Publications by authors named "Osvaldo Espin-Garcia"

44 Publications

Genome-wide association studies of survival in 1,520 cancer patients treated with bevacizumab-containing regimens.

Int J Cancer 2021 Sep 16. Epub 2021 Sep 16.

UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from phase III trials (CALGB 80303, 40503, 80405, and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and SNPs associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (p=1.02x10 , HR=1.57, 95% CI:1.33-1.86), as well as in TCGA (p=0.0219, HR=1.58, 95% CI:1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (p=1.40x10 , HR=1.51, 95% CI:1.25-1.82) as well as in TCGA (p=1.39x10 , HR=3.09, 95% CI:1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the non-bevacizumab arm (p=1.43x10 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33810DOI Listing
September 2021

Genome-wide association studies of survival in 1,520 cancer patients treated with bevacizumab-containing regimens.

Int J Cancer 2021 Sep 16. Epub 2021 Sep 16.

UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from phase III trials (CALGB 80303, 40503, 80405, and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and SNPs associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (p=1.02x10 , HR=1.57, 95% CI:1.33-1.86), as well as in TCGA (p=0.0219, HR=1.58, 95% CI:1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (p=1.40x10 , HR=1.51, 95% CI:1.25-1.82) as well as in TCGA (p=1.39x10 , HR=3.09, 95% CI:1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the non-bevacizumab arm (p=1.43x10 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33810DOI Listing
September 2021

Anti-Microbial Antibody Response is Associated With Future Onset of Crohn's Disease Independent of Biomarkers of Altered Gut Barrier Function, Subclinical Inflammation, and Genetic Risk.

Gastroenterology 2021 Jul 20. Epub 2021 Jul 20.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background And Aims: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDRs) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to 6 microbial antigens at enrollment (Prometheus enzyme-linked immunosorbent assay test: anti-Saccharomyces cerevisiae antibodies immunoglobulin A/immunoglobulin G, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the Crohn's and Colitis Canada Genetics Environment Microbial Project. Those who later developed CD (n = 77) were matched 1:4 by age, sex, follow-up duration, and geographic location with control FDRs remaining healthy (n = 307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted odds ratio, 6.5; 95% confidence interval, 3.4-12.7; P < .001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early predisease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

Can preoperative liver MRI with gadoxetic acid help reduce open-close laparotomies for curative intent pancreatic cancer surgery?

Cancer Imaging 2021 Jun 30;21(1):45. Epub 2021 Jun 30.

Department of Surgery, Hepatobiliary & Pancreatic Surgical Oncology, University Health Network, University of Toronto, Toronto, ON, M5G 2N2, Canada.

Objectives: To evaluate gadoxetic acid-enhanced liver MRI (EOB-MRI) versus contrast-enhanced computed tomography (CECT) for preoperative detection of liver metastasis (LM) and reduction of open-close laparotomies for pancreatic ductal adenocarcinoma (PDAC).

Methods: Sixty-six patients with PDAC had undergone preoperative EOB-MRI and CECT. LM detection by EOB-MRI and CECT and their impact on surgical planning, open-close laparotomies were compared by clinical and radiology reports and retrospective analysis of imaging by two blinded independent readers. Histopathology or imaging follow-up was the reference standard. Statistical analysis was performed at patient and lesion levels with two-sided McNemar tests.

Results: EOB-MRI showed higher sensitivity versus CECT (71.7% [62.1-80.0] vs. 34% [25.0-43.8]; p = 0.009), comparable specificity (98.6%, [96.9-99.5] vs. 100%, [99.1-100], and higher AUROC (85.1%, [80.4-89.9] vs. 66.9%, [60.9-73.1]) for LM detection. An incremental 7.6% of patients were excluded from surgery with a potential reduction of up to 13.6% in futile open-close laparotomies due to LM detected on EOB-MRI only.

Conclusions: Preoperative EOB-MRI has superior diagnostic performance in detecting LM from PDAC. This better informs surgical eligibility with potential reduction of futile open-close laparotomies from attempted curative intent pancreatic cancer surgery.
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http://dx.doi.org/10.1186/s40644-021-00416-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243548PMC
June 2021

Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.

Am J Obstet Gynecol 2021 May 29. Epub 2021 May 29.

Division of Gynaecologic Oncology, Department of Obstetrics and Gynecology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280).

Data Sources: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials.

Study Eligibility Criteria: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data.

Methods: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool.

Results: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m (range, 19.4-43.7 kg/m). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I=0%).

Conclusion: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.
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http://dx.doi.org/10.1016/j.ajog.2021.05.034DOI Listing
May 2021

Comparison of Inline R2* MRI versus FerriScan for liver iron quantification in patients on chelation therapy for iron overload: preliminary results.

Eur Radiol 2021 May 26. Epub 2021 May 26.

Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, and Women's College Hospital, University of Toronto, Toronto, ON, Canada.

Objectives: MRI quantification of liver iron concentration (LIC) using R or R* relaxometry requires offline post-processing causing reporting delays, administrative overhead, and added costs. A prototype 3D multi-gradient-echo pulse sequence, with inline post-processing, allows immediate calculation of LIC from an R* map (inline R*-LIC) without offline processing. We compared inline R*-LIC to FerriScan and offline R* calibration methods.

Methods: Forty patients (25 women, 15 men; age 18-82 years), prospectively underwent FerriScan and the prototype sequence, which produces two R* maps, with and without fat modeling, as well as an inline R*-LIC map derived from the R* map with fat modeling, with informed consent. For each map, the following contours were drawn: ROIs, whole-axial-liver contour, and an exact copy of contour utilized by FerriScan. LIC values from the FerriScan report and those calculated using an alternative R calibration were the reference standards. Results were compared using Pearson and interclass correlation coefficients (PCC, ICC), linear regression, Bland-Altman analysis, and estimation of area under the receiver operator curve (ROC-AUC).

Results: Inline R*-LIC demonstrated good agreement with the reference standards. Compared to FerriScan, inline R*-LIC with whole-axial-liver contour, ROIs, and FerriScan contour demonstrated PCC of 94.8%, 94.8%, and 92%; ICC 93%, 92.7%, and 90.2%; regression slopes 1.004, 0.974, and 1.031; mean bias 5.54%, 10.91%, and 0.36%; and ROC-AUC estimates 0.903, 0.906, and 0.890 respectively. Agreement was maintained when adjusted for sex, age, diagnosis, liver fat content, and fat-water swap.

Conclusion: Inline R*-LIC provides robust and comparable quantification of LIC compared to FerriScan, without the need for offline post-processing.

Key Points: • In patients being treated for iron overload with chelation therapy, liver iron concentration (LIC) is regularly assessed in order to monitor and adjust therapy. • Magnetic resonance imaging (MRI) is commonly used to quantify LIC. Several R and R* methods are available, all of which require offline post-processing. • A novel R* MRI method allows for immediate calculation of LIC and provides comparable quantification of LIC to the FerriScan and recently published alternative R* methods.
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http://dx.doi.org/10.1007/s00330-021-08019-0DOI Listing
May 2021

Estimating walking and bicycling in Canada and their road collision fatality risks: The need for a national household travel survey.

Prev Med Rep 2021 Jun 26;22:101366. Epub 2021 Mar 26.

School of Occupational and Public Health, Ryerson University, Canada.

Canada does not conduct a national household travel survey, resulting in a data gap on walking and bicycling. These data are key to surveillance of physical activity and health, as well as in epidemiological injury risk calculations. This study explored the use of available national data sources, the Canadian census and the Canadian Community Health Survey (CCHS), to tally walking and bicycling and examine trends in fatality risk. Estimates of the percentage and number of Canadians walking or bicycling to work were calculated for 1996-2016 using the census. The CCHS was used to estimate the number and proportion of Canadians walking or bicycling for leisure (2000-2014) and to work or school (2008-2014). We combine these data with National Collision Database data on the number of pedestrian and bicyclist fatalities (1999-2017) and compare trends in fatality risk over time using each dataset. Across all data sources, walking was more common among women, while bicycling was more common among men. Men were at higher fatality risk than women. These results should be interpreted with caution given limitations this study identifies in census and CCHS data, including narrow definitions for bicycling behaviour, lack of detail regarding amount of use, and inconsistency of questions asked over time. A national household travel survey should be a priority for public health purposes in Canada.
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http://dx.doi.org/10.1016/j.pmedr.2021.101366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058556PMC
June 2021

Serum Zonulin Measured by Commercial Kit Fails to Correlate With Physiologic Measures of Altered Gut Permeability in First Degree Relatives of Crohn's Disease Patients.

Front Physiol 2021 25;12:645303. Epub 2021 Mar 25.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.

Intestinal epithelial cell tight junctions (TJs) contribute to the integrity of the intestinal barrier allowing for control of the physical barrier between external antigens or bacterial products and the internal environment. Zonula occludens-1 (ZO-1) is a protein that modulates intestinal TJs, and serum levels of ZO-1 has been suggested as a biomarker of disrupted barrier function in humans. Previous studies suggested that increased intestinal permeability was associated with evidence of TJ abnormalities. However, there is limited information on the serological measurement of ZO-1 and its relation to other tests of barrier function in healthy subjects. We investigated the correlation of serum ZO-1, with physiologic measures of intestinal permeability (as the ratio of the fractional excretion of lactulose-mannitol or LMR) in a cohort of 39 healthy FDRs of Crohn's disease (CD) patients. No significant correlation was found between LMR and ZO-1 levels (2 = 0.004, < 0.71), or intestinal fatty acid binding proteins (I-FABP) (2 = 0.004, < 0.71). In conclusion, our data show that ZO-1 and I-FABP are not a marker of gut permeability as defined by LMR.
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http://dx.doi.org/10.3389/fphys.2021.645303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027468PMC
March 2021

Evaluation of Crohn Disease Activity Using a Potential Abbreviated MRE Protocol Consisting of Balanced Steady-State Free Precession MRI Only Versus Full-Protocol MRE.

AJR Am J Roentgenol 2021 02 9;216(2):384-392. Epub 2020 Dec 9.

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

The purpose of the present study was to compare the diagnostic performance of an abbreviated MR enterography (MRE) protocol consisting of balanced steady-state free-precession (b-SSFP) imaging only versus standard full-protocol MRE for the evaluation of Crohn disease activity. This single-center retrospective study included 112 patients with Crohn disease (66 women and 46 men; age range, 18-84 years) who underwent MRE between January 2017 and March 2018. Utilizing binary and 5-point Likert confidence scales, two blinded readers independently interpreted and scored disease activity on b-SSFP sequences only and on full-protocol MRE images. Interreader and intrareader agreement on confidence regarding disease activity were calculated using weighted kappa indexes. Correlation between MRE findings of Crohn disease and the Harvey-Bradshaw index was also performed. Perfect intrareader agreement and strong interreader agreement on disease activity were observed (intrareader agreement: κ = 0.97, 0.96, and 0.96 for reader A, reader B, and both readers combined; interreader agreement: κ = 0.82 for b-SSFP imaging only and κ = 0.81 for MRE). For detecting active Crohn disease, b-SSFP sequences had a sensitivity and specificity of 97% and 100%, respectively, for reader A and 98% and 86%, respectively, for reader B. Strong-to-perfect intrareader agreement was achieved between b-SSFP imaging only and MRE for identification of penetrating disease (κ = 0.80 and 0.97) and stenosing disease (κ = 0.87 and 0.95). Perfect intrareader agreement was also obtained between b-SSFP imaging only and MRE for detecting abnormal bowel segments (κ = 0.91 for reader A; κ = 0.98 for reader B). Weak agreement was noted between both b-SSFP imaging only and MRE versus the Harvey-Bradshaw index (κ = 0.08 of reader A; κ = 0.04 for reader B). Robust agreement was observed between b-SSFP imaging only and full-protocol MRE for the assessment of Crohn disease activity and complications. An abbreviated MRE protocol that exclusively uses b-SSFP sequences appears feasible and has significant implications for health care resources.
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http://dx.doi.org/10.2214/AJR.20.22856DOI Listing
February 2021

Prognostic significance of nutritional markers in metastatic gastric and esophageal adenocarcinoma.

Cancer Med 2021 01 9;10(1):199-207. Epub 2020 Dec 9.

Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: Malnutrition and sarcopenia are poor prognostic factors in many cancers. Studies in gastric and esophageal (GE) cancer have focused on curative intent patients. This study aims to evaluate the prognostic utility of malnutrition and sarcopenia in de novo metastatic GE adenocarcinoma.

Methods: Patients with de novo metastatic GE adenocarcinoma seen at the Princess Margaret Cancer Centre from 2010 to 2016 with an available pre-treatment abdominal computed tomography (CT) were included. Malnutrition was defined as nutritional risk index (NRI) <97.5. Skeletal muscle index (SMI) was measured at the L3 level (sarcopenia defined as SMI <34.4 cm /m in women and <45.4 cm /m in men). Patients receiving chemotherapy had NRI and SMI recalculated at the time of first restaging CT.

Results: Of 175 consecutive patients, 33% were malnourished and 39% were sarcopenic at baseline. Patients with pretreatment malnourishment had significantly shorter overall survival (OS; 5.8 vs. 10.9 months, p = 0.000475). Patients who became malnourished during chemotherapy had worse OS compared to those who maintained their nutrition (12.2 vs. 17.5 months p = 0.0484). On univariable analysis, ECOG (p < 0.001), number of metastatic sites (p = 0.029) and NRI (p < 0.001) were significant prognostic factors while BMI (p = 0.57) and sarcopenia (p = 0.19) were not. On multivariable analysis, ECOG (p < 0.001), baseline NRI (p = 0.025), and change in NRI during treatment (p < 0.001) were significant poor prognostic factors for OS.

Conclusions: In de novo metastatic GE adenocarcinoma patients, ECOG, pretreatment NRI and change in NRI were significant prognostic factors for OS while sarcopenia was not. Use of NRI at baseline and during treatment can provide useful prognostic information.
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http://dx.doi.org/10.1002/cam4.3604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826473PMC
January 2021

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

J Cancer Surviv 2021 Aug 26;15(4):641-650. 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
August 2021

Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.

BMC Med Genet 2020 10 15;21(1):204. Epub 2020 Oct 15.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset.

Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals.

Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae.

Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
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http://dx.doi.org/10.1186/s12881-020-01115-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566148PMC
October 2020

Chemoradiotherapy Using Carboplatin plus Paclitaxel versus Cisplatin plus Fluorouracil for Esophageal or Gastroesophageal Junction Cancer.

Oncology 2021 14;99(1):49-56. Epub 2020 Oct 14.

Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada,

Background: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT.

Methods: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis.

Results: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2-7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4-8.9) on multivariable and IPTW sensitivity analyses.

Conclusions: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.
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http://dx.doi.org/10.1159/000510446DOI Listing
January 2021

Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.

Gastroenterology 2020 12 10;159(6):2092-2100.e5. Epub 2020 Aug 10.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD.

Methods: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR.

Results: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029).

Conclusions: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.
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http://dx.doi.org/10.1053/j.gastro.2020.08.005DOI Listing
December 2020

Efficacy and safety of stem cell mobilization following gemcitabine, dexamethasone, cisplatin (GDP) salvage chemotherapy in patients with relapsed or refractory lymphoma.

Leuk Lymphoma 2020 09 1;61(9):2153-2160. Epub 2020 Jun 1.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, Canada.

High-dose chemotherapy and autologous stem cell transplant (ASCT) remains a cornerstone of treatment in relapsed/refractory (R/R) aggressive-histology lymphomas. This retrospective study examined efficacy and safety of peripheral blood stem cell (PBSC) mobilization using cyclophosphamide/etoposide and GCSF (CE + GCSF,  = 129) versus gemcitabine, dexamethasone and cisplatin and GCSF (GDP + GCSF,  = 210). All patients received first salvage with GDP. Patients mobilized with CE + GCSF required fewer days of leukapheresis (median 1 vs 2 day;  = .001) and achieved higher total CD34+ yield than GDP + GCSF patients (8.5 vs 7.1 × 10 CD34+ cells/kg,  = .001). Rates of febrile neutropenia and CD34+ collection ≥5 × 10 CD34+ cells/kg were similar (OR 1.19, 95% CI: 0.54-2.6,  = .66). In multivariable analysis, days to engraftment and admission duration were not statistically different between the two mobilization strategies. While CE + GCSF appeared more efficacious for mobilization after GDP salvage, this did not translate to significant differences in clinical outcomes.
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http://dx.doi.org/10.1080/10428194.2020.1762882DOI Listing
September 2020

Impact of adjuvant therapy in patients with a microscopically positive margin after resection for gastric and esophageal cancers.

J Gastrointest Oncol 2020 Apr;11(2):356-365

Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada.

Background: A microscopically positive (R1) resection margin following resection for gastric and esophageal cancers has been documented to be a poor prognostic factor. The optimal strategy and impact of different modalities of adjuvant treatment for an R1 resection margin remain unclear.

Methods: A retrospective analysis was performed for patients with gastric and esophageal adenocarcinoma treated at the Princess Margaret Cancer Centre (PMCC) from 2006-2016. Electronic medical records of all patients with an R1 resection margin were reviewed. Kaplan-Meier and Cox proportional hazards methods were used to analyze recurrence free survival (RFS) and overall survival (OS) with stage and neoadjuvant treatment as covariates in the multivariate analysis.

Results: We identified 69 gastric and esophageal adenocarcinoma patients with a R1 resection. Neoadjuvant chemoradiation was used in 13% of patients, neoadjuvant chemotherapy in 12%, surgery alone in 75%. Margins involved included proximal in 30%, distal in 14%, radial in 52% and multiple margins in 3% of patients. Pathological staging showed 3% with stage I disease, 20% stage II and 74% stage III. Adjuvant therapy was given in 52% of R1 pts (28% CRT, 20% chemotherapy alone, 3% radiation alone, 1% reoperation). Median RFS was 14.1 months [95% confidence interval (CI), 11.1-17.2]. The site of first recurrence was 72% distant, 12% mixed, 16% locoregional alone. Median OS was 34.5 months (95% CI, 23.3-57.9) for all patients. There was no significant difference in RFS (adjusted P=0.26) or OS (adjusted P=0.83) comparing modality of adjuvant therapy.

Conclusions: Most patients with positive margins after resection for gastric and esophageal cancer had advanced pathologic stage and prognosis was poor. Our study did not find improved RFS or OS with adjuvant treatment and only one patient had reresection. The main failure pattern was distant recurrence, suggesting that patients being considered for adjuvant radiotherapy (RT) should be carefully selected. Further studies are required to determine factors to select patients with good prognosis despite a positive margin, or those who may benefit from adjuvant treatment.
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http://dx.doi.org/10.21037/jgo.2020.03.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212098PMC
April 2020

Oncologic outcomes and morbidity following heated intraperitoneal chemotherapy at cytoreductive surgery for primary epithelial ovarian cancer: A systematic review and meta-analysis.

Gynecol Oncol 2020 07 6;158(1):218-228. Epub 2020 May 6.

Department of Obstetrics & Gynecology, University of Toronto, Toronto, ON, Canada; Division of Gynecologic Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.

Objectives: Heated intraperitoneal chemotherapy (HIPEC) has not been universally adopted at the time of interval cytoreductive surgery for primary epithelial ovarian cancer (EOC) despite evidence of a 12-month overall survival (OS) benefit in a recent landmark randomized trial. We performed a systematic review and meta-analysis to assess oncologic outcomes and perioperative morbidity following HIPEC among primary EOC patients.

Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from inception to August 2019, for observational and randomized studies of primary EOC patients undergoing HIPEC. We assessed risk of bias using the Institute of Health Economics Quality Appraisal Checklist for single-arm cohort studies, Newcastle-Ottawa Scale for comparative cohort studies, and Cochrane Collaboration's Tool for randomized trials. We qualitatively summarized survival outcomes and calculated the pooled proportion of 30-day grade III-IV morbidity and postoperative death.

Results: We identified 35 articles including 2252 primary EOC patients; one study was a randomized trial, and only six studies included a comparator group of surgery alone. The timing, temperature, and chemotherapeutic agents used for HIPEC differed across studies. Reported OS was highly variable (3-year OS range: 46-77%); three comparative cohort studies and the sole randomized trial reported statistically significant survival benefits for HIPEC over surgery alone, while two comparative cohort studies did not. The pooled proportions for grade III-IV morbidity and postoperative death at 30 days were 34% (95% CI 20-52) and 0% (95% CI 0-5) respectively.

Conclusion: One randomized trial suggests that HIPEC at time of interval cytoreductive surgery should be considered in patients with primary EOC. However, there is significant heterogeneity in literature with respect to an appropriate HIPEC regimen, short- and long-term outcomes. High-quality prospective randomized trials are urgently needed to clarify the role of HIPEC in the first-line treatment of primary EOC.
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http://dx.doi.org/10.1016/j.ygyno.2020.03.034DOI Listing
July 2020

Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma.

Cancer Med 2020 05 4;9(9):3023-3032. Epub 2020 Mar 4.

Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: The goal of surveillance testing is to enable curative salvage therapy through early disease detection, however supporting evidence in gastroesophageal adenocarcinoma is limited. We evaluated frequency of successful salvage therapy and outcomes in patients who underwent surveillance.

Methods: A single-site, retrospective cohort study was conducted to identify all patients who received curative resection for gastroesophageal adenocarcinoma. Surveillance testing were those investigations not triggered by abnormal symptoms, physical examination, or blood tests. Successful salvage therapy was any potentially curative therapy for disease recurrence which resulted in postrecurrence disease-free survival ≥2 years. Time-to-event data were analyzed using the Kaplan-Meier method and log rank tests.

Results: Between 2011 and 2016, 210 consecutive patients were reviewed. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%) or multimodality therapy (71%). Adjuvant therapy was administered in 35%. At median follow-up of 38.3 months, 5-year overall survival (OS) rate was 56%. Among 97 recurrences, 53% were surveillance-detected, and 46% were symptomatic. None was detected by surveillance endoscopy. Median time-to-recurrence (TTR) was 14.8 months. Recurrences included locoregional only (4%), distant (86%), and both (10%). Salvage therapy was attempted in 15 patients, 4 were successful. Compared to symptomatic recurrences, patients with surveillance-detected recurrences had longer median OS (36.2 vs 23.7 months, P = .004) and postrecurrence survival (PRS, 16.5 vs 4.6 months, P < .001), but similar TTR (16.2 vs 13.3 months, P = .40) and duration of palliative chemotherapy (3.9 vs 3.3 months, P = .64).

Conclusions: Among patients surveyed, 96% of recurrences were distant, and salvage therapy was successful in only 1.9% of patients. Longer OS in patients with surveillance-detected compared to symptomatic recurrences was not associated with significant earlier disease detection, and may be contributed by differences in disease biology. Further prospective data are warranted to establish the benefit of surveillance testing in gastroesophageal adenocarcinoma.
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http://dx.doi.org/10.1002/cam4.2948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196047PMC
May 2020

Cricotracheal resection for adult subglottic stenosis: Factors predicting treatment failure.

Laryngoscope 2020 07 9;130(7):1634-1639. Epub 2019 Sep 9.

Department of Otolaryngology-Head and Neck Surgery, University Health Network, Toronto, Ontario, Canada.

Objectives/hypothesis: Identify predictors of decannulation failure after cricotracheal resection (CTR) and thyrotracheal anastomosis (TTA) in patients with subglottic stenosis (SGS).

Study Design: Retrospective cohort study.

Methods: Charts of patients undergoing CTR and TTA for SGS at the University Health Network, Toronto, Ontario, Canada between 1988 and 2017 were reviewed. Patient, pathology, treatment, and outcome data were collected. The end points for statistical analysis were development of restenosis and permanent tracheostomy.

Results: One hundred fourteen patients (n = 114) were eligible for inclusion in this review. The mean age at primary resection was 46.9 years, 95 (83%) were females, and 19 (17%) were males. The rate of restenosis and permanent tracheostomy was 13% and 5%, respectively. Sixty-two patients (54%) underwent a CTR and TTA, and 52 patients (46%) underwent a CTR, laryngofissure, and TTA. Traumatic stenosis (odds ratio [OR] = 10.3, P = .017), longer T-tube duration (OR = 1.2, P = .011), combined glottic/subglottic stenosis (OR = 10.47, P = .010), start of the stenosis at the vocal cords (OR = 6.6, P = .029), postoperative minor complications (OR = 13.6, P = .028), and need for repeat surgery (OR = 44.1, P < .001) were associated with an increased risk of requiring permanent tracheostomy.

Conclusions: CTR and TTA are excellent surgical approaches for adult patients with subglottic stenosis. In this study, 5% of patients required permanent tracheostomy. Factors predicting treatment failure include traumatic stenosis, longer T-tube duration, combined glottic/subglottic stenosis, start of stenosis at the level of vocal cords, postoperative minor complications, and need for repeat surgery.

Level Of Evidence: 4 Laryngoscope, 130:1634-1639, 2020.
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http://dx.doi.org/10.1002/lary.28273DOI Listing
July 2020

The Role of Partial Breast Radiation in the Previously Radiated Breast.

Am J Clin Oncol 2019 12;42(12):932-936

Department of Radiation Oncology, University of Toronto.

Objectives: The aim of this study was to analyze breast cancer patients who previously had mantle-field or breast radiation (RT) followed by retreatment with external beam partial breast irradiation (EB PBI).

Materials And Methods: We retrospectively reviewed all women with newly diagnosed early-stage breast cancer treated with lumpectomy and partial breast irradiation between 2007 and 2017 who had undergone prior chest or breast RT.

Results: Of 11 patients recorded, 8 (73%) had Hodgkin lymphoma, and 3 (27%) had ipsilateral breast cancer diagnosis. Median age at initial and second diagnosis was 28 and 48 years, respectively. The lymphoma patients received a dose of 35 Gy in 16 to 20 fractions to a classic mantle-upper abdomen field. Patients with an initial diagnosis of breast cancer received whole-breast RT (2 with 50 Gy/25 fractions, 1 with 40 Gy in 16 fractions). Median time from initial to second diagnosis was 22.6 years (range, 13.5 to 32.6 y). All had early-stage (I to II) invasive ductal carcinoma and were treated with lumpectomy or repeat lumpectomy and EB PBI. Four received a dose of 45 Gy/25 fractions, 4 to 50 Gy/25 fractions, and 3 to 42.4 Gy/16 fractions. All patients received adjuvant systemic treatment. Two patients had toxicity, 1 had grade 1 induration, and the other had grade 2 fat atrophy and grade 1 fibrosis. One patient developed a contralateral breast cancer. No locoregional recurrences were reported at the median follow-up of 4.6 years (range, 0.6 to 10.5 y).

Conclusion: EB PBI after lumpectomy seems to be a safe and effective RT treatment option for selected patients with prior RT and localized early-stage breast cancer.
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http://dx.doi.org/10.1097/COC.0000000000000584DOI Listing
December 2019

Analysis of Genetic Association of Intestinal Permeability in Healthy First-degree Relatives of Patients with Crohn's Disease.

Inflamm Bowel Dis 2019 10;25(11):1796-1804

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada.

Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn's disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10-7 - 1.4 × 10-5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.
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http://dx.doi.org/10.1093/ibd/izz116DOI Listing
October 2019

The Unsolved Link of Genetic Markers and Crohn's Disease Progression: A North American Cohort Experience.

Inflamm Bowel Dis 2019 08;25(9):1541-1549

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.

Background: While progress has been made in the identification of Crohn's disease (CD) susceptibility loci, efforts to identify a genetic basis for disease progression have been less fruitful. The specific aim of this study was to build upon the major genetic advances made in IBD by applying genome-wide technologies toward predicting disease progression in CD.

Methods: Crohn's disease cases (n = 1495) from 3 IBD centers were reviewed by experienced physicians. Clinical and demographic details were collected, focusing on the time to first disease progression. Genome-wide association (GWA) analysis was carried out on 3 clinical outcomes: 1) time to disease progression; 2) time to first abdominal surgery; and 3) a binary analysis of indolent vs progressive disease. Cox-proportional hazard and logistic regression models were used.

Results: A GWA analysis was carried out to determine any genetic variation associated with the time to disease progression; 662 cases were included after quality control (QC) and exclusion of any cases with B2/B3 behavior at baseline (n = 450). There were 1360 cases included after QC in the time to abdominal surgery analysis. No variant reached genome-wide significance in any of the 3 analyses performed. Eight known IBD susceptibility single nucleotide polymorphism (SNPs) were found to be associated with time-to-abdominal surgery SMAD3 (rs17293632), CCR6 (rs1819333), CNTF (rs11229555), TSPAN14 (rs7097656), CARD9 (rs10781499), IPMK (rs2790216), IL10 (rs3024505), and SMURF1 (rs9297145) (P < 0.05).

Conclusion: Our GWA study failed to show any SNP-phenotype association reaching genome-wide significance. It is likely that multiple variables affect disease progression, with genetic factors potentially having only a small effect size.
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http://dx.doi.org/10.1093/ibd/izz016DOI Listing
August 2019

A finite mixture model for X-chromosome association with an emphasis on microbiome data analysis.

Genet Epidemiol 2019 06 18;43(4):427-439. Epub 2019 Jan 18.

Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

Analysis of the X chromosome has been largely neglected in genetic studies mainly because of complex underlying biological mechanisms. On the other hand, the study of human microbiome data (typically over-dispersed counts with an excess of zeros) has generated great interest recently because of advancements in next-generation sequencing technologies. We propose a novel approach to infer the association between host genetic variants in the X-chromosome and microbiome data. The method accounts for random X-chromosome inactivation (XCI), skewed (or nonrandom) XCI (XCI-S), and escape of XCI (XCI-E). The inference is performed through a finite mixture model (FMM), in which an indicator variable denoting the "true" biological mechanism is treated as missing data. An expectation-maximization algorithm on zero-inflated and two-part models is implemented to estimate genetic effects. We investigate the performance of the FMM along with strategies that assume XCI and XCI-E mechanisms for all subjects compared with alternative approaches. Briefly, an XCI mechanism codes males' genotypes as homozygous females, whereas under XCI-E, males are treated as heterozygous females. By comprehensive simulations, we evaluate tests of the hypothesis under a computationally efficient score statistic. In summary, the FMM renders reduced bias and commensurate power compared to XCI, XCI-E, and alternative strategies while maintaining adequate Type 1 error control. The proposed method has far-reaching applications. In particular, we illustrate its usage on a large-scale human microbiome study, the Genetic, Environmental and Microbial (GEM) project, to test for the genetic association on the X chromosome.
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http://dx.doi.org/10.1002/gepi.22190DOI Listing
June 2019

Patterns, perceptions and their association with changes in alcohol consumption in cancer survivors.

Eur J Cancer Care (Engl) 2019 Jan 16;28(1):e12933. Epub 2018 Oct 16.

Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital/University Health Network and University of Toronto, Toronto, ON, Canada.

Continued consumption of alcohol after a cancer diagnosis is associated with poorer outcomes. We evaluated whether perceptions of the effects of continued alcohol use and receiving information on moderating alcohol reduced alcohol consumption in adult cancer survivors. A total of 509 cancer survivors were cross-sectionally surveyed at follow-up for their alcohol use before and after cancer diagnosis and perceptions of continued drinking. Multivariable logistic regression models evaluated factors associated with changes in alcohol consumption after diagnosis. Among 299 patients who were drinking alcohol at diagnosis (13% exceeding gender-specific guidelines), 52% reduced/ceased alcohol consumption 1 year after diagnosis. Patients perceiving that alcohol worsened their own (a) quality of life, (b) cancer-related fatigue or (c) overall survival were more likely (aORs = 2.43-3.35, p < 0.002) to reduce (moderating or quitting) their alcohol use 1 year after diagnosis. Only 14% of individuals currently drinking regularly recalled receiving information/counselling from healthcare providers on alcohol consumption (7% from oncologists). However, there was a significant fourfold to sixfold increase in cessation with such information/counselling (p < 0.01). Similar trends were observed in patients exceeding gender-specific guidelines. Perception of negative effects of alcohol use on their health by cancer survivors was associated with reducing harmful alcohol consumption. Counselling, especially from the oncologist, may play a significant role for reducing consumption.
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http://dx.doi.org/10.1111/ecc.12933DOI Listing
January 2019

Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer.

Cancer Med 2018 11 14;7(11):5478-5487. Epub 2018 Oct 14.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Background: Two germ line Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A; His(H)131Arg(R)] and rs396991 [FCGR3A; Phe(F)158Val(V)], produce altered proteins through amino acid substitutions. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial.

Methods: After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis.

Results: Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism.

Conclusions: The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.
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http://dx.doi.org/10.1002/cam4.1819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246957PMC
November 2018

Integrating epigenetic, genetic, and phenotypic data to uncover gene-region associations with triglycerides in the GOLDN study.

BMC Proc 2018 17;12(Suppl 9):57. Epub 2018 Sep 17.

1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Ave, Toronto, ON M5G 1X5 Canada.

Background: There has been significant interest in investigating genome-wide and epigenome-wide associations with lipids. Testing at the gene or region level may improve power in such studies.

Methods: We analyze chromosome 11 cytosine-phosphate-guanine (CpG) methylation levels and single-nucleotide polymorphism (SNP) genotypes from the original Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, aiming to explore the association between triglyceride levels and genetic/epigenetic factors. We apply region-based tests of association to methylation and genotype data, in turn, which seek to increase power by reducing the dimension of the gene-region variables. We also investigate whether integrating 2 omics data sets (methylation and genotype) into the triglyceride association analysis helps or hinders detection of candidate gene regions.

Results: Gene-region testing identified 1 CpG region that had been previously reported in the GOLDN study data and another 2 gene regions that are also associated with triglyceride levels. Testing on the combined genetic and epigenetic data detected the same genes as using epigenetic or genetic data alone.

Conclusions: Region-based testing can uncover additional association signals beyond those detected using single-variant testing.
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http://dx.doi.org/10.1186/s12919-018-0142-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157034PMC
September 2018

International Multicenter Validation of an Intermediate Risk Subclassification of Prostate Cancer Managed with Radical Treatment without Hormone Therapy.

J Urol 2019 02;201(2):284-291

Division of Urology, Department of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Purpose: The NCCN Guidelines® recently endorsed a subclassification of intermediate risk prostate cancer into favorable and unfavorable subgroups. However, this subclassification was developed in a treatment heterogeneous cohort. Thus, to our knowledge the natural history of androgen deprivation treatment naïve favorable and unfavorable intermediate risk prostate cancer cases remains unknown.

Materials And Methods: Groups at 3 academic centers pooled data on patients with intermediate risk prostate cancer treated with radical monotherapy (dose escalated external beam radiotherapy, brachytherapy or radical prostatectomy) without combined androgen deprivation treatment. We used the cumulative incidence with competing risk analysis to estimate biochemical recurrence, distant metastasis and prostate cancer specific mortality.

Results: A total of 2,550 men at intermediate risk were included in study, of whom 1,063 and 1,487 were at favorable and unfavorable risk, respectively. Of the men 1,149 underwent radical prostatectomy, 1,143 underwent dose escalated external beam radiotherapy and 258 underwent brachytherapy. Median followup after the different treatments ranged from 60.4 to 107.4 months. The 10-year cumulative incidence of distant metastasis in the favorable vs unfavorable risk groups was 0.2% (95% CI 0.2-0.2) vs 11.6% (95% CI 7.7-15.5) for radical prostatectomy (p <0.001), 2.8% (95% CI 0.8-4.8) vs 13.5% (95% CI 9.6-17.4) for dose escalated external beam radiotherapy (p <0.001) and 3.5% (95% CI 0-7.4) vs 10.2% (95% CI 4.3-16.1) for brachytherapy (p = 0.063). The 10-year rate of prostate cancer specific mortality in the favorable vs unfavorable risk groups was 0% (95% CI 0-0) vs 3.7% (95% CI 1.7-5.7) for radical prostatectomy (p = 0.016), 0.5% (95% CI 0.5-0.5) vs 5.6% (95% CI 3.6-7.6) for dose escalated external beam radiotherapy (p = 0.015) and 0% (95% CI 0-0) vs 2.5% (95% CI 0.5-4.5) for brachytherapy (p = 0.028).

Conclusions: This multicenter international effort independently validates the prognostic value of the intermediate risk prostate cancer subclassification in androgen deprivation treatment naïve cases across all radical treatment modalities. It is unlikely that treatment intensification would meaningfully improve oncologic outcomes in men at favorable intermediate risk.
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http://dx.doi.org/10.1016/j.juro.2018.08.044DOI Listing
February 2019

Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma.

PLoS One 2018 1;13(5):e0194809. Epub 2018 May 1.

Department of Medical Biophysics, University of Toronto, Toronto, Canada.

Background: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors.

Methods: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling.

Results: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model.

Conclusion: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929523PMC
July 2018

FUT2 genotype and secretory status are not associated with fecal microbial composition and inferred function in healthy subjects.

Gut Microbes 2018 07 27;9(4):357-368. Epub 2018 Apr 27.

a Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital , Toronto , ON , Canada.

Heritability analysis of the microbiota has demonstrated the importance of host genotype in defining the human microbiota. The alpha (1,2)-fucosyltransferase 2 encoded by FUT2 is involved in the formation of the H antigen and the SNP, rs601338 is associated with ABO histo-blood group antigen secretion in the intestinal mucosa. Previous studies have provided non replicated results for the association of this polymorphism with the composition and inferred function of intestinal microbiota. We aimed to assess this relationship in a large cohort of 1,190 healthy individuals. Genotyping was performed using the HumanCoreEXOME chip, microbial composition was addressed by 16S rRNA gene sequencing. Firmicutes, Bacteroidetes, and Actinobacteria were the dominant phyla in this cohort. Although we have sufficient power to detect significant associations of FUT2 genotype/ inferred phenotype with the microbiota, our data demonstrate that FUT2 genotype and secretor status is not associated with microbial alpha diversity, microbial composition or inferred microbial function after correction for multiple testing. Thus, FUT2 genotype and inferred phenotype are not associated with human fecal microbial composition and imputed function.
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http://dx.doi.org/10.1080/19490976.2018.1445956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219652PMC
July 2018
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