patients demographics, clinical data, and follow-up outcomes were extracted and analyzed. RESULTS: Overall, 19 patients were included. An index Fusion US was conducted in 13 patients (68.4%) during admission, while the rest were performed as part of an ambulatory follow-up. Nine patients (47.3%) had more than 1 US Fusion performed as part of their follow-up, and 3 patients underwent a third US Fusion. Eventually, 5 patients (26.3%) underwent elective interval appendectomy based on the outcomes of the US Fusion, due to a non-resolution of imaging findings and ongoing symptoms. In 10 patients (52.6%), there was no evidence of an abscess in the repeated US Fusion, while in 3 patients (15.8%), it significantly diminished to less than 1 cm in diameter. CONCLUSION: Ultrasound-tomographic image fusion is feasible and can play a significant role in the decision-making process for the management of complicated AA.

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.

Deep learning for noninvasive liver fibrosis classification: A systematic review.

BACKGROUND AND AIMS: While biopsy is the gold standard for liver fibrosis staging, it poses significant risks. Noninvasive assessment of liver fibrosis is a growing field. Recently, deep learning (DL) technology has revolutionized medical image analysis. This technology has the potential to enhance noninvasive fibrosis assessment. We systematically examined the application of DL in noninvasive liver fibrosis imaging. METHODS: Embase, MEDLINE, Web of Science, and IEEE Xplore databases were used to identify studies that reported on the accuracy of DL for classification of liver fibrosis on noninvasive imaging. The search keywords were "liver or hepatic," "fibrosis or cirrhosis," and "neural or DL networks." Risk of bias and applicability were evaluated using the QUADAS-2 tool. RESULTS: Sixteen studies were retrieved. Imaging modalities included ultrasound (n = 10), computed tomography (n = 3), and magnetic resonance imaging (n = 3). The studies analyzed a total of 40 405 radiological images from 15 853 patients. All but two of the studies were retrospective. In most studies the "ground truth" reference was the METAVIR score for pathological staging (n = 9.56%). The majority of the studies reported an accuracy >85% when compared to histopathology. Fourteen studies (87.5%) had a high risk of bias and concerns regarding applicability. CONCLUSIONS: Deep learning has the potential to play an emerging role in liver fibrosis classification. Yet, it is still limited by a relatively small number of retrospective studies. Clinicians should facilitate the use of this technology by sharing databases and standardized reports. This may optimize the noninvasive evaluation of liver fibrosis on a large scale.

Postoperative Rise of Circulating Mitochondrial DNA Is Associated with Inflammatory Response in Patients following Pancreaticoduodenectomy.

INTRODUCTION: Accumulation of plasma mitochondrial DNA (mtDNA) following severe trauma has been shown to correlate with the development of systemic inflammatory response syndrome (SIRS) and may predict mortality. Our objective was to investigate the relationship between levels of circulatory mtDNA following pancreaticoduodenectomy (PD) and the postoperative course. METHODS: Levels of plasma mtDNA were assessed by real-time PCR of the mitochondrial genes ND1 and COX3 in 23 consecutive patients who underwent PD 1 day prior to surgery, within 8 h after surgery, and on postoperative day (POD)1 and POD5. The abundance of mtDNA was assessed relative to preoperative levels and in relation to parameters reflecting the postoperative clinical course. RESULTS: When pooled for all patients, the circulating mtDNA levels were significantly increased after surgery. However, while a significant (at least >2-fold and up to >20-fold) rise was noted in 11 patients, no change in mtDNA levels was noted in the other 12 following surgery. Postoperative rise in circulating mtDNA was associated with an increased rate of postoperative fever until day 5, decreased hemoglobin and albumin levels, and increased white blood cell counts. These patients also suffered from increased rates of delayed gastric emptying. No significant differences were demonstrated in other postoperative parameters. CONCLUSION: Circulating mtDNA surge is associated with an inflammatory response following PD and may potentially be used as an early marker for postoperative course. Studies of larger patient cohorts are warranted.

Increased Rate of Complete Pathologic Response After Neoadjuvant FOLFIRINOX for BRCA Mutation Carriers with Borderline Resectable Pancreatic Cancer.

BACKGROUND: Neoadjuvant FOLFIRINOX is a standard-of-care treatment for BRPC patients. Patients with gBRCAm who have demonstrated improved response to platinum-based chemotherapy may have impaired homologous repair deficiency. This study aimed to describe the pathologic complete response rate and long-term survival for patients with germline BRCA1 or BRCA2 mutation (gBRCAm) and borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX. METHODS: A dual-center retrospective analysis was performed. Patients who had BRPC treated with neoadjuvant FOLFIRINOX followed by curative resection were identified from clinical databases. Pathologic complete response was defined as no viable tumor cells present in the specimen. Common founder Jewish germline BRCA1 or BRCA2 mutation was determined for available patients. RESULTS: The 61 BRPC patients in this study underwent resection after neoadjuvant FOLFIRINOX. Analysis of BRCA mutation was performed for 39 patients, and 9 patients were found to be BRCA2 germline mutation carriers. The pathologic complete response rate was 44.4% for the gBRCAm patients and 10% for the BRCA non-carriers (p = 0.009). The median disease-free survival was not reached for the gBRCAm patients and was 7 months for the BRCA non-carriers (p = 0.03). The median overall survival was not reached for the gBRCAm patients and was 32 months for the BRCA non-carriers (p = 0.2). After a mean follow-up period of 33.7 months, all eight patients with pathologic complete response were disease-free. CONCLUSIONS: The study showed that gBRCAm patients with BRPC have an increased chance for pathologic complete response and prolonged survival after neoadjuvant FOLFIRINOX. The results support the benefit of exposing gBRCAm patients to platinum-based chemotherapy early in the course of the disease. Neoadjuvant FOLFIRINOX should be considered for BRCA carriers who have resectable pancreatic cancer.

CD11b+Ly6G+ myeloid-derived suppressor cells promote liver regeneration in a murine model of major hepatectomy.

Liver regeneration depends on sequential activation of pathways and cells involving the remaining organ in recovery of mass. Proliferation of parenchyma is dependent on angiogenesis. Understanding liver regeneration-associated neovascularization may be useful for development of clinical interventions. Myeloid-derived suppressor cells (MDSCs) promote tumor angiogenesis and play a role in developmental processes that necessitate rapid vascularization. We therefore hypothesized that the MDSCs could play a role in liver regeneration. Following partial hepatectomy, MDSCs were enriched within regenerating livers, and their depletion led to increased liver injury and postoperative mortality, reduced liver weights, decreased hepatic vascularization, reduced hepatocyte hypertrophy and proliferation, and aberrant liver function. Gene expression profiling of regenerating liver-derived MDSCs demonstrated a large-scale transcriptional response involving key pathways related to angiogenesis. Functionally, enhanced reactive oxygen species production and angiogenic capacities of regenerating liver-derived MDSCs were confirmed. A comparative analysis revealed that the transcriptional response of MDSCs during liver regeneration resembled that of peripheral blood MDSCs during progression of abdominal tumors, suggesting a common MDSC gene expression profile promoting angiogenesis. In summary, our study shows that MDSCs contribute to early stages of liver regeneration possibly by exerting proangiogenic functions using a unique transcriptional program.-Nachmany, I., Bogoch, Y., Sivan, A., Amar, O., Bondar, E., Zohar, N., Yakubovsky, O., Fainaru, O., Klausner, J. M., Pencovich, N. CD11b+Ly6G+ myeloid-derived suppressor cells promote liver regeneration in a murine model of major hepatectomy.

Applying the Delphi process for development of a hepatopancreaticobiliary robotic surgery training curriculum.

BACKGROUND: Robotic hepatopancreaticobiliary (HPB) procedures are performed worldwide and establishing processes for safe adoption of this technology is essential for patient benefit. We report results of the Delphi process to define and optimize robotic training procedures for HPB surgeons. METHODS: In 2019, a robotic HPB surgery panel with an interest in surgical training from the Americas and Europe was created and met. An e-consensus-finding exercise using the Delphi process was applied and consensus was defined as 80% agreement on each question. Iterations of anonymous voting continued over three rounds. RESULTS: Members agreed on several points: there was need for a standardized robotic training curriculum for HPB surgery that considers experience of surgeons and based on a robotic hepatectomy includes a common approach for "basic robotic skills" training (e-learning module, including hardware description, patient selection, port placement, docking, troubleshooting, fundamentals of robotic surgery, team training and efficiency, and emergencies) and an "advanced technical skills curriculum" (e-learning, including patient selection information, cognitive skills, and recommended operative equipment lists). A modular approach to index procedures should be used with video demonstrations, port placement for index procedure, troubleshooting, and emergency scenario management information. Inexperienced surgeons should undergo training in basic robotic skills and console proficiency, transitioning to full procedure training of e-learning (video demonstration, simulation training, case observation, and final evaluation). Experienced surgeons should undergo basic training when using a new system (e-learning, dry lab, and operating room (OR) team training, virtual reality modules, and wet lab; case observations were unnecessary for basic training) and should complete the advanced index procedural robotic curriculum with assessment by wet lab, case observation, and OR team training. CONCLUSIONS: Optimization and standardization of training and education of HPB surgeons in robotic procedures was agreed upon. Results are being incorporated into future curriculum for education in robotic surgery.

Palliative bypass surgery for patients with advanced pancreatic adenocarcinoma: experience from a tertiary center.

BACKGROUND: As advances in oncological treatment continue to prolong the survival of patients with non-resectable pancreatic ductal adenocarcinoma (PDAC), decision-making regarding palliative surgical bypass in patients with a heavy disease burden turns challenging. Here we present the results of a pancreatic surgery referral center. METHODS: Patients that underwent palliative gastrojejunostomy and/or hepaticojejunostomy for advanced, non-resectable PDAC between January 2010 and November 2018 were retrospectively assessed. All patients were taken to a purely palliative surgery with no curative intent. The postoperative course as well as short and long-term outcomes was evaluated in relation to preoperative parameters. RESULTS: Forty-two patients (19 females) underwent palliative bypass. Thirty-one underwent only gastrojejunostomy (22 laparoscopic) and 11 underwent both gastrojejunostomy and hepaticojejunostomy (all by an open approach). Although 34 patients (80.9%) were able to return temporarily to oral intake during the index admission, 15 (35.7%) suffered from a major postoperative complication. Seven patients (16.6%) died from surgery and another seven within the following month. Nine patients (21.4%) never left the hospital following the surgery. Mean length of hospital stay was 18 ± 17 days (range 3-88 days). Mean overall survival was 172.8 ± 179.2 and median survival was 94.5 days. Age, preoperative hypoalbuminemia, sarcopenia, and disseminated disease were associated with palliation failure, defined as inability to regain oral intake, leave the hospital, or early mortality. CONCLUSIONS: Although palliative gastrojejunostomy and hepaticojejunostomy may be beneficial for specific patients, severe postoperative morbidity and high mortality rates are still common. Patient selection remains crucial for achieving acceptable outcomes.

Prognostic significance of pancreatic fistula and postoperative complications after pancreaticoduodenectomy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The influence of postoperative complications, specifically, pancreatic fistula (PF), on long-term oncologic outcome in patients with pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: Prospectively collected data of patients who underwent pancreaticoduodenectomy (PD) for PDAC between 2008 and 2016 were retrospectively reviewed and analyzed. Deaths within 90 days were excluded. Median follow-up time was 22 months for the entire cohort (range 2-102 months). PF was graded as biochemical leak, grade B, or grade C according to the criteria of the International Study Group on Pancreatic Fistula. Postoperative complications were graded according to the Clavien-Dindo classification (CDC). Data on clinical and pathological characteristics as well as on recurrence and survival were collected. RESULTS: Twenty-nine of the 148 identified patients (19%) developed PF, of whom 17 (11.4%) had a PF grade B or C. 29 patients developed a postoperative complication CDC grade 3 or 4. The respective 3-year disease-free survival was 15.5% and 19.2% (P = 0.725), and the 5-year overall survival was 20% and 16% (P = 0.914) in patients with and without PF. On multivariate analysis, the use of adjuvant chemotherapy, lymph node involvement, surgical margin involvement, and tumor grade were associated with patient survival. PF and postoperative complications CDC grade 3 or 4 were not associated with decreased long-term survival, disease-free survival or local recurrence rate. CONCLUSIONS: While acknowledging the limited sample size, no association was seen between PF or postoperative complications and overall or disease-free survival in patients undergoing PD for PDAC.

Surgical Approach to Abdominal Tumors Involving the Inferior Vena Cava.

BACKGROUND: Abdominal tumors invading the inferior vena cava (IVC) present significant challenges to surgeons and oncologists. OBJECTIVES: To describe a surgical approach and patient outcomes. METHODS: The authors conducted a retrospective analysis of surgically resected tumors with IVC involvement by direct tumor encasement or intravascular tumor growth. Patients were classified according to level of IVC involvement, presence of intravascular tumor thrombus, and presence of hepatic parenchymal involvement. RESULTS: Study patients presented with leiomyosarcomas (n=5), renal cell carcinoma (n=7), hepatocellular carcinoma (n=1), cholangiocarcinoma (n=2), Wilms tumor (n=1), neuroblastoma (n=1), endometrial leiomyomatosis (n=1), adrenocortical carcinoma (n=1), and paraganglioma (n=1). The surgeries were conducted between 2010 and 2019. Extension of tumor thrombus above the hepatic veins required a venovenous bypass (n=3) or a full cardiac bypass (n=1). Hepatic parenchymal involvement required total hepatic vascular isolation with in situ hepatic perfusion and cooling (n=3). Circular resection of IVC was performed in five cases. Six patients had early postoperative complications, and the 90-day mortality rate was 10%. Twelve patients were alive, and six were disease-free after a mean follow-up of 1.6 years. CONCLUSIONS: Surgical resection of abdominal tumors with IVC involvement can be performed in selected patients with acceptable morbidity and mortality. Careful patient selection, and multidisciplinary involvement in preoperative planning are key for optimal outcome.

The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse.

Myeloid derived suppressor cells (MDSCs) play key roles in cancer development. Accumulation of peripheral-blood MDSCs (PB-MDSCs) corresponds to the progression of various cancers, but provides only a crude indicator. We aimed toward identifying changes in the transcriptional profile of PB-MDSCs in response to tumor growth. CT26 colon cancer cells and B16 melanoma cells (106) were inoculated into peritoneal cavities of BALB/c mice and subcutaneously to C57-black mice, respectively. The circulating levels and global transcriptional patterns of PB CD11b+Ly6g+ MDSCs were assessed in control mice, and 4, 8, and 11 days following tumor cell inoculation. Although a significant accumulation of PB-MDSCs was demonstrated only 11 days following tumor induction, a pronounced transcriptional response was identified already on day 4 while the tumor was ~1 mm in size. Further transcriptional changes correlated with different stages of tumor growth. Key MDSC genes and canonical signaling pathways were activated along tumor progression. This phenomenon was demonstrated in both cancer models, and a consensus set of 817 genes, involved in myeloid cell recruitment and angiogenesis, was identified. The data suggest that the transcriptional signatures of PB-MDSC may serve as markers for tumor progression, as well as providing potential targets for future therapies.

R1 resection of colorectal liver metastasis - What is the cost of marginal resection?

BACKGROUND AND OBJECTIVES: The impact of resection margins on the outcome of patients with colorectal liver metastasis (CRLM) remains controversial. We evaluated the short and long-term results of R1 resection. METHODS: Between 2006 and 2016, 202 patients underwent liver resection for CRLM. R1 resection was defined as a distance of less than 1 mm between tumor cells and the transection plain. Patient and tumor characteristics, perioperative, and long-term outcomes were assessed. RESULTS: In 161 (79.7%) and 41 (20.3%) patients, an R0 and R1 resections were achieved, respectively. Patients that underwent an R1 resection had higher rates of disease progression while on chemotherapy (12.1% vs 5.5%, P = 0.001), need for second-line chemotherapy (17% vs 6.2%, P < 0.001), increased use of preoperative volume manipulation (14.6% vs 5.5%, P = 0.001), and inferior vena-cava involvement (21.9% vs 8.7%, P < 0.001). These patients had higher rates of major postoperative complications (19.5% vs 6.8%, P < 0.001) and reoperations (7.3% vs 2.4%, P < 0.001). Multivariate analysis demonstrated that R1 resections were not associated with decreased recurrence-free survival or overall survival. CONCLUSIONS: Although R1 resection is associated with worse disease behavior and postoperative complications, the long-term outcome of patients following an R1 resection is non-inferior to those who underwent an R0 resection.