Publications by authors named "A Ab Razak"

298 Publications

Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.

Nat Commun 2021 07 23;12(1):4496. Epub 2021 Jul 23.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.
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http://dx.doi.org/10.1038/s41467-021-24677-6DOI Listing
July 2021

Canadian Consensus on TRK-Inhibitor Therapy for NTRK Fusion-positive Sarcoma.

Int J Cancer 2021 Jul 2. Epub 2021 Jul 2.

Institut d'hématologie-oncologie, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11-13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long lasting responses in patients with NTRK fusion-positive solid tumours, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified 1) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? 2) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? 3) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma?. Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33723DOI Listing
July 2021

Efficacy and safety of vasopressin and terlipressin in preterm neonates: a protocol for a systematic review.

BMJ Paediatr Open 2021 9;5(1):e001067. Epub 2021 Jun 9.

Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.

Background: The use of vasoactive agents like arginine vasopressin (AVP) and terlipressin to treat hypotension or persistent pulmonary hypertension in critically ill preterm neonates is increasing. Therefore, a systematic review of the available data on dosing, efficacy and safety of AVP and terlipressin in this patient population appears beneficial.

Methods: We will conduct a systematic review of the available evidence on the use of AVP and terlipressin for the treatment of hypotension or persistent pulmonary hypertension in preterm neonates. We will search Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and Google Scholar from inception to March 2021. Two reviewers will independently screen titles and abstracts, review the full text of eligible studies, extract data, assess the risk of bias and judge the certainty of the evidence. Our primary outcome will be an (1) improvement of end-organ perfusion after initiation of AVP or terlipressin and (2) mortality prior to discharge. Our secondary outcomes will include (1) major neurosensory abnormality and (2) the occurrence of adverse events.

Discussion: The currently available evidence on the efficacy and safety of AVP and terlipressin in preterm neonates is limited. Yet, evidence on the pharmacology of these drugs and the pathophysiology of vasoplegic shock support the biological plausibility for their clinical effectiveness in this population. Therefore, we aim to address this gap concerning the use of vasopressin and terlipressin among critically ill preterm neonates.

Trial Registration: This protocol has been submitted for registration to the international database of prospectively registered systematic reviews (PROSPERO, awaiting registration number).
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http://dx.doi.org/10.1136/bmjpo-2021-001067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191613PMC
June 2021

Reply to letter to editor: Neurodevelopmental outcomes following bevacizumab treatment for retinopathy of prematurity: a systematic review and meta-analysis.

J Perinatol 2021 Jun 24. Epub 2021 Jun 24.

Division of Neonatology, Department of Pediatrics, Emirates Specialty Hospital, Dubai, United Arab Emirates.

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http://dx.doi.org/10.1038/s41372-021-01127-1DOI Listing
June 2021

High CPAP vs. NIPPV in preterm neonates - A physiological cross-over study.

J Perinatol 2021 Jul 5;41(7):1690-1696. Epub 2021 Jun 5.

Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Department of Critical Care, St. Michael's Hospital, Toronto, ON, Canada.

Objective: To evaluate the physiological impact of high CPAP (≥9 cmHO) vs. NIPPV at equivalent mean airway pressures.

Study Design: In this cross-over study, preterm neonates on high CPAP or NIPPV were placed on the alternate mode. After 30 min, left and right ventricular cardiac output and work of breathing indices were assessed, following which patients were placed back on the original mode and a similar procedure ensued.

Results: Fifteen infants with mean (SD) postmenstrual age 32.7 (3.0) weeks, and weight 1569 (564) grams were included. No differences in LVO [320 (63) vs. 331 (86) mL/kg/min, P = 0.46] or RVO [420 (135) vs. 437 (141) mL/kg/min, P = 0.19] were noted during high CPAP vs. NIPPV, along with no differences in work of breathing indices.

Conclusion: High CPAP pressures did not adversely impact cardiac output or work of breathing compared to NIPPV at equivalent mean airway pressure.
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http://dx.doi.org/10.1038/s41372-021-01122-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179075PMC
July 2021
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