Re: A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a ?perpetual dispute?

Objectives: To review the literature and present new data of continuous androgen deprivation therapy (ADT) vs intermittent androgen deprivation (IAD) as therapies for prostate cancer in terms of survival and quality of life and clarify practical issues in the use of IAD. Materials and Methods: We conducted a systematic search on Medline and Embase databases using “prostatic neoplasm” and “intermittent androgen deprivation” as search terms. We reviewed meta-analyses, randomised controlled trials, reviews, clinical trials and practise guidelines written in English from 2000 and onwards until 01/04/2013. Ten randomized controlled trials were identified. Seven of them published extensive data and results randomizing 4675 patients to IAD versus CAD. Data from the other three randomized trials were limited. Results: Over the last years studies confirmed that IAD is an effective alternative approach to hormonal deprivation providing simultaneously several potential benefits in terms of quality of life and cost effectiveness. Thus, in patients with non metastatic, advanced prostate cancer IAD could be used as standard treatment, while in metastatic prostate cancer IAD role still remains ambiguous. Conclusions: Nowadays, revaluation of the gold standard of ADT in advanced prostate cancer appears essential. Recent data established that IAD should no longer be considered as investigational, since its effectiveness has been proven, especially in patients suffering from non-metastatic advanced prostate cancer

Electron Emission Observations from As-Grown and Vacuum-Coated Chemical Vapor Deposited Diamond

Field emission has been observed from chemical vapor deposited diamond grown on Mo and Si substrates. Emission was observed at fields as low as 20 kV/cm. The samples were tested in the as-grown form, and after coating with thin films of Au, CsI, and Ni. The emission current was typically maximum at the onset of the applied field, but was unstable, and decreased rapidly with time from the as-grown films. Thin Au layers, approximately 15 nm thick, vacuum deposited onto the diamond samples significantly improved the stability of the emission current at values approximately equal to those from uncoated samples at the onset of the applied field. Thin layers of CsI, approximately 5 nm thick, were also observed to improve the stability of the emission current but at values less than those from the uncoated samples at the onset of the applied field. While Au and CsI improved the stability of the emission, Ni was observed to have no effect

Negative Electron Affinity Effect on the Surface of Chemical Vapor Deposited Diamond Polycrystalline Films

Strong negative electron affinity effects have been observed on the surface of as-grown chemical vapor deposited diamond using Secondary Electron Emission. The test samples were randomly oriented and the surface was terminated with hydrogen. The effect appears as an intensive peak in the low energy part of the spectrum of the electron energy distribution and may be described in the model of effective negative electron affinity

Effects of Chronic Atrial Fibrillation on Active and Passive Force Generation in Human Atrial Myofibrils

Rationale: Chronic atrial fibrillation (cAF) is associated with atrial contractile dysfunction. Sarcomere remodeling may contribute to this contractile disorder. Objective: Here, we use single atrial myofibrils and fast solution switching techniques to directly investigate the impact of cAF on myofilament mechanical function eliminating changes induced by the arrhythmia in atrial myocytes membranes and extracellular components. Remodeling of sarcomere proteins potentially related to the observed mechanical changes is also investigated. Methods and Results: Myofibrils were isolated from atrial samples of 15 patients in sinus rhythm and 16 patients with cAF. Active tension changes following fast increase and decrease in [Ca2+] and the sarcomere length\u2013passive tension relation were determined in the 2 groups of myofibrils. Compared to sinus rhythm myofibrils, cAF myofibrils showed (1) a reduction in maximum tension and in the rates of tension activation and relaxation; (2) an increase in myofilament Ca2+ sensitivity; (3) a reduction in myofibril passive tension. The slow \u3b2-myosin heavy chain isoform and the more compliant titin isoform N2BA were up regulated in cAF myofibrils. Phosphorylation of multiple myofilament proteins was increased in cAF as compared to sinus rhythm atrial myocardium. Conclusions: Alterations in active and passive tension generation at the sarcomere level, explained by translational and post-translational changes of multiple myofilament proteins, are part of the contractile dysfunction of human cAF and may contribute to the self-perpetuation of the arrhythmia and the development of atrial dilatation

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for similar to 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease

KIAA1840 mutations cause ARCMT2

Charcot–Marie–Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/ KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot–Marie–Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot–Marie–Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/ KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot–Marie–Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot–Marie–Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot–Marie-Tooth disease (CMT2A2/HMSN2A2/ MFN2 , CMT2B1/ LMNA , CMT2B2/ MED25 , CMT2B5/ NEFL , ARCMT2F/dHMN2B/ HSPB1 , CMT2K/ GDAP1 , CMT2P/ LRSAM1 , CMT2R/ TRIM2 , CMT2S/ IGHMBP2 , CMT2T/ HSJ1 , CMTRID/ COX6A1 , ARAN-NM/ HINT and GAN/ GAN ), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/ PGN , SPG15/ ZFYVE26, SPG21/ ACP33 , SPG35/ FA2H , SPG46/ GBA2 , SPG55/ C12orf65 and SPG56/ CYP2U1 ), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum ( SLC12A6 ) . Mitochondrial disorders related to Charcot–Marie–Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot–Marie–Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/ KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/ KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot–Marie–Tooth disease

Robotic-assisted, laparoscopic, and open radical cystectomy: surgical data of 1400 patients from The Italian Radical Cystectomy Registry on intraoperative outcomes

Introduction: The Italian Radical Cystectomy Registry (Registro Italiano Cistectomie - RIC) aimed to analyse outcomes of a multicenter series of patients treated with radical cystectomy (RC) for bladder cancer. Material and methods: An observational, prospective, multicenter, cohort study was performed to collect data from RC and urinary diversion via open (ORC), laparoscopic (LRC), or robotic-assisted (RARC) techniques performed in 28 Italian Urological Departments. The enrolment was planned from January 2017 to June 2020 (goal: 1000 patients), with a total of 1425 patients included. Chi-square and t-tests were used for categorical and continuous variables. All tests were 2-sided, with a significance level set at p <0.05. Results: Overall median operative-time was longer in RARCs (390 minutes, IQR 335-465) than ORCs (250, 217-309) and LRCs (292, 228-350) (p <0.001). Lymph node dissection (LND) was performed more frequently in RARCs (97.1%) and LRCs (93.5%) than ORCs (85.6%) (p <0.001), with extended-LND performed 2-fold more frequently in RARCs (61.6%) (p <0.001). The neobladder rate was significantly higher (more than one-half) in RARCs. The median estimated blood loss (EBL) rate was lower in RARCs (250 ml, 165-400) than LRCs (330, 200-600) and ORCs (400, 250-600) (p <0.001), with intraoperative blood transfusion rates of 11.4%, 21.7% and 35.6%, respectively (p <0.001). The conversion to open rate was slightly higher in RARCs (6.8%) than LRCs (4.3%). Intraoperative complications occurred in 1.3% of cases without statistically significant differences among the approaches. Conclusions: Data from the RIC confirmed the need to collect as much data as possible in a multicenter manner. RARCs proves to be feasible with perioperative complication rates that do not differ from the other approaches

HIV-associated bladder cancer: a case series evaluating difficulties in diagnosis and management

<p>Abstract</p> <p>Background</p> <p>Chronic human immunodeficiency virus (HIV) infection is associated with an increased incidence of Non-Acquired Immunodeficiency Syndrome (non-AIDS) defining cancers. To date, only a limited number of cases of bladder cancer have been linked with HIV infection. We sought to describe the clinical characteristics of HIV-associated bladder cancer.</p> <p>Methods</p> <p>A retrospective study was performed involving HIV-positive patients with bladder cancer, combining cases from multiple institutions with published case reports. Data regarding patient demographics, HIV status, clinical presentation, pathology, cancer treatment, and outcome were analyzed using descriptive statistics.</p> <p>Results</p> <p>Eleven patients were identified with a median age of 55 years (range, 33 - 67). The median CD4+ count at cancer diagnosis was 280 cells/mm³(range, 106 - 572 cells/mm³). Six patients (55%) had a known risk factor for bladder cancer, and nine (82%) presented with hematuria. Ten patients had transitional cell carcinoma, and most had superficial disease at presentation. Treatment included mainly transurethral resection of bladder tumor followed by a combination of local and systemic therapies. One patient received intravesical bacillus Calmette-Guèrin (BCG) without complication. Several patients (55%) were alive following therapy, although many (64%) suffered from local relapse and metastatic disease.</p> <p>Conclusion</p> <p>Bladder cancer is part of the growing list of cancers that may be encountered in patients living longer with chronic HIV-infection. Our patients presented at a younger age and with only mild immunosuppression, however, they experienced an expected course for their bladder cancer. Hematuria in an HIV-infected patient warrants a complete evaluation.</p

Generation of bi-allelic MYBPC3 truncating mutant and isogenic control from an iPSC line of a patient with hypertrophic cardiomyopathy

MYBPC3 is the most frequently affected gene in hypertrophic cardiomyopathy (HCM), which is an autosomal-dominant cardiac disease caused by mutations in sarcomeric proteins. Bi-allelic truncating MYBPC3 mutations are associated with severe forms of neonatal cardiomyopathy. We reprogrammed skin fibroblasts from a HCM patient carrying a heterozygous MYBPC3 truncating mutation into human induced pluripotent stem cells (iPSC) and used CRISPR/Cas9 to generate bi-allelic MYBPC3 truncating mutation and isogenic control hiPSC lines. All lines expressed pluripotency markers, had normal karyotype and differentiated into endoderm, ectoderm and cardiomyocytes in vitro. This set of three lines provides a useful tool to study HCM pathomechanisms

Expression and biological-clinical significance of hTR, hTERT and CKS2 in washing fluids of patients with bladder cancer

<p>Abstract</p> <p>Background</p> <p>at present, pathogenesis of bladder cancer (BC) has not been fully elucidated. Aim of this study is to investigate the role of human telomerase RNA (<it>hTR</it>), human telomerase reverse transcriptase (<it>hTERT</it>) and CDC28 protein kinase regulatory subunit 2 (<it>CKS2</it>) in bladder carcinogenesis and their possible clinical significance;</p> <p>Methods</p> <p>the transcript levels of <it>hTR</it>, <it>hTERT </it>and <it>CKS2 </it>were quantified by Real time reverse transcriptase chain reaction in exfoliated cells from bladder washings of 36 patients with BC and 58 controls. The statistical significance of differences between BC bearing patients and control groups, in the general as well as in the stratified analysis (superficial or invasive BC), was assessed by Student's t test. Non parametric Receiver Operating Characteristics analysis (ROC) was performed to ascertain the accuracy of study variables to discriminate between BC and controls. The clinical value of concomitant examination of <it>hTR</it>, <it>hTERT </it>and <it>CKS2 </it>was evaluated by logistic regression analysis;</p> <p>Results</p> <p>a significant decrease in <it>hTR </it>and a significant increase in <it>hTERT </it>or <it>CKS2 </it>gene expression were found between BC bearing patients and controls, as well as in the subgroups analysis. The area under the curve (AUC) indicated an average discrimination power for the three genes, both in the general and subgroups analysis, when singularly considered. The ability to significantly discriminate between superficial and invasive BC was observed only for <it>hTR </it>transcript levels. A combined model including <it>hTR </it>and <it>CKS2 </it>was the best one in BC diagnosis;</p> <p>Conclusions</p> <p>our results, obtained from a sample set particularly rich of exfoliated cells, provide further molecular evidence on the involvement of <it>hTR, hTERT </it>and <it>CKS2 </it>gene expression in BC carcinogenesis. In particular, while <it>hTERT </it>and <it>CKS2 </it>gene expression seems to have a major involvement in the early stages of the disease, <it>hTR </it>gene expression, seems to be more involved in progression. In addition, our findings suggest that the studied genes have a clinical role in discriminating between BC and controls in the general as well as in the stratified analysis, when singularly considered. A combined model improved over the single marker BC diagnosis.</p