[Detection of pathogenic gene mutations in thirteen cases of congenital bilateral absence of vas deferens infertility patients].

OBJECTIVE: To detect the cystic fibrosis transmembrane transduction regulator (CFTR) gene mutations and congenital bilateral absence of vas deferens (CBAVD) susceptibility gene mutations in patients with CBAVD, and to explore their association with the risk of CBAVD. METHODS: Whole-exome sequencing and Sanger sequencing validation were conducted on the pathogenic genes CFTR, adhesion G protein-coupled receptor G2 (ADGRG2), sodium channel epithelial 1 subunit beta (SCNN1B), carbonic anhydrase 12 (CA12), and solute carrier family 9 member A3 (SLC9A3) in thirteen cases of isolated CBAVD patients. The polymorphic loci, intron and flanking sequences of CFTR gene were amplified by polymerase chain reaction (PCR) followed by Sanger sequencing. Bioinformatics methods were employed for conservative analysis and deleterious prediction of novel susceptibility gene mutations in CBAVD. Genetic analysis was performed on the pedigree of one out of thirteen patients with CBAVD to evaluate the risk of inheritance in offspring. RESULTS: Exome sequencing revealed CFTR gene exon mutations in only six of the thirteen CBAVD patients, with six missense mutations c.2684G>A(p.Ser895Asn), c.4056G>C(p.Gln1352His), c.2812G>(p.Val938Leu), c.3068T>G(p.Ile1023Arg), c.374T>C(p.Ile125Thr), c.1666A>G(p.Ile556Val)), and one nonsense mutation (c.1657C>T(p.Arg553Ter). Among these six patients, two also had the CFTR homozygous p.V470 site, additionally, mutations in CFTR gene exon regions were not detected in the remaining seven patients. Within the thirteen CBAVD patients, three carried the homozygous p.V470 polymorphic site, four carried the 5T allele, two carried the TG13 allele, and ten carried the c.-966T>G site. Four CBAVD patients simultaneously carried 2-3 of the aforementioned CFTR gene mutation sites. Susceptibility gene mutations in CBAVD among the thirteen patients included one ADGRG2 missense mutation c.2312A>G(p.Asn771Ser), two SLC9A3 missense mutations c.2395T>C(p.Cys799Arg), c.493G>A(p.Val165Ile), one SCNN1B missense mutation c.1514G>A(p.Arg505His), and one CA12 missense mutation c.1061C>T (p.Ala354Val). Notably, the SLC9A3 gene c.493G>A (p.Val165Ile) mutation site was first identified in CBAVD patients. The five mutations exhibited an extremely low population mutation frequency in the gnomAD database, classifying them as rare mutations. Predictions from Mutation Taster and Polyphen-2 software indicated that the harmfulness level of the SLC9A3 gene c.493G>A (p.Val165Ile) site and the SCNN1B gene c.1514G>A (p.Arg505His) site were disease causing and probably damaging. The genetic analysis of one pedigree revealed that the c.1657C>T (p.Arg553Ter) mutation in the proband was a de novo mutation, as neither the proband's father nor mother carried this mutation. The proband and his spouse conceived a daughter through assisted reproductive technology, and the daughter inherited the proband's pathogenic mutation c.1657C>T (p.Arg553Ter). CONCLUSION: CFTR gene mutations remain the leading cause of CBAVD in Chinese patients; however, the distribution and frequency of mutations differ from data reported in other domestic and international studies, highlighting the need to expand the CFTR mutation spectrum in Chinese CBAVD patients. The susceptibility genes ADGRG2, SLC9A3, SCNN1B, and CA12 may explain some cases of CBAVD without CFTR mutations. Given the lack of specific clinical manifestations in CBAVD patients, it is recommended that clinicians conduct further physical examinations and consider scrotal or transrectal ultrasound before making a defi-nitive diagnosis. It is advisable to employ CFTR gene mutation testing in preconception genetic screening to reduce the risk of CBAVD and cystic fibrosis in offspring.

Association between Mental Disorders and Subsequent Medical Conditions.

BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions. METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses. RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder. CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

Genetic mutation analysis of 22 patients with congenital absence of vas deferens: a single-center study†.

Congenital absence of the vas deferens (CAVD), a congenital malformation of the male reproductive system, causes obstructive azoospermia and male infertility. Currently, the cystic fibrosis transmembrane conductance regulator (CFTR) has been recognized as the main pathogenic gene in CAVD, with some other genes, such as adhesion G-protein-coupled receptor G2 (ADGRG2), solute carrier family 9 isoform 3 (SLC9A3), sodium channel epithelial 1 subunit beta (SCNN1B), and carbonic anhydrase 12 (CA12), being candidate genes in the pathogenesis of CAVD. However, the frequency and spectrum of these mutations, as well as the pathogenic mechanisms of CAVD, have not been fully investigated. Here, we sequenced all genes with potentially pathogenic mutations using next-generation sequencing and verified all identified variants by Sanger sequencing. Further bioinformatic analysis was performed to predict the pathogenicity of mutations. We described the distribution of the p.V470M, poly-T, and TG-repeat CFTR polymorphisms and identified novel missense mutations in the CFTR and SLC9A3 genes, respectively. Taken together, we identified mutations in the CFTR, ADGRG2, SLC9A3, SCNN1B, and CA12 genes in 22 patients with CAVD, thus broadening the genetic spectrum of Chinese patients with CAVD.

Relationship of sperm motility with clinical outcome of percutaneous epididymal sperm aspiration-intracytoplasmic sperm injection in infertile males with congenital domestic absence of vas deferens: a retrospective study.

Congenital domestic absence of vas deferens (CBAVD) is a common factor in male infertility, and percutaneous epididymal sperm aspiration (PESA) combined with intracytoplasmic sperm injection (ICSI) is a primary clinical treatment, but the effect of the sperm obtained on pregnancy outcome remains to be explored. This study aimed to investigate the relationship between sperm motility with clinical outcome of PESA-ICSI in infertile males with CBAVD. A cohort of 110 couples was enrolled. In total, 76 infertile males were included in the high motility group, while the remaining 34 males were placed in the low motility group. Clinical pregnancy, embryo implantation rate and live birth rate were included as the primary outcome. After all follow-ups, we found that the high motility group achieved higher normal fertilization rates, cleavage rates, transplantable embryo rates and high-quality embryo rates than those in low motility group (normal fertilization rate, 78.2 ± 11.7% vs. 70.5 ± 10.2%, P = 0.003; cleavage rate, 97.1 ± 2.9% vs. 92.3 ± 3.0%, P = 0.000; transplantable embryo rate, 66.8 ± 14.9% vs. 58.6 ± 12.6%, P = 0.009 and high-quality embryo rate, 49.9 ± 10.5% vs. 40.5 ± 11.2%, P = 0.000). Additionally, compared with the low motility group, the clinical pregnancy rates, embryo implantation rates, and live birth rates in the high motility group were significantly increased (pregnancy rate, 61.8% vs. 26.5%, P = 0.009; embryo implantation rate, 36.5% vs. 18.0%, P = 0.044; live birth rate, 55.3% vs. 17.6%, P = 0.000). We concluded that the motility of sperm obtained by PESA affected the clinical outcome of ICSI in infertile males with CBAVD.

Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens.

PURPOSE: Congenital bilateral absence of the vas deferens (CBAVD) is a major cause of obstructive azoospermia and male factor infertility. CBAVD is mainly caused by mutations in the genes encoding CFTR (cystic fibrosis transmembrane conductance regulator) and ADGRG2 (adhesion G protein-coupled receptor G2). This study aimed to describe CFTR and ADGRG2 variations in 46 Chinese CBAVD patients and evaluated sperm retrieval and assisted reproductive technology outcomes. METHODS: The CFTR and ADGRG2 genes were sequenced and analyzed by whole-exome sequencing (WES), and variations were identified by Sanger sequencing. Bioinformatic analysis was performed. We retrospectively reviewed the outcomes of patients undergoing sperm retrieval surgery and intracytoplasmic sperm injection (ICSI). RESULTS: In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found. In addition to the IVS9-5 T allele, there were 27 CFTR variations, of which 4 variations were novel and predicted to be damaging by bioinformatics. Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI. CONCLUSION: There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele. Therefore, WES might be the best detection method, and genetic counseling should be different from that provided to Caucasian populations. After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI.

Genetics of the congenital absence of the vas deferens.

Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

Meningococcal disease and sexual transmission: urogenital and anorectal infections and invasive disease due to Neisseria meningitidis.

Neisseria meningitidis is an obligate human commensal bacterium that frequently colonises the upper respiratory tract. Person-to-person transmission occurs via direct contact or through dispersion of respiratory droplets from a carrier of the bacteria, and can lead to invasive meningococcal disease. Rare sporadic cases of meningococcal urogenital and anorectal infections, including urethritis, proctitis, and cervicitis, have been reported, typically following orogenital contact with an oropharyngeal meningococcal carrier. The resulting infections were clinically indistinguishable from infections caused by Neisseria gonorrhoeae. Over the past two decades, there have also been multiple outbreaks across North America and Europe of invasive meningococcal disease among men who have sex with men (MSM). The responsible meningococci belong to a highly virulent and predominantly serogroup C lineage, including strains that are able to express nitrite reductase and grow in anaerobic environments, such as the urogenital and anorectal tracts. More recently, a distinct clade within this lineage has expanded to cause urethritis predominantly among men who have sex with women. Evolutionary events giving rise to this clade included the loss of the ability to express a capsule, and acquisition of several gonococcal alleles, including one allele encoding a highly efficient gonococcal nitrite reductase. Members of the clade continue to acquire gonococcal alleles, including one allele associated with decreased antibiotic susceptibility. This evolution has implications for the clinical and public health management of those who are infected and their close contacts, in terms of both antibiotic treatment, and prevention through vaccination.

Single-Dose Zoliflodacin (ETX0914) for Treatment of Urogenital Gonorrhea.

BACKGROUND: Antibiotic-resistant Neisseria gonorrhoeae has prompted the development of new therapies. Zoliflodacin is a new antibiotic that inhibits DNA biosynthesis. In this multicenter, phase 2 trial, zoliflodacin was evaluated for the treatment of uncomplicated gonorrhea. METHODS: We randomly assigned eligible men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had had sexual contact in the preceding 14 days with a person who had gonorrhea to receive a single oral dose of zoliflodacin (2 g or 3 g) or a single 500-mg intramuscular dose of ceftriaxone in a ratio of approximately 70:70:40. A test of cure occurred within 6±2 days after treatment, followed by a safety visit 31±2 days after treatment. The primary efficacy outcome measure was the proportion of urogenital microbiologic cure in the microbiologic intention-to-treat (micro-ITT) population. RESULTS: From November 2014 through December 2015, a total of 179 participants (167 men and 12 women) were enrolled. Among the 141 participants in the micro-ITT population who could be evaluated, microbiologic cure at urogenital sites was documented in 55 of 57 (96%) who received 2 g of zoliflodacin, 54 of 56 (96%) who received 3 g of zoliflodacin, and 28 of 28 (100%) who received ceftriaxone. All rectal infections were cured in all 5 participants who received 2 g of zoliflodacin and all 7 who received 3 g, and in all 3 participants in the group that received ceftriaxone. Pharyngeal infections were cured in 4 of 8 participants (50%), 9 of 11 participants (82%), and 4 of 4 participants (100%) in the groups that received 2 g of zoliflodacin, 3 g of zoliflodacin, and ceftriaxone, respectively. A total of 84 adverse events were reported: 24 in the group that received 2 g of zoliflodacin, 37 in the group that received 3 g of zoliflodacin, and 23 in the group that received ceftriaxone. According to investigators, a total of 21 adverse events were thought to be related to zoliflodacin, and most such events were gastrointestinal. CONCLUSIONS: The majority of uncomplicated urogenital and rectal gonococcal infections were successfully treated with oral zoliflodacin, but this agent was less efficacious in the treatment of pharyngeal infections. (Funded by the National Institutes of Health and Entasis Therapeutics; ClinicalTrials.gov number, NCT02257918 .).

Analysis of rearrangements of the CFTR gene in patients from Turkey with CFTR-related disorders: frequent exon 2 deletion.

Cystic fibrosis is a hereditary disease that mostly affects the sweat glands, respiratory system, digestive system, and reproductive system. Many and various types of mutations have been reported in CFTR in different ethnicities and countries/regions. Analysis of CFTR gene rearrangements is recommended in patients with unidentified mutated alleles in CFTR sequencing analysis. We collected MLPA analyses of 527 patients from Turkey who had at least one unidentified mutation in CFTR sequence analysis. Heterozygous/homozygous deletions were detected in the CFTR gene in 49 individuals (9.2%) from 35 families. Twelve different single/multi exon deletions were demonstrated, two of which were not previously reported in the literature. Mutations have previously reported in patients from various regions including Asia, Europe, and Africa, and Turkey is located at a crossroads between them. The most frequent mutation was the exon 2 deletion, accounting for 60%. Moreover, patients with exon 2 deletions, were especially originated from northern Turkey. This finding is valuable in leading and shaping planned screening programs in Turkey. Our study, the most comprehensive study for rearrangement analysis in patients from Tukey, revealed a candidate hotspot region of patients suspected of having CFTR-related disorders from Turkey.

Urogenital function following robotic and laparoscopic rectal cancer surgery: meta-analysis.

BACKGROUND: Mixed results are reported on clinical and cancer outcomes in laparoscopic rectal cancer surgery (LRCS) compared with robotic rectal cancer surgery (RRCS). However, more favourable functional outcomes are reported following RRCS. This study compared urinary and sexual function following RRCS and LRCS in male and female patients. METHODS: A systematic review and meta-analysis of urinary and sexual function after RRCS and LRCS was performed following PRISMA and MOOSE guidelines, and registered prospectively with PROSPERO (ID:CRD42020164285). The functional outcome reporting tools most commonly included: the International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF) and Female Sexual Function Index (FSFI). Mean scores and changes in mean scores from baseline were analysed using RevMan version 5.3. RESULTS: Ten studies were included reporting on 1286 patients. Some 672 patients underwent LRCS, of whom 380 (56.5 per cent) were men and 116 (17.3 per cent) were women (gender not specified in 176 patients, 26.2 per cent). A total of 614 patients underwent RRCS, of whom 356 (58.0 per cent) were men and 83 (13.5 per cent) were women (gender not specified in 175 patients, 28.5 per cent). Regarding urinary function in men at 6 months after surgery, IPSS scores were significantly better in the RRCS group than in the LRCS group (mean difference (MD) -1.36, 95 per cent c.i. -2.31 to -0.40; P = 0.005), a trend that persisted at 12 months (MD -1.08, -1.85 to -0.30; P = 0.007). ΔIIEF scores significantly favoured RRCS at 6 months [MD -3.11 (95%CI -5.77, -0.44) P <0.021] and 12 months [MD -2.76 (95%CI -3.63, -1.88) P <0.001] post-operatively. Mixed urinary and sexual function outcomes were reported for women. CONCLUSION: This meta-analysis identified more favourable urinary and erectile function in men who undergo robotic compared with conventional laparoscopic surgery for rectal cancer. Outcomes in women did not identify a consistently more favourable outcome in either group. As robotic rectal cancer surgery may offer more favourable functional outcomes it should be considered and discussed with patients.

Synchronous genitourinary lichen sclerosus signals a distinct urinary microbiome profile in men with urethral stricture disease.

PURPOSE: Alterations in the urinary microbiome have been associated with urological diseases. The microbiome of patients with urethral stricture disease (USD) remains unknown. Our objective is to examine the microbiome of USD with a focus on inflammatory USD caused by lichen sclerosus (LS). METHODS: We collected mid-stream urine samples from men with LS-USD (cases; n = 22) and non-LS USD (controls; n = 76). DNA extraction, PCR amplification of the V4 hypervariable region of the 16S rRNA gene, and sequencing was done on the samples. Operational taxonomic units (OTUs) were defined using a > 97% sequence similarity threshold. Alpha diversity measurements of diversity, including microbiome richness (number of different OTUs) and evenness (distribution of OTUs) were calculated and compared. Microbiome beta diversity (difference between microbial communities) relationships with cases and controls were also assessed. RESULTS: Fifty specimens (13 cases and 37 controls) produced a 16S rRNA amplicon. Mean sample richness was 25.9 vs. 16.8 (p = 0.076) for LS-USD vs. non-LS USD, respectively. LS-USD had a unique profile of bacteria by taxonomic order including Bacillales, Bacteroidales and Pasteurellales enriched urine. The beta variation of observed bacterial communities was best explained by the richness. CONCLUSIONS: Men with LS-USD may have a unique microbiologic richness, specifically inclusive of Bacillales, Bacteroidales and Pasteurellales enriched urine compared to those with non-LS USD. Further work will be required to elucidate the clinical relevance of these variations in the urinary microbiome.

Complications in adulthood for patients with paediatric genitourinary reconstruction.

BACKGROUND: Caring for adults with prior paediatric genitourinary reconstruction remains a challenge for adult providers. Reconstructions typically have occurred decades before; surgical records are not always available and patients and families may be unable to convey procedures performed. Spina bifida (SB) patients are vulnerable to cognitive decline which may compound these challenges. Changes in patient body habitus and loss of function may contribute to problems with previous reconstructions. METHODS: This is a non-systematic review of the literature and represents expert opinion where data are non-existent. This review focuses on the evaluation and management of complications arising from genitourinary reconstruction in congenital neurogenic bladder patients. RESULTS: Common complications experienced by congenital neurogenic bladder patients include recurrent urinary tract infection, incontinence of catheterizable channel and urinary reservoir as well as malignancy as this population ages. Preservation of renal function and prevention of urinary tract infection while optimizing continence are essential guiding principles in the care of these patients. Many of the recommendations, however, are gleaned from available data in the adult spinal cord patient (a more commonly studied population) or the paediatric urologic literature due to limited studies in adult management of such patients. CONCLUSION: Close follow-up and vigilance is warranted to monitor for infectious, mechanical and malignant complications while optimizing preservation of the upper urinary tracts and patient quality of life.

Stereotactic body radiation therapy for Japanese patients with localized prostate cancer: 2-year results and predictive factors for acute genitourinary toxicities.

OBJECTIVE: We aimed to report the 2-year results of stereotactic body radiation therapy for prostate cancer and identify the clinical and dosimetric factors that predict acute genitourinary toxicities. METHODS: We retrospectively reviewed the medical records of patients with non-metastatic prostate cancer treated at Toyota Memorial Hospital between 2017 and 2020. The patients were treated with stereotactic body radiation therapy with a total dose of 36.25 Gy in five fractions on consecutive weekdays. While low-risk patients received radiotherapy alone, intermediate- to high-risk patients also received androgen deprivation therapy. RESULTS: We analysed a total of 104 patients, including 10, 60 and 34 low-, intermediate- and high-risk patients, respectively. The median follow-up duration was 2 years. We did not observe biochemical/clinical recurrence, distant metastasis or death from prostate cancer. One patient died of another cause. Grade 2 acute genitourinary toxicity was observed in 40 (38%) patients. Age (P = 0.021), genitourinary toxicity of grade ≥1 at baseline (P = 0.023) and bladder mean dose (P = 0.047) were significantly associated with the incidence of grade 2 acute genitourinary toxicity. The cut-off value of 65 years for age and 10.3 Gy for the bladder mean dose were considered the most appropriate. Grade 2 acute gastrointestinal toxicity was observed in five (5%) patients. None of the patients experienced grade ≥3 acute or late toxicity. CONCLUSIONS: Stereotactic body radiation therapy is feasible for Japanese patients with prostate cancer, with acceptable acute toxicity. Age, genitourinary toxicity at baseline and bladder mean dose predict grade 2 acute genitourinary toxicity.

The validity of grayscale and color Doppler ultrasound in assessment of scrotal swellings: a retrospective study in a large case series.

BACKGROUND: Scrotal swellings have a non-specific clinical picture, so their clinical diagnosis is challenging. Scrotal grayscale and color Doppler ultrasound are non-invasive methods used in both adult and childhood groups and act as accurate screening and diagnostic modalities. PURPOSE: To evaluate the diagnostic validity of grayscale and color Doppler ultrasound in the assessment of scrotal swelling to reach accurate diagnosis. MATERIAL AND METHODS: A retrospective study included 181 patients (mean age = 35.5 ± 7.3, age range = 1-71 years) with scrotal swelling. Examinations were performed by an experienced radiologist using grayscale and color Doppler ultrasound. The diagnostic validity of grayscale and color Doppler ultrasound for diagnosing scrotal swelling were estimated using surgical findings, histopathological results, and imaging and clinical follow-up as reference standards. RESULTS: Overall, 202 scrotal swellings were detected. The final diagnoses were 13 (6.4%) malignant and 189 (93.6%) benign alterations. Varicocele was the most common scrotal swelling (26%), followed by hydrocele (23.8%). Matched to the reference standards, grayscale and color Doppler ultrasound represented a sensitivity of 84.6% (95% confidence interval [CI] = 54.6-98.1), a specificity of 76.2% (95% CI = 69.5-82.1), a positive predictive value of 19.6% (95% CI = 10.2-32.4), and a negative predictive value of 98.6% (95% CI = 95.1-99.8) for diagnosing scrotal tumors. CONCLUSION: Scrotal grayscale and color Doppler ultrasound provide high diagnostic validity for assessment of scrotal swellings.

Epididymal Appearance in Congenital Absence of Vas Deferens.

Scrotal sonography was performed in the infertile males. Sonography of epididymis was performed to document its presence, appearance, echo texture and duct ectasia. The spermatic cord was examined to document the status of the vas deferens. TRUS was performed to look for distal vas. Epididymal abnormalities were universal in men with congenital bilateral absence of vas deferens, with a sensitivity of 100%. Three types of abnormal appearances were recognized - a honeycomb appearance, a fine meshwork pattern of head, or complete or partial absence of epididymis. Identification of these abnormalities can be a very sensitive marker for congenital bilateral absence of vas deferens.

Are Urogenital Symptoms Caused by Sexually Transmitted Infections and Colonizing Bacteria?

OBJECTIVE: This study aimed to investigate the prevalence of sexually transmitted infections (STIs) and colonizing bacteria in relation to urogenital symptoms. MATERIALS AND METHODS: In this cross-sectional study, patients visiting the STI clinic at Umeå University Hospital were asked for symptoms and condom use. Samples from 759 patients (465 male and 294 female) were analyzed for 4 STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium) and 3 colonizing bacteria (Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum). RESULTS: Chlamydia trachomatis prevalence was 11% among women and 9.5% among men. Neisseria gonorrhoeae prevalence was 0.7% among women and 0.9% among men. Mycoplasma genitalium was found in 11% and 5.6% of women and men, respectively. Asymptomatic men and women had similar distribution patterns of microorganisms as those with urogenital symptoms, with the exceptions of Neisseria gonorrhoeae- and Mycoplasma genitalium-infected men who declared symptoms more frequently. Of 158 men with urogenital symptoms, 55% were test-negative. Of 129 women with urogenital symptoms, 12% were test-negative. CONCLUSIONS: This study reveals a complex picture, where a large number of multi-positive tests made it complicated to correlate urogenital symptoms with microorganisms. A high number of test-negative but symptomatic patients indicate a need of searching for additional pathogens.

[Gene mutations in congenital bilateral absence of the vas deferens: An update].

Congenital bilateral absence of the vas deferens (CBAVD) is a congenital malformation of the male reproductive system and one of the important causes of obstructive azoospermia and male infertility. It is currently recognized that the main cause of CBAVD is the mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR). And the mutations of adhesion G protein-coupled receptor G2 (ADGRG2), solute carrier family 9 isoform 3 (SLC9A3) and other genes are also found to be involved in the development and progression of CBAVD. A reasonable CBAVD molecular diagnosis process combined with assisted reproductive technology is currently the most effective method for the diagnosis and treatment of CBAVD, but the offspring of the patient may face the risk of hereditary inheritance. This article focuses on the pathogenesis of CFTR, ADGRG2 and SLC9A3 causing CBAVD, and aims to provide some new ideas for the clinical diagnosis and treatment of CBAVD and CBAVD-related genetic counseling.

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.

BACKGROUND: Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. METHODS: GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. FINDINGS: Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50-100), 74 months (47-100) in the adjuvant radiotherapy group and 78 months (52-101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86-95) in the adjuvant radiotherapy group and 90% (85-94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48-1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). INTERPRETATION: Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. FUNDING: French Health Ministry and Ipsen.

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

BACKGROUND: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients. PURPOSE: To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB). MATERIAL AND METHODS: The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity. RESULTS: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95 = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01). CONCLUSIONS: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.