Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese.

FLNC-related myofibrillar myopathy could manifest as autosomal dominant late-onset slowly progressive proximal muscle weakness; involvements of cardiac and/or respiratory functions are common. We describe 34 patients in nine families of FLNC-related myofibrillar myopathy in Hong Kong ethnic Chinese diagnosed over the last 12 years, in whom the same pathogenic variant c.8129G>A (p.Trp2710*) was detected. Twenty-six patients were symptomatic when diagnosed; four patients died of pneumonia and/or respiratory failure. Abnormal amorphous material or granulofilamentous masses were detected in half of the cases, with mitochondrial abnormalities noted in two-thirds. We also show by haplotype analysis the founder effect associated with this Hong Kong variant, which might have occurred 42 to 71 generations ago or around Tang and Song dynasties, and underlain a higher incidence of myofibrillar myopathy among Hong Kong Chinese. The late-onset nature and slowly progressive course of the highly penetrant condition could have significant impact on the family members, and an early diagnosis could benefit the whole family. Considering another neighboring founder variant in FLNC in German patients, we advocate development of specific therapies such as chaperone-based or antisense oligonucleotide strategies for this particular type of myopathy.

Risk of urethral stricture recurrence increases over time after urethroplasty.

OBJECTIVE: To report a single institutional experience with urethroplasty outcomes and success rates at long-term follow up. METHODS: A retrospective review was carried out of all urethroplasties performed by a single surgeon from 2000 to 2010. A total of 347 patients underwent urethroplasty during this time period, of which 227 had minimum 1-year follow-up data available. Demographic, clinical, pathological and outcome data were reviewed. Recurrence was defined by patient reported urinary symptoms or need for subsequent intervention. Statistical analyses were carried out using SPSS statistical software. RESULTS: A total of 26% of all patients had a recurrence at a mean follow up of 62 months (range 13-147 months). The recurrence rate after anastomotic urethroplasty was 18%, as compared with 31% after substitution urethroplasty. Mean time to recurrence was 34 months (range 5-87). On univariate analysis, use of abdominal skin graft, history of prior urethroplasty, lichen sclerosus and length of follow up were statistically significant predictors of recurrence. On multivariate analysis, only history of prior urethroplasty and length of follow-up time exceeding 48 months were statistically significant predictors of recurrence. CONCLUSIONS: Urethroplasty for urethral stricture is the most durable treatment modality, regardless of surgical approach. However, there is an ongoing risk of recurrence with the passage of time. Patients should be counseled appropriately on the potential for late recurrence of stricture disease after urethroplasty.

Urethral strictures and the cancer survivor.

PURPOSE OF REVIEW: Urethral stricture disease is poorly understood in prostate cancer survivors who have undergone radiation or ablative treatments. We review the cause and incidence of urethral strictures (excluding bladder neck contracture) in this setting, as well as risk factors and treatment options. RECENT FINDINGS: Stricture rates differ for various modalities of radiation therapy, with the highest rate in high-dose-rate brachytherapy. Risk factors include higher dose of radiation delivered to prostate apex, radiation delivered per treatment, and prior transurethral resection of prostate. Cryoablation and high-intensity focused ultrasound of the prostate also carry high risk of urethral stricture formation, particularly in the salvage setting. Dilation or direct vision incision of the urethra can be utilized as a temporizing technique, with frequent recurrence. Urethral stenting is also an option; however, this is associated with a high rate of incontinence. Urethroplasty has durable outcomes for radiation-induced strictures, with a preference for excision and primary anastomosis because of the bulbomembranous location and relatively short length of these strictures. Salvage radical prostatectomy has been described in a small series as treatment for posterior urethral strictures and bladder neck contractures resulting from ablative therapies. SUMMARY: Prostate cancer survivors treated with radiation or ablative therapies are at risk for urethral stricture formation. Urethroplasty is a feasible and durable treatment option and should be considered in the appropriate patient.

Rare Pediatric Cerebellar High-Grade Gliomas Mimic Medulloblastomas Histologically and Transcriptomically and Show p53 Mutations.

Pediatric high-grade gliomas (HGG) of the cerebellum are rare, and only a few cases have been documented in detail in the literature. A major differential diagnosis for poorly differentiated tumors in the cerebellum in children is medulloblastoma. In this study, we described the histological and molecular features of a series of five pediatric high-grade gliomas of the cerebellum. They actually showed histological and immunohistochemical features that overlapped with those of medulloblastomas and achieved high scores in NanoString-based medulloblastoma diagnostic assay. Methylation profiling demonstrated these tumors were heterogeneous epigenetically, clustering to GBM_MID, DMG_K27, and GBM_RTKIII methylation classes. MYCN amplification was present in one case, and PDGFRA amplification in another two cases. Interestingly, target sequencing showed that all tumors carried TP53 mutations. Our results highlight that pediatric high-grade gliomas of the cerebellum can mimic medulloblastomas at histological and transcriptomic levels. Our report adds to the rare number of cases in the literature of cerebellar HGGs in children. We recommend the use of both methylation array and TP53 screening in the differential diagnoses of poorly differentiated embryonal-like tumors of the cerebellum.

Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon.

BACKGROUND & AIMS: Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD) characterized by plasma cell hepatitis or rejection. METHODS: We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG-IGD. Data from each patient were compared with those from 2 matched patients who did not develop PEG-IGD (n = 104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. RESULTS: Overall incidence of PEG-IGD during a 10-year study period was 7.2%. Risk factors included no prior PEG therapy (odds ratio = 5.3; P < .0001), therapy with PEGα-2a (odds ratio = 4.7; P = .03), and immune features (mainly plasma cell hepatitis) on pre-PEG therapy liver biopsies (odds ratio = 3.9; P = .005). The PEG-IGD group had lower long-term patient (61.5% vs 91.3% of controls) and graft (38.5% vs 85.6% of controls) survival and higher rates of retransplantation (34.6% vs 6.7% of controls) (all, P < .0001), without increases in sustained virologic response. Variables associated with increased mortality included acute rejection as the PEG-IGD sub-type (hazard ratio [HR] = 2.4; P = .002), a high level of alkaline phosphatase at PEG initiation (HR = 1.003; P = .005), and lack of a sustained virologic response (HR = 3.3; P = .04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR = 1.002; P = .04) and lack of a sustained virologic response (HR = 2.1; P = .04). CONCLUSIONS: PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.

Comparison of different immunoprophylaxis regimens after liver transplantation with hepatitis B core antibody-positive donors: a systematic review.

Orthotopic liver transplantation (OLT) recipients without hepatitis B virus (HBV) infection who receive liver grafts from antibody to hepatitis B core antigen-positive [HBcAb(+)], hepatitis B surface antigen-negative [HBsAg(-)] donors have an increased risk of developing de novo hepatitis B infection. We compared the 2 most commonly employed prophylactic regimens-lamivudine (LAM) monotherapy and hepatitis B immunoglobulin (HBIG)+LAM combination therapy-to determine the relative efficacies of these 2 protocols in preventing de novo hepatitis B infection. A comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to June 2009), and bibliographies of retrieved trials was conducted. Eligible studies included OLT recipients who received HBcAb(+) liver grafts and were treated prophylactically with either LAM monotherapy or HBIG+LAM combination therapy. 13 studies were identified as meeting the eligibility criteria. The rates of de novo hepatitis B infection, mortality, and mortality due to de novo hepatitis B infection were assessed. The incidence of de novo hepatitis B infection was 2.7% (n = 73) in patients receiving LAM-only prophylaxis versus 3.6% (n = 110) in patients receiving HBIG+LAM combination therapy. In the HBIG+LAM group, the dose and duration of HBIG therapy were highly variable. The median follow-up time for the LAM monotherapy group was 25.4 months with a range of 14.78 to 27.6 months, whereas the median follow-up time for the LAM+HBIG group was 31.1 months with a range of 15.3 to 38.5 months. The risk of developing de novo hepatitis B infection based on the pretransplant recipient HBV serology in each treatment group could not be calculated because of incomplete data and the limited number of de novo hepatitis B infection cases in the series reviewed. In conclusion, on the basis of these findings, we conclude that published studies have not shown HBIG+LAM combination therapy to be more effective than LAM-only treatment. Nucleoside analogue monotherapy should therefore be considered when one is treating HBV(-) patients who have received liver allografts from HBcAb(+) donors.

Oral antibiotic prophylaxis reduces spontaneous bacterial peritonitis occurrence and improves short-term survival in cirrhosis: a meta-analysis.

OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a serious complication of advanced liver disease resulting in high mortality rates. Although studies that assessed the use of oral antibiotics in advanced liver disease demonstrated a clear benefit in reducing the risk of recurrent peritonitis, it is unclear whether mortality rates are similarly affected by this practice. The goal of this study was to determine whether oral antibiotic therapy provides a survival benefit for patients with advanced cirrhosis and ascites. Through subgroup analysis, we also evaluated the effect of prophylactic oral antibiotic therapy on the prevention of SBP and the incidence of all infections (including SBP) when compared with non-treated or placebo controls. METHODS: We conducted a comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to May 2008), bibliographies of retrieved trials, and reports presented at major scientific meetings. Eligible studies included prospective, randomized controlled trials comparing high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Eight studies with a total of 647 patients were identified and included in this analysis. The combined analysis showed an overall mortality benefit (RR=0.65; 95% CI, 0.48-0.88) for treatment groups. The overall mortality rate was 16% (52/324) for treated patients and 25% (81/323) for the control group. Groups treated with prophylactic antibiotics also demonstrated a lower incidence of all infections (including SBP) of 6.2% as compared with the control groups with a rate of 22.2% (RR=0.32; P<0.00001; 95% CI, 0.20-0.51). Subgroup analysis showed a survival benefit at 3 months (RR=0.28; P=0.005; 95% CI, 0.12-0.68). CONCLUSIONS: Antibiotic prophylaxis improved short-term survival in treated patients when compared with untreated control groups and reduced the overall risk of infections, including SBP, during follow-up. In summary, antibiotic prophylaxis should be considered for high-risk cirrhotic patients with ascites.

Overview of surgical techniques in gender-affirming genital surgery.

Gender related genitourinary surgeries are vitally important in the management of gender dysphoria. Vaginoplasty, metoidioplasty, phalloplasty and their associated surgeries help patients achieve their main goal of aligning their body and mind. These surgeries warrant careful adherence to reconstructive surgical principles as many patients can require corrective surgeries from complications that arise. Peri-operative assessment, the surgical techniques employed for vaginoplasty, phalloplasty, metoidioplasty, and their associated procedures are described. The general reconstructive principles for managing complications including urethroplasty to correct urethral bulging, vaginl stenosis, clitoroplasty and labiaplasty after primary vaginoplasty, and urethroplasty for strictures and fistulas, neophallus and neoscrotal reconstruction after phalloplasty are outlined as well.

Acute right varicocele: a clue to congenital vascular anomaly.

Workup of acute unilateral right varicocele should encompass imaging to look for abdominal and retroperitoneal pathology, as well as congenital vascular anomalies. Management of the acute symptomatic varicocele due to upstream venous thrombosis should be primarily medical, with initiation of anticoagulation and early involvement of our hematology colleagues.

Modern Guidelines for Bowel Preparation and Antimicrobial Prophylaxis for Open and Laparoscopic Urologic Surgery.

Mechanical bowel preparation (MBP) and antibiotics (oral and/or intravenous) have historically been used to decrease infectious complications in surgeries that involve manipulation of bowel or potential risk of injury. The use of MBP has recently been challenged in the colorectal surgery literature, thus inspiring similar critical evaluation of our practices in urology. This review gives a brief overview of the history of mechanical and oral antibiotic bowel preparation, as well as the evolution of the practice trends in colorectal surgery and urology. We also examine contemporary guidelines in skin preparation as well as antimicrobial prophylaxis before surgery.

Practice Expectations Compared to Reality for Women in Urology: A National Survey.

INTRODUCTION: We determined the patient gender distribution for practicing male and female urologists in the U.S. compared to current resident expectations. METHODS: Two mirrored surveys were distributed to AUA members practicing in the U.S. Questions were asked regarding years in training and practice, subspecialty, gender representation of patients and job satisfaction. Answer choices were based on a 5-point balanced Likert scale. RESULTS: Overall there were 894 respondents, including 704 practicing urologists and 190 urology residents, of whom women accounted for 14%. This figure reflects current AUA demographic data. Only 15.2% of female residents expected that once in practice more than 60% of their patients would be women compared to 45.5% of practicing female physicians who indicated that more than 60% of their patients are women. When stratified by fellowship training the 38.5% of female physicians who were trained in a specialty other than female pelvic medicine and reconstructive surgery and pediatrics still most commonly saw more than 60% female patients compared to 0.8% of male physicians. Overall satisfaction with the gender balance of patients was 76.0% for female physicians and 70.9% for male physicians. CONCLUSIONS: Female urologists report seeing greater numbers of female patients than their male counterparts and specialty training only modestly alters this gap. Current female residents may underestimate the number of women they will eventually see in practice based on current trends in our survey. However, overall satisfaction with the gender balance of patients seen is high.

Urology patients in the nephrology practice.

Urologists and nephrologists provide care to many mutual patients. This review addresses the initial management of upper urinary tract issues commonly seen in nephrology practice. Patients with hematuria without clear benign causes should be referred to urologists for workup to rule out urologic malignancies. Asymptomatic microscopic hematuria after negative workup should be followed with annual urinalysis with repeat urologic evaluation if it persists after 5 years. Hydronephrosis is another commonly encountered diagnosis. Functional urinary obstruction should be excluded using a diuretic nuclear renography in the appropriate population. Asymptomatic, stable hydronephrosis can be observed, but those with acute, symptomatic obstruction, or patients with suspected obstruction with signs of infection, should seek urologic care for intervention. Hydronephrosis is common in pregnant women; symptomatic patients merit intervention similar to nonpregnant patients. The management of patients with an acute stone episode is similar to that for those with hydronephrosis. Patients with first stone episodes need evaluation for risk factors for stone formation, whereas patients with identified risk factors or recurrent stones need comprehensive metabolic workup. Patients with incidentally found kidney masses should be referred to urology for possible intervention when they have solid kidney masses or cystic masses that need further evaluation.

Impact of a bladder cancer diagnosis on smoking behavior.

PURPOSE: Bladder cancer is the second most common tobacco-related malignancy. A new bladder cancer diagnosis may be an opportunity to imprint smoking cessation. Little is known about the impact of a diagnosis of bladder cancer on patterns of tobacco use and smoking cessation among patients with incident bladder cancer. PATIENTS AND METHODS: A simple random sample of noninvasive bladder cancer survivors diagnosed in 2006 was obtained from the California Cancer Registry. Respondents completed a survey on history of tobacco use, beliefs regarding bladder cancer risk factors, and physician influence on tobacco cessation. Respondents were compared by smoking status. Those respondents smoking at diagnosis were compared with general population controls obtained from the California Tobacco Survey to determine the impact of a diagnosis of bladder cancer on patterns of tobacco use. RESULTS: The response rate was 70% (344 of 492 eligible participants). Most respondents (74%) had a history of cigarette use. Seventeen percent of all respondents were smoking at diagnosis. Smokers with a new diagnosis of bladder cancer were almost five times as likely to quit smoking as smokers in the general population (48% v 10%, respectively; P < .001). The bladder cancer diagnosis and the advice of the urologist were the reasons cited most often for cessation. Respondents were more likely to endorse smoking as a risk factor for bladder cancer when the urologist was the source of their understanding. CONCLUSION: The diagnosis of bladder cancer is an opportunity for smoking cessation. Urologists can play an integral role in affecting the patterns of tobacco use of those newly diagnosed.

Quality of end-of-life care in low-income, uninsured men dying of prostate cancer.

BACKGROUND: The quality of end-of-life care was assessed in disadvantaged men prospectively enrolled in a public assistance program. That end-of-life care would be aggressive, more so than recommended by quality-of-care guidelines, was hypothesized. METHODS: Included in the study were all 60 low-income, uninsured men in a state-funded public assistance program who had died since its inception in 2001. To measure quality of end-of-life care, information was collected regarding timing of the institution of new chemotherapeutic regimens, time from administration of last chemotherapy dose to death, the number of inpatient admissions and intensive care unit stays made in the 3 months preceding death, and the number of emergency room visits made in the 12 months before dying. Also noted were hospice use and the timing of hospice referrals. RESULTS: Eighteen men (30%) enrolled in hospice before death and the average hospice stay lasted 45 days (standard deviation, 32; range, 2-143 days; median, 41 days). Two patients (11%) were enrolled for fewer than 7 days, and none were enrolled for more than 180 days. The average time from administration of the last dose of chemotherapy to death was 104 days. Chemotherapy was never initiated within 3 months of death, and in only 2 instances (6%) was the final chemotherapeutic regimen administered within 2 weeks of dying. Use of hospital resources (emergency room visits, inpatient admissions, and intensive care unit stays) was uniformly low (mean, 1.0 +/- 1.0, 0.65 +/- 0.82, and 0.03 +/- 0.18, respectively). CONCLUSIONS: End-of-life care in disadvantaged men dying of prostate cancer, who enroll in a comprehensive statewide assistance program, is high-quality.