The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

A mutation update for the FLNC gene in myopathies and cardiomyopathies.

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.

Safety and efficacy of embolotherapy for severe hemorrhage after partial nephrectomy.

BACKGROUND: Partial nephrectomy may be complicated by postoperative hemorrhage, which may be treated by transcatheter embolization. PURPOSE: To assess the safety and efficacy of embolotherapy for hemorrhagic complications of partial nephrectomy and to analyze the potential correlation between multiple bleeding sites on angiography and surgical complexity. MATERIAL AND METHODS: A cohort of 25 patients presenting with severe, postoperative bleeding after partial nephrectomy and treated with catheter-directed superselective embolization was included. Patients' demographics, radiological investigations before the embolization, and clinical outcome after embolization were analyzed. Mann-Whitney U test was used to analyze the potential difference in the RENAL score between patients with one or more bleeding sites in the resection area. RESULTS: Selective renal angiography revealed multiple bleeding sites at the resection bed in 8 (32%) patients with amorphous contrast extravasation in 10 (40%) patients. Embolization with use of a microcatheter and microcoils was effective to stop the bleeding in all but one patient, the latter requiring a second embolization two days later. Transient decrease in renal function was noted in 3/25 (12%) patients with full recovery in two of the three. Patients with multiple bleeding sites did not show significantly different RENAL scores compared to patients with a single bleeding site (P = 0.148). CONCLUSION: Embolotherapy for postoperative partial nephrectomy-related bleeding is safe and effective with a low rate of recurrent bleeding. The number of bleeding sites at the resection area did not correlate to the RENAL score.

Development and External Validation of a Multiparametric Magnetic Resonance Imaging and International Society of Urological Pathology Based Add-On Prediction Tool to Identify Prostate Cancer Candidates for Pelvic Lymph Node Dissection.

PURPOSE: We sought to expand current prediction tools for lymph node invasion in patients with prostate cancer using current state-of-the-art available tumor information, including multiparametric magnetic resonance imaging based tumor stage and detailed biopsy information. MATERIALS AND METHODS: We selected patients with prostate cancer for study who had available registered information on ISUP (International Society of Urological Pathology) based biopsy grading and multiparametric magnetic resonance imaging, and who had undergone radical prostatectomy with extended pelvic lymph node dissection. We developed a lymph node invasion prediction tool in 420 patients and externally validated it in 187. A concordance index was estimated to quantify the discriminative performance of the model. RESULTS: In the development cohort a median of 21 lymph nodes were removed per patient and 71 patients (16.9%) were diagnosed with lymph node invasion. Statistically significant predictors of lymph node invasion were the initial prostate specific antigen value, multiparametric magnetic resonance imaging based T stage, maximum tumor length in 1 core in mm and ISUP grade group corresponding to the maximum tumor involvement in 1 core. The predictive accuracy of this lymph node invasion prediction tool was 79.7% after fivefold internal cross validation and 72.5% after external validation. CONCLUSIONS: We report a contemporary, externally validated prediction tool for lymph node invasion in patients with prostate cancer. This prediction tool is a response to the paradigm shift from systematic to targeted biopsies by incorporating additional core specific biopsy information instead of the percent of positive cores. This new tool will also overcome stage migration, which is a potential risk when multiparametric magnetic resonance imaging information is used in digital rectal examination based nomograms.

Impact of Magnetic Resonance Imaging on Prostate Cancer Staging and European Association of Urology Risk Classification.

OBJECTIVE: To investigate the impact of magnetic resonance imaging (MRI) information on clinical staging, risk stratification, and treatment recommendations for prostate cancer (PCa) according to the European Association of Urology (EAU) guidelines. METHODS: We performed a single-center analysis of 180 men with PCa, undergoing clinical staging by digital rectal examination (DRE) as well as MRI before their robot-assisted radical prostatectomy. Patients were stratified according to the EAU guidelines into 4 well-defined risk categories, based on their clinical T-stage assessed by either DRE or MRI. Descriptive statistics of categorical variables are shown as frequencies and proportions. Differences between both scenarios (DRE- vs MRI-staged) were analyzed using a paired-samples sign test. RESULTS: Use of MRI information instead of DRE information leads to significant upstaging of clinical T-stage (33%) and EAU risk grouping (31%). When comparing these results with the pathologic T-stage, MRI showed a higher sensitivity than DRE to detect nonorgan-confined PCa (59% vs 41%; P <.01). In contrast, the specificity of MRI was lower than DRE (69% vs 95%; P <.01). Incorporation of MRI-based instead of DRE-based staging in the treatment decision process would alter the surgical treatment strategy in 49/180 patients (27%). CONCLUSION: The incorporation of MRI information substantially affects the treatment choice in PCa patients as compared to using the current available EAU guidelines based on DRE information. More specifically, treatment intensification would be recommended in 1 out of 4 patients.

Endovascular Management of Severe Arterial Haemorrhage After Radical Prostatectomy: A Case Series.

PURPOSE: The aim of this study is to assess the safety, effectiveness and long-term outcome of endovascular management of arterial haemorrhage after radical prostatectomy (RP). MATERIALS AND METHODS: Ten patients who received endovascular treatment for refractory bleeding after RP between January 2008 and December 2016 were retrospectively identified. Contrast-enhanced computed tomography (CT) was performed and followed by catheter-directed treatment by means of transarterial embolization (TAE) or stent graft placement. Follow-up included analysis of bleeding recurrence, embolization-related adverse events and tumour recurrence. RESULTS: Contrast-enhanced CT and catheter-directed angiography showed pelvic contrast extravasation in nine patients. Nine patients were successfully treated with TAE of the internal pudendal, superior and/or inferior vesical or (the anterior division or main branch of) the internal iliac arteries using microparticles in two patients, coils in two patients, a combination of microparticles and coils in three patients, glue in one patient and Gelfoam in one patient. The remaining patient was treated with stent graft placement in the external iliac artery, which was most likely injured during robot-assisted lymphadenectomy. One patient developed a puncture site pseudoaneurysm. No other complications related to the endovascular procedures occurred, in particular no pelvic ischaemic complications were identified. Mean follow-up period was 45 months (range 22-80). CONCLUSIONS: The endovascular management of arterial haemorrhage after RP is safe and effective, without post-embolization ischaemic events.

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Staging of prostatic carcinoma at 1.5-T MRI: correlation of a simplified MRI exam with whole-mount radical prostatectomy specimens.

OBJECTIVE: To retrospectively analyze the accuracy of simplified multiparametric MRI at 1.5 T for local staging by using whole-mount-section histopathological analysis as the standard of reference. METHODS: 123 consecutive patients underwent T2 weighted, T1 weighted and diffusion-weighted MRI without endorectal coil prior to radical prostatectomy. The accuracy of predicting extracapsular extension (ECE) (T3a) was assessed using direct signs or the combination of direct and indirect signs of extraprostatic extension. The accuracy of predicting seminal vesicle invasion (T3b) was evaluated, taking into account different routes of seminal vesicle involvement. Finally, adjacent organ invasion (T4) was evaluated in this patient population. RESULTS: Histopathology showed T3a, T3b and T4 in 61, 28 and 9 cases, respectively. The use of direct signs of extraprostatic extension showed a sensitivity of 57.4% and specificity of 91.9%. The combination of direct signs and indirect signs improved sensitivity (85.2%) at the expense of moderate loss of specificity (83.9%). MR sensitivity for the detection of seminal vesicle invasion was low (53.6%); however, it was dependent on the route of seminal vesicle tumour infiltration. MR sensitivity and specificity for adjacent organ invasion were 88.9% and 99.1%. CONCLUSION: Simplified MRI study at 1.5 T provides a relatively high sensitivity for detecting ECE (T3a) when using the combination of indirect and direct signs. However, this high sensitivity reading is at the cost of a moderate loss of specificity. Invasion of the seminal vesicles (T3b) occurs most often along the ejaculatory duct complex with low MR sensitivity. ADVANCES IN KNOWLEDGE: Simplified MRI study at 1.5 T without endorectal coil could be used for the local T staging of prostate cancer.

TRUS-MR Fusion Biopsy of the Prostate: Radiological and Histological Correlation.

OBJECTIVE: Targeted magnetic resonance/ultrasound fusion prostate biopsy has been shown to improve the detection of high-grade prostate cancer and to reduce sampling errors. Our objective is to assess MR-TRUS targeted fusion biopsy versus standard biopsy for the detection of clinically significant tumors. MATERIALS AND METHODS: Patients were referred for abnormal digital rectal examination (DRE) or risen prostate-specific antigen (PSA). If an MRI-visible lesion was detected, they were included in the study. In total, 102 men underwent MRI followed by MR-TRUS fusion biopsy between November 2014 and January 2016. Tumor grading was done with the clinical relevance in mind; a cutoff was used at Gleason 7 or higher. Standard biopsy results were collected from clinical practice during 2005 at the same institution to provide baseline values. RESULTS: A comparable rate of prostate cancer is found whether sampling is done at random (42.4%) or with the use of fusion biopsy (44.1%). However, these percentages are histologically different: fewer low-grade tumors are detected with MR-TRUS fusion biopsy (-19.1%), while more high-grade tumors are diagnosed (+26%). If there is an ultrasound-visible lesion in the prostate, the gain of combined MRI and fusion biopsy is less impressive. CONCLUSION: Fusion biopsy can provide more accurate information for optimal patient management, as it detects a higher percentage of high-grade prostate cancers than random sampling. Furthermore, nonrelevant tumors are less commonly detected using fusion biopsy.

Optimizing temperature threshold testing in small-fiber neuropathy.

INTRODUCTION: We examined optimization of a temperature threshold testing (TTT) protocol for patients with suspected small-fiber neuropathy (SFN) to lessen the burden for both patients and technicians, without sacrificing accuracy. METHODS: Data from 81 patients with SFN (skin biopsy and TTT abnormal) and 81 without SFN (skin biopsy and TTT normal) were used. Warm, cold, and heat pain sensation thresholds were determined bilaterally on the thenar eminence and foot dorsum by methods of limits and levels. Diagnostic accuracy was determined for various sensory modality combinations through comparative corresponding area under the receiver-operator characteristic curves. RESULTS: Assessment of warm and cold thresholds in all extremities by the method of levels showed the best discriminatory ability (area under the curve 0.95, sensitivity 84.2%, specificity 93.8%). CONCLUSIONS: These assessments are suggested for TTT examination in possible SFN patients. By applying this combination, the time needed for TTT can be reduced, maintaining diagnostic accuracy.

Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy.

OBJECTIVE: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I-SFN). We sought to identify a genetic basis for I-SFN by screening patients with biopsy-confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage-gated sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. METHODS: Patients referred with possible I-SFN, who met the criteria of ≥2 SFN-related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. RESULTS: Twenty-eight patients who met stringent criteria for I-SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy-confirmed I-SFN, 8 were found to carry novel mutations in SCN9A. Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. INTERPRETATION: We show for the first time that gain of function mutations in sodium channel Na(V)1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I-SFN. These results point to a broader role of Na(V)1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I-SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate.