Centre Hospitalier De l’Universite De Montreal Research Articles

The Supply Side of Coagulation: Fibrinogen and Bleeding in Liver Disease and Transplantation.

In this issue of Transplantation, Carrier et al1 describe a study that assesses the effect of preoperative fibrinogen levels on perioperative bleeding and outcomes. In 613 patients with end-stage liver disease who underwent liver transplantation between 2008 and 2019, preoperative low fibrinogen levels were associated with more blood loss but not worse 1-y survival in univariate and multivariate statistical models. This effect was most prominent when fibrinogen levels were below 3 g/L before surgery. In any model of coagulation, fibrinogen is the substrate required to create an effective clot and provide hemostasis. Like most components of hemostasis, fibrinogen is synthesized by the liver and reduced in severe liver disease. Additionally, and maybe more commonly‚ dysfibrinogenemia occurs in liver disease resulting in defects of the fibrinogen structure with undetermined effects on hemostasis.2 The coagulation abnormalities associated with liver disease result in dysbalanced hemostasis that can cause impaired clot formation or excessive thrombosis. Conventional coagulation tests cannot detect this dysbalanced hemostasis‚ as they measure only (a part of) the procoagulant side of hemostasis. Viscoelastic testing, now routinely used in many transplant centers‚ may provide a better assessment of all aspects of clot formation by creating a visual representation of changes in the viscosity of blood when a clot forms. Viscoelastic testing can guide transfusion management in many clinical scenarios‚ including liver transplantation‚ but possibly, more importantly, allows us to identify patients who are hypercoagulable even when the conventional coagulation tests are abnormally high. The results of Carrier et al suggest that low preoperative fibrinogen levels may be an indicator that a patient is at risk for increased intraoperative bleeding. This may be particularly useful if perioperative viscoelastic testing is not used or available as with the study center. This risk of bleeding increased when fibrinogen levels were below 3 g/L before surgery, a level that is far higher than what has traditionally been considered a concerning threshold. Most experts and societies, for example, the review on perioperative coagulation management in liver transplant recipients by Bezinover et al here in Transplantation in 2018,3 recommend fibrinogen concentrate and/or cryoprecipitate transfusion for fibrinogen levels below 1.5 to 2 g/L. Although raising new questions, the present study does not provide enough evidence to change this recommendation at this time. An association with bleeding (even in a multivariate model) does not necessarily mean that replacing fibrinogen with levels over 3 g/L will reduce the risk of bleeding. The assumption is that fibrinogen levels that are below 3 g/L before surgery may decrease more during transplantation to a level that actually impairs hemostasis. Excessive transfusion of cryoprecipitate (and, to a lesser degree, fibrinogen concentrates) is not without risk and may increase the risk of thromboembolic complications.4 The results by Carrier et al are raising new questions about fibrinogen thresholds and may provide the impetus for future (prospective) studies but should not necessarily change our current management. The Centre Hospitalier de L’Universite de Montreal (CHUM) has demonstrated for many years with great success what can be achieved with a concerted effort to reduce blood transfusion5: More than 70% of the patients in the present study did not receive any red blood cell transfusion at all! The center undertakes a number of interventions to achieve these remarkable results. For example, over 50% of the patients in this study underwent phlebotomy at the beginning of surgery. I am not aware of any other center that implemented such a vigorous and successful program to reduce blood transplantation. Unfortunately, this also limits the generalizability of the present study (and reduces the statistical power of the study). Furthermore, because viscoelastic testing was not used in this study, we do not know if lower preoperative fibrinogen levels result in deficient fibrinogen contribution to clot strength later during surgery (assessed, for example, using fibrinogen assays such as FIBTEM with rotational thromboelastometry, ROTEM). In summary, Carrier et al provide important insight into the role of fibrinogen in achieving hemostasis during and good outcomes after liver transplantation. Their data encourage us to check for fibrinogen levels whenever we measure conventional or viscoelastic coagulation tests and design future randomized trials of fibrinogen replacement in liver transplantation.

Predictors of Small Intestinal Bacterial Overgrowth in Symptomatic Patients Referred for Breath Testing.

BackgroundIndications for a breath test (BT) are well established in the symptomatic patient with risk factors predisposing them to small intestinal bacterial overgrowth (SIBO). Characteristics and the profile of this population are not well known. Our objective was to study the characteristics of patients undergoing a BT for SIBO and to identify factors associated with a positive BT.MethodsRetrospective study was conducted from 2012 to 2016 at the neurogastroenterology unit of the Centre Hospitalier de l’Universite de Montreal (CHUM). All patients who completed a BT (lactulose and/or glucose) were included. Demographics and clinical factors were analyzed to identify predictors of positive BT. Type of antibiotic treatment and clinical response were compiled. Groups of patients with (SIBO+) and without SIBO (SIBO-) were also compared.ResultsA total of 136 patients were included in the study (mean age 51.2, range 20 - 80 years; 63% women), and SIBO was detected in 33.8% (n = 46). Both groups were similar in terms of age, body mass index, and gender. SIBO was significantly associated with the presence of abdominal pain (odds ratio (OR) = 4.78; P < 0.05), bloating (OR = 5.39; P < 0.05), smoking (OR = 6.66; P < 0.05), and anemia (OR = 4.08; P < 0.05). No association was identified with gender, age, obesity, and risk factors for SIBO. Antibiotics were used in 43% of patients with a positive BT, but clinical response was not significantly different in the subgroup that received antibiotics versus the subgroup that did not.ConclusionsThe prevalence of SIBO is high in symptomatic patients who underwent breath testing. Abdominal pain, bloating, smoking, and anemia are strongly associated with SIBO. Treatment of SIBO with antibiotics needs to be further investigated to better determine its efficacy on gastrointestinal symptoms.

Overexpression of IGF2BP3 As a Potential Oncogene in Ovarian Clear Cell Carcinoma

Ovarian Clear Cell Carcinoma (OCCC) displays distinctive clinical and molecular characteristics and confers the worst prognosis among all ovarian carcinoma histotypes when diagnosed at advanced stage because of the lack of effective therapy. IGF2BP3 is an RNA binding protein that modulates gene expression by posttranscriptional action. In this study, we investigated the roles of IGF2BP3 in the progression of OCCC. We used 328 OCCCs from the AOVT (the Alberta Ovarian Tumor Type study) and the COEUR (the Canadian Ovarian Experimental Unified Resource) cohorts to elucidate the associations between IGF2BP3 expression and clinicopathological parameters, with positive IGF2BP3 expression defined as diffuse block staining, being more frequently observed at stage III (P=0.0056) and significantly associated with unfavorable overall survival (HR=1.59, 95% CI 1.09 - 2.33) in multivariate analysis. IGF2BP3 mRNA gene expression was markedly increased in OCCC cell lines compared to normal tissue such as ovarian surface epithelium. We chose two IGF2BP3-overexpressing cell lines ES2 and OVMANA for in vitro and in vivo knockdown experiments. The proliferation and viability of both cell lines were significantly inhibited by 2 IGF2BP3 siRNAs and similar suppression was observed in cell migration and invasion by Wound Healing and Transwell assays. The percentage of apoptotic cancer cells was enhanced by both IGF2BP3 siRNAs. In vivo experiments showed a significantly reduced size of tumors when treated with IGF2BP3 siRNA compared to controls. Furthermore, cancer metastasis-indicators MMP2 and MMP9 proteins were down-regulated. In conclusion, our study shows that IGF2BP3 expression is a promising biomarker for prognostication of women diagnosed with OCCC with multiple effects on key cell functions, supporting its role as an important cellular regulator with potential oncogenic activity, and as a potential target for future intervention strategies. Funding Statement: This study used resources provided by the Canadian Ovarian Cancer Research Consortium’s COEUR biobank funded by the Terry Fox Research Institute (grant #2009-15) and supervised by the Centre hospitalier de l’Universite de Montreal (CHUM). The Consortium acknowledges contributions to its COEUR biobank from institutions across Canada. Wenrang Kan participated in basic experimental work as a volunteer. This work was supported by grants of the National Natural Science Foundation of China (NSFC30970119, 81030029, 81271786, NSFC-NIH 81161120416, 81671980, 81871623) and College students’ Innovation & Entrepreneurship project in Heilongjiang Province (201410226047 J.J.K, D.Y.; 201510226020 D.S.L, L.Y., T.L., L.Q., L.L.G.; 201610226095 H.Y.W., Z.H.S. T.T.G., S.J.H., S.G.; 201610226094 Y.Y.Q., M.Y.; 201710226073 S.J.H., S.G.). H.D.L. is supported by a scholarship from China Scholarship Council, CSC No. 201508230143, for an academic visit to the University of Calgary (Univ. of Calgary ID number: 30016355). We also thank the Health and Family Planning Commission of Heilongjiang Province (2016-188), the Fundamental Research Funds for the Provincial Universities (2017JCZX57), the Young Innovative Talents in Universities of Heilongjiang Province (UNPYSCT-2018064), the China Postdoctoral Science Foundation (2018M630380) and the Heilongjiang Postdoctoral Financial Assistance (LBH-Z18198) program for their support. Declaration of Interests: There are no competing interest concerns with any of the authors. Ethics Approval Statement: All animal experiments were executed in accordance with the Institutional Ethics Committee of Harbin Medical University.

Management of Esophageal Achalasia in Quebec.

BackgroundEsophageal achalasia is a defective relaxation of the lower esophageal sphincter with a loss of esophageal peristalsis causing dysphagia. Treatment can be Heller myotomy, pneumatic balloon dilation, Botox injections, peroral endoscopic myotomy (POEM) or medical. The main objective of the study was to measure the extent of post-treatment dysphagia depending on the type of treatment.MethodsThis was a retrospective study conducted at the Centre Hospitalier de l’Universite de Montreal (CHUM) between 2011 and 2017. All patients with manometric diagnostic of achalasia in our department were included. Data were collected with the electronic health record and a standardized post-treatment telephone survey to evaluate the extent of dysphagia and the use of proton pump inhibitor (PPI).ResultsA total of 169 patients were included. The most frequent treatments were Heller myotomy (60%), Botox injection (18%) and endoscopic balloon dilation (16%). There was a significant difference in the management of patients treated at the CHUM and outside the CHUM for the frequency of pneumatic dilation (28 vs. 7%; P = 0.001) and Heller myotomy (49 vs. 69%; P = 0.02). An Eckardt score ≤ 3 was found in 80% of patients. No significant score difference was found between the CHUM and outside CHUM groups or between the different treatments. The post-treatment use of PPI was of 49% and was not significantly different depending on the site or the type of treatment.ConclusionHeller myotomy stays the most frequent treatment, especially outside our tertiary center. The rate of post-treatment dysphagia is low no matter the treatment choice. The use of PPI stays frequent regardless of the management site or the type of treatment used.

Neoadjuvant Therapy (NAT) in Pancreatic Adenocarcinoma (PAC): A Single Center Experience

Background: Surgical resection of PAC followed by adjuvant therapy is the standard of care for localized resectable tumors. Surgical resection, with clear margins, of borderline resectable (BR) or locally advanced (LA) tumors remains quite challenging. NAT could potentially improve outcomes but there are no clear recommendations in this regards for upfront unresectable PAC. Herein, we report our experience with different NAT modalities used in BR and LA PAC. Methods: Medical records of patients identified in our medical database as BR or LA PAC and treated with NAT at Centre Hospitalier de l’Universite de Montreal (CHUM) were retrospectively reviewed. Recist criteria were used for response assessment. Descriptive statistics and Kaplan-Meier were used for statistical purposes. Results: In total, ninety patients met the inclusion criteria (50 BR, 40 LA tumors). Chemotherapy, mostly FOLFIRINOX, was the only modality used in 51 patients (56.6%). Twenty-three patients (25.3%) received concurrent chemoradiation and sixteen patients (17.7%) received sequential chemotherapy and chemoradiation. Tumor resection was possible in 44 patients, 32 BR patients (R0: 68.7%) and 12 LA patients (R0: 75%). Median Disease free survival (DFS) of patients undergoing resection was 12.3 months. Median progression free survival (mPFS) was 29 vs 10 (HR: 0.2; p<0.001) and mOS was 41.7 vs 15.7 months (HR: 0.3; p<0.001) in resected and non-resected patients, respectively. Treatment with more than one modality showed better clinical outcomes (PFS and OS) and a non-statistically higher R0 resection rate that was 100% in BR tumors. OS in patients with resected cancers was not reached for the multimodality group, 41.7 months for chemotherapy alone group and 22.4 months in patients treated with chemoradiotherapy group (p=0.017). Conclusion: In this retrospective single center analysis, NAT appears to improve and enable resection of newly diagnosed PAC. These results validate previous retrospective studies, but warrant large prospective trials to better define the optimal neoadjuvant approach.

Professor Réal Lapointe: the impact of portal embolization on postoperative morbidity and mortality after liver resection.

Professor Real Lapointe (Figure 1) is the Director of General Surgery Division in University of Montreal, and Chief of Hepatobiliary and Pancreatic (HBP) Surgery and Liver Transplantation Department in Centre Hospitalier de l’Universite de Montreal (CHUM). As holder of the Roger Des Groseillers Chair in HBP Surgical Oncology, his clinical and translational research focuses on evaluating new drugs in HBP oncology and different surgical approaches for colorectal liver metastases, and on developing new biological markers from human tissue bank from patients with primary and secondary liver cancer (e.g., hepatic colorectal metastases), pancreatic and bile duct cancer.

Induction Chemotherapy Followed by Concomitant Chemoradiation in Head and Neck Squamous Cell Carcinoma: A Single Institution Experience

Objective: Phase 3 studies are underway to compare induction chemotherapy (IC) followed by concomitant chemoradiation (CRT) with CRT alone in advanced head and neck cancer. The purpose is to report the outcome of patients with advanced head and neck cancer treated at Centre Hospitalier de l’Universite de Montreal (CHUM) with IC followed by CRT. Methods: From March 1998 to December 2007, 56 consecutive patients were treated for advanced squamous cell carcinoma of the head and neck with high-dose IC followed by CRT. Sixteen patients with carcinoma of the nasopharynx, paranasal sinuses or nasal cavity were excluded. Patients presented with either T4 (60%) or N3 (60%) disease. Outcomes were computed using Kaplan-Meier curves. The number of IC cycles were compared with logrank tests. Results: The 2 year estimates of OS, DFS, LRC and DMFS rates were 58%, 46%, 78% and 75% respectively. At last follow-up, we observed 17 patients with relapse of which 10 were at a distant site. When stratified by the number of IC cycles, a DMFS rate of 87% was observed for 1-2 cycles vs 49% for 3 cycles, p=0.05. Conclusions: Despite intensive treatment with platinum based IC and CRT, prognosis for this highly advanced population of T4 or N3 cancers is poor. The number of IC cycles seem to influence the rate of DM. Further trials are needed to answer the question regarding IC followed by CRT vs CRT alone. Targeted therapies might also yield more promising results.

Pratiques cliniques préventives et besoins pour leur intégration chez des médecins d’un centre hospitalier universitaire à Montréal

Present a picture of physicians' preventive clinical practices (PCP) at a university medical centre, and identify the obstacles that hinder their implementation. Self-administered questionnaire survey addressed to 367 general practitioners and specialists working at the Centre hospitalier de l'Université de Montréal (CHUM) in 2006. Respondents claim to be recommending PCP (often or very often) in approximately 60-82% of cases. Women physicians report a larger integration for screening and vaccination (p < 0.05). General physicians claim to apply or recommend PCP more frequently than specialists (p < 0.05), except for anti-tobacco counseling. Lack of time (82%) and deficiencies in continuity of treatment (75%) are considered by the majority of respondents as major obstacles to the realization of PCP. Most participants (99%) consider delivering preventive services to be part of their role and 98% claim to be motivated to integrate PCP into their practice. However, almost half of physicians do not apply preventive recommendations to their own life and at least two thirds of them doubt the efficacy of counseling. Despite observed encouraging results, actions must be taken to improve the integration of PCP to general and specialized health care and to bring physicians around to adopting healthy lifestyle habits themselves.

Pratiques cliniques préventives et besoins pour leur intégration chez des médecins d'un centre hospitalier universitaire à Montréal

Objectives: Present a picture of physicians’ preventive clinical practices (PCP) at a university medical centre, and identify the obstacles that hinder their implementation. Method: Self-administered questionnaire survey addressed to 367 general practitioners and specialists working at the Centre hospitalier de l’Universite de Montreal (CHUM) in 2006. Results: Respondents claim to be recommending PCP (often or very often) in approximately 60-82% of cases. Women physicians report a larger integration for screening and vaccination (p Conclusion: Despite observed encouraging results, actions must be taken to improve the integration of PCP to general and specialized health care and to bring physicians around to adopting healthy lifestyle habits themselves. Key words: Clinical prevention; preventive clinical practices; preventive clinical practice guidelines; preventive practice obstacles