Publications by authors named "Eshetu G Atenafu"

164 Publications

Hidradenitis Suppurativa in the Pediatric Population: An International, Multicenter, Retrospective, Cross-sectional Study of 481 Pediatric Patients.

JAMA Dermatol 2021 Feb 24. Epub 2021 Feb 24.

Section of Dermatology, Division of Pediatric Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Importance: Hidradenitis suppurativa (HS) in pediatric patients has been understudied. Increased awareness and recognition of HS prevalence in children demand efforts to better understand this condition.

Objective: To describe the demographics, clinical features, treatment, associated comorbidities, and outcomes in a large cohort of pediatric patients with HS.

Design, Setting, And Participants: International, multicenter, retrospective medical record review of pediatric patients (aged 1-18 years) with a clinical diagnosis of HS carried out in 10 dermatology clinics across the US, Canada, Israel, Australia, and Italy from January 1996 to January 2017.

Main Outcomes And Measures: Patient demographics, clinical features, severity, associated comorbidities, and treatments in pediatric patients with HS.

Results: This cross-sectional study included 481 patients diagnosed with HS. Overall, 386 (80%) were girls. The mean (SD) age of disease onset was 12.5 (2.9) years, and the mean (SD) age at diagnosis was 14.4 (3.5) years. Family history of HS was present in 111 of 271 (41%) patients. First signs/symptoms reported at disease onset were cyst/abscess in 229 of 481 (48%), pain/tenderness in 118 of 481 (25%), and papules/pustules in 117 of 481 (24%). At initial dermatologic assessment, 233 of 481 (48%) patients already had evidence of skin scarring. Disease severity (Hurley staging) was documented in 288 of 481 (60%) patients (47% stage 1, 45% stage 2 and 8% stage 3). Comorbid conditions were reported in 406 of 481 (85%) patients, the most common being obesity (263/406 [65%]) and acne vulgaris (118/406 [29%]). Complications occurred in 378 of 481 (79%) patients, the most common of which were scars or contractures (301/378 [80%]).

Conclusions And Relevance: The findings of this study indicate that there is a gap in recognizing and diagnosing pediatric HS. Pediatric patients with HS are likely to present with other comorbidities. Prospective observational and interventional studies are needed to better understand clinical course and optimal treatments for pediatric HS.
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http://dx.doi.org/10.1001/jamadermatol.2020.5435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905696PMC
February 2021

Measuring Gastric pH in Tube-Fed Children with Neurologic Impairments and Gastroesophageal Disease.

J Pediatr Gastroenterol Nutr 2021 Feb 17. Epub 2021 Feb 17.

Department of Pharmacy, The Hospital for Sick Children, Toronto, Ontario, Canada Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada Caroline Family Health Team, Burlington Ontario, Canada Division of Pediatric Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada University Health Network, Biostatistics Department, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Department of Pharmacy, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada Division of Biochemistry, The Hospital for Sick Children, Toronto, Ontario, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Objectives: To determine the extent of agreement between pH paper and handheld pH meter with a laboratory pH meter for gastric pH measurement in children with neurologic impairments and gastrostomy tubes who have gastroesophageal reflux disease (GERD).

Methods: In this prospective observational study, gastric contents were aspirated from gastric- or nasogastric-tubes and the pH measured using 3 techniques: pH paper, handheld pH meter, and laboratory pH meter (the gold standard). Agreement between techniques was assessed with intra-class correlation coefficient (ICC), Bland-Altman analysis and kappa statistic.

Results: Among 43 patients contributing 67 gastric samples, the ICC was 0.75 (95% CI: 0.69-0.97) between the handheld and laboratory meters, 0.69 (95% CI: 0.63, 0.94) between the pH paper and laboratory meter and 0.69 (95% CI: 0.63 - 0.94) between the handheld meter and paper. The Bland-Altman analysis between the handheld and lab meters showed a mean difference of -0.03 pH units (limits of agreement: -0.52 to 0.47 pH units) and 0.17 pH units (limits of agreement: -0.99 to 1.33 pH units) between the paper and lab meter. The kappa coefficients for a pH ≥ 4 were 1.0 (95% CI: 1.0 to 1.0) between the handheld and lab meters and 0.9 (95% CI: 0.77 to 1.0) between the paper and lab meter.

Conclusions: The findings suggest that both point-of-care tests, the pH meter and pH paper, correlate well with the gold standard for testing pH with a laboratory pH meter, indicating usefulness in point-of-care testing for monitoring gastric pH in tube-fed children with neurologic impairments and GERD.
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http://dx.doi.org/10.1097/MPG.0000000000003087DOI Listing
February 2021

Real-world outcomes with bortezomib-containing regimens and lenalidomide plus dexamethasone for the treatment of transplant-ineligible multiple myeloma: a multi-institutional report from the Canadian Myeloma Research Group database.

Br J Haematol 2021 Feb 9. Epub 2021 Feb 9.

Canadian Myeloma Research Group, Toronto, Ontario, Canada.

Bortezomib-containing regimens (BCRs) represented standard, first-line therapy for transplant-ineligible multiple myeloma (TIMM) in Canada until the introduction of lenalidomide and low-dose dexamethasone (Ld). However, little comparative data exist to inform the selection of regimens. We assessed the outcomes for TIMM patients treated with cyclophosphamide, bortezomib and dexamethasone or prednisone (CyBorD/P), bortezomib, melphalan and prednisone (VMP), bortezomib and dexamethasone or prednisone (VD/P) and lenalidomide and low-dose dexamethasone (Ld) using the Canadian Myeloma Research Group database. Of 1156 TIMM patients evaluated, 82% received bortezomib combinations while 18% received Ld. Median progression-free survival (PFS) was 21·0, 21·1, 13·2 and 28·5 months (P = 0·0002) and median overall survival (OS) was 52·0, 63·6, 30·8 and 65·7 months (P < 0·0001) in the CyBorD/P, VMP, VD/P and Ld groups respectively. There was no significant difference in PFS and OS between the two triplet bortezomib regimens (VMP and CyBorD/P). Ld was associated with a longer PFS but not a significantly superior OS to date. Outcomes with the bortezomib-steroid doublet were inferior (VD/P). However, multivariable analysis identified features related to disease biology as the most important prognostic factors for PFS and OS. Such factors, as well as those affecting the physician's choice of regimen, are likely to influence the results observed with different regimens. This study demonstrated real-world outcomes in TIMM similar to those reported in clinical trials.
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http://dx.doi.org/10.1111/bjh.17350DOI Listing
February 2021

Computerized cognitive training in post-treatment hematological cancer survivors: a feasibility study.

Pilot Feasibility Stud 2021 Jan 30;7(1):36. Epub 2021 Jan 30.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Background: Computerized cognitive training (CCT) programs have shown some effectiveness in alleviating cognitive symptoms in long-term cancer survivors. For patients presenting with cognitive symptoms in the early post-treatment phase, the benefit of CCT is unclear. To assess the possibility of testing the effectiveness of CCT in the early post-treatment period, our aim was to investigate the feasibility of an 8-week home-based, online CCT intervention among patients who have recently completed treatment for hematological malignancy.

Methods: This study was a single-arm, non-blinded, feasibility study. All participants were provided with the CCT intervention for an 8-week period. Feasibility was evaluated based on participant adherence and patient perceptions of the intervention, assessed through responses to an acceptability questionnaire and semi-structured interviews at the end of the intervention period.

Results: The feasibility study included 19 patients who had completed treatment for hematological malignancy at a Canadian tertiary cancer center. Adherence to the CCT intervention was limited, with only one participant meeting the criteria for intervention adherence. At the end of the intervention period, participants characterized the program as easy to follow (92%) and felt well-prepared for how to complete the exercises (100%). In semi-structured interviews, participants highlighted post-treatment barriers to intervention adherence that included symptom burden and competing time demands. Participants also suggested improvements to the intervention that could help maintain adherence despite these barriers, such as fostering a sense of accountability, providing personalized feedback and coaching, and enabling opportunities for peer support.

Conclusions: Participation in CCT can be challenging in the post-treatment period for hematological cancers. Further research on the effectiveness of CCT in this setting may require the implementation of strategies that support participants' engagement with the intervention in the context of symptoms and competing demands, such as establishing a minimum dose requirement and integrating approaches to help promote and sustain motivation.
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http://dx.doi.org/10.1186/s40814-021-00778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847007PMC
January 2021

Prognostic Factors Associated With Surviving Less Than 3 Months vs Greater Than 3 Years Specific to Spine Stereotactic Body Radiotherapy and Late Adverse Events.

Neurosurgery 2021 Jan 20. Epub 2021 Jan 20.

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Background: Patient selection is critical for spine stereotactic body radiotherapy (SBRT) given potential for serious adverse effects and the associated costs.

Objective: To identify prognostic factors associated with dying within 3 mo, or living greater than 3 yr, following spine SBRT, to better inform patient selection.

Methods: Patients living ≤3 mo after spine SBRT and >3 yr after spine SBRT were identified, and multivariable regression analyses were performed. We report serious late toxicities observed, including vertebral compression fractures (VCF) and plexopathy.

Results: A total of 605 patients (1406 spine segments) were treated from 2009 to 2018. A total of 51 patients (8.4%) lived ≤3 mo, and 79 patients (13%) survived >3 yr. Significant differences in baseline features were observed. On multivariable analysis, nonbreast/prostate primaries (odds ratio [ORs]: 28.8-104.2, P = .0004), eastern cooperative oncology group (ECOG) ≥2 (OR: 23.7, 95% CI: 3.2-177, P = .0020), polymetastatic disease (OR: 6.715, 95% CI: 1.89-23.85, P = .0032), painful lesions (OR: 3.833-8.898, P = .0118), and paraspinal disease (OR: 2.874, 95% CI: 1.118-7.393, P = .0288) were prognostic for ≤3 mo survival. The 3- and 5-yr rates of VCF were 10.4% and 14.4%, respectively, and 3- and 5-yr rates of plexopathy were 2.2% and 5.1%, respectively. A single duodenal perforation was observed, and there was no radiation myelopathy events.

Conclusion: Shorter survival after spine SBRT was seen in patients with less radiosensitive histologies (ie, not breast or prostate), ECOG ≥2, and polymetastatic disease. Pain and paraspinal disease were also associated with poor survival. Fractionated spine SBRT confers a low risk of late serious adverse events.
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http://dx.doi.org/10.1093/neuros/nyaa583DOI Listing
January 2021

Local control and patterns of failure for "Radioresistant" spinal metastases following stereotactic body radiotherapy compared to a "Radiosensitive" reference.

J Neurooncol 2021 Mar 16;152(1):173-182. Epub 2021 Jan 16.

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N3M5, Canada.

Purpose: The concept of a radioresistant (RR) phenotype has been challenged with use of stereotactic body radiotherapy (SBRT). We compared outcomes following SBRT to RR spinal metastases to a radiosensitive cohort.

Methods: Renal cell, melanoma, sarcoma, gastro-intestinal, and thyroid spinal metastases were identified as RR and prostate cancer (PCA) as radiosensitive. The primary endpoint was MRI-based local failure (LF). Secondary endpoints included overall survival (OS) and vertebral compression fracture (VCF).

Results: From a prospectively maintained database of 1394 spinal segments in 605 patients treated with spine SBRT, 173 patients/395 RR spinal segments were compared to 94 patients/185 PCA segments. Most received 24-28 Gy in 2 fractions (68.9%) and median follow-up was 15.5 months (range, 1.4-84.2 months). 1- and 2-year LF rates were 19.2% and 22.4% for RR metastases, respectively, which were significantly greater (p < 0.001) than PCA (3.2% and 8.4%, respectively). Epidural disease (HR: 2.47, 95% CI 1.65-3.71, p < 0.001) and RR histology (HR: 2.41, 95% CI 1.45-3.99, p < 0.001) predicted for greater LF. Median OS was 17.4 and 61.0 months for RR and PCA cohorts, respectively. Lung/liver metastases, polymetastatic disease and epidural disease predicted for worse OS. 2-year VCF rates were ~ 13% in both cohorts. Coverage of the CTV V90 (clinical target volume receiving 90% of prescription dose) by ≥ 87% (HR: 2.32, 95% CI 1.29-4.18, p = 0.005), no prior spine radiotherapy (HR: 1.96, 95% CI 1.09-3.55, p = 0.025), and a greater Spinal Instability Neoplasia Score (p = 0.013) predicted for VCF.

Conclusions: Higher rates of LF were observed after spine SBRT in RR metastases. Optimization strategies include dose escalation and aggressive management of epidural disease.
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http://dx.doi.org/10.1007/s11060-020-03691-6DOI Listing
March 2021

Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype glioblastoma.

Radiother Oncol 2021 Mar 5;156:258-265. Epub 2021 Jan 5.

Department of Radiation Oncology, Sunnybrook Health Sciences Center, University of Toronto, Canada.

Background: Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome.

Methods: 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC, ADC) and perfusion fraction (f, f) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated.

Results: Higher ADC at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01-1.15, p = 0.025], lower f at fraction 10 (OR = 2.11, 95% CI 1.04-4.27, p = 0.018), and lack of increase in ADC at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02-1.22, p = 0.02) were associated with early progression. Combining ADC at baseline, f at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f at fraction 10 (HR = 0.72, 95% CI 0.56-0.95, p = 0.018) was associated with longer PFS.

Conclusion: ADC at baseline, its lack of increase from baseline to fraction 20, or f at fraction 10 significantly predicted early progression. f at fraction 10 was associated with PFS.
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http://dx.doi.org/10.1016/j.radonc.2020.12.037DOI Listing
March 2021

Utility of Serum miR-371a-3p in Predicting Relapse on Surveillance in Patients with Clinical Stage I Testicular Germ Cell Cancer.

Eur Urol Oncol 2020 Dec 4. Epub 2020 Dec 4.

Departments of Surgery (Urology), Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Optimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown.

Objective: To explore the association between serum miR-371a-3p and CSI surveillance relapse.

Design, Setting, And Participants: Serial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested.

Outcome Measurements And Statistical Analysis: Using the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse.

Results And Limitations: Thirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p =  0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p =  0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87-2.02, p =  0.18; NSGCT: OR 0.45, 95% CI 0.21-1.00, p =  0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p =  0.05). Limitations include small numbers of relapses and variable time points of serum collection.

Conclusions: In our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy.

Patient Summary: The promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.
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http://dx.doi.org/10.1016/j.euo.2020.11.004DOI Listing
December 2020

Stereotactic body radiation therapy for hepatocellular carcinoma with Macrovascular invasion.

Radiother Oncol 2021 Mar 5;156:120-126. Epub 2020 Dec 5.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Canada. Electronic address:

Background: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. The purpose of this study is to describe long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT).

Methods: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were analyzed. Patients who had extrahepatic disease or previous liver transplant were excluded. Demographical, clinical, and treatment variables were analyzed.

Results: 128 eligible patients with HCC and MVI were treated with SBRT. Median age was 60.5 years (39 to 90 years). Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%. Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 5 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). Median overall survival (OS) was 18.3 months (95% CI 11.2 to 21.4 months); ECOG performance status > 1 (HR:1.85, p = 0.0138) and earlier treatment era (HR: 2.20, p = 0.0015) were associated with worsening OS. In 43 patients who received sorafenib following SBRT, median OS was 37.9 months (95% CI 19.5 to 54.4 months). Four patients developed GI bleeding possibly related to SBRT at 2 to 8 months, and 27% (31/112 evaluable patients) had worsening of CP class at three months after SBRT.

Conclusions: SBRT was associated with encouraging outcomes for patients with HCC and MVI, especially in those patients who received sorafenib after SBRT. Randomized phase III trials of SBRT with systemic and/or regional therapy are warranted and ongoing.
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http://dx.doi.org/10.1016/j.radonc.2020.11.033DOI Listing
March 2021

Targeting CD47/TNFAIP8 by miR-155 overcomes drug resistance and inhibits tumor growth through induction of phagocytosis and apoptosis in multiple myeloma.

Haematologica 2020 12 1;105(12):2813-2823. Epub 2020 Dec 1.

University Health Network, University of Toronto, Toronto, Canada.

The mechanisms of drug resistance in multiple myeloma are poorly understood. Here we show that CD47, an integrin-associated receptor, is significantly upregulated in drug resistant myeloma cells in comparison with parental cells, and that high expression of CD47 detected by immunohistochemistry is associated with shorter progression free and overall survivals in multiple myeloma patients. We show that miR-155 is expressed at low levels in drug resistant myeloma cells and is a direct regulator of CD47 through its 3'UTR. Furthermore, low miR-155 levels are associated with advanced stages of disease. MiR-155 overexpression suppressed CD47 expression on myeloma cell surface, leading to induction of phagocytosis of myeloma cells by macrophages and inhibition of tumor growth. MiR-155 overexpression also re-sensitized drug-resistant myeloma cells to bortezomib leading to cell death through targeting TNFAIP8, a negative mediator of apoptosis in vitro and in vivo. Thus, miR-155 mimics may serve as a promising new therapeutic modality by promoting phagocytosis and inducing apoptosis in patients with refractory/relapsed multiple myeloma.
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http://dx.doi.org/10.3324/haematol.2019.227579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716364PMC
December 2020

Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial.

JAMA 2020 11;324(20):2038-2047

Sections of Pediatric Emergency Medicine and Gastroenterology, Departments of Pediatrics and Emergency Medicine, Alberta Children's Hospital, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Importance: While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown.

Objective: To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy.

Design, Setting, And Participants: A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed.

Interventions: Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408).

Main Outcomes And Measures: The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes.

Results: Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, -4.2%; absolute risk difference 95% [exact] CI, -11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, -0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, -1.32 to 1.67]; P = .82); oxygen saturation (-0.04% [95% CI, -0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, -1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%).

Conclusions And Relevance: Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma.

Trial Registration: ClinicalTrials.gov Identifier: NCT01429415.
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http://dx.doi.org/10.1001/jama.2020.19839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686869PMC
November 2020

Quantitative CEST and MT at 1.5T for monitoring treatment response in glioblastoma: early and late tumor progression during chemoradiation.

J Neurooncol 2021 Jan 16;151(2):267-278. Epub 2020 Nov 16.

Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.

Purpose: Quantitative MRI (qMRI) was performed using a 1.5T protocol that includes a novel chemical exchange saturation transfer/magnetization transfer (CEST/MT) approach. The purpose of this prospective study was to determine if qMRI metrics at baseline, at the 10th and 20th fraction during a 30 fraction/6 week standard chemoradiation (CRT) schedule, and at 1 month following treatment could be an early indicator of response for glioblastoma (GBM).

Methods: The study included 51 newly diagnosed GBM patients. Four regions-of-interest (ROI) were analyzed: (i) the radiation defined clinical target volume (CTV), (ii) radiation defined gross tumor volume (GTV), (iii) enhancing-tumor regions, and (iv) FLAIR-hyperintense regions. Quantitative CEST, MT, T and T parameters were compared between those patients progressing within 6.9 months (early), and those progressing after CRT (late), using mixed modelling. Exploratory predictive modelling was performed to identify significant predictors of early progression using a multivariable LASSO model.

Results: Results were dependent on the specific tumor ROI analyzed and the imaging time point. The baseline CEST asymmetry within the CTV was significantly higher in the early progression cohort. Other significant predictors included the T of the MT pools (for semi-solid at fraction 20 and water at 1 month after CRT), the exchange rate (at fraction 20) and the MGMT methylation status.

Conclusions: We observe the potential for multiparametric qMRI, including a novel pulsed CEST/MT approach, to show potential in distinguishing early from late progression GBM cohorts. Ultimately, the goal is to personalize therapeutic decisions and treatment adaptation based on non-invasive imaging-based biomarkers.
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http://dx.doi.org/10.1007/s11060-020-03661-yDOI Listing
January 2021

Evaluation of Definitive Stereotactic Body Radiotherapy and Outcomes in Adults With Extracranial Oligometastasis.

JAMA Netw Open 2020 11 2;3(11):e2026312. Epub 2020 Nov 2.

Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Importance: The outcomes and factors that influence survival in patients with oligometastasis (OM) are not well understood and have not been well described in large-scale studies.

Objective: To evaluate overall progression-free survival (PFS), widespread progression (WSP) outcomes, and survival factors from a pooled data set of 1033 patients with OM treated with stereotactic body radiotherapy (SBRT).

Design, Setting, And Participants: Case series from January 1, 2008, to December 31, 2016. The dates of analysis were April 2019 to May 2020. The setting was multi-institutional tertiary care hospitals. Participants were consecutive patients with 5 or fewer extracranial OMs whose primary tumor was treated curatively.

Exposure: Definitive SBRT.

Main Outcomes And Measures: Overall survival (OS), progression-free survival, rate of WSP, patterns of failure, and factors altering OS.

Results: In the largest international OM case series to date (1033 participants) (mean age, 68.0 years [range, 18.0-94.3 years]; 601 [58.2%] men), 1416 SBRT courses were delivered to patients with 1 OM (596 [57.7%]), 2 OMs (245 [23.7%]), 3 OMs (105 [10.2%]), 4 OMs (55 [5.3%]), and 5 OMs (32 [3.1%]). The median follow-up was 24.1 months (range, 0.3-104.7 months), and the median OS was 44.2 months (95% CI, 39.2-48.8 months). The median PFS was 12.9 months (95% CI, 11.6-14.2 months), and the median time to WSP was 42.5 months (95% CI, 36.8-53.5 months). The OS rates were 84.1% (95% CI, 81.7%-86.2%) at 1 year, 56.7% (95% CI, 53.0%-60.2%) at 3 years, and 35.2% (95% CI, 30.1%-40.3%) at 5 years. The 3-year OS, PFS, and WSP rates were 56.7% (95% CI, 53.0%-60.2%), 23.0% (95% CI, 20.2%-25.9%), and 45.2% (95% CI, 41.4%-48.9%), respectively. The 5-year OS, PFS, and WSP rates were 35.2% (95% CI, 30.1%-40.3%), 14.8% (95% CI, 11.9%-17.9%), and 54.5% (95% CI, 49.8%-59.2%), respectively. At the time of first progression, 342 patients (33.1%) had recurrence of OM disease, and 230 patients (22.3%) underwent subsequent ablative therapies to all known metastatic sites. Multivariable analyses identified primary tumor type (hazard ratio [HR], 3.73; 95% CI, 1.75-7.94; P < .001 for breast; 5.75; 95% CI, 2.88-11.46; P < .001 for colorectal; 4.67; 95% CI, 2.12-10.31; P < .001 for kidney; 10.61; 95% CI, 5.36-20.99; P < .001 for lung; and 12.00; 95% CI, 6.06-23.76; P < .001 for other [with prostate being the reference group]), metachronous OM presentation more than 24 months since initial diagnosis (HR, 0.63; 95% CI, 0.49-0.80; P < .001), metastases confined to the lung only (HR, 0.58; 95% CI, 0.48-0.72; P < .001), and nodal or soft-tissue metastases only (HR, 0.49; 95% CI, 0.26-0.90; P = .02) as survival factors. Sixty-six (6.4%) grade 3 or higher toxic effects were observed, including 1 (0.1%) grade 5 event.

Conclusions And Relevance: This study found favorable long-term OS and WSP rates associated with extracranial OM ablated with SBRT; however, modest PFS rates were observed. A substantial proportion of patients with OM developed progressive disease and were treated with local ablation. Factors that can inform clinical decision-making and clinical trial design include primary tumor type, a metachronous presentation more than 24 months since diagnosis, and the site of OM presentation.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.26312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670310PMC
November 2020

Does it matter how we evaluate HRQOL? Longitudinal comparison of the EORTC QLQ-C30/QLQ-OG25 and FACT-E.

J Cancer Surviv 2020 Oct 26. Epub 2020 Oct 26.

Department of Surgery, Section of Thoracic Surgery, University of Manitoba and the Research Institute in Oncology & Hematology, 820 Sherbrook Street, Winnipeg, Manitoba, R3A 1R9, Canada.

Purpose: To determine whether EORTC QLQ-C30/QLQ-OG25 and FACT-E compared longitudinally provide similar reflections of health-related quality of life (HRQOL).

Methods: Eighty-six esophageal cancer patients treated with curative intent, scheduled to complete both questionnaires at baseline and post-treatment time points until 36 months. A generalized estimating equation model utilizing a Gaussian family compared instruments longitudinally. The two-one-sided-test (TOST) method assessed equivalence between the instruments.

Results: Trajectories for social domain and overall quality of life differed significantly between instruments. Also, FACT-G's functional well-being post-treatment returns to baseline 3-6 months earlier than the EORTC QLQ-C30's role functioning subscale, suggesting measurement of different components. Trajectories for physical and esophageal symptom subscales are similar and are deemed equivalent. Emotional domains are comparable and bear little resemblance to the physical domain trajectories indicating reflection of emotional experience rather than a physical proxy. EORTC QLQ-C30 subscales have a trajectory similar to its physical functioning scale except for the emotional and esophageal symptoms scales. Overall HRQOL in both instruments showed a consistent return to baseline/pre-treatment levels by 6 months post-treatment.

Conclusions: Overall HRQOL recovers earlier after curative-intent treatment than previously reported despite persistence of physical symptoms, with a consistent return to pre-treatment levels by 6 months after treatment. This supports the concept that HRQOL is not primarily defined by physical function. Based on this longitudinal comparison, FACT-E provides a more multidimensional assessment of HRQOL.

Implications For Cancer Survivors: Curative intent treatment for esophageal cancer has adverse effects on HRQOL but despite intense treatment, overall HRQOL recovers within 6 months.
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http://dx.doi.org/10.1007/s11764-020-00957-wDOI Listing
October 2020

Quantitating Interfraction Target Dynamics During Concurrent Chemoradiation for Glioblastoma: A Prospective Serial Imaging Study.

Int J Radiat Oncol Biol Phys 2021 Mar 14;109(3):736-746. Epub 2020 Oct 14.

Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada. Electronic address:

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation.

Methods And Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (V), and the migration distance (d; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model.

Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm (range, 1.1-110.5 cm), 14.7 cm (range, 0.9-115.1 cm), 13.7 cm (range, 0.6-174.2 cm), and 13.0 cm (range, 0.9-76.3 cm), respectively, with corresponding median V of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (V ≤1) with a d >5 mm during chemoradiation therapy.

Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.10.002DOI Listing
March 2021

Long-term Surveillance of Patients with Complete Response Following Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumor.

Eur Urol Oncol 2020 Sep 6. Epub 2020 Sep 6.

Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address:

Background: There is controversy regarding the management of patients with normal markers and residual masses (≤1 cm) after chemotherapy for nonseminomatous germ cell tumors (NSGCTs).

Objective: To determine long-term outcomes of a surveillance strategy in such patients.

Design, Setting, And Participants: A retrospective review of our multidisciplinary testicular cancer database was performed. All patients who underwent primary chemotherapy for metastatic NSGCTs were identified between 1981 and 2016. A complete response (CR) was defined as normalization of serum tumor markers and a ≤1 cm residual mass in the largest axial dimension following chemotherapy. All such patients were surveilled.

Outcome Measurements And Statistical Analysis: Outcome variables of interest were time to death, time to cancer-specific survival, and time to relapse. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, and the cumulative incidence of cause-specific survival rates was calculated using competing risk analysis. The impact of risk group and chemotherapy regimen on relapse-free survival was assessed using log-rank test.

Results And Limitations: During the study period, 1429 metastatic germ cell tumor patients were treated with primary chemotherapy. CR was achieved in 191 (18.5%) NSGCT patients. The median age at diagnosis was 27.4 yr, with a median follow-up of 81.1 mo. The majority had American Joint Committee on Cancer stage II at diagnosis (I: 23.8%; II: 49.2%; III: 27%) and International Germ Cell Cancer Collaborative Group good-risk disease (good: 78%; intermediate: 17.8%; poor: 4.2%). Of the 191 patients with a CR, 175 (91.6%) never relapsed and remain disease free. Sixteen (8.4%) patients relapsed after a median of 11.3 mo (range 1-332 mo), with over half (nine patients; 4.7%) relapsing in the retroperitoneum only and salvaged successfully with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) alone. Of these nine patients, only two (1%) had viable disease in the PC-RPLND specimen. The remaining seven patients had relapses outside the retroperitoneum and received salvage chemotherapy ± postchemotherapy resection. Overall, nine (4.7%) patients have died, but only four (2.1%) from testis cancer.

Conclusions: Our data, the largest series to date, confirm that surveillance is safe and effective for men who achieve a CR following chemotherapy for metastatic NSGCTs.

Patient Summary: Surveillance is a safe strategy for patients who achieve a complete response following chemotherapy for metastatic testis cancer.
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http://dx.doi.org/10.1016/j.euo.2020.08.007DOI Listing
September 2020

Glioma consensus contouring recommendations from a MR-Linac International Consortium Research Group and evaluation of a CT-MRI and MRI-only workflow.

J Neurooncol 2020 Sep 29;149(2):305-314. Epub 2020 Aug 29.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.

Introduction: This study proposes contouring recommendations for radiation treatment planning target volumes and organs-at-risk (OARs) for both low grade and high grade gliomas.

Methods: Ten cases consisting of 5 glioblastomas and 5 grade II or III gliomas, including their respective gross tumor volume (GTV), clinical target volume (CTV), and OARs were each contoured by 6 experienced neuro-radiation oncologists from 5 international institutions. Each case was first contoured using only MRI sequences (MRI-only), and then re-contoured with the addition of a fused planning CT (CT-MRI). The level of agreement among all contours was assessed using simultaneous truth and performance level estimation (STAPLE) with the kappa statistic and Dice similarity coefficient.

Results: A high level of agreement was observed between the GTV and CTV contours in the MRI-only workflow with a mean kappa of 0.88 and 0.89, respectively, with no statistically significant differences compared to the CT-MRI workflow (p = 0.88 and p = 0.82 for GTV and CTV, respectively). Agreement in cochlea contours improved from a mean kappa of 0.39 to 0.41, to 0.69 to 0.71 with the addition of CT information (p < 0.0001 for both cochleae). Substantial to near perfect level of agreement was observed in all other contoured OARs with a mean kappa range of 0.60 to 0.90 in both MRI-only and CT-MRI workflows.

Conclusions: Consensus contouring recommendations for low grade and high grade gliomas were established using the results from the consensus STAPLE contours, which will serve as a basis for further study and clinical trials by the MR-Linac Consortium.
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http://dx.doi.org/10.1007/s11060-020-03605-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541359PMC
September 2020

Acute myeloid leukemia with myelodysplasia-related changes diagnosed with multilineage dysplasia alone demonstrates a superior clinical outcome.

Hum Pathol 2020 10 13;104:117-126. Epub 2020 Aug 13.

Department of Laboratory Hematology, University Health Network, University of Toronto, Toronto, Canada. Electronic address:

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) generally confers poor prognosis; however, the clinical outcome remains heterogeneous. We sought to further stratify this subentity of AML by performing a retrospective analysis of 179 adult patients with AML-MRC diagnosed at our institution. Based on 2016 World Health Organization diagnostic criteria, 44 (25%) patients had multilineage dysplasia alone (AML-MRC-M), 74 (41%) had history of myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative disease (AML-MRC-H), and 61 (34%) had MDS-related cytogenetics (AML-MRC-C). AML-MRC-M and hematopoietic stem cell transplantation (HSCT) were associated with prolonged event-free survival (EFS) (P = 0.0051 and P < 0.0001, respectively) and overall survival (OS) (P = 0.0015 and P < 0.0001, respectively), whereas AML-MRC-C and age ≥60 years were associated with shorter EFS (P = 0.028 and P = 0.015, respectively) and OS (P = 0.021 and P = 0.013, respectively). Of note, NPM1 did not affect the patient's outcome. Multivariable analysis confirmed HSCT and AML-MRC-C as independent predictors for EFS (P < 0.0001 and P = 0.0342, respectively) and OS (P < 0.0001 and P = 0.0295, respectively). AML-MRC-M was an independent predictor for OS (P = 0.0449). When compared with a control group of 105 patients with normal karyotype AML not otherwise specified (NK-AML-NOS), patients with AML-MRC-M had similar EFS and OS (P = 0.99 and P = 0.91, respectively). However, AML-MRC-H and AML-MRC-C were associated with shorter EFS and OS (P = 0.0002 and P < 0.0001, respectively) than the same control group. In a subset of patients, next-generation sequencing analysis showed AML-MRC-M was associated with ASXL1 mutation compared with NK-AML (56% vs 6%). In conclusion, AML-MRC-M demonstrates a superior clinical outcome compared with the rest of the AML-MRC group. They have comparable outcomes to NK-AML-NOS, and these data suggest AML-MRC-M may be considered not to be classified in the same group as patients with other AML-MRC.
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http://dx.doi.org/10.1016/j.humpath.2020.08.003DOI Listing
October 2020

Combination of FLT3-ITD Allelic Ratio, NPM1 Mutation, and Immunophenotypic Markers to Modulate Outcome Prediction in Patients with Normal Karyotype Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2020 11 23;26(11):1995-2000. Epub 2020 Jul 23.

Department of Laboratory Hematology, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

NPM1 mutation status and the allelic ratio (AR) of FLT3-internal tandem duplication (FLT3-ITD) are routinely tested for disease risk stratification in patients with normal karyotype (NK) acute myelogenous leukemia (AML); however, the predictive impact of immunophenotypic markers on different NPM1/FLT3 genotypes remains unclear. We performed a retrospective analysis of 423 patients with NK-AML subclassified into groups based on NPM1/FLT3 genotype. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 124 of 423 patients (29%) and was significantly associated with longer event-free survival (EFS) and overall survival (OS), except for patients with the favorable genotype, defined as mutated NPM1 (NPM1) combined with normal FLT3 status (FLT3-ITD) or FLT3-ITD AR <.5 (FLT3-ITD). A subset of AML patients bearing the favorable NPM1/FLT3-ITD genotype share similar outcomes with AML patients who have the intermediate FLT3/NPM1 genotype defined by normal NPM1 (NPM1) and FLT3-ITD. In these individuals, the lack of CD13 expression (CD13) was associated with shorter EFS (P = .041) and OS (P = .017). CD13 was an independent predictor for shorter OS (hazard ratio, 1.985; P = .028).
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http://dx.doi.org/10.1016/j.bbmt.2020.07.017DOI Listing
November 2020

Pilot prospective study of Frailty and Functionality in routine clinical assessment in allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Jan 30;56(1):60-69. Epub 2020 Jun 30.

Department of Medicine, Section of Medical Oncology and Hematology, University of Toronto, Toronto, ON, Canada.

A Frailty and Functionality evaluation for alloHCT was implemented using existing resources. We describe the implementation of this evaluation across all ages and at first consultation, and correlate results with posttransplant outcomes in 168 patients. The evaluation consists of: Clinical Frailty Scale (CFS), Instrumental Activities of Daily Living (IADL), grip strength (GS), timed up and go test (TUGT), self-rated health question (SRH), Single question of Falls, albumin and C-Reactive Protein (CRP) levels. Median time to perform the evaluation was 5-6 min. Median age was 58 years (range: 19-77) and median follow-up was 5.3 months. TUGT > 10 s (HR 2.92; p = 0.003), raised CRP (HR 4.40; p < 0.001), and hypoalbuminemia (HR 2.10; p = 0.043) were significant risk factors for worse overal survival (OS). CFS ≥ 3 (HR 3.11; p = 0.009), TUGT > 10 s (HR 3.47; p = 0.003), GS (HR 2.56; p = 0.029), SRH ( 10 s and raised CRP were significant predictors for worse OS and NRM. SRH (
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http://dx.doi.org/10.1038/s41409-020-0979-1DOI Listing
January 2021

Clinical prevalence and outcome of cardiovascular events in the first 100 days postallogeneic hematopoietic stem cell transplant.

Eur J Haematol 2021 Jan 13;106(1):32-39. Epub 2020 Oct 13.

Allogeneic Blood and Marrow Transplant Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Introduction: Recent advances in allogeneic hematopoietic stem cell transplant (HSCT) have allowed us to offer HSCT to older, advanced disease patients with more co-morbidities. Cardiovascular toxicity post-transplant is a major concern due to the increased risk of mortality. Few studies have examined the prevalence of CV events including CAD (MI, angina, PCI, CABG, CHF, arrhythmias), HTN, stroke/TIA, and death in the first 100 days post-transplant.

Patients: We assessed the impact of pretransplant MUGA results in predicting postallogeneic HSCT CV events and overall survival in the first 100 days, and whether or not transient anthracycline-induced cardiomyopathy or cumulative anthracycline dose affected overall survival. This retrospective, cohort study included 665 patients with a median age of 52 years who underwent HSCT from 2009 to 2015.

Results: The most frequent CV event in the first 100 days post-HSCT was arrhythmia seen in 2.9% of patients followed up by CHF (12.3%), MI (9%), and angina (8%). Two patients had PCI, and both survived the first 100 days. Cardiovascular risk factors predict for a poor MUGA scan but not survival. Higher dose anthracycline pretransplant predicted for a poor outcome.

Conclusion: A history of CV disease, MI, or CAD was the most important predictive of CV events, P-value = .00002. 88.6% survived the first 100 days. Patients with an EF < 50% had a significant likelihood of having a CV event compared to patients with an EF > 60% (OR = 5.3, 95% CI [1.6-18.1], P = .0219). Cumulative anthracycline dose did not have a significant impact on overall survival.
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http://dx.doi.org/10.1111/ejh.13482DOI Listing
January 2021

Long term outcomes of stereotactic body radiation therapy for hepatocellular carcinoma without macrovascular invasion.

Eur J Cancer 2020 07 24;134:41-51. Epub 2020 May 24.

Department of Radiation Oncology, University of Toronto, Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: Stereotactic Body Radiation Therapy (SBRT) is a non-invasive ablative treatment for hepatocellular carcinoma (HCC). This report aimed to address the limited availability of long-term outcomes after SBRT for HCC from North America.

Methods: Localized HCC patients without vascular invasion, who were ineligible for other liver-directed therapies and treated with SBRT at the University of Toronto or University of Michigan, were pooled to determine overall survival (OS), cumulative recurrence rates, and ≥ grade-3 toxicity. Multivariable analysis determined factors affecting OS and local recurrence rates.

Results: In 297 patients with 436 HCCs (42% > 3 cm), one-, three- and five-year OS was 77·3%, 39·0% and 24·1%, respectively. On Cox proportional hazards regression analysis, liver transplant after SBRT, Child-Pugh A liver function, alpha-fetoprotein ≤ 10 ng/ml, and Eastern Co-operative Oncology Group performance status 0 significantly improved OS (hazard ratio [HR] = 0·06, 95% confidence interval [CI- 0·02-0·25; p<0·001; HR = 0·42, 95% CI = 0·29-0·60, p<0·001; HR = 0·61, 95% CI- 0·44-0·83; p=0·002 and HR = 0·71, 95% CI = 0·51-0·97, p=0·034, respectively). Cumulative local recurrence was 6·3% (95% CI = 0.03-0.09) and 13·3% (95% CI = 0.06-0.21) at one and three years, respectively. Using Cox regression modelling, local control was significantly higher using breath-hold motion management and in HCC smaller than 3 cm (HR = 0.52, 95% CI = 0.58-0.98; p=0.042 and HR = 0.53, 95% CI = 0.26-0.98; p=0.042, respectively). Worsening of Child-Pugh score by ≥2 points three months after SBRT was seen in 15.9%.

Conclusions: SBRT confers high local control and long-term survival in a substantial proportion of HCC patients unsuitable for, or refractory to standard loco-regional treatments. Liver transplant should be considered if appropriate downsizing occurs after SBRT.
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http://dx.doi.org/10.1016/j.ejca.2020.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340168PMC
July 2020

Anticoagulation prophylaxis reduces venous thromboembolism rate in adult acute lymphoblastic leukaemia treated with asparaginase-based therapy.

Br J Haematol 2020 12 12;191(5):748-754. Epub 2020 May 12.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Venous thromboembolism (VTE) is a well-known complication in adults receiving asparaginase (ASNase)-based intensification chemotherapy for acute lymphoblastic leukaemia (ALL). The optimal preventative strategy is unclear. Our objective is to determine the effects of low-molecular-weight heparin (LMWH) as primary VTE prophylaxis. A single-centred retrospective cohort study of adult patients with Philadelphia chromosome negative (Ph-) ALL who received ASNase-based intensification from 2001 to 2017, with prophylaxis given from 2011 to 2017. In all, 214 patients were included in this study with 99 in the historical control group and 125 in the prophylaxis group. The mean (range) enoxaparin dose was 0·79 (0·39-1·2) mg/kg. Of the 125 patients in the prophylaxis group 17 (13·6%) developed VTE during the intensification phase, while 27/99 patients (27·3%) in the control cohort experienced at least one thrombotic event (odds ratio [OR] 0·42, 95% confidence interval [CI] 0·21-0·83). Overall, the main sites of VTE incidences included deep vein thrombosis in the lower extremity (54·6%), pulmonary embolism (13·6%) and catheter-related thrombosis (22·7%). In addition, we found that after adjusting for age, T-phenotype ALL was associated with VTE development (OR 3·07, 95% CI 1·04-9·08). There was no documented major bleeding in the prophylaxis group. LMWH prophylaxis reduced the incidence of symptomatic VTE in adult patients with ALL receiving intensification chemotherapy with ASNase.
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http://dx.doi.org/10.1111/bjh.16695DOI Listing
December 2020

Clinical Variables Associated with PSA Response to Lutetium-177-PSMA ([177Lu]-PSMA-617) Radionuclide Treatment in Men with Metastatic Castration-Resistant Prostate Cancer.

Cancers (Basel) 2020 Apr 26;12(5). Epub 2020 Apr 26.

Oncology Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel.

Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan-Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ/Fisher's exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a -value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the 'real-life' setting of heavily pretreated men with mCRPC.
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http://dx.doi.org/10.3390/cancers12051078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281592PMC
April 2020

Equivalent Survival of p53 Mutated Endometrial Endometrioid Carcinoma Grade 3 and Endometrial Serous Carcinoma.

Int J Gynecol Pathol 2021 Mar;40(2):116-123

TP53 status is the most important prognostic biomarker in endometrial carcinoma. We asked the question whether p53 mutated endometrial endometrioid carcinomas grade 3 (EEC3) or endometrial serous carcinomas (ESC), the latter ubiquitously harboring TP53 mutation, have different outcomes. TP53 mutation status was assessed by surrogate p53 immunohistochemistry on 326 EEC3 and ESC from 2 major cancer centers in Canada. Mutant-type p53 expression, including overexpression, complete absence, or cytoplasmic expression, was distinguished from the wild-type pattern. Statistical associations with clinico-pathological parameter, other key biomarkers, and survival analyses were performed. P53 mutant-type immunohistochemistry was observed in all 126 ESC and in 47/200 (23.5%) EEC3. ESC and p53 mutated EEC3 had an unfavorable outcome compared with p53 wild-type EEC3 (hazard ratio=2.37, 95% confidence interval=1.48-3.80, P=0.003, hazard ratio=2.19, 95% confidence interval=1.16-4.12, P=0.016, respectively) in multivariable analyses adjusted for age, stage, center, and presence of lymph-vascular invasion. There was no significant difference in survival between ESC and p53 mutated EEC3 in multivariable analysis. Furthermore, p53 mutated EEC3 and ESC almost completely overlapped in univariate survival analysis when mismatch repair (MMR)-deficient cases were excluded, which suggests that EEC3 harboring combined MMR deficiency and TP53 mutations behave more according to the MMR status. Significant differences between p53 mutated MMR-proficient EEC3 and ESC in PTEN and p16 expression status remained. p53 mutated, MMR-proficient EEC3 and ESC have overlapping survival significantly different from p53 wild-type EEC3, which justifies a similar treatment with current non-targeted standard therapy. Although this is so, separate classification should continue due to biological differences that will become important for future targeted therapy.
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http://dx.doi.org/10.1097/PGP.0000000000000674DOI Listing
March 2021

Dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning allo-HSCT results in very low rates of GVHD.

Bone Marrow Transplant 2020 09 5;55(9):1773-1783. Epub 2020 Feb 5.

Messner Allogeneic Blood and Marrow Transplantation Program, Division of Medical Oncology and Hematology. Princes Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

The efficacy of posttransplant cyclophosphamide (PTCy) and antithymocyte globulin (ATG) in controlling GVHD has been previously reported. We aim to study the safety and efficacy of the use of dual T-cell depletion with ATG and PTCy for peripheral blood reduced intensity conditioning regimen allo-HSCT in 270 patients with hematological malignancies. Median follow-up was 12.7 months. Nineteen percent of patients received grafts from a matched related donor, 46% from 10/10 matched unrelated donors (MUD), 16% from 9/10 MUD and 19% from haploidentical donors. Graft failure rate was 9%. CMV and EBV reactivation rates were 58 and 64%. The cumulative incidence of grade II-IV and III-IV acute GVHD at day + 100 was 20.1% and 4.6%, respectively. The CI of moderate/severe chronic GVHD at 1 year was 12.4%. There were no differences in the incidence of GVHD according to donor type. One-year OS, RFS, NRM, CIR, and GVHD-free/RFS respectively were 65.2%, 56.9%, 22.7%, 20.3%, and 47.6%. Higher disease-risk index and worse Karnofsky performance status were significant factors for poor outcomes. In conclusion, the use of T-cell dual depletion with ATG and PTCy results in very low rates of acute and chronic GVHD and acceptable relapse rates and NRM.
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http://dx.doi.org/10.1038/s41409-020-0813-9DOI Listing
September 2020

Simultaneous Vs Sequential Retroperitoneal, Thoracic and Cervical Resection of Post Chemotherapy Residual Masses in Patients With Metastatic Nonseminomatous Germ Cell Tumors of the Testis.

Urology 2020 Apr 28;138:69-76. Epub 2020 Jan 28.

Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address:

Objective: To compare a simultaneous vs sequential approach to residual post chemotherapy mass resections in metastatic testis cancer.

Methods: A retrospective review was performed of patients who underwent retroperitoneal and thoracic/cervical resection of post chemotherapy residual masses between 2002 and 2018. Group 1: "Simultaneous" (Combined Retroperitoneal and Thoracic/Cervical resections on the same date); Group 2: "Sequential" (Retroperitoneal and Thoracic/Cervical resections at separate dates).

Results: During the study period, 35 simultaneous and 17 sequential resections were performed. The median age at surgery was 28 years (Range 16-61). The median follow-up from last surgical procedure was 62.7 months (Range 0.4-194). Histology revealed teratoma in 38 (73.1%) patients, necrosis in 8 (15.4%) and viable tumor in 6 (11.5%). Discordant pathology findings between thoracic/cervical and abdominal resections were noted in 16 (30.8%) patients. No differences were observed between the simultaneous vs sequential groups in median operating time (585 minutes vs 545 minutes, P = .64), blood loss (1300 vs 1300 mls, P = .42), or length of stay (9 vs 11 days, P = .14). There was no difference between the 5-year (65.7% vs 68.6%) relapse-free survival between the 2 groups (P = .84) or the 5-year (88.6% vs 100%) overall and disease-specific survival (P = .25).

Conclusion: Simultaneous resection of retroperitoneal and thoracic/cervical post chemotherapy metastases is a feasible in some patients. It requires multidisciplinary collaboration and a longer primary procedure.
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http://dx.doi.org/10.1016/j.urology.2019.12.032DOI Listing
April 2020

Psychosocial screening and mental health in pediatric cancer: A randomized controlled trial.

Health Psychol 2020 May 23;39(5):381-390. Epub 2020 Jan 23.

Division of Hematology/Oncology.

Objective: Diagnosis and treatment of childhood cancer can impact the mental health of the family. Early psychosocial risk screening may help guide interventions. The primary aim of this study was to evaluate if an intervention (providing psychosocial risk information to the patient's treating team) would result in decreased depression symptoms in caregivers, in general, and relative to initial psychosocial risk. A secondary aim was to examine intervention effects in a small sample of patient and sibling self-reported outcomes.

Methods: We randomly allocated families to the intervention group (IG, treating team received PAT summary) or control group (CG, no summary). One hundred and twenty-two caregivers of children newly diagnosed with cancer completed measures of depression and anxiety and psychosocial risk 2-4 weeks from diagnosis (T1) and 6 months later (T2). Patients and siblings completed self-report measures of depression and anxiety.

Results: There was no significant difference in caregiver depression symptoms between the IG and CG at T2. However, in the context of psychosocial risk, caregivers in the IG showed improvement in depression scores compared to CG when risk was high near diagnosis (s = 6.68 vs. 9.76, respectively, = .60). Similar results were found in anxiety scores. Intervention effects with patients and siblings were inconclusive.

Conclusions: Sharing psychosocial risk information with the treating team had measurable impact on mental health outcomes only if caregivers had initial high psychosocial risk. This study contributes to our understanding of mapping psychosocial screening and resources to improve outcomes in families managing childhood cancer. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/hea0000825DOI Listing
May 2020

Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia.

Haematologica 2021 01 1;106(1):56-63. Epub 2021 Jan 1.

Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and the fusion proteins RUNX1-RUNX1T1 and CBFB-MYH11. International guidelines recommend monitoring for measurable residual disease every 3 months for 2 years after treatment. However, it is unknown if serial molecular monitoring can predict and prevent morphologic relapse. We conducted a retrospective single-center study of 114 patients in complete remission who underwent molecular monitoring with RT-qPCR of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts every 3 months. Morphologic relapse was defined as re-emergence of >5% blasts and molecular relapse as ≥1 log increase in transcript level between 2 samples. Over a median follow-up time of 3.7 years (range 0.2-14.3), remission persisted in 71 (62.3%) patients but 43 (37.7%) developed molecular or morphologic relapse. Patients who achieved <3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts at end of chemotherapy had a significantly higher risk of relapse compared to patients who achieved ≥3 log reduction (61.1% vs. 33.7%, p=0.004). The majority of relapses (74.4%, n=32) were not predicted by molecular monitoring and occurred rapidly with <100 days from molecular to morphologic relapse. Molecular monitoring enabled the detection of impending relapse and permitted pre-emptive intervention prior to morphologic relapse in only 11 (25.6%) patients. The current practice of molecular monitoring every 3 months provided insufficient lead-time to identify molecular relapses and prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia treated at our institution. Further research is necessary to determine the optimal monitoring strategies for these patients.
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http://dx.doi.org/10.3324/haematol.2019.235721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776265PMC
January 2021