Publications by authors named "Roman E Zyla"

4 Publications

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What Are the Burden, Causes, and Costs of Early Hospital Readmissions After Kidney Transplantation?

Prog Transplant 2021 Jun 24;31(2):160-167. Epub 2021 Mar 24.

Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Introduction: Kidney transplant recipients are at risk for complications resulting in early hospital readmission. This study sought to determine the incidences, risk factors, causes, and financial costs of early readmissions.

Design: This single-centre cohort study included 1461 kidney recipients from 1 Jul 2004 to 31 Dec 2012, with at least 1-year follow-up. Early readmission was defined as hospitalization within 30 or 90-days postdischarge from transplant admission. Associations between various parameters and 30 and 90-days posttransplant were determined using multivariable Cox proportional hazards models. The hospital-associated costs of were assessed.

Results: The rates of early readmission were 19.4% at 30 days and 26.8% at 90 days posttransplant. Mean cost per 30-day readmission was 11 606 CAD. Infectious complications were the most common reasons and resulted in the greatest cost burden. Factors associated with 30 and 90-days in multivariable models were recipient history of chronic lung disease (hazard ratio or HR 1.78 [95%CI: 1.14, 2.76] and HR 1.68 [1.14, 2.48], respectively), median time on dialysis (HR 1.07 [95% CI: 1.01, 1.13]and HR 1.06 [95% CI: 1.01, 1.11], respectively), being transplanted preemptively (HR 1.75 [95% CI: 1.07, 2.88] and HR 1.66 [95% CI: 1.07, 2.57], respectively), and having a transplant hospitalization lasting of and more than 11 days (HR 1.52 [95% CI: 1.01, 2.27] and HR 1.65 [95% CI: 1.16, 2.34], respectively).

Discussion: Early hospital readmission after transplantation was common and costly. Strategies to reduce the burden of early hospital readmissions are needed for all patients.
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June 2021

CTNNB1 Mutations and Aberrant β-Catenin Expression in Ovarian Endometrioid Carcinoma: Correlation With Patient Outcome.

Am J Surg Pathol 2021 01;45(1):68-76

Department of Laboratory Medicine and Pathobiology, University of Toronto.

CTNNB1 mutations and aberrant β-catenin expression have adverse prognosis in endometrial endometrioid carcinoma, and recent evidence suggests a prognostic role of β-catenin in ovarian endometrioid carcinoma. Thus, we aimed to determine the prognostic value of the CTNNB1 mutational status, and its correlation with β-catenin expression, in a well-annotated cohort of 51 ovarian endometrioid carcinomas. We performed immunohistochemistry for β-catenin and developed an 11-gene next-generation sequencing panel that included whole exome sequencing of CTNNB1 and TP53. Results were correlated with clinicopathologic variables including disease-free and disease-specific survival. Tumor recurrence was documented in 14 patients (27%), and cancer-related death in 8 patients (16%). CTNNB1 mutations were found in 22 cases (43%), and nuclear β-catenin in 26 cases (51%). CTNNB1 mutation highly correlated with nuclear β-catenin (P<0.05). Mutated CTNNB1 status was statistically associated with better disease-free survival (P=0.04, log-rank test) and approached significance for better disease-specific survival (P=0.07). It also correlated with earlier International Federation of Gynecology and Obstetrics stage (P<0.05). Nuclear β-catenin, TP53 mutations, age, ProMisE group, surface involvement, tumor grade and stage also correlated with disease-free survival. There was no association between membranous β-catenin expression and disease-free or disease-specific survival. CTNNB1 mutations and nuclear β-catenin expression are associated with better progression-free survival in patients with OEC. This relationship may be in part due to a trend of CTNNB1-mutated tumors to present at early stage. β-catenin immunohistochemistry may serve as a prognostic biomarker and a surrogate for CTNN1B mutations in the evaluation of patients with ovarian endometrioid neoplasia, particularly those in reproductive-age or found incidentally without upfront staging surgery.
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January 2021

The prognostic role of horizontal and circumferential tumor extent in cervical cancer: Implications for the 2019 FIGO staging system.

Gynecol Oncol 2020 08 26;158(2):266-272. Epub 2020 May 26.

Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. Electronic address:

Objective: The FIGO 2019 update on cervical cancer staging removed horizontal tumor extent (HZTE) as a staging variable. Evidence is needed to substantiate this change. The prognostic significance of HZTE and a related variable, circumferential tumor extent (%CTE), is similarly unknown. We aimed to investigate the association of HZTE and %CTE with survival outcomes in cervical cancer patients.

Methods: We identified patients treated with primary surgery for stage I cervical cancer in a single institution during a 9-year period. HZTE and, when available, %CTE were obtained from pathology records. Cases were staged using 2019 FIGO staging. Correlations between HZTE, %CTE and FIGO stage with recurrence-free (RFS) and disease-specific survival (DSS) were determined using univariable and multivariable analyses.

Results: 285 patients were included with a median follow-up of 48 (range 7-123) months. HZTE was statistically associated with RFS and DSS on univariate and multivariate analysis. None of the 168 stage IA patients in our series had tumor recurrence or death during follow-up, including 42 with HZTE ≥7 mm. None of the patients with a tumor horizontal extent <7 mm experienced recurrence or death. %CTE correlated only with RFS on univariate analysis. 2019 FIGO stage did not independently correlate with RFS or DSS in our sample.

Conclusions: HZTE is an independent predictor of survival in cervical carcinoma. In stage IA tumors, however, HZTE does not offer superior prognostic value, supporting the 2019 FIGO recommendations to remove this variable from staging in these cases. HZTE may be useful in larger tumors in which staging depends on maximum tumor size. %CTE is not an independent prognostic variable in cervical cancer, and we advise against its use.
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August 2020

Clathrin-dependent entry and vesicle-mediated exocytosis define insulin transcytosis across microvascular endothelial cells.

Mol Biol Cell 2015 Feb 24;26(4):740-50. Epub 2014 Dec 24.

Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada Keenan Research Centre, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5C1, Canada Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

Transport of insulin across the microvasculature is necessary to reach its target organs (e.g., adipose and muscle tissues) and is rate limiting in insulin action. Morphological evidence suggests that insulin enters endothelial cells of the microvasculature, and studies with large vessel-derived endothelial cells show insulin uptake; however, little is known about the actual transcytosis of insulin and how this occurs in the relevant microvascular endothelial cells. We report an approach to study insulin transcytosis across individual, primary human adipose microvascular endothelial cells (HAMECs), involving insulin uptake followed by vesicle-mediated exocytosis visualized by total internal reflection fluorescence microscopy. In this setting, fluorophore-conjugated insulin exocytosis depended on its initial binding and uptake, which was saturable and much greater than in muscle cells. Unlike its degradation within muscle cells, insulin was stable within HAMECs and escaped lysosomal colocalization. Insulin transcytosis required dynamin but was unaffected by caveolin-1 knockdown or cholesterol depletion. Instead, insulin transcytosis was significantly inhibited by the clathrin-mediated endocytosis inhibitor Pitstop 2 or siRNA-mediated clathrin depletion. Accordingly, insulin internalized for 1 min in HAMECs colocalized with clathrin far more than with caveolin-1. This study constitutes the first evidence of vesicle-mediated insulin transcytosis and highlights that its initial uptake is clathrin dependent and caveolae independent.
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February 2015