Publications by authors named "Nawaid Usmani"

71 Publications

The Digital Divide: A Retrospective Survey of Digital Rectal Examinations during the Workup of Rectal Cancers.

Healthcare (Basel) 2021 Jul 6;9(7). Epub 2021 Jul 6.

Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.

Digital rectal examination (DRE) is considered an important part of the physical examination. However, it is unclear how many patients have a DRE performed at the primary care level in the work-up of rectal cancer, and if the absence of a DRE causes a delay to consultation with a specialist. A retrospective patient questionnaire was sent to 1000 consecutive patients with stage II or stage III rectal cancer. The questionnaire asked patients to recall if they had a DRE performed by their general practitioner (GP) when they first presented with symptoms or a positive FIT test. Demographic data, staging data, and time to consultation with a specialist were also collected. A thousand surveys were mailed out, and a total of 262 patients responded. Of the respondents, 46.2% did not recall undergoing a digital rectal examination by their primary care provider. Women were less likely to undergo a DRE than men (28.6% vs. 44.3%, = 0.019). While there was a trend towards longer times to specialist consultation in patients who did not undergo a DRE (27.0 vs. 12.2 weeks), this was not statistically significant ( = 0.121). A significant proportion of patients who are FIT positive or have symptomatic rectal bleeding do not recall having a DRE by their primary care provider. Barriers may include lack of comfort with performing DRE or lack of time. Clearer guidelines and more support for GP's may increase uptake of DRE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/healthcare9070855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306048PMC
July 2021

Concomitant Use of Proton Pump Inhibitors With Capecitabine Based Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer: Is it Safe?

Am J Clin Oncol 2021 09;44(9):487-494

Division of Radiation Oncology.

Aim: Capecitabine (Cape) is routinely used for the neoadjuvant chemoradiation treatment (NACRT) of locally advanced rectal cancers (LARCs). Previous reports have suggested that the concomitant use of proton pump inhibitors (PPIs) may affect the efficacy of Cape, although the true effect of PPIs when used with Cape as a radiosensitizer for neoadjuvant radiation is unclear. The aim of our study was to evaluate the impact of concurrent PPI use along with fluorouracil (FU) and Cape based NACRT in terms of pathologic and oncological outcomes, in patients with LARC.

Methods: LARC patients treated at our center with NACRT from 2010 to 2016 were identified. Postoperative pathology and follow-up outcomes were examined for any differences with relation to the use of PPIs concurrently with FU and Cape based NACRT and adjuvant chemotherapy regimens.

Results: Three hundred four and 204 patients received treatment with FU and Cape based NACRT. No difference in pathologic complete response rate was noted between the 2 arms with the concurrent use of PPIs (25.8% and 25%, respectively, P=0.633); or with and without the use of PPIs in the Cape-NACRT arm specifically (20% and 20.7%, P=0.945). At a median follow-up of 5 years, no statistical difference in local or distant control was noted in the Cape-NACRT patients, with and without concomitant PPI use (P=0.411 and 0.264, respectively).Multivariate analysis showed no association of PPI use and NACRT with Cape, in terms of local control (hazard ratio=0.001, P=0.988) or overall survival (hazard ratio=1.179, confidence interval=0.249-5.579, P=0.835).

Conclusions: Our study revealed that there was no adverse pathologic or oncological outcome with the concurrent use of PPIs along with Cape-NACRT in the treatment of LARC. We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000850DOI Listing
September 2021

Effects of Exercise on Cancer Treatment Efficacy: A Systematic Review of Preclinical and Clinical Studies.

Cancer Res 2021 Oct 2;81(19):4889-4895. Epub 2021 Jul 2.

Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, Alberta, Canada.

We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-21-1258DOI Listing
October 2021

Feasibility, Safety, and Preliminary Efficacy of Exercise During and After Neoadjuvant Rectal Cancer Treatment: A Phase II Randomized Controlled Trial.

Clin Colorectal Cancer 2021 09 26;20(3):216-226. Epub 2021 May 26.

Faculty of Kinesiology, Sport, and Recreation, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: Neoadjuvant chemoradiation (NACRT) improves outcomes for patients with rectal cancer; however, there are dose-limiting toxicities and only a 15% to 27% pathologic complete response (pCR) rate. Exercise may help manage toxicities and improve treatment response, but feasibility and early efficacy have not been established. EXERT was a phase II trial designed to establish the feasibility and safety of exercise and provide the first evidence of efficacy.

Materials And Methods: Patients with rectal cancer scheduled to receive NACRT were randomly assigned to usual care (n = 18) or exercise (n = 18) involving supervised exercise during NACRT and unsupervised exercise after NACRT. The primary outcome was cardiorespiratory fitness (VO peak). Clinical outcomes included treatment toxicities, treatment completion, and treatment response.

Results: Median attendance at supervised exercise sessions during NACRT was 82%, and median self-reported exercise after NACRT was 90 min/wk. From baseline to post-NACRT, VO peak increased by 0.4 mL·kg·min in the exercise group and decreased by 0.8 mL·kg·min in the usual care group (P = .47). There were no significant differences between groups for grade 3/4 toxicities or treatment completion. Of 18 patients in the exercise group, 10 (56%) achieved pCR/near pCR compared with 3 of 17 (18%) in the usual care group (P = .020).

Conclusion: Exercise during and after NACRT is feasible for many patients with rectal cancer and may improve pCR despite limited fitness improvements. Larger trials are warranted to confirm if exercise is an effective intervention for improving treatment outcomes in this clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clcc.2021.05.004DOI Listing
September 2021

More Is Not Better When It Comes to Treating Rectal Cancer With Multimodal Chemoradiation Beyond the Standard Radiation Dose of 5040 cGy.

Dis Colon Rectum 2021 Jun 1. Epub 2021 Jun 1.

Division of Radiation Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada Department of Oncology, University of Alberta, 11560 University Ave, Edmonton, AB T6G 1Z2, Canada Department of Oncology, University of Calgary - Calgary, Alberta, Canada.

Background: Radiation dose schedules for neoadjuvant chemoradiation for rectal cancers differs, with the most common dose schedule using 5040 cGy in 28 fractions.

Objectives: The aim of this retrospective study was to assess the benefit of higher radiation doses beyond 5040cGy in the context of pathological response and follow up events.

Setting: Database from a provincial tertiary cancer center in Canada.

Patients: Five hundred eight consecutive rectal cancer patients with locally advanced disease (clinical T3/T4 or N1/N2) who received neoadjuvant chemoradiation followed by surgery were included in this study. Of the 508 patients, 281 received the standard radiation dose of 4500-5040 cGy and 227 received a dose >5040 cGy.

Main Outcome Measure: The postsurgical pathology, late toxicities and follow-up outcomes were analyzed. The outcomes were evaluated in relation to the dose of radiation received.

Results: Data regarding the clinical outcomes were comparable between the 4500-5040 cGy and >5040 cGy radiation groups with pathological complete response rates of 20.9% and 15.4% respectively (p=0.104); distant recurrence rates of 17.4% and 19.4%, respectively (p=0.36); local recurrence rates of 3.2% and 3.5%, respectively (p=0.36); and the median overall survival rates of 61 and 60.5 months respectively (p=0.8). No statistically significant correlation of improvement in outcomes was noted with radiation doses beyond 5040 cGy.

Limitations: This is a retrospective study.

Conclusion: Our study showed that dose escalation beyond the standard dose of 4500-5040cGy failed to achieve meaningful clinical outcomes. See Video Abstract at http://links.lww.com/DCR/B633.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/DCR.0000000000001986DOI Listing
June 2021

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

Prostate 2021 Jul 6;81(10):683-693. Epub 2021 May 6.

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer).

Methods: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian.

Results: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years.

Conclusions: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.24148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491321PMC
July 2021

Robotic Ultrasound Scanning With Real-Time Image-Based Force Adjustment: Quick Response for Enabling Physical Distancing During the COVID-19 Pandemic.

Front Robot AI 2021 22;8:645424. Epub 2021 Mar 22.

Telerobotic and Biorobotic System Group, Electrical and Computer Engineering, University of Alberta, Edmonton, AB, Canada.

During an ultrasound (US) scan, the sonographer is in close contact with the patient, which puts them at risk of COVID-19 transmission. In this paper, we propose a robot-assisted system that automatically scans tissue, increasing sonographer/patient distance and decreasing contact duration between them. This method is developed as a quick response to the COVID-19 pandemic. It considers the preferences of the sonographers in terms of how US scanning is done and can be trained quickly for different applications. Our proposed system automatically scans the tissue using a dexterous robot arm that holds US probe. The system assesses the quality of the acquired US images in real-time. This US image feedback will be used to automatically adjust the US probe contact force based on the quality of the image frame. The quality assessment algorithm is based on three US image features: correlation, compression and noise characteristics. These US image features are input to the SVM classifier, and the robot arm will adjust the US scanning force based on the SVM output. The proposed system enables the sonographer to maintain a distance from the patient because the sonographer does not have to be holding the probe and pressing against the patient's body for any prolonged time. The SVM was trained using bovine and porcine biological tissue, the system was then tested experimentally on plastisol phantom tissue. The result of the experiments shows us that our proposed quality assessment algorithm successfully maintains US image quality and is fast enough for use in a robotic control loop.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/frobt.2021.645424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019797PMC
March 2021

Intraoperative optimization of seed implantation plan in breast brachytherapy.

Int J Comput Assist Radiol Surg 2021 Jun 29;16(6):1027-1035. Epub 2021 Mar 29.

Department of Electrical and Computer Engineering, University of Alberta, 9211, 116 St NW, Edmonton, AB, T6G 1H9, Canada.

Purpose: Low-dose-rate permanent-seed (LDR-PS) brachytherapy has shown a great potential for treating breast cancer. An implantation scheme indicating the template pose and needle trajectories is determined before the operation. However, when performing the pre-planned scheme intraoperatively, a change of the patient's posture will cause seed placements away from the desired locations. Hence, the implantation scheme should update based on the current patient's posture.

Methods: A numerical method of optimizing the implantation scheme for the LDR-PS breast brachytherapy is presented here. The proposed algorithm determines the fewest needle trajectories and template poses for delivering the seeds to the intraoperative desired locations. The clinical demand, such as the minimum distance between the chest wall and the needle, is considered in the optimization process.

Results: The method was simulated for a given LDR-PS brachytherapy procedure to evaluate the optimal scheme as the number of the template poses changing. The optimization parameters of the needles' number and the implantation errors are used to adjust the algorithm outcome. The results show that the implantation schemes obtained by our method have a satisfactory accuracy in the cases of 2 or 3 template poses. The computation time is about 76s to 150s according to the number of the template poses from 1 to 3.

Conclusion: The proposed method can find the optimal implantation scheme corresponding to the current desired seed locations immediately once there is a change of patient's posture. This work can be applied to the robot-assisted LDR-PS breast brachytherapy for improving the operation accuracy and efficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11548-021-02350-zDOI Listing
June 2021

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer.

Pract Radiat Oncol 2021 Sep-Oct;11(5):384-393. Epub 2021 Mar 9.

Division of Radiation Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, University of Alberta, Edmonton, AB, Canada. Electronic address:

Purpose: Hypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation.

Methods And Materials: After giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis.

Results: From 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116).

Conclusions: HFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2021.02.011DOI Listing
September 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nat Genet 2021 01 4;53(1):65-75. Epub 2021 Jan 4.

Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00748-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148035PMC
January 2021

The Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12113254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694218PMC
November 2020

Cohort profile: the Alberta Prostate Cancer Research Initiative (APCaRI) Registry and Biorepository facilitates technology translation to the clinic through the use of linked, longitudinal clinical and patient-reported data and biospecimens from men in Alberta, Canada.

BMJ Open 2020 10 16;10(10):e037222. Epub 2020 Oct 16.

Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

Purpose: The Alberta Prostate Cancer Research Initiative (APCaRI) Registry and Biorepository was established in 2014 by the APCaRI to facilitate the collection of clinical and patient-reported data, biospecimen, to measure prostate cancer outcomes and to support the development and clinical translation of innovative technologies to better diagnose and predict outcomes for patients with prostate cancer.

Participants: Men suspected with prostate cancer and referred to Urology centres in Alberta were enrolled in the APCaRI 01 study, while men with a prior prostate cancer diagnosis participated in the APCaRI 03 study from 1 July 2014 to 30 June 2019. The APCaRI Registry and Biorepository links biospecimens and data from a wide representation of patients drawn from an Alberta population of more than 4 million.

Findings To Date: From 1 July 2014 to 30 June 2019, total APCaRI 01 and 03 study recruitment was 3754 men; 142 (4%) of these men withdrew in full, 65 men (2%) withdrew biospecimens and 123 men (3%) died of any cause. Over this same time, 8677 patient-reported outcome measure (PROM) surveys and 7368 biospecimens were collected and are available from the registry and biorepository, respectively. The data entry error rate was 0.8% and 0.95% for critical and non-critical values, respectively, and 1.8% for patient-reported surveys.

Future Plans: The APCaRI Registry and Biorepository will collect longitudinal data and PROM surveys until 2024, patient outcomes up to 25 years after recruitment and biospecimen storage for up to 25 years. The APCaRI cohorts will continue to provide data and samples to researchers conducting retrospective studies. The richness of the data and biospecimens will complement many different research questions, ultimately to improve the quality of care for men with prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-037222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569975PMC
October 2020

Impact of dose-capping chemotherapy in concurrent chemoradiotherapy in rectal cancer patients.

J Oncol Pharm Pract 2021 Oct 6;27(7):1596-1603. Epub 2020 Oct 6.

Division of Radiation Oncology, Faculty of Medicine and Dentistry, University of Alberta and Cross Cancer Institute, Edmonton, AB, Canada.

Introduction: The study evaluated the effect of chemotherapy dose-capping on disease recurrence, toxicity and survival of rectal cancer patients treated with chemoradiotherapy (CRT).

Methods: 601 consecutive rectal cancer patients treated with concurrent CRT were retrospectively analysed. Dose-capped patients were defined as having a body surface area (BSA) ≥2.0 m and who received <95% full weight-based chemotherapy dose. Binary logistic regression was used to study the factors associated with the outcome variables (capped vs. uncapped). Kaplan-Meier estimation evaluated significant predictors of survival.

Results: The median follow-up time was 7.54 years. The rate of disease recurrence was significantly higher in dose-capped patients (35%) compared to those without dose-capping (24%,  0.016). The adjusted odds ratio for dose-capped patients experiencing recurrence was 1.64 compared to uncapped patients (95% CI, 1.10-2.43). Overall, dose-capped patients were less likely to experience significant toxicity requiring dose reduction and/or treatment break when compared to uncapped patients (15% and 28% respectively,  0.008).There was significant differences in PFS between capped and uncapped group (77% vs. 85%;  = 0.017). The 5-year OS in the capped group was 75.0%, and 80% in the uncapped group ( = 0.149).

Conclusions: Rectal cancer patients treated with dose-capped CRT were at increased risk of disease recurrence. Patients dosed by actual BSA did experience excessive toxicity compared to dose-capped group. We recommend that chemotherapy dose-capping based on BSA should not be practiced in rectal cancer patients undergoing CRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155220962192DOI Listing
October 2021

PEG-PLGA nanospheres loaded with nanoscintillators and photosensitizers for radiation-activated photodynamic therapy.

Acta Biomater 2020 11 19;117:335-348. Epub 2020 Sep 19.

Department of Oncology, University of Alberta, 11560 University Avenue NW, Edmonton, AB T6G 1Z2, Canada; Department of Surgery, University of Alberta, 8440 - 112 Street NW, Edmonton, AB T6G 2B7, Canada.

Photodynamic Therapy (PDT) is an effective treatment modality for cancers, with Protoporphyrin IX (PPIX)-based PDT being the most widely used to treat cancers in patients. However, PDT is limited to superficial, thin (few mm in depth) lesions that can be accessed by visible wavelength light. Interstitial light-delivery strategies have been developed to treat deep-seated lesions (i.e. prostate cancer). The most promising of these are X-ray-induced scintillation nanoparticles, which have shown potential benefits for PDT of deep-seated tumors. Herein, the design and use of a new nanoscintillator-based radiation-activated PDT (radioPDT) system is investigated in the treatment of deep-seated tumors. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PEG-PLGA) nanospheres were loaded with a scintillator (LaF:Ce) and photosensitizer (PPIX) to effect radioPDT. UV-Vis spectroscopy and electron microscopy studies demonstrated efficient encapsulation of nanoscintillators and PPIX (>90% efficiency) into the PEG-PLGA nanospheres. The nanoparticles were uniform in size and approximately 100 nm in diameter. They were highly stable and functional for up to 24 h under physiological conditions and demonstrated slow release kinetics. In vitro and in vivo toxicity studies showed no appreciable drug toxicity to human skin fibroblast (GM38), prostate cancer cells (PC3), and to C57/BL mice. Cell uptake studies demonstrated accumulation of the nanoparticles in the cytoplasm of PC3 cells. When activated, fluorescent resonant energy transfer (FRET) was evident via fluorescent spectroscopy and singlet oxygen yield. Determination of stability revealed that the nanoparticles were stable for up to 4 weeks. The nanoparticle production was scaled-up with no change in properties. This nanoparticle represents a unique, optimally designed therapeutic and diagnostic agent (theranostic) agent for radioPDT with characteristics capable of potentially augmenting radiotherapy for deep-seated tumors and integrating into current cancer radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2020.09.029DOI Listing
November 2020

Dosimetric Parameters Predicting Late Small Bowel Toxicity in Patients With Rectal Cancer Receiving Neoadjuvant Chemoradiation.

Pract Radiat Oncol 2021 Jan-Feb;11(1):e70-e79. Epub 2020 Aug 7.

Department of Radiation Oncology, Cross Cancer Institute, Edmonton, Canada. Electronic address:

Purpose: The aim of this study was to identify dosimetric parameters that predict late small bowel (SB) toxicity after neoadjuvant long course chemoradiation (CRT) for rectal cancer.

Methods And Materials: Four hundred eighty-six consecutive patients with locally advanced rectal cancers (clinical T3/T4 or N1/N2) who received CRT followed by surgery and had dosimetric data available for analysis were included in this study. The dose-volume relationship between small bowel irradiation and late small bowel toxicity was evaluated and a mathematical model to predict for late SB toxicity was derived.

Results: Among the 486 patients with a median follow-up of 60 months from completion of radiation, 36 (7.4%) patients experienced ≥ grade 2 and 21 (4.3%) developed ≥ grade 3 late SB toxicity. A statistically significant association between the development of grade ≥3 late small bowel toxicity and the volume of small bowel irradiated was found at each dose level from 5 to 40 Gy (P < .001 for all dose volumes) in 5 Gy intervals. The average SB volume for patients who experienced grade ≥2 SB toxicity was 2149.9 cm and the average SB volume for patients who experienced grade ≥3 SB toxicity was 2179.9 cm. The predicted V30 for a 5% risk for grade ≥2 SB toxicity was 101.5 cm and for grade ≥3 SB toxicity was 201.5 cm. The volume of small bowel receiving at least 30 Gy (V30) was most strongly associated with grade ≥3 SB toxicity.

Conclusions: This study demonstrates the significant dose-volume relationship between volume of small bowel receiving 30 Gy (V30 Gy) and late grade ≥3 SB toxicity. When planning CRT for patients with rectal cancer, restricting V30 to <200 cm will be a useful guideline to minimize the 5 year grade ≥3 late SB toxicity to <5%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2020.07.004DOI Listing
August 2021

Cost-effectiveness analysis of metformin with enzalutamide in the metastatic castrate-resistant prostate cancer setting.

Can J Urol 2019 Dec;26(6):10045-10053

Department of Radiation Oncology, University of Alberta, Edmonton, Alberta, Canada.

Introduction: Enzalutamide (Enza) is an effective treatment for metastatic castrate-resistant prostate cancer (mCPRC). However, Enza is not cost-effective (CE) at willingness to pay (WTP) thresholds from $0-$125 000/quality adjusted life years (QALYs) and is therefore a strain on valuable health care dollars. Metformin (Met) is inexpensive (~$8.00/month) and is thought to improve prostate cancer specific and overall survival compared to those not taking Met. We hypothesized that there must be an added effect Met could provide that would make Enza CE thereby alleviating this financial strain on government health care budgets.

Materials And Methods: We constructed a Markov model and performed a threshold analysis to narrow in on the added effect needed to make such a combination therapy cost-effective at various WTP thresholds.

Results: At a WTP threshold of $50 000/QALY Enza + Met is unlikely to be CE unless it increases Enza's efficacy by more than 30%. At a WTP threshold of $100 000, Enza + Met could be CE barring Met adds 18.73% to the efficacy of Enza.

Conclusions: Enza + Met is unlikely to be CE at WTP thresholds less than $100 000/QALY; these results make sense because a therapy that is not CE at these WTP thresholds by itself is unlikely to be CE with an adjuvant therapy that keep a patient on such a treatment for even longer. Finally, our model suggests that the mCRPC setting is not the optimal place to trial adding Met as the relative costs are high and utility values low.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2019

Informal caregiver quality of life in a palliative oncology population.

Support Care Cancer 2020 Apr 10;28(4):1695-1702. Epub 2019 Jul 10.

Department of Radiation Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.

Purpose: Many patients with advanced cancer receive primary supports from informal caregivers (IC). As patient health deteriorates, IC assume increasing responsibility, often accompanied by distress. We investigated the quality of life (QOL) of IC of patients referred to a palliative radiotherapy (PRT) program.

Methods: IC accompanying patients to a dedicated PRT clinic completed a survey based on the validated Caregiver Quality of Life Index-Cancer (CQOLC). Demographics, burden, and engagement in support services were evaluated. Summary statistics were calculated, and parameters were assessed for association with CQOLC scores by a generalized linear model.

Results: Two hundred one surveys were analyzed representing 197 unique patients. The mean age was 68.3 years, with predominantly lung (25.0%) and prostate (19.3%) malignancies. 24.4% had been in hospital/long-term care within the previous 7 days. IC were 60.8% female, and 60.6% were the patient's spouse. 69.5% lived with the patient and 38.3% were additionally employed. IC spent a daily mean of 6.6 h (SD 7) assisting with instrumental (72.5%) and basic (37.5%) activities of daily living. Mean CQOLC score was 82.1/140 (SD 20). 63.8% of IC had previously accessed support service(s), most commonly home care (37.2%) and pharmacy (29.1%). 55.9% indicated interest in services not yet accessed. Multivariate analysis revealed additional employment, cohabitation, poor patient performance status, and interest in accessing more support services significantly correlated with higher IC burden.

Conclusions: Employing the CQOLC to screen IC of patients referred to a PRT program permits early identification of vulnerable IC to facilitate linkage with appropriate supports.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-019-04970-3DOI Listing
April 2020

Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy.

J Natl Cancer Inst 2020 02;112(2):179-190

Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada.

Background: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies.

Methods: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.

Results: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.

Conclusions: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djz075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019089PMC
February 2020

Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma.

Radiother Oncol 2019 07 4;136:21-28. Epub 2019 Apr 4.

Division of Radiation Oncology, Department of Oncology, Cross Cancer Institute, Edmonton, Canada.

Background And Purpose: We prospectively assessed the contributions of PET to initial staging, early detection of treatment failures, and prognostication in patients with anal squamous cell carcinoma (ASCC).

Materials And Methods: Consecutive patients with ASCC referred for radical chemoradiotherapy (CRT) consented to undergo FDG-PET imaging pre-treatment and at 3 and 6 months post-treatment. Clinicopathologic data were collected and CT and PET imaging reviewed for contribution to staging and recurrence detection. Maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were assessed for association with progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) using the Kaplan-Meier and Cox regression models.

Results: Between 2009 and 2016, 73 patients with clinical stages I-IIIB ASCC completed curative-intent CRT. Median follow-up was 48 months. 14 patients died and 18 patients experienced disease progression. 4-year PFS, CSS, and OS were 73%, 87%, and 84%, respectively. A pre-treatment MTV >35 cm predicted for worse PFS (p = 0.011) and CSS (p = 0.024) on univariate and multivariate analyses, employing an MTV definition of voxels ≥25% of SUVmax. Higher 6-month post-treatment SUVmax and SUVpeak predicted for worse PFS and OS (p ≤ 0.011). Pre-treatment SUVmax, SUVpeak, and TLG, and 3-month post-treatment SUVmax and SUVpeak did not significantly correlate with survival outcomes.

Conclusions: Our findings support that pre-treatment MTV provides meaningful prognostic information, with suggestion that an MTV delineation threshold of voxels ≥25% of SUVmax is appropriate in the anal region. Post treatment, the combination of clinical examination and PET effectively detected all treatment failures. Higher 6-month post-treatment SUVmax and SUVpeak predicted worse PFS and OS; however, the optimal timing of post-treatment PET imaging remains unclear.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2019.03.014DOI Listing
July 2019

Shared heritability and functional enrichment across six solid cancers.

Nat Commun 2019 01 25;10(1):431. Epub 2019 Jan 25.

Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r = 0.57, p = 4.6 × 10), breast and ovarian cancer (r = 0.24, p = 7 × 10), breast and lung cancer (r = 0.18, p =1.5 × 10) and breast and colorectal cancer (r = 0.15, p = 1.1 × 10). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-08054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347624PMC
January 2019

Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Nat Commun 2019 01 17;10(1):382. Epub 2019 Jan 17.

Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-08293-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336778PMC
January 2019

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

Nat Genet 2019 02;51(2):363

Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, South Australia, Australia.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0330-6DOI Listing
February 2019

Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Nat Commun 2018 11 5;9(1):4616. Epub 2018 Nov 5.

Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06863-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218483PMC
November 2018

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

Cancer Epidemiol Biomarkers Prev 2019 01 23;28(1):208-216. Epub 2018 Oct 23.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR).

Methods: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.

Results: Thirty-five metabolites were strongly associated with prostate cancer ( < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal.

Conclusions: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk.

Impact: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-18-0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746173PMC
January 2019
-->