Outcomes of ventricular tachycardia ablation in patients with ischemic and non-ischemic cardiomyopathy: A propensity-score matched analysis.

INTRODUCTION AND OBJECTIVES: Catheter ablation (CA) is effective in the treatment of ventricular tachycardia (VT). Although some observational data suggest patients with non-ischemic cardiomyopathy (NICM) have less favorable outcomes when compared to those with an ischemic etiology (ICM), direct comparisons are rarely reported. We aimed to compare the outcomes of VT ablation in a propensity-score matched population of ICM or NICM patients. METHODS: Single-center retrospective study of consecutive patients undergoing VT ablation from 2012 to 2023. A propensity score (PS) was used to match ICM and NICM patients in a 1:1 fashion according to age, sex, left ventricular ejection fraction (LVEF), NYHA class, electrical storm (ES) at presentation, and previous endocardial ablation. The outcomes of interest were VT-free survival and all-cause mortality. RESULTS: The PS yielded two groups of 71 patients each (mean age 63±10 years, 92% male, mean LVEF 35±10%, 36% with ES at presentation, and 23% with previous ablation), well matched for baseline characteristics. During a median follow-up of 2.3 (interquartile range IQR 1.3-3.8) years, patients with NICM had a significantly lower VT-free survival (53.5% vs. 69.0%, log-rank p=0.037), although there were no differences regarding all-cause mortality (22.5% vs. 16.9%, log-rank p=0.245). Multivariate analysis identified NICM (HR 2.34 [95% CI 1.32-4.14], p=0.004), NYHA class III/IV (HR 2.11 [95% CI 1.11-4.04], p=0.024), and chronic kidney disease (HR 2.23 [95% CI 1.25-3.96], p=0.006), as independent predictors of VT recurrence. CONCLUSION: Non-ischemic cardiomyopathy patients were at increased risk of VT recurrence after ablation, although long-term mortality did not differ.

The myotubular and centronuclear myopathy patient registry: a multifunctional tool for translational research.

The Myotubular and Centronuclear Myopathy Registry is an international research database containing key longitudinal data on a diverse and growing cohort of individuals affected by this group of rare and ultra-rare neuromuscular conditions. It can inform and support all areas of translational research including epidemiological and natural history studies, clinical trial feasibility planning, recruitment for clinical trials or other research studies, stand-alone clinical studies, standards of care development, and provision of real-world evidence data. For ten years, it has also served as a valuable communications tool and provided a link between the scientific and patient communities. With the anticipated advent of disease-modifying therapies for these conditions, the registry is a key resource for the generation of post-authorisation data for regulatory decision-making, real world evidence, and patient-reported outcome measures. In this paper we present some key data from the current 444 registered individuals with the following genotype split: MTM1 n=270, DNM2 n=42, BIN1 n=4, TTN n=4, RYR1 n=12, other n=4, unknown n=108. The data presented are consistent with the current literature and the common understanding of a strong genotype/phenotype correlations in CNM, most notably the data supports the current knowledge that XLMTM is typically the most severe form of CNM. Additionally, we outline the ways in which the registry supports research, and, more generally, the importance of continuous investment and development to maintain the relevance of registries for all stakeholders. Further information on the registry and contact details are available on the registry website at www.mtmcnmregistry.org.

Palliative Care Costs in Different Ambulatory-Based Settings: A Systematic Review.

BACKGROUND: Cost-of-illness studies in palliative care are of growing interest in health economics. There is no standard methodology to capture direct and non-direct healthcare and non-healthcare expenses incurred by health services, patients and their caregivers in the course of the ambulatory palliative care process. OBJECTIVE: We aimed to describe the type of healthcare and non-healthcare expenses incurred by patients with cancer and non-cancer patients and their caregivers for palliative care in ambulatory-based settings and the methodology used to capture the data. METHODS: We conducted a systematic review of studies on the costs of ambulatory-based palliative care in patients with cancer (breast, lung, colorectal) and non-cancer conditions (chronic heart failure, chronic obstructive pulmonary disease, dementia) found in six bibliographic databases (PubMed, EMBASE [via Ovid], Cochrane Database of Systematic Reviews, EconLit, the National Institute for Health Research Health Technology Assessment Database and the National Health Service Economic Evaluation Database at the University of York, and Google Scholar). The studies were published between January 2000 and December 2022. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology for study selection and assessed study quality using the Quality of Health Economic Studies instrument. The study was registered in PROSPERO (CRD42021250086). RESULTS: Of 1434 identified references, 43 articles met the inclusion criteria. The primary data source was databases. More than half of the articles presented data from public healthcare systems (65.12%) were retrospective (60.47%), and entailed a bottom-up costing analysis (93.2%) made from a healthcare system perspective (53.49%). The sociodemographic characteristics of patients and families/caregivers were similar across the studies. Cost outcomes reports were heterogeneous; almost all of the studies collected data on direct healthcare costs (97.67%). The main driver of costs was inpatient care (55.81%), which increased during the end-of-life period. Nine studies (20.97%) recorded costs due to productivity losses for caregivers and three recorded such costs for patients. Caregiving costs were explored through an opportunity cost analysis in all cases, based on interviews conducted with and questionnaires administered to patients and caregivers, mainly via telephone calls (23.23%). CONCLUSIONS: This systematic review reveals that studies on the costs of ambulatory-based palliative care are increasing. These studies are mostly conducted from a healthcare system perspective, which leaves out costs related to patients'/caregivers' economic burden. There is a need for prospective studies to assess this financial burden and evaluate, with strong evidence, the interventions and actions designed to improve the quality of life of palliative care patients. Future studies should propose cost calculation approaches using a societal perspective to better estimate the economic burden imposed on patients in ambulatory-based palliative care.

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. FUNDING: Astellas Gene Therapies.

Erector spinae plane block, neuropathic pain and quality of life after video-assisted thoracoscopy surgery. Pilot, observational study.

BACKGROUND: The erector spinae plane block (ESPB) is a valuable alternative for pain management after video-assisted thoracoscopy surgery (VATS). The incidence of postoperative chronic neuropathic pain (CNP) is high while the quality of life (QoL) after VATS remains unknown. We hypothesised that patients with ESPB would have a low incidence of acute and CNP and would report a good QoL up to three months after VATS. METHODS: We conducted a single-centre prospective pilot cohort study from January to April 2020. ESPB after VATS was the standard practice. The primary outcome was the incidence of CNP three months postoperatively. Secondary outcomes included QoL assessed by the EuroQoL questionnaire three months after surgery and pain control at the Post-Anaesthesia Care Unit (PACU), 12 and 24 hours postoperatively. RESULTS: We conducted a single-centre prospective pilot cohort study from January to April 2020. ESPB after VATS was the standard practice. The primary outcome was the incidence of CNP three months postoperatively. Secondary outcomes included QoL assessed by the EuroQoL questionnaire three months after surgery and pain control at the Post-Anaesthesia Care Unit (PACU), 12 and 24 hours postoperatively. CONCLUSIONS: We conducted a single-centre prospective pilot cohort study from January to April 2020. ESPB after VATS was the standard practice. The primary outcome was the incidence of CNP three months postoperatively. Secondary outcomes included QoL assessed by the EuroQoL questionnaire three months after surgery and pain control at the Post-Anaesthesia Care Unit (PACU), 12 and 24 hours postoperatively.

Disrupted T-tubular network accounts for asynchronous calcium release in MTM1-deficient skeletal muscle.

In mammalian skeletal muscle, the propagation of surface membrane depolarization into the interior of the muscle fibre along the transverse (T) tubular network is essential for the synchronized release of calcium from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) in response to the conformational change in the voltage-sensor dihydropyridine receptors. Deficiency in 3-phosphoinositide phosphatase myotubularin (MTM1) has been reported to disrupt T-tubules, resulting in impaired SR calcium release. Here confocal calcium transients recorded in muscle fibres of MTM1-deficient mice were compared with the results from a model where propagation of the depolarization along the T-tubules was modelled mathematically with disruptions in the network assumed to modify the access and transmembrane resistance as well as the capacitance. If, in simulations, T-tubules were assumed to be partially or completely inaccessible to the depolarization and RyRs at these points to be prime for calcium-induced calcium release, all the features of measured SR calcium release could be reproduced. We conclude that the inappropriate propagation of the depolarization into the fibre interior is the initial critical cause of severely impaired SR calcium release in MTM1 deficiency, while the Ca2+ -triggered opening of RyRs provides an alleviating support to the diseased process. KEY POINTS: Myotubular myopathy is a fatal disease due to genetic deficiency in the phosphoinositide phosphatase MTM1. Although the causes are known and corresponding gene therapy strategies are being developed, there is no mechanistic understanding of the disease-associated muscle function failure. Resolving this issue is of primary interest not only for a fundamental understanding of how MTM1 is critical for healthy muscle function, but also for establishing the related cellular mechanisms most primarily or stringently affected by the disease, which are thus of potential interest as therapy targets. The mathematical modelling approach used in the present work proves that the disease-associated alteration of the plasma membrane invagination network is sufficient to explain the dysfunctions of excitation-contraction coupling, providing the first integrated quantitative framework that explains the associated contraction failure.

Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders.

Bioengineering of viral vectors for therapeutic gene delivery is a pivotal strategy to reduce doses, facilitate manufacturing, and improve efficacy and patient safety. Here, we engineered myotropic adeno-associated viral (AAV) vectors via a semirational, combinatorial approach that merges AAV capsid and peptide library screens. We first identified shuffled AAVs with increased specificity in the murine skeletal muscle, diaphragm, and heart, concurrent with liver detargeting. Next, we boosted muscle specificity by displaying a myotropic peptide on the capsid surface. In a mouse model of X-linked myotubular myopathy, the best vectors-AAVMYO2 and AAVMYO3-prolonged survival, corrected growth, restored strength, and ameliorated muscle fiber size and centronucleation. In a mouse model of Duchenne muscular dystrophy, our lead capsid induced robust microdystrophin expression and improved muscle function. Our pipeline is compatible with complementary AAV genome bioengineering strategies, as demonstrated here with two promoters, and could benefit many clinical applications beyond muscle gene therapy.

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.

Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.

Biomarkers for characterization and therapeutic orientation in castration-resistant prostate cancer. / Biomarcadores para la caracterización y orientación terapéutica en Cáncer de Próstata Resistente a la Castración (CPRC).

Whole exome sequencing studies haverevealed the molecular landscape of metastatic CastrateResistant Prostate Cancer (mCRPC) providingnew information about prognostic and predictive factorsof response to therapies. These studies highlightedpotentially actionable targets leading to the beginingof the biomarker-driven era in prostate cancer.Alterations in androgen receptor (AR), DNA repair genes,PI3K-AKT-MTOR pathway or in genes involved incell cycle are frequently observed in mCRPC patientsand may be relevant in the resistance induced mechanismto approve therapy in this setting. Poly(ADP-ribose)polymerase (PARP) inhibitor in BRCA mutatedpatients, pembrolizumab (inmune checkpoint inhibitors)in mCRPC patients with mismatch repair genedefects and microsatellite instability and ipatasertib(AKT inhibitor) in patients with loss of function inPTEN are examples on how molecular information canbe useful to improve treatment selection. Nonethelessthe heterogeneity of advanced PC, the lack of consensusregarding the optimal biological source of analysisand the optimal time and technique for the analisysare still challenges that need to be defined in the nextfuture. The aim is to review the current literature concerningprognostic and predictive marker of responseto therapies in the mCRPC setting.

Estudios de secuenciación completa delexoma han revelado el perfil molecular del pacientecon Cáncer de Próstata Resistente a la Castración metastásico(CPRCm) proporcionando nueva informaciónsobre factores pronósticos y predictivos de respuestaa las distintas alternativas terapéuticas. Muchos deestos estudios han resaltado numerosas dianas molecularesaccionables desde un punto de vista farmacológico,conduciéndonos al comienzo de la medicina deprecisión en el Cáncer de Próstata (CP). Alteracionesen el Receptor de Andrógenos (RA), en genes reparadoresde DNA, en la vía de PI3K-AKT-MTOR o en genesimplicados en el ciclo celular son frecuentementeobservadas en CPRCm y pueden ser relevantes en la selección terapéutica y en la comprensión de los mecanismosde resistencia.Los inhibidores de la poli (ADP-ribosa) polimerasaen pacientes con mutaciones en BRCA, pembrolizumab(inhibidor de los puntos de control inmunológico)en pacientes CPRCm con alteraciones en genesimplicados en el "mismatch repair" o inestabilidad demicrosatélites e ipatasertib (inhibidor de AKT) en pacientescon pérdida de función de PTEN son ejemplosde cómo la información molecular puede ser útil paraoptimizar la selección terapéutica en este escenario.No obstante, la heterogeneidad del CP avanzado, lafalta de consenso sobre la fuente biológica óptima parael análisis, el momento y la técnica de análisis continúansiendo desafíos a definir en un fututo próximo.El objetivo es revisar la literatura actual sobre marcadorespronósticos y predictivos de respuesta a tratamientoen el entorno del CPRCm.

Biomarcadores para la caracterización y orientación terapéutica en cáncer de próstata resistente a la castración (cprc) / Biomarkers for characterization and therapeutic orientation in castration-resistant prostate cáncer

- Estudios de secuenciación completa delexoma han revelado el perfil molecular del pacientecon Cáncer de Próstata Resistente a la Castración metastásico (CPRCm) proporcionando nueva informaciónsobre factores pronósticos y predictivos de respuestaa las distintas alternativas terapéuticas. Muchos deestos estudios han resaltado numerosas dianas moleculares accionables desde un punto de vista farmacológico, conduciéndonos al comienzo de la medicina deprecisión en el Cáncer de Próstata (CP). Alteracionesen el Receptor de Andrógenos (RA), en genes reparadores de DNA, en la vía de PI3K-AKT-MTOR o en genes implicados en el ciclo celular son frecuentementeobservadas en CPRCm y pueden ser relevantes en la selección terapéutica y en la comprensión de los mecanismos de resistencia.Los inhibidores de la poli (ADP-ribosa) polimerasaen pacientes con mutaciones en BRCA, pembrolizumab (inhibidor de los puntos de control inmunológico) en pacientes CPRCm con alteraciones en genesimplicados en el “mismatch repair” o inestabilidad demicrosatélites e ipatasertib (inhibidor de AKT) en pacientes con pérdida de función de PTEN son ejemplosde cómo la información molecular puede ser útil paraoptimizar la selección terapéutica en este escenario.No obstante, la heterogeneidad del CP avanzado, lafalta de consenso sobre la fuente biológica óptima parael análisis, el momento y la técnica de análisis continúan siendo desafíos a definir en un fututo próximo.El objetivo es revisar la literatura actual sobre marcadores pronósticos y predictivos de respuesta a tratamiento en el entorno del CPRCm. (AU)

Whole exome sequencing studies haverevealed the molecular landscape of metastatic Castrate Resistant Prostate Cancer (mCRPC) providingnew information about prognostic and predictive factors of response to therapies. These studies highlighted potentially actionable targets leading to the begining of the biomarker-driven era in prostate cancer.Alterations in androgen receptor (AR), DNA repair genes, PI3K-AKT-MTOR pathway or in genes involved incell cycle are frequently observed in mCRPC patientsand may be relevant in the resistance induced mechanism to approve therapy in this setting. Poly(ADP-ribose) polymerase (PARP) inhibitor in BRCA mutatedpatients, pembrolizumab (inmune checkpoint inhibitors) in mCRPC patients with mismatch repair genedefects and microsatellite instability and ipatasertib (AKT inhibitor) in patients with loss of function inPTEN are examples on how molecular information canbe useful to improve treatment selection. Nonethelessthe heterogeneity of advanced PC, the lack of consensus regarding the optimal biological source of analysisand the optimal time and technique for the analisysare still challenges that need to be defined in the nextfuture. The aim is to review the current literature concerning prognostic and predictive marker of responseto therapies in the mCRPC setting. (AU)

Prevalence of High-Risk Prostate Cancer Metastasis to Cloquet's Ilioinguinal Lymph Node.

PURPOSE: Cloquet's node, located at the junction between the deep inguinal nodes and the external iliac chain, is easily accessible and commonly excised during pelvic lymph node dissection for prostate cancer. However, we hypothesize that Cloquet's node is not part of lymphatic metastatic spread of prostate cancer. MATERIALS AND METHODS: Between September 2016 and June 2019, 105 consecutive patients with high-risk prostate cancer (cT3a or Grade Group 4/5, or prostate specific antigen >20 ng/ml) underwent a laparoscopic radical prostatectomy and pelvic lymph node dissection. First, Cloquet's node was identified, retrieved and submitted separately to pathology as right and left Cloquet's node. Next, a pelvic lymph node dissection was completed including the external iliac, obturator fossa and hypogastric nodal packets. Each lymph node was cut into 3 mm slices which were separately embedded in paraffin, stained with hematoxylin and eosin, and examined microscopically. RESULTS: The final analysis included 95 patients. In this high-risk population, the median number of nodes removed was 22 (IQR 18-29); 39/95 patients (41%) had lymph node metastasis. The median number of Cloquet's nodes removed was 2 (IQR 2-3). Cloquet's node was negative in all but 1 patient (1.1%), who had very high-risk features and high metastatic burden in the lymph nodes. CONCLUSIONS: In high-risk prostate cancer, metastasis to the ilioinguinal node of Cloquet is rare. Given this low prevalence, Cloquet's node can be safely excluded from the pelvic lymph node dissection template.

A Multicenter Study of 2-year Outcomes Following Hyperthermia Therapy with Mitomycin C in Treating Non-Muscle Invasive Bladder Cancer: HIVEC-E.

INTRODUCTION: High grade, non-muscle invasive bladder cancer (NMIBC) is usually treated with intravesical Bacillus Calmette-Guérin. Chemohyperthermia therapy (CHT) may be a novel alternative therapy for the treatment of NMIBC. OBJECTIVE: To evaluate the recurrence-free survival (RFS) of patients treated with CHT using the Combat bladder recirculation system (BRS) for NMIBC. METHODS: This was a prospective multi-institutional study of 1,028 consecutive patients with NMIBC undergoing CHT between 2012 and 2020. A total of 835 patients were treated with CHT with Mitomycin C (MMC). Disease was confirmed on transurethral resection of bladder tumor (TURBT) prior to starting CHT. Follow-up included cystoscopy and subsequent TURBT if recurrence/progression was suspected. The primary endpoint was RFS. Secondary endpoints were progression-free survival (PFS) and adverse events from CHT. RESULTS AND LIMITATIONS: Median follow up was 22.4 months (Interquartile range (IQR): 12.8 -35.8). Median age was 70.4 years (IQR: 62.1 -78.6). A total of 557 (66.7%), 172 (20.6) and 74 (8.9%) of patients were classified to BCG naïve, BCG unresponsive and BCG failure, respectively. The RFS at 12 months and 24 months for BCG naïve was 87.6% (95% CI 85.0% - 90.4%) and 75.0% (95% CI 71.3% - 78.8%), respectively. The RFS at 12 months and 24 months for BCG unresponsive cohort was 78.1% (95% CI 72.0% - 84.7%) and 57.4% (95% CI 49.7% - 66.3%), respectively. The RFS at 24 months for the BCG unresponsive cohort for CIS with/without papillary disease and papillary only disease were 43.6% (95% CI 31.4% -60.4%) and 64.5% (95% CI 55.4% - 75.1%), respectively. Minor adverse events occurred in 216 (25.6%) patients and severe events occurred in 17 (2.0%) patients. CONCLUSIONS: CHT with MMC using the Combat BRS is effective in the medium term and has a favorable adverse event profile.

Changes in resting-state measures of prostate cancer patients exposed to androgen deprivation therapy.

The aim of the present work is to describe the differences in rs-fMRI measures (Amplitude of low frequency fluctuations [ALFF], Regional Homogeneity [ReHo] and Functional Connectivity [FC]) between patients exposed to Androgen deprivation therapy (ADT) and a control group. Forty-nine ADT patients and fifteen PC-non-ADT patients (Controls) were included in the study. A neuropsychological evaluation and a resting-state fMRI was performed to evaluate differences in ALFF and ReHo. Region of interest (ROI) analysis was also performed. ROIs were selected among those whose androgen receptor expression (at RNA-level) was the highest. FC analysis was performed using the same ROIs. Higher ALFF in frontal regions and temporal regions was identified in Controls than in ADT patients. In the ROI analysis, higher activity for Controls than ADT patients was shown in the left inferior frontal gyrus and in the left precentral gyrus. Lower ALFF in the right hippocampus and the lateral geniculate nucleus of the right thalamus was identified for Controls than ADT patients. Higher ReHo was observed in Controls in the left parietal-occipital area. Finally, ADT patients presented an increase of FC in more regions than Controls. These differences may reflect an impairment in brain functioning in ADT users.

Characterization of Neuromuscular Junctions in Mice by Combined Confocal and Super-Resolution Microscopy.

Neuromuscular junctions (NMJs) are highly specialized synapses between lower motor neurons and skeletal muscle fibers that play an essential role in the transmission of molecules from the nervous system to voluntary muscles, leading to contraction. They are affected in many human diseases, including inherited neuromuscular disorders such as Duchenne muscular dystrophy (DMD), congenital myasthenic syndromes (CMS), spinal muscular atrophy (SMA), and amyotrophic lateral sclerosis (ALS). Therefore, monitoring the morphology of neuromuscular junctions and their alterations in disease mouse models represents a valuable tool for pathological studies and preclinical assessment of therapeutic approaches. Here, methods for labeling and analyzing the three-dimensional (3D) morphology of the pre- and postsynaptic parts of motor endplates from murine teased muscle fibers are described. The procedures to prepare samples and measure NMJ volume, area, tortuosity and axon terminal morphology/occupancy by confocal imaging, and the distance between postsynaptic junctional folds and acetylcholine receptor (AChR) stripe width by super-resolution stimulated emission depletion (STED) microscopy are detailed. Alterations in these NMJ parameters are illustrated in mutant mice affected by SMA and CMS.

Recent Progress in Genome Editing for Gene Therapy Applications: The French Perspective.

Recent advances in genome editing tools, especially novel developments in the clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases (CRISPR/Cas9)-derived editing machinery, have revolutionized not only basic science but, importantly, also the gene therapy field. Their flexibility and ability to introduce precise modifications in the genome to disrupt or correct genes or insert expression cassettes in safe harbors in the genome underline their potential applications as a medicine of the future to cure many genetic diseases. In this review, we give an overview of the recent progress made by French researchers in the field of therapeutic genome editing, while putting their work in the general context of advances made in the field. We focus on recent hematopoietic stem cell gene editing strategies for blood diseases affecting the red blood cells or blood coagulation as well as lysosomal storage diseases. We report on a genome editing-based therapy for muscular dystrophy and the potency of T cell gene editing to increase anticancer activity of chimeric antigen receptor T cells to combat cancer. We will also discuss technical obstacles and side effects such as unwanted editing activity that need to be surmounted on the way toward a clinical implementation of genome editing. We propose here improvements developed today, including by French researchers to overcome the editing-related genotoxicity and improve editing precision by the use of novel recombinant nuclease-based systems such as nickases, base editors, and prime editors. Finally, a solution is proposed to resolve the cellular toxicity induced by the systems employed for gene editing machinery delivery.

Pathological findings in very low risk prostate cancer in surgical specimens. / Hallazgos patológicos en el cáncer de próstata de muy bajo riesgo en piezas de prostatectomía radical.

OBJECTIVE: Perform a detailed anatomopathological analysis of consecutive surgical specimens in men with clinically very low risk prostate cancer according to National Comprehensive Cancer Network (NCCN) criteria.MATERIALS AND METHODS: The study included 799 prostate cancer patients who under went radical prostatectomy between January 2005 and December 2013. We identified 81 consecutive patients with clinically very low risk prostate cancer. The slides of the patients who fulfilled the inclusion criteria were re-reviewed. The parameters studied were: pathological stage, histological grade by Gleason score (GSS), margins involvement, tumor percentage (PT), and number of apparently independent tumor foci (FT). RESULTS: The patients had organ-confined tumors in almost all of them (pT2: 97.5%). Most of the cancers studied were bilateral (pT2c: 67.9%), multifocal (FT≥2:88.8%), with a low tumor percentage (PTand with a low Gleason Score (GSS≤6: 91,3%). Non-confined disease: 2.5%, all cases extra-prostatic extension (pT3a). GSS>6: 8,6%, all cases GSS7 (3+4). CONCLUSIONS: The NCCN criteria for very low risk prostate cancer help to make a good selection of non-aggressive tumors and are a useful tool for including patients in an active surveillance program.

OBJETIVO: Realizar un análisis patológic odetallado de las piezas de prostatectomía radical en pacientes diagnosticados con cáncer de próstata de muy bajo riesgo según los criterios de la NCCN. MATERIAL Y MÉTODOS: El estudio incluye 799 pacientes con cáncer de próstata a los que se realizó una prostatectomía radical entre 2005 y 2013. 81 pacientes con cáncer de próstata clínicamente de muy bajo riesgo fueron identificados. Las laminillas de los pacientes identificados fueron revisadas. Los parámetros estudiados fueron: estadio patológico, grado de Gleason, márgenes quirúrgicos, % de tumor, y el numero de focos tumorales aparentemente independientes. RESULTADOS: La gran mayoría de pacientes presentaron tumores órgano-confinados (pT2: 97,5%). El 68% de los canceres fue bilateral (pT2c), multifocal (mas de2 focos 88%), con un porcentaje tumoral de menos del 10% en el 80% de los casos y mas del 90% con Gleason 6. La enfermedad no órgano-confinada se evidencio en 2,5% pT3a. CONCLUSIONES: Los criterios de NCCN para muy bajo riesgo nos ayudan a clasificar pacientes con tumores poco agresivos y son una buena herramienta para seleccionar pacientes para programas de vigilancia activa.