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Causal inference for treatments with many versions requires a careful specification of the versions of treatment. Specifically, the existence of multiple relevant versions of treatment has implications for the selection of confounders. To illustrate this, we estimate the effect of organ transplantation using grafts from donors who died due to anoxic drug overdose, on recipient graft survival in the US. We describe how explicitly outlining the target trial (i.e. the hypothetical randomized trial which would answer the causal question of interest) to be emulated by an observational study analysis helps conceptualize treatment versions, guides selection of appropriate adjustment variables, and helps clarify the settings in which causal effects of compound treatments will be of value to decision-makers.

Early reports of associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) outcomes have been suboptimal. The literature has confirmed that learning curves influence surgical outcomes. We have 54 months of continuous experience performing ALPPS with strict selection criteria. This study aimed to evaluate the impact of the learning curve on ALPPS outcomes. We retrospectively compared patients who underwent ALPPS between April 2012 and March 2016. Patients were grouped into 2 24-month (early and late) periods. All candidates had a high tumour load requiring staged hepatectomy after chemotherapy response, a predicted future liver remnant (FLR) less than 30% and good performance status. Thirty-three patients underwent ALPPS during the study period: 16 in the early group (median age 65 yr, mean body mass index [BMI] 27) and 17 in the late group (median age 60 yr, mean BMI 25). Bilobar disease was comparable in both groups (94% v. 88%, p > 0.99). Duration of surgery was not statistically different. Intraoperative blood loss and need for transfusion were significantly lower in the late group (200 ± 109 mL v. 100 ± 43 mL, p < 0.05). The late group had a higher proportion of monosegment ALPPS (4:1). There were no deaths within 90 days in either cohort. Rates of postoperative complications were not statistically significant between groups. The R0 resection rate was similar. The entire 1-year disease-free and overall survival were 52% and 84%, respectively. Excellent results can be obtained in innovative complex surgery with careful patient selection and good technical skills. Additionally, the learning curve brought confidence to perform more complex procedures while maintaining good outcomes. Les premiers résultats sur l’association de la partition hépatique et de la ligature portale pour l’hépatectomie en 2 temps (ALPPS) sont sous-optimaux. La littérature a confirmé que les courbes d’apprentissage influencent les résultats des interventions chirurgicales. Notre étude reposait sur 54 mois consécutifs d’utilisation de la technique ALPPS selon des critères de sélection rigoureux. Elle visait à évaluer l’effet de la courbe d’apprentissage sur les résultats liés à l’ALPPS. Nous avons procédé à une comparaison rétrospective des patients traités par l’ALPPS entre avril 2012 et mars 2016. Nous avons divisé les patients en 2 groupes de 24 mois (précoce et tardif). Tous les candidats avaient une charge tumorale élevée nécessitant une hépatectomie en 2 temps après une réponse à la chimiothérapie, un volume estimé de futur foie résiduel (FFR) inférieur à 30 % et un indice fonctionnel favorable. Trente-trois patients ont été traités par l’ALPPS pendant la période de l’étude : 16 dans le groupe précoce (âge médian 65 ans, indice de masse corporelle [IMC] moyen 27) et 17 dans le groupe tardif (âge médian 60 ans, IMC moyen 25). Le taux de maladie bilobaire était comparable entre les 2 groupes (94 % c. 88 %, p > 0,99). La durée de la chirurgie n’était pas statistiquement différente. Les pertes de sang peropératoires et le besoin de transfusion étaient significativement inférieurs dans le groupe tardif (200 ± 109 mL c. 100 ± 43 mL, p < 0,05). Le groupe tardif avait une proportion plus élevée d’ALPPS mono-segmentaires (4:1). Il n’y a eu aucun décès dans les 90 jours parmi les 2 cohortes. Les taux de complications postopératoires n’étaient pas statistiquement significatifs entre les groupes. Le taux de résection R0 était similaire. Les taux de survie sans récidive après une année complète et de survie globale étaient de 52 % et de 84 %, respectivement. L’innovation dans le domaine des chirurgies complexes peut donner d’excellents résultats lorsqu’on sélectionne attentivement les patients et que l’on possède de bonnes habiletés techniques. De plus, la courbe d’apprentissage a eu pour effet d’accroître la confiance dans la capacité de réaliser des interventions complexes tout en produisant de bons résultats.

A 29-year-old Yemeni male presented with fatigue, general malaise, scleral icterus and dark-colored urine. He denied alcohol or drug use. He had no right upper quadrant tenderness. Liver function tests revealed ALT>3000 and AST>!400 with total bilirubin of 10.9 and alkaline phosphatase of 181. Radiologic imaging revealed no evidence of cholecystitis. Acetaminophen level, and Epstein-Barr virus, Cytomegalovirus, and autoimmune serologies were negative. At this time, his liver enzymes began to improve slowly. Patient underwent liver biopsy which revealed acute hepatitis and cholestasis with predominantly lobular lymphocytic inflammation with individual hepatocyte necrosis. The pattern of injury was nonspecific. As an outpatient he admitted that he smoked Khat and it was suspected that his liver enzymes had improved during admission due to cessation of Khat. He was started on prednisone and mycophenolate for presumed Khat-induced autoimmune hepatitis and his liver functions normalized. Khat-induced direct liver injury is a recognized entity and can be so severe as to lead to fulminant liver failure. Rarely, khat leaves can lead to an autoimmune-type picture with positive autoimmune markers and liver biopsy suggestive of autoimmune hepatitis.

Background The disparity between the number of patients waiting for an organ transplant and availability of donor organs increases each year in Canada. Donation after cardiac death (DCD), following withdrawal of life support in patients with hopeless prognoses, is a means of addressing the shortage with the potential to increase the number of transplantable organs. Methods We conducted a retrospective, single-centre chart review of organs donated after cardiac death to the Multi-Organ Transplant Program at the London Health Sciences Centre between July 2006 and December 2007. In total, 34 solid organs (24 kidneys and 10 livers) were procured from 12 DCD donors. Results The mean age of the donors was 38 (range 18–59) years. The causes of death were craniocerebral trauma ( n = 7), cerebrovascular accident ( n = 4) and cerebral hypoxia ( n = 1). All 10 livers were transplanted at our centre, as were 14 of the 24 kidneys; 10 kidneys were transplanted at other centres. The mean renal cold ischemia time was 6 (range 3–9.5) hours. Twelve of the 14 kidney recipients (86%) experienced delayed graft function, but all kidneys regained function. After 1-year follow-up, kidney function was good, with a mean serum creatinine level of 145 (range 107–220) μmol/L and a mean estimated creatinine clearance of 64 (range 41–96) mL/min. The mean liver cold ischemia time was 5.8 (range 5.5–8) hours. There was 1 case of primary nonfunction requiring retransplantation. The remaining 9 livers functioned well. One patient developed a biliary anastomotic stricture that resolved after endoscopic stenting. All liver recipients were alive after a mean follow-up of 11 (range 3–20) months. Since the inception of this DCD program, the number of donors referred to our centre has increased by 14%. Conclusion Our initial results compare favourably with those from the transplantation of organs procured from donors after brain death. Donation after cardiac death can be an important means of increasing the number of organs available for transplant, and its widespread implementation in Canada should be encouraged.

To the Editor: In their review of the hepatopulmonary syndrome, Rodríguez-Roisin and Krowka (May 29 issue) 1 provide a pathophysiological explanation of the symptoms of this syndrome, but they downplay the importance of the history and physical examination in making the diagnosis, stating that there are no signs, symptoms, or hallmarks of the hepatopulmonary syndrome on physical examination. We disagree. Platypnea (the opposite of orthopnea) not only is a common symptom, but also is almost diagnostic in itself in a patient with cirrhosis. Many patients with the hepatopulmonary syndrome also have cyanosis and clubbing, an unusual combination in cirrhosis. We believe . . .

Background/Aim: In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence. Patients and Methods: A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed. Results: A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 ± 0.88 vs. 1.89 ± 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 ± 230 vs. 856 ± 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 ± 13.4 weeks vs. 40.2 ± 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years′ post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007). Conclusions: This study identified factors that predict SVR in HCV-positive patients who received dual therapy post-transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one.

Purpose Biliary complications following liver transplantation are a significant source of morbidity, potentially leading to graft failure necessitating retransplantation. We sought to evaluate smoking as an independent risk factor for post-transplant biliary complications. Methods The clinical course of all adult primary deceased donor liver transplants at our center from 1992 to 2012 was reviewed. Eligible patients were assigned to cohorts based on their lifetime tobacco exposure: never smokers indicating 0 pack-year exposure and all others were ever smokers. Biliary complications were defined as strictures, leaks, or bilomas requiring intervention. Complication rates were analyzed using univariate regression models correlated with donor and recipient characteristics. Associations found during univariate analysis were included in the final multivariate Cox model. Results Eight hundred sixty-five subjects were followed for a median of 65 months; 482 (55.7%) of patients had a positive smoking history at the time of transplant. In univariate analysis, positive tobacco smoking history (HR = 1.36; p  = 0.037) and increased time from quit date to transplantation (HR = 0.998; p  = 0.011) were positive and negative predictors of biliary complication, respectively. Lifetime tobacco exposure remained a significant predictor of biliary complication on multivariate analysis (HR = 1.408; p  = 0.023). Conclusions Smoking status is an independent predictor of post-transplant biliary complications, and the data presented reinforces the importance of early smoking cessation in the pre-transplantation period.

Outcomes in liver transplantation with organs obtained via donation after cardiocirculatory death (DCD) have been suboptimal compared to donation after brain death, attributed mainly to the high incidence of ischemic cholangiopathy (IC). We evaluated the effect of a 10-year learning curve on IC rates among DCD liver graft recipients at a single centre. We analyzed all DCD liver transplantation procedures from July 2006 to July 2016. Patients were grouped into early (July 2006 to June 2011) and late (July 2011 to July 2016) eras. Those with less than 6 months of follow-up were excluded. Primary outcomes were IC incidence and IC-free survival rate. Among the 73 DCD liver transplantation procedures performed, 70 recipients fulfilled the selection criteria, 32 in the early era and 38 in the late era. Biliary complications were diagnosed in 19 recipients (27%). Ischemic cholangiopathy was observed in 8 patients (25%) in the early era and 1 patient (3%) in the late era (p = 0.005). The IC-free survival rate was higher in the late era than the early era (98% v. 79%, p = 0.01). The warm ischemia time (27 v. 24 min, p = 0.049) and functional warm ischemia time (21 v. 17 min, p = 0.002) were significantly lower in the late era than the early era. We found a significant reduction in IC rates and improvement in IC-free survival among DCD liver transplantation recipients after a learning curve period that was marked by more judicious donor selection with shorter procurement times. L’issue des greffes de foie suite à un don d’organe après décès cardiocirculatoire (DDC) a été sous-optimale comparativement aux dons suivant la mort cérébrale. Cela serait surtout attribuable à une forte incidence de cholangiopathie ischémique (CI). Nous avons évalué l’effet d’une courbe d’apprentissage échelonnée sur 10 ans sur les taux de CI chez des receveurs de greffe de foie après DDC dans un seul centre. Nous avons analysé toutes les greffes de foie consécutives à des DDC entre juillet 2006 et juillet 2016. Les patients ont été regroupés en 2 époques, la première, de juillet 2006 à juin 2011, et la seconde, de juillet 2011 à juillet 2016. Ceux pour lesquels on disposait de moins de 6 mois de suivi ont été exclus. Les paramètres principaux étaient l’incidence de CI et le taux de survie sans CI. Parmi les 73 greffes de foie par suite de DDC, 70 receveurs répondaient aux critères de sélection, 32 pour la première époque et 38 pour la seconde époque. Des complications biliaires ont été diagnostiquées chez 19 receveurs (27 %). La cholangiopathie ischémique a été observée chez 8 patients (25 %) de la première époque et 1 patient (3 %) de la seconde (p = 0,005). Le taux de survie sans CI a été plus élevé pendant la seconde époque que pendant la première (98 % c. 79 %, p = 0,01). Le temps d’ischémie chaude (27 minutes c. 24, p = 0,049) et le temps d’ischémie chaude fonctionnelle (21 minutes c. 17, p = 0,002) ont été significativement plus courts durant la seconde époque que durant la première. Nous avons observé une réduction significative des taux de CI et une amélioration de la survie sans CI chez les receveurs de greffes de foie par DDC après une courbe d’apprentissage qui a été marquée par une sélection plus judicieuse des donneurs et des délais d’obtention plus courts.