Effective Project Management of a Pan-African Cancer Research Network : Men of African Descent and Carcinoma of the Prostate (MADCaP)

CITATION: Odiaka, E. 2018. Effective Project Management of a Pan-African Cancer Research Network : Men of African Descent and Carcinoma of the Prostate (MADCaP). Journal of Global Oncology, 4:1-12, doi:10.1200/JGO.18.00062.The original publication is available at https://ascopubs.orgPurpose Health research in low- and middle-income countries can generate novel scientific knowledge and improve clinical care, fostering population health improvements to prevent premature death. Project management is a critical part of the success of this research, applying knowledge, skills, tools, and techniques to accomplish required goals. Here, we describe the development and implementation of tools to support a multifaceted study of prostate cancer in Africa, focusing on building strategic and operational capacity. Methods Applying a learning organizational framework, we developed and implemented a project management toolkit (PMT) that includes a management process flowchart, a cyclical centerspecific schedule of activities, periodic reporting and communication, and center-specific monitoring and evaluation metrics. Results The PMT was successfully deployed during year one of the project with effective component implementation occurring through periodic cycles of dissemination and feedback to local center project managers. A specific evaluation was conducted 1 year after study initiation to obtain enrollment data, evaluate individual quality control management plans, and undertake risk log assessments and follow-up. Pilot data obtained identified areas in which centers required mentoring, strengthening, and capacity development. Strategies were implemented to improve project goals and operational capacity through local problem solving, conducting quality control checks and following compliancy with study aims. Moving forward, centers will perform quarterly evaluations and initiate strengthening measures as required. Conclusion The PMT has fostered the development of both strategic and operational capacity across project centers. Investment in project management resources is essential to ensuring high-quality, impactful health research in low- and middle-income countries.https://ascopubs.org/doi/abs/10.1200/JGO.18.00062Publisher's versio

Surgical Outcomes and Cultural Perceptions in International Hypospadias Care.

This study was designed with three objectives: to assess perceptions of untreated hypospadias and quality of life in culturally disparate low- or middle-income countries (LMICs), to highlight the demographic and care differences of patient groups treated for hypospadias in the surgical workshop context, and to evaluate the long-term outcomes achieved by these workshop groups

Urethral Prolapse Case Report: Surgical and Social Considerations in Senegal.

We present three cases of urethral prolapse in prepubertal females in Senegal who presented with vulvar bleeding. Careful gynecologic and urologic physical exams were performed and revealed urethral origin and prolapse. Conservative versus surgical approaches were taken in different patients, but ultimately, each patient received a urethral meatoplasty. Surgical excision of these masses yielded a full recovery in the patients. A careful review of the literature was then undertaken and showed that surgical excision or ligation of the prolapse is preferable to more conservative treatment. The case series article discusses the rare occurrence of urethral prolapse, as well as the epidemiology and prognostic and therapeutic implications of urethral prolapse in prepubertal females

Prostate tumors of native men from West Africa show biologically distinct pathways-A comparative genomic study

Background Native African men (NAM) experience a disproportionate burden of prostate cancer (PCa) and have higher mortality rates compared to European American men (EAM). While socioeconomic status has been implicated as a driver of this disparity, little is known about the genomic mechanisms and distinct biological pathways that are associated with PCa of native men of African origin. Methods To understand biological factors that contribute to this disparity we utilized a total of 406 multi-institutional localized PCa samples, collected by Men of African Descent and Carcinoma of the Prostate biospecimen network and Moffitt Cancer Center/University of Pennsylvania Health science system. We performed comparative genomics and immunohistochemistry to identify the biomarkers that are highly enriched in NAM from west Africa and compared them with African American Men (AAM) and EAM. Quantified messenger RNA expression and Median H scores based on immune reactivity of staining cells, were compared using Mann Whitney test. For gene expression analysis, p values were further adjusted for multiple comparisons using false discovery rates. Results Immunohistochemical analysis on selected biomarkers showed a consistent association between ETS related gene (ERG) status and race with 83% of NAM exhibiting tumors that lacked TMPRSS2-ERG translocation (ERG(negative)) as compared to AAM (71%) and EAM (52%). A higher proportion of NAM (29%) were also found to be double negative (ERG(negative) and PTENLoss) as compared to AAM (6%) and EAM (7%). NAM tumors had significantly higher immunoreactivity (H-score) for PSMA, and EZH2, whereas they have lower H-score for PTEN, MYC, AR, RB and Racemase, (all p < .05). Comparative genomics revealed that NAM had significant transcriptomic variability in AR-activity score. In pathways enrichment analysis NAM tumors exhibited the enrichment of proinflammatory pathways including cytokine, interleukins, inflammatory response, and nuclear factor kappa B signaling. Conclusions Prostate tumors in NAM are genomically distinct and are characterized by the dysregulation of several biomarkers. Furthermore, these tumors are also highly enriched for the major proinflammatory pathways. These distinct biological features may have implications for diagnosis and response to targeted therapy among Black men, globally

Association between clonal hematopoiesis and risk of prostate cancer in a large sample of African ancestry men

International audienceClonal hematopoiesis of indeterminate potential (CHIP) has been associated with inflammation, which is a risk factor for cancer, including prostate cancer. We previously reported weak evidence of an association between CHIP and prostate cancer risk in men of European ancestry. However, little is known for African ancestry populations. We investigated the association of age-related CHIP with overall and aggressive prostate cancer risk in a large whole-exome sequencing study of 12,049 African ancestry men, including 7,176 prostate cancer cases (of which 3,283 had aggressive disease and 1,074 had metastatic disease) and 4,873 controls. Somatic variant calling was carried out using GATK Mutect2, and only variants with minor allele frequencies (MAF) &amp;amp;amp;lt;0.1% and a variant allelic fraction (VAF) &amp;amp;amp;gt;5% were included. Variants with a MAF ≥0.1% in gnomAD were excluded. CHIP variants were identified from a list of pre-specified mutations in 74 genes. Associations were tested using regression models adjusting for age, sub-study, and top 10 principal components, with statistical significance tested by the likelihood ratio test and applying a Bonferroni correction to account for multiple testing. In total, 998 variants in 57 CHIP genes were identified. Consistent with previous results, we observed a strong association between CHIP and age at blood draw. CHIP genes in aggregate were not statistically significantly associated with risks of total (OR=1.12, 95% CI=0.97-1.28), aggressive (OR=1.14, 95% CI=0.92-1.43) or metastatic (OR=1.17, 95% CI=0.91-1.49) prostate cancer. We observed that carriers of variants in DNMT3A, which is the gene that harbors the most CHIP driver mutations, had a nominally elevated risk of prostate cancer compared to non-carriers (OR=1.35, 95% CI=1.08-1.68, p=0.007). Additionally, carriers of variants in EZH2, which is implicated in cancer progression, showed a suggestive association with aggressive prostate cancer (OR=7.33, 95% CI=1.01-53.21, p=0.029). After adjusting for age at blood draw, CHIP genes in aggregate were not associated with age at prostate cancer diagnosis. However, we found that EZH2 variants carriers were diagnosed 12.9 years earlier on average than non-carriers (95% CI=6.1-19.7, adjusted p=0.01). A prostate cancer polygenic risk score (PRS) constructed using 269 risk variants was not associated with CHIP carrier status in aggregate (OR=0.99, 95% CI=0.92-1.06, p=0.70) or with any individual gene (all adjusted p&amp;amp;amp;gt;0.05). In summary, overall CHIP is not likely to be a risk factor of prostate cancer or aggressive disease in men of African ancestry. However, our results do confirm the association of CHIP in DNMT3A with prostate cancer risk as reported in previous studies in men of European ancestry. Future work will be needed to evaluate the biological causality of DNMT3A- and EZH2- related CHIP on prostate cancer. Citation Format: Anqi Wang, Yili Xu, Xin Sheng, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W. Fernandez, Akin Olupelumi Adebiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, Adam de Smith, Fei Chen, Burcu F. Darst, David V. Conti, Christopher A. Haiman. Association between clonal hematopoiesis and risk of prostate cancer in a large sample of African ancestry men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3508

Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry

International audienceBackground: There is a growing body of evidence supporting the contributions of germline rare variants to the susceptibility of prostate cancer (PCa), especially aggressive PCa. Our previous exome sequencing analysis highlighted 36 aggressive PCa candidate genes in populations of European ancestry. Here we investigated whether rare germline pathogenic, likely pathogenic, or deleterious (P/LD/D) variants in these genes were associated with overall and aggressive PCa risk in men of African ancestry. Methods: This exome sequencing analysis consists of 7,176 prostate cancer cases and 4,873 controls from the Research on Prostate Cancer in Men of African Ancestry (RESPOND) study. Among the PCa cases, 3,283 are aggressive cases (tumor stage T3/T4, regional lymph node involvement, metastatic disease, Gleason score &amp;amp;amp;gt;= 8.0, prostate-specific antigen [PSA] level &amp;amp;amp;gt;= 20 ng/mL or PCa as the underlying cause of death) including 1,074 metastatic cases, and 1,752 are non-aggressive cases (Gleason score ⇐ 7.0, PSA &amp;amp;amp;lt; 20 ng/mL, and tumor stage T1/T2). P/LP/D variants analyzed were rare (minor allele frequency &amp;amp;amp;lt; 1% in controls) and had either a Variant Effect Predictor impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. The association between P/LP/D carrier status with risk of overall PCa, aggressive PCa, and metastatic PCa was evaluated in logistic regression models, adjusting for age and the top ten principal components. All statistical tests are two-sided. Results: Of the 36 PCa candidate genes, BRCA2 was the most frequently affected gene, with 1.7% of cases and 1.1% of controls harboring a germline P/LP/D variant, followed by MUTYH (1.5%/1.3%) ATM (0.93%/0.49%), MSH5 (0.70%/0.51%) and HOXB13 (0.70%/0.35%). Nominally significant associations with overall PCa were observed for ATM (OR=1.83, 95% CI=1.14-2.92, P=0.012), BRCA2 (OR=1.52, 95% CI=1.10-2.10, P=0.011), HOXB13 (OR=2.10, 95% CI=1.12-3.66, P=0.008), and PALB2 (OR=3.46, 95% CI=1.18-10.1, P=0.02). In case-case analyses (aggressive vs. non-aggressive cases), the association with aggressive PCa was nominally significant for ATM (OR=5.10, 95% CI=1.96-13.3, P=8.7 × 10−4) and BRCA2 (OR=2.00, 95% CI=1.19-3.38, P=0.009) and was suggestive for PALB2 (OR=2.99, 95% CI=0.83-10.7, P=0.09). Similar associations with metastatic PCa were also observed for these three genes. Conclusion: The associations of BRCA2, ATM, and PALB2 with overall PCa and aggressive PCa observed in men of African ancestry are consistent with findings from our previous study in men of European ancestry. These findings further support the importance of these genes in the consideration of screening and active surveillance for high-risk and advanced disease. Citation Format: Fei Chen, Burcu F. Darst, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A. Adjei, James Mensah, Pedro W. Fernandez, Akindele O. Adebiyi, Oseremen Aisuodionoe-Shadrach, Lindsay Petersen, Maureen Joffe, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I. Berndt, Chad D. Huff, Joseph Lachance, Luc Multigner, Caroline Andrews, Timothy R. Rebbeck, Laurent Brureau, Stephen J. Chanock, David V. Conti, Christopher A. Haiman. Association of prostate cancer candidate genes with overall and aggressive prostate cancer in men of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1182

Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: a meta-analysis within diverse populations.

Background: We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program (MVP) and additional independent studies. Methods: Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case-control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population. Results: The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8,794 cases, 55,657 controls), and Hispanic (1,082 cases, 20,601 controls) populations. Comparing men in the top decile (90-100% of the PRS) to the average 40-60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI=3.62-3.96), 2.8-fold in African ancestry men (95% CI=2.59-3.03), and 3.2-fold in Hispanic men (95% CI=2.64-3.92). The PRS did not discriminate risk of aggressive versus non-aggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR=7.11; 55-60 years, OR=4.26; >70 years, OR=2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40-60% PRS category. Conclusions: Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine if the PRS could be used for risk-stratified screening and early detection. Funding: This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government

Global cancer surgery : delivering safe, affordable, and timely cancer surgery

Surgery is essential for global cancer care in all resource settings. Of the 15.2 million new cases of cancer in 2015, over 80% of cases will need surgery, some several times. By 2030, we estimate that annually 45 million surgical procedures will be needed worldwide. Yet, less than 25% of patients with cancer worldwide actually get safe, affordable, or timely surgery. This Commission on global cancer surgery, building on Global Surgery 2030, has examined the state of global cancer surgery through an analysis of the burden of surgical disease and breadth of cancer surgery, economics and financing, factors for strengthening surgical systems for cancer with multiple-country studies, the research agenda, and the political factors that frame policy making in this area. We found wide equity and economic gaps in global cancer surgery. Many patients throughout the world do not have access to cancer surgery, and the failure to train more cancer surgeons and strengthen systems could result in as much as US $6.2 trillion in lost cumulative gross domestic product by 2030. Many of the key adjunct treatment modalities for cancer surgery--e.g., pathology and imaging--are also inadequate. Our analysis identified substantial issues, but also highlights solutions and innovations. Issues of access, a paucity of investment in public surgical systems, low investment in research, and training and education gaps are remarkably widespread. Solutions include better regulated public systems, international partnerships, super-centralisation of surgical services, novel surgical clinical trials, and new approaches to improve quality and scale up cancer surgical systems through education and training. Our key messages are directed at many global stakeholders, but the central message is that to deliver safe, affordable, and timely cancer surgery to all, surgery must be at the heart of global and national cancer control planning