Aspirin exposure and its association with metal stent patency in malignant distal biliary obstruction: a large international multicenter propensity score-matched study.

BACKGROUND AND AIMS: Stent dysfunction is common after ERCP with self-expandable metal stent (SEMS) insertion for malignant distal biliary obstruction (MDBO). Chronic aspirin (acetylsalicylic acid; ASA) exposure has been previously shown to potentially decrease this risk. We aim to further ascertain the protective effect of ASA and to identify other predictors of stent dysfunction. METHODS: This multicenter retrospective cohort study was conducted at 9 sites in Canada and 1 in the United States. Patients with MDBO who underwent ERCP with SEMS placement between January 2014 and December 2019 were included and divided into 2 cohorts: ASA exposed (ASA-E) and ASA unexposed (ASA-U). Propensity-score matching (PSM) was performed to limit selection bias. Matched variables were age, sex, tumor stage, and type of metal stent. The primary outcome was the hazard rate of stent dysfunction. A multivariable Cox proportional hazards model was used to identify independent predictors of stent dysfunction. RESULTS: Of 1396 patients assessed, after PSM 496 patients were analyzed (248 ASA-E and 248 ASA-U). ERCP with SEMS placement was associated with a high clinical success of 82.2% in ASA-E and 81.2% in ASA-U cohorts (P = .80). One hundred eighty-four patients had stent dysfunction with a mean stent patency time of 229.9 ± 306.2 days and 245.4 ± 241.4 days in ASA-E and ASA-U groups, respectively (P = .52). On multivariable analysis, ASA exposure did not protect against stent dysfunction (hazard ratio [HR], 1.25; 95% confidence interval [CI], .96-1.63). An etiology of pancreatic cancer (HR, 1.36; 95% CI, 1.15-1.61) predicted stent dysfunction, whereas cancer therapy was protective (HR, .73; 95% CI, .55-.96). Chronic ASA use was not associated with an increased risk for adverse events including bleeding, post-ERCP pancreatitis, and perforation. CONCLUSIONS: In this large, multicenter study using PSM, chronic exposure to ASA did not protect against stent dysfunction in MDBO. Instead, the analysis revealed that the etiology of pancreatic cancer was an independent predictor of stent dysfunction and cancer therapy was protective.

Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3+ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia-Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate.

Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings. Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures-37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values. Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP. Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction.

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

BACKGROUND: After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. METHODS: From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. RESULTS: The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. CONCLUSIONS: Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients.

Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.

Titratable Pharmacological Regulation of CAR T Cells Using Zinc Finger-Based Transcription Factors.

Chimeric antigen receptor (CAR) T cell therapy has emerged as an attractive strategy for cancer immunotherapy. Despite remarkable success for hematological malignancies, excessive activity and poor control of CAR T cells can result in severe adverse events requiring control strategies to improve safety. This work illustrates the feasibility of a zinc finger-based inducible switch system for transcriptional regulation of an anti-CD20 CAR in primary T cells providing small molecule-inducible control over therapeutic functions. We demonstrate time- and dose-dependent induction of anti-CD20 CAR expression and function with metabolites of the clinically-approved drug tamoxifen, and the absence of background CAR activity in the non-induced state. Inducible CAR T cells executed fine-tuned cytolytic activity against target cells both in vitro and in vivo, whereas CAR-related functions were lost upon drug discontinuation. This zinc finger-based transcriptional control system can be extended to other therapeutically important CARs, thus paving the way for safer cellular therapies.

Outcomes of Older Patients with Resectable Colorectal Liver Metastases Cancer (CRLM): Single Center Experience.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at "Centre Hospitalier de l'Université de Montréal" (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70-85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months; p = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.

Effect of intraoperative hypovolemic phlebotomy on transfusion and clinical outcomes in patients undergoing hepatectomy: a retrospective cohort study.

BACKGROUND: There is no consensus on how to best achieve a low central venous pressure during hepatectomy for the purpose of reducing blood loss and red blood cell (RBC) transfusions. We analyzed the associations between intraoperative hypovolemic phlebotomy (IOHP), transfusions, and postoperative outcomes in cancer patients undergoing hepatectomy. METHODS: Using surgical and transfusion databases of patients who underwent hepatectomy for cancer at one institution (11 January 2011 to 22 June 2017), we retrospectively analyzed associations between IOHP and RBC transfusion on the day of surgery (primary outcome), and with total perioperative transfusions, intraoperative blood loss, and postoperative complications (secondary outcomes). We fitted logistic regression models by inverse probability of treatment weighting to adjust for confounders and reported adjusted odds ratio (aOR). RESULTS: There were 522 instances of IOHP performed during 683 hepatectomies, with a mean (standard deviation) volume of 396 (119) mL. The IOHP patients had a 6.9% transfusion risk on the day of surgery compared with 12.4% in non-IOHP patients (aOR, 0.53; 95% confidence interval [CI], 0.29 to 0.98; P = 0.04). Total perioperative RBC transfusion tended to be lower in IOHP patients compared with non-IOHP patients (14.9% vs 22.4%, respectively; aOR, 0.72; 95% CI, 0.44 to 1.16; P = 0.18). In patients with a predicted risk of ≥ 47.5% perioperative RBC transfusion, 24.6% were transfused when IOHP was used compared with 56.5% without IOHP. The incidence of severe postoperative complications (Clavien-Dindo scores ≥ 3) was similar in patients whether or not IOHP was performed (15% vs 16% respectively; aOR, 0.97; 95% CI, 0.53 to 1.54; P = 0.71). CONCLUSIONS: The use of IOHP during hepatectomy was associated with less RBCs transfused on the same day of surgery. Trials comparing IOHP with other techniques to reduce blood loss and transfusion are needed in liver surgery.

RéSUMé: CONTEXTE: Il n'existe pas de consensus quant à la meilleure façon d'obtenir une pression veineuse centrale basse pendant une hépatectomie dans le but de réduire les pertes et les transfusions sanguines. Nous avons analysé les associations entre la phlébotomie hypovolémique peropératoire, les transfusions, et les résultats cliniques postopératoires chez les patients qui subissent une hépatectomie pour cancer. MéTHODE: À l'aide de bases de données chirurgicales et transfusionnelles de patients ayant subi une hépatectomie pour cancer dans un seul établissement (du 11 janvier 2011 au 22 juin 2017), nous avons rétrospectivement analysé les associations entre la phlébotomie hypovolémique peropératoire et les transfusions érythrocytaires le jour de la chirurgie (critère d'évaluation principal) et avec les transfusions périopératoires totales, les pertes sanguines peropératoires, et les complications postopératoires (critères d'évaluation secondaires). Nous avons utilisé des modèles de régression logistique avec pondération de probabilité inverse de traitement afin de tenir compte des facteurs de confusion et rapporté les rapports de cotes ajustés (RCa). RéSULTATS: Il y a eu 522 phlébotomies hypovolémiques peropératoires exécutées au cours de 683 hépatectomies, avec un volume moyen (écart type) de 396 (119) mL. Les patients ayant eu une phlébotomie hypovolémique peropératoire avaient un risque transfusionnel de 6,9 % le jour de la chirurgie, comparativement à 12,4 % pour les patients sans phlébotomie (RCa, 0,53; intervalle de confiance [IC] de 95 %, 0,29 à 0,98; P = 0,04). Les transfusions périopératoires totales d'érythrocytes tendaient à être moins fréquentes chez les patients ayant subi une phlébotomie hypovolémique peropératoire par rapport aux patients sans phlébotomie (14,9 % vs 22,4 %, respectivement; RCa, 0,72; IC 95 %, 0,44 à 1,16; P = 0,18). Pour les patients présentant un risque prédit de transfusion périopératoire d'érythrocytes ≥ à 47,5 %, 24,6 % de ceux qui ont eu une phlébotomie hypovolémique peropératoire ont été transfusés, comparativement à 56,5 % sans phlébotomie. L'incidence des complications postopératoires graves (scores de Clavien-Dindo ≥ 3) était semblable chez tous les patients, avec ou sans phlébotomie hypovolémique peropératoire (15 % vs 16 % respectivement; RCa, 0,97; IC 95 %, 0,53 à 1,54; P = 0,71). CONCLUSIONS: L'utilisation de la phlébotomie hypovolémique peropératoire pendant une hépatectomie était associée à un moins grand nombre de transfusions érythrocytaires le jour de la chirurgie. Des études qui compareront la phlébotomie hypovolémique peropératoire à d'autres techniques visant à réduire les pertes et les transfusions sanguines sont nécessaires en chirurgie hépatique.

The Department of Surgery of the Université de Montréal, 70th anniversary.

SUMMARY: The Department of Surgery of the Université de Montréal was officially chartered in 1961, but the structure had been in place since since 1951. The department grew as a fusion of hospital-based surgery training programs from the largest French-speaking hospitals in Montreal. Currently 448 professors (135 women and 313 men) teach in the department. The research activity, both clinical and applied, is in strong progression. The Department of Surgery is the largest French and bilingual training centre in Canada and North America. In 2021 the department will celebrate its 70th anniversary. As members, we should be proud of the work achieved by our predecessors and by the current rank of professors, teachers and researchers. The department strives to promote the essential role of and highlight the rewards and benefits of academic surgery.

Association between intraoperative rotational thromboelastometry or conventional coagulation tests and bleeding in liver transplantation: an observational exploratory study.

INTRODUCTION: Liver transplantation is associated with major blood loss and transfusions. Our objective was to evaluate the association between coagulation results (rotational thromboelastometry (ROTEM) and conventional coagulation tests) and intraoperative bleeding or perioperative red blood cell (RBC) transfusions in liver transplantation. METHODS: We measured ROTEM values and conventional coagulation tests at the beginning of surgery, after graft reperfusion and at the end of surgery. We did bivariate correlation and multivariable regression analyses to explore the association between test results and either intraoperative bleeding or perioperative RBC transfusions. RESULTS: We enrolled 75 consecutive patients. Median [Q1-Q3] intraoperative blood loss was 1400 mL [675-2300] and 59% of patients did not receive any RBC transfusion either intraoperatively or postoperatively. In multivariable analyses, FIBTEM maximal clot firmness (MCF) measured at the beginning of surgery was associated with lower intraoperative blood loss (ß = -106 mL for each mm; 95% CI, -203 to -9 mL). Both a higher haemoglobin concentration (multiplicative factor = 0.89 for each g/L; 95% CI, 0.84 to 0.95) and FIBTEM MCF measured at the end of surgery (multiplicative factor = 0.68 for each mm; 95% CI, 0.48 to 0.95) were associated with fewer postoperative RBC transfusions. CONCLUSION: FIBTEM MCF was strongly associated with intraoperative blood loss and postoperative transfusions while other coagulation results were not. This study might inform future clinical trials on ROTEM-based interventions in liver transplantation. STUDY REGISTRATION: Clinical Trials.gov: NCT02356068.

mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors.

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

A newly designed uncovered biliary stent for palliation of malignant obstruction: results of a prospective study.

BACKGROUND: Biliary decompression can reduce symptoms and improve quality of life in patients with malignant biliary obstruction. Endoscopically placed stents have become the standard of care for biliary drainage with the aim of improving hepatic function, relieving jaundice, and reducing adverse effects of obstruction. The purpose of this study was to evaluate the performance characteristics of a newly-designed, uncovered metal biliary stent for the palliation of malignant biliary obstruction. METHODS: This post-market, prospective study included patients with biliary obstruction due to a malignant neoplasm treated with a single-type, commercially available uncovered self-expanding metal stent (SEMS). Stents were placed as clinically indicated for palliation of jaundice and to potentially facilitate neo-adjuvant chemotherapy. The main outcome measure was freedom from recurrent biliary obstruction (within the stent) requiring re-intervention within 1, 3, and 6 months of stent insertion. Secondary outcome measures included device-related adverse events and technical success of stent deployment. RESULTS: SEMS were placed in 113 patients (73 men; mean age, 69); a single stent was inserted in 106 patients, and 2 stents were placed in 7 patients. Forty-eight patients survived and/or completed the 6 month study protocol. Freedom from symptomatic recurrent biliary obstruction requiring re-intervention was achieved in 108 of 113 patients (95.6, 95%CI = 90.0-98.6%) at study exit for each patient. Per interval analysis yielded the absence of recurrent biliary obstruction in 99.0% of patients at 1 month (n = 99; 95%CI = 97.0-100%), 96.6% of patients at 3 months (n = 77; 95%CI = 92.7-100%), and 93.3% of patients at 6 months (n = 48; 95%CI = 86.8-99.9%). In total, only 5 patients (4.4%) were considered failures of the primary endpoint. Most of these failures (4/5) were due to stent occlusion from tumor ingrowth or overgrowth. Overall technical success rate of stent deployment was 99.2%. There were 2 cases of stent-related adverse events (1.8%). There were no cases of post-procedure stent migration, stent-related perforation, or stent-related deaths. CONCLUSIONS: This newly designed and marketed biliary SEMS system appears to be effective at relieving biliary obstruction and preventing re-intervention within 6 months of insertion in the overwhelming majority of patients. The device has an excellent safety profile, and associated high technical success rate during deployment. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov on 14 October 2013 and the study registration number is NCT01962168. University of Massachusetts Medical School did not participate in the study.

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis.

Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

Long-term outcomes after temporary placement of a self-expanding fully covered metal stent for benign biliary strictures secondary to chronic pancreatitis.

BACKGROUND AND AIMS: Temporary single, fully covered self-expanding metal stent (FCSEMS) placement for benign biliary strictures (BBSs) associated with chronic pancreatitis (CP) may require fewer interventions than endotherapy with multiple plastic stents and may carry less morbidity than biliary diversion surgery. This study aimed to assess long-term outcomes in CP-associated BBSs after FCSEMS placement and removal. METHODS: In this open-label, multinational, prospective study, subjects with CP and a BBS treated with FCSEMS placement with scheduled removal at 10 to 12 months were followed for 5 years after FCSEMS indwell. Kaplan-Meier analyses assessed BBS resolution and cumulative probability of freedom from recurrent stent placement to 5 years after FCSEMS indwell. RESULTS: One hundred eighteen patients were eligible for FCSEMS removal. At a median of 58 months (interquartile range, 44-64) post-FCSEMS indwell, the probability of remaining stent-free was 61.6% (95% confidence interval [CI], 52.5%-70.7%). In 94 patients whose BBSs resolved at the end of FCSEMS indwell, the probability of remaining stent-free 5 years later was 77.4% (95% CI, 68.4%-86.4%). Serious stent-related adverse events occurred in 27 of 118 patients (22.9%); all resolved with medical therapy or repeated endoscopy. Multivariate analysis identified severe CP (hazard ratio, 2.4; 95% CI, 1.0-5.6; P = .046) and longer stricture length (hazard ratio, 1.2; 95% CI, 1.0-1.4; P = .022) as predictors of stricture recurrence. CONCLUSION: In patients with symptomatic BBSs secondary to CP, 5 years after placement of a single FCSEMS intended for 10 to 12 months indwell, more than 60% remained asymptomatic and stent-free with an acceptable safety profile. Temporary placement of a single FCSEMS may be considered as first-line treatment for patients with CP and BBSs. (Clinical trial registration number: NCT01014390.).

A Distinct Subset of Highly Proliferative and Lentiviral Vector (LV)-Transducible NK Cells Define a Readily Engineered Subset for Adoptive Cellular Therapy.

Genetic engineering is an important tool for redirecting the function of various types of immune cells and their use for therapeutic purpose. Although NK cells have many beneficial therapeutic features, genetic engineering of immune cells for targeted therapy focuses mostly on T cells. One of the major obstacles for NK cell immunotherapy is the lack of an efficient method for gene transfer. Lentiviral vectors have been proven to be a safe tool for genetic engineering, however lentiviral transduction is inefficient for NK cells. We show in this study that lentiviral vectors pseudotyped with a modified baboon envelope glycoprotein can transduce NK cells 20-fold or higher in comparison to VSV-G pseudotyped lentiviral vector. When we investigated the mechanism of transduction, we found that activated NK cells expressed baboon envelope receptor ASCT-2. Further analysis revealed that only a subset of NK cells could be expanded and transduced with an expression profile of NK56bright, CD16dim, TRAILhigh, and CX3CR1neg. Using CD19-CAR, we could show that CD19 redirected NK cells efficiently and specifically kill cell lines expressing CD19. Taken together, the results from this study will be important for future genetic modification and for redirecting of NK cell function for therapeutic purpose.

Covered and uncovered biliary metal stents provide similar relief of biliary obstruction during neoadjuvant therapy in pancreatic cancer: a randomized trial.

BACKGROUND AND AIMS: Preoperative biliary drainage with self-expanding metal stents (SEMSs) brings liver function within an acceptable range in preparation for neoadjuvant therapy (NATx) and provides relief of obstructive symptoms in patients with pancreatic cancer. We compared fully-covered SEMSs (FCSEMSs) and uncovered SEMSs (UCSEMSs) for sustained biliary drainage before and during NATx. METHODS: Patients with pancreatic cancer and planned NATx who need treatment of jaundice and/or cholestasis before pancreaticoduodenectomy were randomized to FCSEMSs versus UCSEMSs. The primary endpoint was sustained biliary drainage, defined as the absence of reinterventions for biliary obstructive symptoms, and was assessed from SEMS placement until curative intent surgery or at 1 year. RESULTS: The intention-to-treat population included 119 patients (59 FCSEMSs, 60 UCSEMSs). Sustained biliary drainage was equally successful with FCSEMSs and UCSEMSs (72.2% vs 72.9%, noninferiority P = .01). Reasons for FCSEMS and UCSEMS failure differed significantly between the groups and included tumor ingrowth in 0% versus 16.7% (P < .01), and stent migration in 6.8% versus 0% (P = .03), respectively. Serious adverse event rates related to stent placement were not significantly different in both groups (23.7% [14/59] vs 20.0% [12/60], P = .66), as were acute cholecystitis rates when the gallbladder was in situ (9.3% [4/43] vs 4.8% [2/42], P = .68) for FCSEMSs and UCSEMSs, respectively. In our study, independent of stent type, predictors of reinterventions were 4-cm stent length and presence of the gallbladder. CONCLUSION: FCSEMSs and UCSEMSs provide similar preoperative management of biliary obstruction in patients with pancreatic cancer receiving NATx, but mechanisms of stent dysfunction depend on stent type, stent length, and presence of the gallbladder. (Clinical trial registration number: NCT02238847.).

Portal vein embolization does not affect the long-term survival and risk of cancer recurrence among colorectal liver metastases patients: A prospective cohort study.

BACKGROUND: Previous studies comparing the survival outcomes of liver resections with and without preoperative portal vein embolization (PVE) for colorectal liver metastases (CLM) have linked PVE to higher rate of tumor progression, lower overall survival (OS) and lower disease-free survival (DFS). The lack of adjusted models to compare these outcomes is a limitation of these studies since patients requiring PVE may differ significantly from the ones receiving upfront surgery. MATERIALS AND METHODS: Prospective cohort study of 128 patients undergoing CLM resection. The OS analysis followed an intent-to-treat (ITT) approach. The adjusted impact of PVE on OS and DFS was evaluated using multivariate Cox regression models. RESULTS: Seventy-one patients underwent PVE before attempting a liver resection while 57 received upfront surgery (NoPVE). All NoPVE patients were resected while 14 PVE participants (19.7%) were not operated (tumor progression = 9/14). PVE patients had a significantly higher preoperative lesions count (3 [1.75-4] vs 1 [1-2.5]; p < 0.001), a higher prevalence of bilateral metastases (23.5% vs 8.8, p = 0.028) and a higher count of neo-adjuvant chemotherapy cycles compared to NoPVE patients. The OS of PVE patients was similar to NoPVE participants (44.7 months [26.9-69.5] vs 49.0 [24.9-64.8], p = 0.761). The DFS of resected PVE patients was higher than NoPVE patients (33.2 months [10.7-54.6] vs 23.4 months [14.1-58.1], p = 0.991). In the adjusted models, preoperative lesions count was the only significant predictor of overall mortality (HR+IC95 = 1.06 (1.02-1.11) p = 0.005) and cancer recurrence (HR+IC95 = 1.14 (1.03-1.27) p = 0.012). CONCLUSION: In the context of CLM, patients requiring PVE differ significantly from patients receiving upfront surgery. This confirms the need for adjusted models when comparing the clinical outcomes of both groups. Our adjusted analysis suggests that PVE is not a significant predictor of a lower OS or DFS. PVE allowed the resection of 80% of participants with initially unresectable CLM. INSTITUTIONAL PROTOCOL NUMBER: 12.106 STUDY REGISTRATION NUMBER: NCT03168230.

Proposal of a novel MELD exception point system for hepatocellular carcinoma based on tumor characteristics and dynamics.

BACKGROUND & AIMS: Patients listed with exception points for hepatocellular carcinoma (HCC) have been more likely to be transplanted than those listed for chronic liver failure (LF) based on the model for end-stage liver disease (MELD) score. The aim of this study was to determine outcomes in the 5-year experience of a scoring system designed to reflect heterogeneity of tumor load of patients listed for HCC. METHODS: A novel MELD exception point system based on size and number of HCC was implemented in July 2009. This system allows stratification of patients based on risk of dropping out from the waiting list according to Milan criteria. LF patients were listed according to biological MELD sodium score; HCC patients were reassigned points every three months upon repeat imaging. RESULTS: Among 624 patients listed for liver transplant (LT), 505 were eligible. 94 (18.6%) were assigned MELD HCC points. Only 24.7% required changes in allocated points over time. Transplantation rates (HCC 83% vs. LF 73%, p=0.04) and waiting time in days (HCC 258 vs. LF 325; p=0.07) were similar. The method of competing risk analysis revealed that HCC patients were more likely to be transplanted than LF during the 5-year period preceding implementation, whereas transplant rates became equivalent for HCC and non-HCC in 2009-2014. One- and two-year survivals were similar between the two groups. CONCLUSIONS: Our study demonstrates that a novel MELD point system for HCC, taking into account dynamics in tumor size and number, allows for equitable liver allocation without compromising graft and patient survival. LAY SUMMARY: It has historically been difficult to achieve equitable liver allocation for liver cancer and chronic liver failure with the allocation systems currently in place in many countries worldwide. We designed a new system to help improve access to organs for liver failure patients in Québec, Canada. Our 5-year experience demonstrates that this unique system renders access to transplant similar for both liver cancer and liver failure indications.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. RESULTS: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). CONCLUSIONS: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

A sensitive method for the analysis of glutathione in porcine hepatocytes.

BACKGROUND: Reduced glutathione (γ-glutamylcysteinylglycine), GSH, is essential when protecting cells from oxidative stress and also an indicator of disease risk. Reported concentrations of GSH and its oxidized form, glutathione disulfide (GSSG), varies considerably, primarily due to the instability of GSH and various analytical methods. METHODS: We designed a sensitive method to analyze GSH and GSSG in porcine hepatocytes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) after stabilization with N-ethylmaleimide (NEM). This method includes stable isotope labeled internal standards and simple synthesis of labeled GSSG which commercial sources rarely offer. GSH and GSSG were analyzed in porcine liver biopsies giving a reference interval based on a large number of samples (26 pigs; 3 parallels). RESULTS: The LC-MS/MS results revealed excellent linearity for both GSH and GSSG, with interday coefficient of variation (%CV) for GSH-NEM and GSSG <10 %. Accuracy for recovery tests was between 95.6% and 106.7% (n = 3) for GSH and between 92.3% and 107.7% (n = 3) for GSSG. The limits of quantification were 0.1 µM for GSH-NEM and 0.08 µM for GSSG. The mean concentration of GSH was 3.5 (95% CI = 1.5-8.1) mmol/liter and of GSSG 0.0023 (95% CI = 0.0003-0.019) mmol/liter. CONCLUSION: For the first time GSH and GSSG are analyzed in porcine hepatocytes by LC-MS/MS yielding a reference level of GSH and GSSG. The method is reproducible in any laboratory with LC-MS/MS service and will probably be applicable in all soft tissues and cell suspensions, essentially with no modification.