Heterogeneous genetic architectures and evolutionary genomics of prostate cancer in Sub-Saharan Africa.

Men of African descent have the highest prostate cancer (CaP) incidence and mortality rates, yet the genetic basis of CaP in African men has been understudied. We used genomic data from 3,963 CaP cases and 3,509 controls recruited in Ghana, Nigeria, Senegal, South Africa, and Uganda, to infer ancestry-specific genetic architectures and fine-mapped disease associations. Fifteen independent associations at 8q24.21, 6q22.1, and 11q13.3 reached genome-wide significance, including four novel associations. Intriguingly, multiple lead SNPs are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of CaP differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African CaP associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Potential New Approaches for Prostate Cancer Management in Resource-Limited Countries in Africa.

Prostate cancer is a major male malignancy in many sub-Saharan countries in Africa. Because of resource limitations, screening, early detection, diagnosis, and curative treatments are not available for many men on the subcontinent, and there are even barriers to the treatment of advanced-stage metastatic prostate cancer. We are making the case for new approaches to the detection, diagnosis, and treatment of this malignancy in sub-Saharan Africa and other low-resource regions-approaches that differ from the ones available and used in high-income countries. The development of one-step dipstick-type detection assays of serum prostate-specific antigen (PSA) offers an approach to prostate cancer detection, treatment and monitoring that circumvents issues related to laboratory quality control and is also low-cost. Curative-intent treatments of early-stage prostate cancer are often unavailable in low-resource contexts, and most prostate cancers are not detected in Africa until they are at an advanced stage. Hence, androgen deprivation treatments, including orchiectomy and older low-cost drugs, offer feasible and affordable approaches to prolong survival and sustain a reasonable quality of life. However, clinical trials are needed to identify which of these androgen deprivation treatments are most efficacious and best tolerated to make progress in providing medical care for men with prostate cancer in sub-Saharan Africa and other low- and lower-middle-income areas around the world.

Testing the generalizability of ancestry-specific polygenic risk scores to predict prostate cancer in sub-Saharan Africa.

BACKGROUND: Genome-wide association studies do not always replicate well across populations, limiting the generalizability of polygenic risk scores (PRS). Despite higher incidence and mortality rates of prostate cancer in men of African descent, much of what is known about cancer genetics comes from populations of European descent. To understand how well genetic predictions perform in different populations, we evaluated test characteristics of PRS from three previous studies using data from the UK Biobank and a novel dataset of 1298 prostate cancer cases and 1333 controls from Ghana, Nigeria, Senegal, and South Africa. RESULTS: Allele frequency differences cause predicted risks of prostate cancer to vary across populations. However, natural selection is not the primary driver of these differences. Comparing continental datasets, we find that polygenic predictions of case vs. control status are more effective for European individuals (AUC 0.608-0.707, OR 2.37-5.71) than for African individuals (AUC 0.502-0.585, OR 0.95-2.01). Furthermore, PRS that leverage information from African Americans yield modest AUC and odds ratio improvements for sub-Saharan African individuals. These improvements were larger for West Africans than for South Africans. Finally, we find that existing PRS are largely unable to predict whether African individuals develop aggressive forms of prostate cancer, as specified by higher tumor stages or Gleason scores. CONCLUSIONS: Genetic predictions of prostate cancer perform poorly if the study sample does not match the ancestry of the original GWAS. PRS built from European GWAS may be inadequate for application in non-European populations and perpetuate existing health disparities.

Cosmetic Appeal, HRQoL, and Effectiveness of Simple and Pseudotesticular Techniques of Orchidectomy in Prostate Cancer.

INTRODUCTION: Orchidectomy is the most cost-effective means of hormonal therapy for locally advanced or metastatic prostate cancer (LAMP). However, cost-effectiveness should not detract from health-related quality of life (HRQoL) considerations. Bilateral simple orchidectomy (BSO) has been linked to negative psychometric deficits from an empty scrotum. This study compared the HRQoL, therapeutic efficacy, and cosmetic appeal of BSO with endogenous pseudotesticular techniques of bilateral subcapsular orchidectomy (BSCO) and bilateral-epididymal-sparing orchidectomy (BESO). Research Design. Nigerian patients with LAMP were randomised into three surgical arms: BSO, BSCO, and BESO. Expanded Prostate Cancer Index Composite-26 HRQoL and sociodemographic questionnaires were administered before and three months after orchidectomy. Serum testosterone and PSA were measured at 0, 1, 2, and 3 hours; 7 days; and 3 months postoperatively. Pseudotesticular volumes and cosmetic appeal were assessed at 3 months. RESULT: Sixty-three patients were recruited (24 BSO, 21 BSCO, 18 BESO), 73% of whom were low-income earners. There was no significant difference in the procedure cost nor the PSA or testosterone nadirs achieved over the three-month follow-up period (11.3, 12.6, 15.2 ng/ml (p=0.667) and 0.44, 0.64, 0.79 nmol/l (p=0.603) respectively). Those with pseudotesticles (BSCO, BESO) felt less emasculated (p=0.010). BSCO produced the least sexual bother, highest sexual function, and largest pseudotesticular volumes. The cosmetic appeal scores were similar between groups (77.9 ± 22.8, 81 ± 13.9, and 81.9 ± 22.5, respectively, p=0.858). CONCLUSION: Endogenous pseudotesticular techniques, when compared with BSO, reduce the negative psychological impact experienced by patients without increasing costs. BSCO produced the best pseudotesticular volumes and postoperative sexual function. This study is registered with the ClinicalTrials.gov of the National Institute of Health U.S. National Library of Medicine as TEPSO study, NCT03744494: Comparison of the Therapeutic Efficacy and Patient Satisfaction of Three Techniques of Bilateral Orchidectomy in Prostate Cancer Patients of a Nigerian Sub-population. Registration completed on 16th of November, 2018 (registered retrospectively) NCT03744494.

Urethral steinstrasse: Day case care.

Urethral steinstrasse is rare. Only a few cases of spontaneous or postinterventional urethral steinstrasse have been reported in pediatric and adult patients. We report a case of a 52-year-old Nigerian man with a secondary urethral steinstrasse, and the treatment options possible, as day case procedures, under caudal anesthesia.

Erectile Dysfunction Among Men Attending Surgical Outpatients Department in a Tertiary Hospital in South-Western Nigeria.

BACKGROUND: Erectile dysfunction is becoming a public health issue with high incidences reported in community studies. OBJECTIVE: To evaluate the characteristics and outcome of treatment in men with erectile dysfunction in a tertiary center in Ibadan southwestern Nigeria. METHODS: Data of men with erectile dysfunction was retrieved between July 2004 and June 2014 and analyzed using SPSS version 16 statistical software. RESULTS: Eighty-nine men with erectile dysfunction were managed which constituted 2% of all urological cases seen during the study period. Their median and mean ages were 39 years and 39.6 ± 1.2SD (range 19-76 years). The peak age incidence at 30-44 years was 41.6% and reduced with increasing age after 65 years to 4.5%. The etiologies were psychogenic in 55%, organic in 27%, idiopathic in 17% and 1% was familial. 67.5%, 31.5% and 3.4% were married, single and separated respectively. Seventy percent neither smoked cigarette nor drank alcohol, 21.3% drank alcohol and 9% took both alcohol and smoked cigarette. Seventy seven and half percent of men presented within 5 years of their symptom. The treatments offered were PDE type 5 inhibitors alone or in combination with psychotherapy or modification of medications. The outcome of these treatments ranged from 89% to 91% success rate. CONCLUSION: The number of men with erectile dysfunction managed in the tertiary hospital is very low though the outcome of treatment is within acceptable range. Increase public enlightenment may encourage increase hospital patronage and access to the available treatments for erectile dysfunction.

The feasibility of epidemiological research on prostate cancer in African men in Ibadan, Nigeria.

BACKGROUND: Men of African descent have the highest incidence and mortality rates of prostate cancer (PrCa) worldwide. Notably, PrCa is increasing in Africa with Nigerian men being mostly affected. Thus, it is important to understand risk factors for PrCa in Nigeria and build capacity for cancer research. The goals of this study were to determine the feasibility of conducting an epidemiological study of PrCa and to obtain preliminary data on risk factors for PrCa in Nigeria. METHODS: A case-control study (50 cases/50 controls) was conducted at the University College Hospital (UCH) in Ibadan, Nigeria, between October 2011 and December 2012. Men aged 40 to 80 years were approached for the study and asked to provide informed consent and complete the research protocol. Logistic regression models were used to examine associations between demographic, social and lifestyle characteristics and risk of PrCa. RESULTS: The participation rate among cases and controls was 98% and 93%, respectively. All participants completed a questionnaire and 99% (50 cases/49 controls) provided blood samples. Cases had a median serum diagnostic PSA of 73 ng/ml, and 38% had a Gleason score 8-10 tumor. Family history of PrCa was associated with a 4.9-fold increased risk of PrCa (95% CI 1.0 - 24.8). There were statistically significant inverse associations between PrCa and height, weight and waist circumference, but there was no association with body mass index (kg/m(2)). There were no associations between other socio-demographic and lifestyle characteristics and PrCa risk. CONCLUSION: This feasibility study demonstrated the ability to ascertain and recruit participants at UCH and collect epidemiological, clinical and biospecimen data. Our results highlighted the advanced clinical characteristics of PrCa in Nigerian men, and that family history of PrCa and some anthropometric factors were associated with PrCa risk in this population. However, larger studies are needed to better understand the epidemiological risk factors of PrCa in Nigeria.

Daycase urology at Ibadan, Nigeria: a ten year review.

INTRODUCTION: The objective of the study was to report the extent of urological surgeries performed as day cases in a major tertiary hospital in Ibadan and document the outcome. METHODS: We retrospectively reviewed the data of all urologic patients treated at the day-case theatre between January 2000 and December 2009. The parameters evaluated were: age, diagnosis, type of surgery/procedure, anaesthesia administered and the rank of the surgeon. Day case endoscopic procedures as well as prostate biopsies were excluded from the study. RESULTS: In total, 1292 patients were managed, 290 (22.4%) were children aged between 5 days and 15 years while 1002 (77.6%) adults aged between 17 years and 91 years. The majority of the procedures were carried out by the senior registrars (1169 cases, 90.5%) and consultants were involved in 123 cases (9.5%). General anaesthesia was primarily used in children (158 children vs. 4 adults), while local anaesthesia was used only in adults. 131 (45.2%) children had no anaesthesia for circumcision. The most common procedures performed in adults were varicocelectomy (426 cases, 42.5%), orchidectomy (332 cases, 33.1%), testicular biopsy (120 cases, 12.0%). While in children male circumcision (231 cases, 79.7%) was the main procedure performed. CONCLUSION: The day-case theatre is still suitable for day case urologic procedure in our setting. The common procedures are varicocelectomy, orchidectomy, and open testicular biopsy in the adults. While in children, male circumcision is commonly carried out.

Is varicocelectomy indicated in subfertile men with clinical varicoceles who have asthenospermia or teratospermia and normal sperm density?

OBJECTIVE: Varicocele is the most common treatable cause of male infertility and is associated with progressive decline in testicular function. Varicocelectomy, a commonly performed operation, is indicated in infertile males with varicoceles who have oligospermia, asthenospermia, teratospermia or a combination of these factors. It is not clear if varicocelectomy is indicated if the patients have normal sperm density associated with asthenospermia or teratospermia. METHODS: We reviewed 167 patients with varicocele-associated male infertility over a 7-year period (December 1999-November 2005). Pre- and post-varicocelectomy seminal fluid analyses, assessed using the World Health Organization criteria, were obtained at intervals of 4-6 months. Wilcoxon signed rank tests were used to evaluate for statistical significance and P < or = 0.05 was considered significant. RESULTS: The mean age of the patients and their spouses were 35 and 28 years, respectively. The mean duration of infertility was 3.2 years (range, 1.5-7.5). Oligospermia, teratospermia, asthenospermia, oligospermia, asthenospermia and teratospermia (OAT) syndrome and azoospermia were found preoperatively in 106 (63.5%), 58 (34.7%), 154 (92%), 118 (71%) and 15 (9%) patients, respectively. Overall, significant improvements in semen volume (P < 0.001), sperm density (P < 0.001), sperm motility (P < 0.001) and sperm vitality (P < 0.001) were obtained after varicocelectomy. There was, however, no significant improvement in sperm morphology after varicocelectomy (P = 0.220). When patients with preoperative oligospermia (sperm density, <20 million/mL) were considered separately, varicocelectomy led to significant improvement in all the semen parameters except the sperm morphology (P = 0.183). Conversely, when varicocele patients with a sperm density of > or =20 million/mL (normospermia) associated with asthenospermia and/or teratospermia were considered separately, they did not show significant improvement in any of the semen parameters after varicocelectomy (P > 0.05). In addition, azoospermic patients did not show significant improvement in any of the semen parameters (P > 0.05) CONCLUSION: No significant improvement in semen parameters may be obtained in patients with clinical varicocele and preoperative normospermia. It is possible that only patients with preoperative oligospermia may benefit from varicocelectomy. Larger multi-institutional studies are needed to determine more definitively if asthenospermia or teratospermia in normospermic subfertile males with clinical varicoceles are in fact indications for varicocelectomy.

p16INK4a expression and clinicopathologic parameters in renal cell carcinoma.

OBJECTIVES: The tumour suppressor gene p16INK4a is a cyclin-dependent kinase inhibitor, for which inactivation attributable to promoter hypermethylation or homozygous deletion has been described in malignancies. Little is known about p16INK4a protein levels in renal cell carcinoma (RCC) and its association with clinicopathologic parameters or disease progression. METHODS: The expression of the p16INK4a gene was analysed with the use of immunohistochemistry and tissue microarrays (TMA). Tissue cores were obtained from the primary tumour itself, the tumoural invasion front, and histologically benign peritumoural tissue of 397 nephrectomies. For statistical analysis, sections were classified into four groups according to the relative amount of positively stained cells: negative (0%), low (1-10%), intermediate (11-50%), and high positivity (>50%). Follow-up data were analyzed for 198 patients (follow-up period: 2-240 mo; median: 138 mo). RESULTS: Absent or low expression of p16INK4a was observed in 82% of tumour samples. No statistically significant association was found between protein levels detected in tumour, invasion front, or normal renal tissues and any of the clinicopathologic variables. Survival analysis by Kaplan-Meier revealed a significant association between high expression (>50%) of p16INK4a in tumours and better disease-specific survival (p=0.03, log-rank test). Cox regression analysis showed that p16INK4a expression is an independent covariate in disease-specific survival (p<0.01). CONCLUSIONS: The absence of p16INK4a expression in most tumour cells indicates that p16INK4a could be involved in the tumourigenesis of RCC. Immunohistochemically detected positivity for p16INK4a is a positive prognosticator for specific survival in both uni- and multivariate analyses.

Cadmium toxicity: a possible cause of male infertility in Nigeria.

Serum and seminal plasma cadmium (Cd) concentrations were estimated by atomic absorption spectrophotometry in 60 infertile adult male Nigerians (40 oligozoospermics and 20 azoospermics). The results were compared with Cd level in 40 normozoospermic subjects (matched age, with proven evidence of fertility). The relationship between Cd levels and spermatograms or the hypothalamic-pituitary-gonadal (HPG) -axis was investigated by correlating serum and seminal plasma Cd levels with semen characteristics and hormone levels. The seminal plasma Cd level was significantly higher than those of serum in all studied groups (p<0.001). The serum and seminal plasma Cd levels were increased (p<0.001) in azoospermics in comparison to oligozoospermic and control subjects. A significant negative correlation was observed between serum Cd level and all examined biophysical semen characteristics except sperm volume. A positive correlation was also observed between seminal plasma Cd and FSH. Results of the study for the first time implicate cadmium as a cause of infertility in male Nigerians as well as extend and support previous findings concerning cadmium toxicity and male infertility. The strong deleterious effect of cadmium on spermatogenesis may be due to the systemic and cellular toxicity. A possible relationship between this element and the HPG axis is also suggested.

Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patients.

Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients.

The incidence of lower mid-trunk hyperpigmentation (linea nigra) is affected by sex hormone levels.

The incidence of linea nigra was studied in 1,550 Nigerians of both sexes and of different age groups and among pregnant women and men with benign and malignant prostatic diseases over a nine-month period. From the study, it would appear that linea nigra increases in incidence from the age group 0-15 years (31.4%) to the age group 16-30 years (47.3%) before starting to fall in clinically normal individuals >30 years to 19.2%. For age groups 0-5 years, 6-10 years and 16-30 years, females more often than males have a linea nigra. For age group 11-15, males are equally as likely as females to have a linea nigra. The results suggest that women over 30 are more likely to have a linea nigra than men, but there are too few patients to make a definite statement, given the number of statistical tests performed. Pregnant women far more often have a linea nigra than nonpregnant women of the same age. The findings suggest that the likelihood of having a linea nigra depends on the level of sex hormones. This means that changes in the levels of hormones, either due to disease or drugs, may be reflected in changes in the incidence of a linea nigra. If this finding is confirmed, the linea nigra may serve as a convenient, noninvasive, free marker of alterations in sex hormones.