The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression.

BACKGROUND AND AIMS: The NADPH oxidase NOX4 plays a tumor-suppressor function in HCC. Silencing NOX4 confers higher proliferative and migratory capacity to HCC cells and increases their in vivo tumorigenic potential in xenografts in mice. NOX4 gene deletions are frequent in HCC, correlating with higher tumor grade and worse recurrence-free and overall survival rates. However, despite the accumulating evidence of a protective regulatory role in HCC, the cellular processes governed by NOX4 are not yet understood. Accordingly, the aim of this work was to better understand the molecular mechanisms regulated by NOX4 in HCC in order to explain its tumor-suppressor action. APPROACH AND RESULTS: Experimental models: cell-based loss or gain of NOX4 function experiments, in vivo hepatocarcinogenesis induced by diethylnitrosamine in Nox4 -deficient mice, and analyses in human HCC samples. Methods include cellular and molecular biology analyses, proteomics, transcriptomics, and metabolomics, as well as histological and immunohistochemical analyses in tissues. Results identified MYC as being negatively regulated by NOX4. MYC mediated mitochondrial dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids, and an overall higher energetic capacity and ATP level. NOX4 deletion induced a redox imbalance that augmented nuclear factor erythroid 2-related factor 2 (Nrf2) activity and was responsible for MYC up-regulation. CONCLUSIONS: Loss of NOX4 in HCC tumor cells induces metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression.

European validation of the classification for the anticipated difficulty of liver transplantation.

BACKGROUND: Appropriate risk stratification for the difficulty of liver transplantation (LT) is essential to guide the selection and acceptance of grafts and avoid morbidity and mortality. METHODS: Based on 987 LTs collected from 5 centers, perioperative outcomes were analyzed across the 3 difficulty levels. Each LT was retrospectively scored from 0 to 10. Scores of 0-2, 3-5 and 6-10 were then translated into respective difficulty levels: low, moderate and high. Complications were reported according to the comprehensive complication index (CCI). RESULTS: The difficulty level of LT in 524 (53%), 323 (32%), and 140 (14%) patients was classified as low, moderate and high, respectively. The values of major intraoperative outcomes, such as cold ischemia time (p = 0.04) and operative time (p < 0.0001) increased gradually with statistically significant values among difficulty levels. There was a corresponding increase in CCI (p = 0.04), severe complication rates (p = 0.05) and length of ICU (p = 0.01) and hospital (p = 0.004) stays across the different difficulty levels. CONCLUSION: The LT difficulty classification has been validated.

Long-term expanding human airway organoids for disease modeling.

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

Defining Surgical Difficulty of Liver Transplantation.

OBJECTIVE: To define technically Diff-LT. SUMMARY OF BACKGROUND DATA: Currently, there is no acknowledged definition of Diff-LT. METHODS: This retrospective study included all first consecutive liver-only transplantations performed in 2 centers from 2011 to 2015. Diff-LT was defined as the combination of the number of blood units transfused, cold ischemia time, and duration of operation, all at or above the median value of the entire population. The correlation of Diff-LT with short- (including the comprehensive complication index) and long-term outcomes was assessed. Outcomes were also compared to the 90-day benchmark cutoffs of LT. Predictors of Diff-LT were identified by multivariable analysis, first using only recipient data and then using all recipient, donor, graft, and surgical data. RESULTS: The study population included 467 patients. The incidence of Diff- LT was 18.8%. Diff-LT was associated with short-term outcomes, including the comprehensive complication index and mortality, but not with patient or graft long-term survival. Previous abdominal surgery, intensive care unitbound at the time of LT, split graft use, nonstandard arterial reconstruction, and porto-systemic shunt ligation were independent predictors of Diff-LT. The proportion of variables below the corresponding LT 90-day benchmark cutoffs was 8/13 (61.5%) for non-Diff-LT, and 4/13 (30.8%) for Diff-LT. CONCLUSIONS: Diff-LT, as defined, occurred frequently. Adjusting modifiable variables might decrease the risk of Diff-LT and improve the postoperative course. This definition of Diff-LT might be useful for patient information, comparison between centers and surgeons, and as a metric in future trials.

Agitation in the Trauma Bay Is an Early Indicator of Hemorrhagic Shock.

INTRODUCTION: Agitation on arrival in trauma patients is known as a sign of impending demise. The aim of this study is to determine outcomes for trauma patients who present in an agitated state. We hypothesized that agitation in the trauma bay is an early indicator for hemorrhage in trauma patients. METHODS: We performed a single-institution prospective observational study from September 2018 to December 2020 that included any trauma patient who arrived agitated, defined as a Richmond Agitation-Sedation Scale of +1 to +4. Variables collected included demographics, mechanism of injury, admission physiology, blood alcohol level, toxicity screen, and injury severity. The primary outcomes were need for massive transfusion (≥ 10 units) and need for emergent therapeutic intervention for hemorrhage control (laparotomy, preperitoneal pelvic packing, sternotomy, thoracotomy, or angioembolization). RESULTS: Of 4657 trauma admissions, 77 (2%) patients arrived agitated. Agitated patients were younger (40 versus 46, P = 0.03), predominantly male (94% versus 66%, P < 0.0001) sustained more penetrating trauma (31% versus 12%, P < 0.0001), had a lower systolic blood pressure (127 versus 137, P < 0.0001), and a higher Injury Severity Score (17 versus 9, P < 0.0001). On multivariable logistic regression, agitation was independently associated with massive transfusion (odds ratio: 2.63 [1.20-5.77], P = 0.02) and emergent therapeutic intervention for hemorrhage control (odds ratio: 2.60 [1.35-5.03], P = 0.005). CONCLUSIONS: Agitation in trauma patients may serve as an early indicator of hemorrhagic shock, as agitation is independently associated with a two-fold increase in the need for massive transfusion and emergent therapeutic intervention for hemorrhage control.

If at First You Do Not Succeed: Consideration of Attempts in Patients With Trauma.

INTRODUCTION: Failed extubation in critically ill patients is associated with poor outcomes. In critically ill trauma patients who have failed extubation, providers must decide whether to proceed with tracheostomy or attempt extubation again. The aim of this study was to describe the natural history of failed extubation in trauma patients and determine whether tracheostomy or a second attempt at extubation is more appropriate. METHODS: Trauma patients admitted to our level I trauma center from 2013 to 2019 were identified. Patients who failed extubation, defined as an unplanned reintubation within 48 h of extubation, were included. Patients who immediately underwent tracheostomy were compared with those who had subsequent attempts at extubation. The primary outcome was mortality, and the secondary outcomes were intensive care unit (ICU) length of stay (LOS), ventilator days, and hospital LOS. RESULTS: The population included 93 patients who failed extubation and met inclusion criteria. A total of 53 patients were ultimately successfully extubated, whereas 40 patients underwent a tracheostomy. There was no statistically significant difference in demographics or injury patterns. Patients who underwent tracheostomy had a longer ICU LOS and more ventilator days. There was no difference in mortality or hospital LOS between the two groups. CONCLUSIONS: In trauma patients, those who underwent subsequent attempts at extubation did not experience higher rates of mortality than those who received a tracheostomy. Tracheostomy was associated with longer ICU LOS and ventilator days. In certain situations, it is appropriate to consider subsequent attempts at extubation in trauma patients who fail extubation rather than proceeding directly to tracheostomy.

Imaging Gallbladder Lesions: What Can Positron Emission Tomography/Computed Tomography Add to the Conventional Imaging Approach?

OBJECTIVE: Incidental gallbladder lesions are common in imaging studies, although it is not always easy to discriminate benign lesions from gallbladder cancer with conventional imaging procedures. The present study aims to assess the capacity of positron emission tomography/computed tomography (PET/CT) with 2-[ 18 F]FDG to distinguish between benign and malignant pathology of the gallbladder, compared with conventional imaging techniques (contrast-enhanced CT or magnetic resonance imaging). METHODS: Positron emission tomography/CT and conventional imaging studies of 53 patients with gallbladder lesions were evaluated and visually classified as benign, malignant, or inconclusive. Agreement between PET/CT and conventional imaging was determined, and imaging findings were correlated with histology or follow-up. Positron emission tomography/CT images were also analyzed semiquantitatively (SUV max and maximum tumor-to-liver ratio [TLR max ]). The presence of adenopathies and distant metastases was assessed and compared between both imaging procedures. RESULTS: According to histology or follow-up, 33 patients (62%) had a malignant process and 20 (38%) had benign lesions. Positron emission tomography/CT and conventional imaging showed a moderate agreement ( κ = 0.59). Conventional imaging classified more studies as inconclusive compared with PET/CT (17.0% and 7.5%, respectively), although both procedures showed a similar accuracy. Malignant lesions had significantly higher SUV max and, especially, TLR max (0.89 and 2.38 [ P = 0.00028] for benign and malignant lesions, respectively). Positron emission tomography/CT identified more pathologic adenopathies and distant metastases, and patients with regional or distant spread had higher SUV max and TLR max in the gallbladder. CONCLUSIONS: Positron emission tomography/CT is accurate to distinguish between benign and malignant pathology of the gallbladder, with a similar performance to conventional imaging procedures but with less inconclusive results. Malignant lesions present higher SUV max and TLR max values.

Paraneoplastic acquired hemophilia A associated with hilar cholangiocarcinoma arising in an intraductal papillary neoplasm of the bile duct.

A 74-year-old female was admitted for painless jaundice. Laboratory tests showed hyperbilirubinemia, cholestasis, normal coagulation, and Ca19-9:163U/L. The CT-scan reported dilation of the intrahepatic and extrahepatic bile ducts secondary to a 24mm tumor in the intrapancreatic common bile duct. The magnetic cholangioresonance showed multiple endoluminal polypoid lesions, suggestive of intraductal papillary neoplasm of the bile duct (IPNB). The endoscopic bile duct brushing was non-conclusive.

Results from the european survey on preoperative management and optimization protocols for PeriHilar cholangiocarcinoma.

BACKGROUND: Major surgery, along with preoperative cholestasis-related complications, are responsible for the increased risk of morbidity and mortality in perihilar cholangiocarcinoma (pCCA). The aim of the present survey is to provide a snapshot of current preoperative management and optimization strategies in Europe. METHODS: 61 European centers, experienced in hepato-biliary surgery completed a 59-questions survey regarding pCCA preoperative management. Centers were stratified according to surgical caseload (<5 and ≥ 5 cases/year) and preoperative management protocols' application. RESULTS: The overall case volume consisted of 6333 patients. Multidisciplinary discussion was routinely performed in 91.8% of centers. Most respondents (96.7%) recognized the importance of a well-structured preoperative protocol. The preferred method for biliary drainage was percutaneous transhepatic biliary drainage (60.7%) while portal vein embolization was the preferred technique for liver hypertrophy (90.2%). Differences in preoperative pathologic confirmation of malignancy (35.8% vs 28.7%; p < 0.001), number of mismanaged referred patients (88.2% vs 50.8%; p < 0.001), biliary drainage (65.1% vs 55.6%; p = 0.015) and liver function evaluation (37.2% vs 5.6%; p = 0.001) were found between centers according to groups' stratification. CONCLUSION: The importance of a correct preoperative management is recognized. Nevertheless, the current lack of guidelines leads to wide heterogeneity of behaviors among centers. This survey can provide recommendations to improve pCCA perioperative outcomes.

Renoportal Anastomosis During Liver Transplantation in Patients With Portal Vein Thrombosis: First Long-term Results From a Multicenter Study.

OBJECTIVE: To evaluate the short- and long-term outcomes of RPA in a large multicentric series. SUMMARY BACKGROUND: The current knowledge on RPA for portal reconstruction during LT in patients with diffuse PVT and a large splenorenal shunt is poor and limited to case reports and small case series. METHODS: All consecutive LTs with RPA performed in 5 centers between 1998 and 2020 were included. RPA was physiological provided it drained the splanchnic venous return through a large splenorenal shunt (≥ 1 cm diameter). Complications of PHT, long-term RPA patency, and patient and graft survival were assessed. RPA success was achieved provided the 3 following criteria were all fulfilled: patients were alive with patent RPA and without clinical PHT. RESULTS: RPA was attempted and feasible in 57 consecutive patients and was physiological in 51 patients (89.5%). Ninety-day mortality occurred in 5 (8.5%) patients, and PHT-related complications occurred in 42.9% of patients. With a median follow-up of 63 months, the 1-, 3- and 5-year patient and graft survival rates were 87%, 83%, and 76% and 82%, 80%, and 73%, respectively. The primary and primary-assisted patency rates at 5 years were 84.5% and 94.3%, respectively. Success was achieved in 90% (27/30) of patients with a follow-up ≥5 years. CONCLUSIONS: Despite a high rate of PHT-related complications, excellent long-term patient and graft survival could be achieved. RPA could be considered successful in the vast majority of patients. The expanded use of RPA is warranted.

Novel Composite Endpoint for Assessing Outcomes in Liver Transplantation: Arterial and Biliary Complication-Free Survival.

Transplant and patient survival are the validated endpoints to assess the success of liver transplantation (LT). This study evaluates arterial and biliary complication-free survival (ABCFS) as a new metric. ABC, considered as an event, was an arterial or biliary complication of Dindo-Clavien grade ≥III complication dated at the interventional, endoscopic, or surgical treatment required to correct it. ABCFS was defined as the time from the date of LT to the dates of first ABC, death, relisting, or last follow-up (transplant survival is time from LT to repeat LT or death). Following primary whole LT (n = 532), 106 ABCs occurred and 99 (93%) occurred during the first year after LT. An ABC occurring during the first year after LT (overall rate 19%) was an independent factor associated with transplant survival (hazard ratio [HR], 3.17; P < 0.001) and patient survival (HR, 2.7; P = 0.002) in univariate and multivariate analyses. This result was confirmed after extension of the cohort to split-liver graft, donation after circulatory death, or re-LT (n = 658). Data from 2 external cohorts of primary whole LTs (n = 249 and 229, respectively) confirmed that the first-year ABC was an independent prognostic factor for transplant survival but not for patient survival. ABCFS was correlated with transplant and patient survival (ρ = 0.85 [95% CI, 0.78-0.90] and 0.81 [95% CI, 0.71-0.88], respectively). Preoperative factors known to influence 5-year transplant survival influenced ABCFS after 1 year of follow-up. The 1-year ABCFS was indicative of 5-year transplant survival. ABCFS is a reproducible metric to evaluate the results of LT after 1 year of follow-up and could serve as a new endpoint in clinical trials.

Textbook Outcome Following Liver Transplantation.

BACKGROUND: Textbook outcome (TBO) is a patient-oriented composite criterion achieved when all desired main health outcomes are realized. The aim was to assess the incidence and the independent factors associated with TBO following LT. METHODS: This bicentric study included all patients who underwent their first elective liver-only LT between 2011 and 2015. TBO occurred when all the following criteria were fulfilled: no mortality within 90 days, no major complications within 90 days, no reintervention within 90 days (liver graft biopsy, radiological, endoscopic or surgical interventions, or retransplantation), no prolonged intensive care unit stay, and no prolonged hospital stay. Univariable and multivariable analyses were performed to identify factors associated with TBO and to assess whether TBO is an independent factor associated with patient and graft survival. RESULTS: The study population included 530 patients. TBO occurred in 176/530 (33%) patients. Independent factors associated with TBO included the balance of risk score, the use of an intraoperative temporary portacaval shunt, and duration of the operation. TBO was identified as an independent factor associated with graft survival but not patient survival. CONCLUSIONS: TBO might be implemented in the patient-doctor decision-making regarding whether to proceed with LT and in the reporting of patient-level hospital performance related to LT.

Pancreas sparing duodenectomy in the treatment of primary duodenal neoplasms and other situations with duodenal involvement.

BACKGROUND: There are no clearly defined indications for pancreas-preserving duodenectomy. The present study aimed to analyze postoperative morbidity and the outcomes of patients undergoing pancreas-preserving duodenectomy. METHODS: Patients undergoing pancreas-preserving duodenectomy from April 2008 to May 2020 were included. We divided the series according to indication: scenario 1, primary duodenal tumors; scenario 2, tumors of another origin with duodenal involvement; and scenario 3, emergency duodenectomy. RESULTS: We included 35 patients. Total duodenectomy was performed in 1 patient of adenomatous duodenal polyposis, limited duodenectomy in 7, and third + fourth duodenal portion resection in 27. The indications for scenario 1 were gastrointestinal stromal tumor (n = 13), adenocarcinoma (n = 4), neuroendocrine tumor (n = 3), duodenal adenoma (n = 1), and adenomatous duodenal polyposis (n = 1); scenario 2: retroperitoneal desmoid tumor (n = 2), recurrence of liposarcoma (n = 2), retroperitoneal paraganglioma (n = 1), neuroendocrine tumor in pancreatic uncinate process (n = 1), and duodenal infiltration due to metastatic adenopathies of a germinal tumor with digestive hemorrhage (n = 1); and scenario 3: aortoenteric fistula (n = 3), duodenal trauma (n = 1), erosive duodenitis (n = 1), and biliopancreatic limb ischemia (n = 1). Severe complications (Clavien-Dindo ≥ IIIb) developed in 14% (5/35), and postoperative mortality was 3% (1/35). CONCLUSIONS: Pancreas-preserving duodenectomy is useful in the management of primary duodenal tumors, and is a technical option for some tumors with duodenal infiltration or in emergency interventions.

Clathrin switches transforming growth factor-ß role to pro-tumorigenic in liver cancer.

BACKGROUND & AIMS: Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-ß (TGF-ß) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-ß-induced signalling in liver cells and its relevance in liver cancer. METHODS: Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-ß and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGFB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC). RESULTS: Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-ß phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-ß-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-ß signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. CONCLUSIONS: This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-ß pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-ß-targeted therapy. LAY SUMMARY: Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Cltc), altering the cellular response to TGF-ß in favour of anti-apoptotic/pro-tumorigenic signals. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-ß.

Laparoscopic Liver Resection for Hepatocellular Carcinoma in Child-Pugh A Patients With and Without Portal Hypertension: A Multicentre Study.

BACKGROUND: Laparoscopic liver resection (LLR) may improve outcomes for cirrhotic patients with hepatocellular carcinoma (HCC) and portal hypertension (PHT). The aim of this study was to compare the short-term outcomes after LLR for HCC in cirrhotic patients with and without PHT. METHODS: This multicentric study included 96 HCC patients who underwent LLR. Clinically significant portal hypertension (CSPH) was defined by a hepatic venous pressure gradient ≥10 mmHg. Short-term outcomes and liver-specific complications including post-hepatectomy liver failure (PHLF), ascites and encephalopathy were compared between patients with and without CSPH. RESULTS: Thirty-one patients (32%) had CSPH. The CSPH group had higher post-operative morbidity (52% vs. 15%; p < 0.001), PHLF (10% vs. 0%; p = 0.03) and encephalopathy (10% vs. 0%; p = 0.03). There was no difference in terms of post-operative ascites between the two groups (CSPH: 16% vs. no CPSH: 8%, p = 0.28). The length of stay was longer in patients with CSPH than in those without CSPH (6 vs. 4 days; p < 0.001). CONCLUSIONS: The laparoscopic approach is feasible in selected HCC patients with CSPH, at the price of significant increases in liver-specific complications and length of stay.

Impact on Oncological Outcomes and Intent-to-Treat Survival of Resection Margin for Transplantable Hepatocellular Carcinoma in All-Comers and in Patients with Cirrhosis: A Multicenter Study.

BACKGROUND: The outcomes of liver resection (LR) with a narrow margin in patients with transplantable hepatocellular carcinoma (HCC) have not been studied. The aim was to assess whether narrow margin following up-front LR impacts the incidence, timing, pattern, and transplantability of tumor recurrence in patients with initially transplantable HCC. METHODS: All initially transplantable HCC patients undergoing hepatectomy with either narrow (<10 mm) or wide (≥10 mm) margins from 2007 to 2016 at four Western university centers were compared in terms of recurrence, transplantability of recurrence, recurrence-free survival (RFS), and intention-to-treat overall survival (ITT-OS). Independent predictors of non-transplantability of recurrence were assessed. RESULTS: This study included 187 patients (narrow group, n = 107 vs. wide group, n = 80). Recurrence was significantly more frequent in the narrow margin group (44% vs. 26%; p = 0.01) with a shorter RFS (p = 0.03). The transplantability of recurrence and ITT-OS were, however, not different between the two groups. The presence of satellite nodules on the resected specimens emerged as the sole independent predictor of non-transplantability of tumor recurrence. The stratification of the analysis according to the presence of cirrhosis achieved essentially the same results as in the whole study population. CONCLUSIONS: Narrow margin was associated with a higher tumor recurrence rate and a shorter RFS for patients with initially transplantable HCC. However, transplantability of recurrence and long-term ITT-OS were not impaired.

Prognostic value and risk stratification of residual disease in patients with incidental gallbladder cancer.

BACKGROUND AND AIM: Given their poor prognosis, patients with residual disease (RD) in the re-resection specimen of an incidental gallbladder carcinoma (IGBC) could benefit from a better selection for surgical treatment. The Gallbladder Cancer Risk Score (GBRS) has been proposed to preoperatively identify RD risk more precisely than T-stage alone. The aim of this study was to assess the prognostic value of RD and to validate the GBRS in a retrospective series of patients. MATERIAL AND METHODS: A prospectively collected database including 59 patients with IGBC diagnosed from December 1996 to November 2015 was retrospectively analyzed. Three locations of RD were established: local, regional, and distant. The effect of RD on overall survival (OS) was analyzed with the Kaplan-Meier method. To identify variables associated with the presence of RD, characteristics of patients with and without RD were compared using Fisher's exact test. The relative risk of RD associated with clinical and pathologic factors was studied with a univariate logistic regression analysis. RESULTS: RD was found in 30 patients (50.8%). The presence of RD in any location was associated with worse OS (29% vs. 74.2%, p = 0.0001), even after an R0 resection (37.7% vs 74.2%, p = 0.003). There was no significant difference in survival between patients without RD and with local RD (74.2% vs 64.3%, p = 0.266), nor between patients with regional RD and distant RD (16.1% vs 20%, p = 0.411). After selecting patients in which R0 resection was achieved (n = 44), 5-year survival rate for patients without RD, local RD, and regional RD was, respectively, 74.2%, 75%, and 13.9% (p = 0.0001). The GBRS could be calculated in 25 cases (42.3%), and its usefulness to predict the presence of regional or distant RD (RDRD) was confirmed (80% in high-risk patients and 30% in intermediate risk p = 0.041). CONCLUSION: RDRD, but not local RD, represents a negative prognostic factor of OS. The GBRS was useful to preoperatively identify patients with high risk of RDRD. An R0 resection did not improve OS of patients with regional RD.

Assessment of quality-of-care indicators for colorectal cancer surgery at a single centre in a developing country.

BACKGROUND: The implementation of quality-of-care indicators aiming to improve colorectal cancer (CRC) outcomes has been previously described by Cancer Care Ontario. The aim of this study was to assess the quality-of-care indicators in CRC at a referral centre in a developing country and to determine whether improvement occurred over time. METHODS: We performed a retrospective study of our prospectively collected database of patients after CRC surgery from 2001 to 2016. We excluded patients who underwent local transanal excision, pelvic exenteration or palliative procedures. We evaluated trends over time using the Cochran-Armitage test for trend. RESULTS: A total of 343 patients underwent surgical resection of CRC over the study period. There was improvement of the following indicators over time: the proportion of patients detected by screening (p = 0.03), the proportion of patients with preoperative liver imaging (p = 0.001), the proportion of patients with stage II or III rectal cancer who received neoadjuvant chemotherapy (p = 0.03), the proportion of patients with pathology reports that indicated the number of lymph nodes examined and the number of positive nodes (p = 0.001), and the proportion of patients with pathology reports describing the details on margin status (p = 0.001). CONCLUSION: This study showed the feasibility of applying the Cancer Care Ontario indicators for evaluating outcomes in CRC treatment at a single centre in a developing country. Although there was an improvement of some of the quality-of-care indicators over time, policies and interventions must be implemented to improve the fulfillment of all indicators.

CONTEXTE: Action Cancer Ontario a déjà décrit l'application d'indicateurs de la qualité des soins dans le but d'améliorer l'issue du cancer colorectal (CCR). Le but de cette étude était d'évaluer les indicateurs de la qualité de soins pour le CCR dans un centre de référence d'un pays en voie de développement et de déterminer si des améliorations ont pu être observées avec le temps. MÉTHODES: Nous avons procédé à une étude rétrospective de notre base de données recueillies prospectivement auprès de patients ayant subi une chirurgie pour CCR entre 2001 et 2016. Nous avons exclu les patients qui ont subi une exérèse transanale locale, une exentération pelvienne ou des traitements palliatifs. Nous avons évalué les tendances au fil du temps à l'aide du test Cochran­Armitage pour dégager les tendances. RÉSULTATS: En tout, 343 patients ont subi une résection chirurgicale de CCR au cours de la période de l'étude. On a noté une amélioration des indicateurs suivants au fil du temps : proportion de patients ayant subi un dépistage (p = 0,03), proportion de patients ayant subi des épreuves d'imagerie hépatique préopératoires (p = 0,001), proportion de patients atteints d'un cancer rectal de stade II ou III ayant reçu une chimiothérapie néoadjuvante (p = 0,03), proportion de patients dont les rapports d'anatomopathologie indiquaient le nombre de ganglions lymphatiques examinés et le nombre de ganglions positifs (p = 0,001) et proportion de patients dont les rapports d'anatomopathologie décrivaient le statut des marges (p = 0,001). CONCLUSION: Cette étude a démontré l'applicabilité des indicateurs d'Action Cancer Ontario pour évaluer les résultats du traitement pour CCR dans un seul centre d'un pays en voie de développement. Même si certains des indicateurs de la qualité des soins se sont améliorés au fil du temps, il faut appliquer des politiques et des interventions pour améliorer tous les indicateurs.

Steroidal antibiotics are antimetabolites of Acanthamoeba steroidogenesis with phylogenetic implications.

Pathogenic organisms may be sensitive to inhibitors of sterol biosynthesis, which carry antimetabolite properties, through manipulation of the key enzyme, sterol methyltransferase (SMT). Here, we isolated natural suicide substrates of the ergosterol biosynthesis pathway, cholesta-5,7,22,24-tetraenol (CHT) and ergosta-5,7,22,24(28)-tetraenol (ERGT), and demonstrated their interference in Acanthamoeba castellanii steroidogenesis: CHT and ERGT inhibit trophozoite growth (EC50 of 51 nM) without affecting cultured human cell growth. Washout experiments confirmed that the target for vulnerability was SMT. Chemical, kinetic, and protein-binding studies of inhibitors assayed with 24-AcSMT [catalyzing C28-sterol via Δ24(28)-olefin production] and 28-AcSMT [catalyzing C29-sterol via Δ25(27)-olefin production] revealed interrupted partitioning and irreversible complex formation from the conjugated double bond system in the side chain of either analog, particularly with 28-AcSMT. Replacement of active site Tyr62 with Phe or Leu residues involved in cation-π interactions that model product specificity prevented protein inactivation. The alkylating properties and high selective index of 103 for CHT and ERGT against 28-AcSMT are indicative of a new class of steroidal antibiotic that, as an antimetabolite, can limit sterol expansion across phylogeny and provide a novel scaffold in the design of amoebicidal drugs. Animal studies of these suicide substrates can further explore the potential of their antibiotic properties.

Hepatic Angiosarcoma: A Multi-institutional, International Experience with 44 Cases.

BACKGROUND: Hepatic angiosarcoma is a rare primary liver tumor. The aim of this current study was to evaluate the presentation and treatment outcomes in a modern cohort. METHODS: This was a retrospective, multi-institutional, observational study of patients with histopathologic diagnoses of primary hepatic angiosarcoma from four institutions. Clinicopathologic characteristics, treatments, and patient outcomes were examined. RESULTS: Forty-four patients with hepatic angiosarcoma were identified. Patients were predominantly Caucasian and presented at a median age of 63.7 years; 81.4% of patients had bilobar disease and 37.2% had metastatic disease at the time of presentation. Only 10 patients underwent surgical resection. Median overall survival for the entire cohort was 5.8 months (interquartile range 1.9-16.4), and 1-, 3-, and 5-year actual survival was 30.0%, 8.1%, and 5.6%, respectively. There were only two 5-year survivors, both of whom presented with localized disease and underwent curative resection. CONCLUSION: The prognosis for hepatic angiosarcoma remains quite poor. Surgical resection for localized disease results in the best outcomes. Unfortunately, current imaging modalities are often non- diagnostic, and most patients are unresectable at the time of presentation.