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.

Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy.

It was previously suggested that increasing the number of genes on diagnostic gene panels could increase the genetic yield in patient with dilated cardiomyopathy (DCM). We explored the diagnostic and prognostic relevance of testing DCM patients with an expanded gene panel. The current study included 225 consecutive DCM patients who had no genetic diagnosis after a 48-gene cardiomyopathy-panel. These were then evaluated using an expanded gene panel of 299 cardiac-associated genes. A likely pathogenic/pathogenic (P/LP) variant was detected in 13 patients. Five variants were reclassifications of variants found in genes which were already detected using the 48 gene panel. Only one of the other eight variants could explain the phenotype of the patient (KCNJ2). The panel detected 186 VUSs in 127 patients (of which 6 also had a P/LP variant). The presence of a VUS was significantly associated with the combined end-point of mortality, heart failure hospitalization, heart transplantation or life-threatening arrhythmias(HR, 2.04 [95% CI, 1.15 to 3.65]; p = 0.02). The association of a VUS with prognosis remained when we only included VUSs in robust DCM-associated genes (high suspicious VUSs), but disappeared when we only included VUSs in non-robust DCM-associated genes (low suspicious VUSs), highlighting the importance of weighing of VUSs. Overall, the use of large gene panels for genetic testing in DCM does not increase the diagnostic yield, although a VUS in a robust DCM-associated gene is associated with an adverse prognosis. Altogether, current diagnostic gene panels should be limited to the robust DCM-associated genes.

Prevalence and Clinical Consequences of Multiple Pathogenic Variants in Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM. To gain insight into these knowledge gaps, we (1) systematically collected clinical information from a well-characterized DCM cohort and (2) created a mouse model. METHODS: Complete cardiac phenotyping and genotyping was performed in 685 patients with consecutive DCM. Compound heterozygous digenic (LMNA [lamin]/titin deletion A-band) with monogenic (LMNA/wild-type) and wild-type/wild-type mice were created and phenotypically followed over time. RESULTS: One hundred thirty-one likely pathogenic/pathogenic (LP/P) variants in robust DCM-associated genes were found in 685 patients with DCM (19.1%) genotyped for the robust genes. Three of the 131 patients had a second LP/P variant (2.3%). These 3 patients had a comparable disease onset, disease severity, and clinical course to patients with DCM with one LP/P. The LMNA/Titin deletion A-band mice had no functional differences compared with the LMNA/wild-type mice after 40 weeks of follow-up, although RNA-sequencing suggests increased cardiac stress and sarcomere insufficiency in the LMNA/Titin deletion A-band mice. CONCLUSIONS: In this study population, 2.3% of patients with DCM with one LP/P also have a second LP/P in a different gene. Although the second LP/P does not seem to influence the disease course of DCM in patients and mice, the finding of a second LP/P can be of importance to their relatives.

Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X.

Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Prevalence of intronic repeat expansions in RFC1 in Dutch patients with CANVAS and adult-onset ataxia.

Recently, an intronic biallelic (AAGGG)n repeat expansion in RFC1 was shown to be a cause of CANVAS and adult-onset ataxia in multiple populations. As the prevalence of the RFC1 repeat expansion in Dutch cases was unknown, we retrospectively tested 9 putative CANVAS cases and two independent cohorts (A and B) of 395 and 222 adult-onset ataxia cases, respectively, using the previously published protocol and, for the first time optical genome mapping to determine the size of the expanded RFC1 repeat. We identified the biallelic (AAGGG)n repeat expansion in 5/9 (55%) putative CANVAS patients and in 10/617 (1.6%; cohorts A + B) adult-onset ataxia patients. In addition to the AAGGG repeat motif, we observed a putative GAAGG repeat motif in the repeat expansion with unknown significance in two adult-onset ataxia patients. All the expanded (AAGGG)n repeats identified were in the range of 800-1299 repeat units. The intronic biallelic RFC1 repeat expansion thus explains a number of the Dutch adult-onset ataxia cases that display the main clinical features of CANVAS, and particularly when ataxia is combined with neuropathy. The yield of screening for RFC1 expansions in unselected cohorts is relatively low. To increase the current diagnostic yield in ataxia patients, we suggest adding RFC1 screening to the genetic diagnostic workflow by using advanced techniques that attain long fragments.

Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy.

PURPOSE: Accurate interpretation of variants detected in dilated cardiomyopathy (DCM) is crucial for patient care but has proven challenging. We applied a set of proposed refined American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria for DCM, reclassified all detected variants in robust genes, and associated these results to patients' phenotype. METHODS: The study included 902 DCM probands from the Maastricht Cardiomyopathy Registry who underwent genetic testing. Two gene panel sizes (extended n = 48; and robust panel n = 14) and two standards of variant classification (standard versus the proposed refined ACMG/AMP criteria) were applied to compare genetic yield. RESULTS: A pathogenic or likely pathogenic (P/LP) variant was found in 17.8% of patients, and a variant of uncertain significance (VUS) was found in 32.8% of patients when using method 1 (extended panel (n = 48) + standard ACMG/AMP), compared to respectively 16.9% and 12.9% when using method 2 (robust panel (n = 14) + standard ACMG/AMP), and respectively 14% and 14.5% using method 3 (robust panel (n = 14) + refined ACMG/AMP). Patients with P/LP variants had significantly lower event-free survival compared to genotype-negative DCM patients. CONCLUSION: Stringent gene selection for DCM genetic testing reduced the number of VUS while retaining ability to detect similar P/LP variants. The number of genes on diagnostic panels should be limited to genes that have the highest signal to noise ratio.

Implications of Genetic Testing in Dilated Cardiomyopathy.

BACKGROUND: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome. METHODS: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias. RESULTS: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (P<0.01). After a median follow-up of 4 years, event-free survival was reduced in genetic versus patients with nongenetic DCM (P=0.01). This effect on outcome was mediated by the associated electrical phenotypes of genetic DCM (P<0.001). CONCLUSIONS: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM.

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.

De novo variants in CAMTA1 cause a syndrome variably associated with spasticity, ataxia, and intellectual disability.

Previously, intragenic CAMTA1 copy number variants (CNVs) have been shown to cause non-progressive, congenital ataxia with or without intellectual disability (OMIM#614756). However, ataxia, intellectual disability, and dysmorphic features were all incompletely penetrant, even within families. Here, we describe four patients with de novo nonsense, frameshift or missense CAMTA1 variants. All four patients predominantly manifested features of ataxia and/or spasticity. Borderline intellectual disability and dysmorphic features were both present in one patient only, and other neurological and behavioural symptoms were variably present. Neurodevelopmental delay was found to be mild. Our findings indicate that also nonsense, frameshift and missense variants in CAMTA1 can cause a spastic ataxia syndrome as the main phenotype.

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.

Metabolic Profiling Associates with Disease Severity in Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Metabolomic profiling may have diagnostic and prognostic value in heart failure. This study investigated whether targeted blood and urine metabolomics reflects disease severity in patients with nonischemic dilated cardiomyopathy (DCM) and compared its incremental value on top of N-terminal prohormone of brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: A total of 149 metabolites were measured in plasma and urine samples of 273 patients with DCM and with varying stages of disease (patients with DCM and normal left ventricular reverse remodeling, n = 70; asymptomatic DCM, n = 72; and symptomatic DCM, n = 131). Acylcarnitines, sialic acid and glutamic acid are the most distinctive metabolites associated with disease severity, as repeatedly revealed by unibiomarker linear regression, sparse partial least squares discriminant analysis, random forest, and conditional random forest analyses. However, the absolute difference in the metabolic profile among groups was marginal. A decision-tree model based on the top metabolites did not surpass NT-proBNP in classifying stages. However, a combination of NT-proBNP and the top metabolites improved the decision tree to distinguish patients with DCM and left ventricular reverse remodeling from symptomatic DCM (area under the curve 0.813 ± 0.138 vs 0.739 ± 0.114; P = 0.02). CONCLUSION: Functional cardiac recovery is reflected in metabolomics. These alterations reveal potential alternative treatment targets in advanced symptomatic DCM. The metabolic profile can complement NT-proBNP in determining disease severity in nonischemic DCM.

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.

Mutations in PDLIM5 are rare in dilated cardiomyopathy but are emerging as potential disease modifiers.

BACKGROUND: A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. METHODS: We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole-exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. RESULTS: PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN-variant. The PDLIM5 loss-of-function (LoF) variant affected all cardiac-specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN-variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb-deletion of exon 2 in PDLIM5 resulting in early-onset cardiac disease, showing the importance of PDLIM5 in cardiac function. CONCLUSIONS: Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early-onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers.

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.

Prevalence of Pathogenic Gene Mutations and Prognosis Do Not Differ in Isolated Left Ventricular Dysfunction Compared With Dilated Cardiomyopathy.

BACKGROUND: Genetic evaluation is recommended in patients with unexplained dilated cardiomyopathy (DCM), but its diagnostic yield and prognostic relevance in unexplained isolated left ventricular dysfunction (LVdys) is unknown. METHODS AND RESULTS: A total of 127 LVdys and 262 DCM patients underwent genetic screening. Long-term outcome consisted of a combined end point of life-threatening arrhythmia, heart transplantation, and death. At baseline, LVdys patients were younger and had less frequently New York Heart Association class ≥3 when compared with DCM (55±13 versus 58±12; P=0.019 and 21% versus 36%; P=0.003, respectively). The prevalence of familial disease and pathogenic mutations was similar in LVdys and DCM (45% versus 40%; P=0.37 and 19% versus 17%; P=0.61, respectively). After a follow-up of 56 (31-82) months, outcome did not differ in LVdys compared with DCM patients (hazard ratio, 0.83; 95% confidence interval, 0.47-1.45; P=0.51). Overall, outcome was less favorable in patients with a genetic mutation or familial disease when compared with those without (hazard ratio, 2.7; 95% confidence interval, 1.07-7.7; P=0.048 and hazard ratio, 2.2; 95% confidence interval, 1.2-4.2; P=0.013, respectively). Thus, the diagnostic yield of genetic testing in LVdys and DCM is similarly high. The presence of a gene mutation or familial predisposition results in an equally worse prognosis. CONCLUSIONS: Genetic evaluation is advised in LVdys patients and should not merely be restricted to DCM.

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.

Does ability to walk reflect general functionality in inflammatory neuropathies?

The "ability to walk" is considered a benchmark for good clinical recovery and prognosis, particularly in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, it has never been determined whether being "able to walk" represents general functionality. The purpose of this study was to examine whether the ability to walk outside independently reflects general functional improvement in patients with GBS, CIDP, and gammopathy-related neuropathy (MGUSP). A total of 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59), and MGUSP (23) were serially examined (1-year). Predefined arbitrary cut-offs (so-called patients' Functional-Acceptable-Clinical-Thresholds [FACTs]) were taken at the 50th, 75th, and 90th percentile of the Inflammatory-Rasch-built-Overall-Disability-Scale (I-RODS(©) ). We determined the proportion of patients able to walk outside independently that reached the postulated cut-offs. A mean total of 85%, 39%, and 12% of all patients able to walk reached 50th, 75th, and 90th percentile thresholds, respectively. These findings were not neuropathy type related. Our findings show that assessing only one construct of functionality (e.g., walking ability) does not reflect the full scope of daily/social functional deficits perceived by patients. The ability to walk shows a patient is doing better, but not necessarily doing well. The I-RODS(©) bypasses these limitations.

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.