Risk factors for residual disease at re-TUR in a large cohort of T1G3 patients.

INTRODUCTION AND OBJECTIVES: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging. Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival. We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR. MATERIAL AND METHODS: In our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS. In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. RESULTS: The following were not risk factors for residual disease: age, gender, tumor status and previous intravesical chemotherapy. The following were univariate risk factors for presence of residual disease: no muscle in TUR, multiple tumors, tumors > 3 cm, and presence of concomitant CIS. Due to the correlation between tumor multi-focality and tumor size, the multivariate model retained either the number of tumors or the tumor diameter (but not both), p < 0.001. The presence of muscle in the specimen was no longer significant, while the presence of CIS only remained significant in the model with tumor size, p < 0.001. CONCLUSIONS: The most significant factors for a higher risk of residual disease at re-TUR in T1G3 patients are multifocal tumors and tumors more than 3 cm. Patients with concomitant CIS and those without muscle in the specimen also have a higher risk of residual disease.

Looking at ancillary systems for verb recovery: Evidence from non-invasive brain stimulation.

Several behavioural and neuroimaging studies have suggested that the language function is not restricted into the left areas but it involves regions not predicted by the classical language model. Accordingly, the Embodied Cognition theory postulates a close interaction between the language and the motor system. Indeed, it has been shown that non-invasive brain stimulation (NIBS) is effective for language recovery also when applied over sensorimotor regions, such as the motor cortex, the cerebellum and the spinal cord. We will review a series of NIBS studies in post-stroke aphasic people aimed to assess the impact of NIBS on verb recovery. We first present results which, following the classical assumption of the Broca's area as the key region for verb processing, have shown that the modulation over this area is efficacious for verb improvement. Then, we will present experiments which, according to Embodied Cognition, have directly investigated through NIBS the role of different sensorimotor regions in enhancing verb production. Since verbs play a crucial role for sentence construction which are most often impaired in the aphasic population, we believe that these results have important clinical implications. Indeed, they address the possibility that different structures might support verb processing.

The 1973 WHO and 2004 WHO grading systems are not equal in prediction of survival among stage T1 bladder cancer patients. / Los sistemas de clasificación de la OMS de 1973 y 2004 difieren en la predicción de supervivencia entre los pacientes con cáncer de vejiga en estadio T1.

INTRODUCTION AND OBJECTIVES: The aim of this study was to analyse prognostic impact of tumour histological grade on survival differences between primary G2 and G3 WHO1973 stage T1 tumours which were graded as HG according to WHO2004 grading system. MATERIALS AND METHODS: Data from 481 patients with primary T1HG bladder cancer who were treated between 1986 and 2016 in 2university centres were retrospectively reviewed. Log-rank test and Cox regression analysis was performed to compare the groups. RESULTS: 95 (19,8%) tumours were classified as G2 and 386 (80,2%) were G3. Median follow-up was 68 months. The recurrence was observed in 228 (47,5%), and progression in 109 patients (22,7%). Radical cystectomy was performed in 114 pts (23,7%) and there were 64 (13,3%) cancer specific deaths. Recurrence-free rates at 5-years follow-up for G2, G3 and all patients were 68,7%, 51,2% and 56,3% and progression-free rates were 89,3%, 73,2% and 78,1% respectively. For total observation period patients with G3 tumours presented also worse recurrence-free, and progression-free survival levels than patients with G2 tumours. In multivariate analysis, after adjustment for clinical features, the risk of recurrence and progression for G3 tumours was 1,65 and 2,42 fold higher than for G2 tumours. CONCLUSIONS: It was shown that G3 T1 tumours are characterized by worse recurrence free and progression free survivals when compared to G2 cancers.

Soft and flexible piezoelectric smart patch for vascular graft monitoring based on Aluminum Nitride thin film.

Vascular grafts are artificial conduits properly designed to substitute a diseased blood vessel. However prosthetic fail can occur without premonitory symptoms. Continuous monitoring of the system can provide useful information not only to extend the graft's life but also to optimize the patient's therapy. In this respect, various techniques have been used, but all of them affect the mechanical properties of the artificial vessel. To overcome these drawbacks, an ultrathin and flexible smart patch based on piezoelectric Aluminum Nitride (AlN) integrated on the extraluminal surface of the prosthesis is presented. The sensor can be conformally wrapped around the external surface of the prosthesis. Its design, mechanical properties and dimensions are properly characterized and optimized in order to maximize performances and to avoid any interference with the graft structure during its activity. The sensorized graft is tested in vitro using a pulsatile recirculating flow system that mimics the physiological and pathological blood flow conditions. In this way, the ability of the device to measure real-time variations of the hemodynamics parameters has been tested. The obtained high sensitivity of 0.012 V Pa-1 m-2, joint to the inherent biocompatibility and non-toxicity of the used materials, demonstrates that the device can successfully monitor the prosthesis functioning under different conditions, opening new perspectives for real-time vascular graft surveillance.

Validation of the CUETO scoring model for predicting recurrence and progression in T1G3 urothelial carcinoma of the bladder. / Validación de las tablas del grupo CUETO para predecir la recurrencia y progresión del carcinoma urotelial de vejiga T1G3.

INTRODUCTION AND OBJECTIVES: Various studies tried to validate Club Urológico Español de Tratamiento Oncológico (CUETO) tables, yet, none of this papers focused on the high and very high risk bladder cancers. The aim of the study was to externally validate the CUETO model for predicting disease recurrence and progression in group of T1G3 tumors treated with BCG immunotherapy. PATIENTS OR MATERIALS AND METHODS: Data from 414 patients with primary T1G3 bladder cancer were analysed. To evaluate the model discrimination, Cox proportional hazard regression models were created and concordance indexes were calculated. RESULTS: The median follow-up was 68 months. The recurrence was observed in 212 (51.2%) and 64 patients (15.5%) experienced the recurrence more than once during the study follow-up. Progression of the cancer was observed in 106 patients (25.6%). Radical cystectomy was performed in 115 patients (27.8%) and there were 64 (15.5%) cancer specific deaths. For recurrence and progression probability, the concordance index of the CUETO models was 0.633 and 0.697 respectively. CUETO tables underestimated significantly the risk of recurrence and marginally the risk of progression in the first year of observation. For 5 years of observation, the trend for the recurrence was much less clear. On the contrary, there was slight overestimation in the risk of progression. The study is limited by retrospective nature. CONCLUSIONS: It was shown that the CUETO risk tables exhibit a fair discrimination for both disease recurrence and progression in T1G3 patients treated with BCG. CUETO scoring model underestimates the risk of tumor recurrence, but predicts well risk of progression.

Salvage lymphadenectomy in recurrent prostate cancer: is there evidence of real benefit?

PURPOSE: Nodal recurrent prostate cancer (PCa) after primary radical treatment represents a heterogeneous entity with many treatment options. In some cases, surgical removal of metastatic nodes seems to improve cancer control and delay systemic treatments. The objectives of this study were to analyze the available literature on salvage lymphadenectomy for the treatment of nodal recurrent PCa and to elucidate the real oncological benefit deriving from this procedure. METHODS: A PubMed search was performed using the following terms: prostate cancer, metastatic, oligometastatic, salvage lymphadenectomy, salvage lymph node dissection, salvage lymph node excision, and cytoreductive surgery. We included in the study all papers on salvage lymphadenectomy in nodal recurrent PCa, with no temporal limits. In addition, several papers addressing cytoreductive surgery and the biology of oligometastatic disease, published in different medical and basic research journals, were included. RESULTS: Salvage lymphadenectomy is still characterized by a lack of standardization in patient selection and surgical template. Its primary objectives are to prolong progression-free survival and to delay the need for systemic therapy. The improvements in preoperative imaging techniques in conjunction with the wide use of minimally invasive surgery have generated growing interest in this procedure. CONCLUSION: Salvage lymphadenectomy is a promising treatment approach; however, its real oncological benefit is still far from proven. Prospective randomized trials need to be designed to improve understanding of this issue.

Recurrence, progression and cancer-specific mortality according to stage at re-TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought.

PURPOSE: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re-TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG. METHODS: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model. RESULTS: During a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen. CONCLUSIONS: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease.

Multicentre registry of brain-injured patients with disorder of consciousness: rationale and preliminary data.

Diagnostic accuracy and reliable estimation of clinical evolution are challenging issues in the management of patients with disorders of consciousness (DoC). Longitudinal systematic investigations conducted in large cohorts of patients with DoC could make it possible to identify reliable diagnostic and prognostic markers. On the basis of this consideration, we devised a multicentre prospective registry for patients with DoC admitted to ten intensive rehabilitation units. The registry collects homogeneous and detailed data on patients' demographic and clinical features, neurophysiological and neuroimaging findings, and medical and surgical complications. Here we present the rationale and the design of the registry and the preliminary results obtained in 53 patients with DoC (vegetative state or minimally conscious state) enrolled during the first seven months of the study. Data at 6-month post-injury follow-up were available for 46 of them. This registry could be an important tool for collecting high-quality data through the application of rigorous methods, and it could be used in the routine management of patients with DoC admitted to rehabilitation settings.

Towards a new image processing system at Wendelstein 7-X: From spatial calibration to characterization of thermal events.

Wendelstein 7-X (W7-X) is the most advanced fusion experiment in the stellarator line and is aimed at proving that the stellarator concept is suitable for a fusion reactor. One of the most important issues for fusion reactors is the monitoring of plasma facing components when exposed to very high heat loads, through the use of visible and infrared (IR) cameras. In this paper, a new image processing system for the analysis of the strike lines on the inboard limiters from the first W7-X experimental campaign is presented. This system builds a model of the IR cameras through the use of spatial calibration techniques, helping to characterize the strike lines by using the information given by real spatial coordinates of each pixel. The characterization of the strike lines is made in terms of position, size, and shape, after projecting the camera image in a 2D grid which tries to preserve the curvilinear surface distances between points. The description of the strike-line shape is made by means of the Fourier Descriptors.

Conventional testicular sperm extraction (TESE) and non-obstructive azoospermia: is there still a chance in the era of microdissection TESE? Results from a single non-academic community hospital.

Spermatozoa can be retrieved in non-obstructive azoospermia (NOA) patients despite the absence of ejaculated spermatozoa in their semen because of the presence of isolated foci with active spermatogenesis. Conventional testicular sperm extraction (c-TESE) in patients with NOA has been partially replaced by micro-TESE. It is still under debate the problem regarding the higher costs related to micro-TESE when compared with c-TESE. In this study, we evaluated sperm retrieval rate (SRR) of c-TESE in naive NOA patients. Sixty-three NOA patients were referred to our centre for a c-TESE. For every subject, we collected demographic data, cause of infertility, time to first infertility diagnosis, serum levels of LH, FSH, total testosterone and prolactin. A statistical analysis was conducted to correlate all the clinical variables, the histology and the Johnsen score with the SRR. Sixty-three consecutive NOA patients with a mean age of 37.3 years were included. The positive SRR was 47.6%. No statistical differences were observed between positive vs. negative SRR regarding mean FSH (17.12 vs. 19.03 mUI/mL; p = 0.72), and LH (9.72 vs. 6.92 mUI/mL; p = 0.39) values. Interestingly, we found a statistically significant difference in terms of time to first infertility diagnosis (+SRR vs. -SRR; 44.5 vs. 57 months; p = 0.02) and regarding to age (+SSR vs. -SRR; 40.1 vs. 35.3; p = 0.04). There was a statistically significant decrease in SRRs with the decline in testicular histopathology from hypospermatogenesis to maturation arrest, and SCO. The mean Johnsen score was 5.9 with a mean percentage of Johnsen score ≥8 tubules equal to 19%. The overall pregnancy rate was 26.6%. In our prospective cohort of patients successful SRR with c-TESE was 47.6%. Lower costs and high reproducibility of this technique still support this procedure as an actual reliable option in NOA patients for sperm retrieval.

A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation.

Bruton's tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumour tissue samples. p65BTK protein is expressed, through heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site-driven translation, from a transcript containing an alternative first exon in the 5'-untranslated region, and is post-transcriptionally regulated, via hnRNPK, by the mitogen-activated protein kinase (MAPK) pathway. p65BTK is endowed with strong transforming activity that depends on active signal-regulated protein kinases-1/2 (ERK1/2) and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.

Improving proprioceptive deficits after stroke through robot-assisted training of the upper limb: a pilot case report study.

The purpose of this study was to determine whether a conventional robot-assisted therapy of the upper limb was able to improve proprioception and motor recovery of an individual after stroke who exhibited proprioceptive deficits. After robotic sensorimotor training, significant changes were observed in kinematic performance variables. Two quantitative parameters evaluating position sense improved after training. Range of motion during shoulder and wrist flexion improved, but only wrist flexion remained improved at 3-month follow-up. These preliminary results suggest that intensive robot-aided rehabilitation may play an important role in the recovery of sensory function. However, further studies are required to confirm these data.

The importance of psychosexual counselling in the re-establishment of organic and erotic functions after penile prosthesis implantation.

Although many studies about penile prosthesis implantation (PPI) have been published so far, only a small amount of them take into account patients and partners outcome in terms of satisfaction and erotic function. The aim of this study is to explore the value of psycosexual counselling in and the sexual and erotic function of penile prosthesis recipients. Thirty patients and their partners were randomised into two groups. In arm A (case group) patients and their partners underwent a multistep psychosexual counselling before and after surgery. In arm B (control group) surgery was performed without the specific psychosexual counselling scheme. Specific questionnaires (International Index of Erectile Function (IIEF) and the Sexual Daydreaming Scale (SDS)) were administered before surgery and 12 months afterwards. Twenty-four months postoperatively patients were asked to complete the Global Assessment Questions (GAQ) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), while their partners were asked to answer to the EDITS partner's section. Between January 2009 and October 2011, we enrolled 30 patients undergoing PPI in our institution (15 in each arm). Twenty-four months postoperative follow-up is available for all of them. No significant differences between the two groups in terms of baseline questionnaires scores were observed. Mean IIEF score was significantly higher in case group (arm A 68.3, arm B 53.4, P-value<0.001). At 12 months after PPI the improvement of erotic function according to SDS was significantly higher in the study group for both patients and their partners. Improvement in satisfaction rates were confirmed at 24 months, with statistically significant scores for EDITS in arm A patients and partners as compared with arm B. PPI with a pre- and postoperative psychosexual counselling scheme resulted in better postoperative sexual activity and erotic function for both patients and partners than PPI alone.

Evaluation of upper limb sense of position in healthy individuals and patients after stroke.

The aims of this study were to develop and evaluate reliability of a quantitative assessment tool for upper limb sense of position on the horizontal plane. We evaluated 15 healthy individuals (controls) and 9 stroke patients. A robotic device passively moved one arm of the blindfolded participant who had to actively move his/her opposite hand to the mirror location in the workspace. Upper-limb's position was evaluated by a digital camera. The position of the passive hand was compared with the active hand's 'mirror' position. Performance metrics were then computed to measure the mean absolute errors, error variability, spatial contraction/expansion, and systematic shifts. No significant differences were observed between dominant and non-dominant active arms of controls. All performance parameters of the post-stroke group differed significantly from those of controls. This tool can provide a quantitative measure of upper limb sense of position, therefore allowing detection of changes due to rehabilitation.

Robot-aided neurorehabilitation in sub-acute and chronic stroke: does spontaneous recovery have a limited impact on outcome?

BACKGROUND: Robotic neurorehabilitation, thanks to high dosage/intensity training protocols, has the potential for a greater impact on impairment. OBJECTIVE: We aimed to analyze how time since the acute event may influence the motor recovery process during robot-assisted rehabilitation of the upper limb. METHODS: A total of 41 patients after stroke were enrolled: 20 in subacute phase, i.e. ≤ 6 months elapsed since their unilateral cerebrovascular accident (CVA), and 21 at chronic stage, i.e. > 6 months since CVA. All subjects underwent 30 minutes of robot-aided rehabilitation twice a day, 5 days a week for at least three weeks of training. Patients were evaluated at the start and end of treatment using the Fugl-Meyer and Modified Ashworth clinical scales and by a set of robot measured kinematic parameters. The time interval from stroke was considered as a grouping factor to analyze its impact on time course of recovery. RESULTS: After training both groups significantly improved their impairment (F = 44.25, p < 0.001) but sub-acute patients showed a greater improvement on the Fugl-Meyer scale than chronic patients. The time course of recovery of the kinematic variables showed higher time constants of motor improvement in the sub-acute than chronic group, but they were one order lower than spontaneous recovery time constants. CONCLUSIONS: Spontaneous recovery seems to have a limited impact on the improvement of sub-acute patients, most of their changes being likely due to re-learning during rehabilitation. In addition, a longer recovery time was required to maximize outcome in sub-acute than in chronic patients.

Modeling upper limb clinical scales by robot-measured performance parameters.

The status of motor function in stroke survivors and the effect of any therapeutic intervention are generally measured by physiotherapists using clinical assessment scales that probe specific aspects of a subject's motor behavior. Although they are widely accepted, these measurement tools are limited by interrater and intrarater reliability and are time-consuming to apply. This paper analyzes the changes in movement kinematics and kinetics during robot-aided neurorehabilitation of subjects after stroke and verifies the possibility of estimating outcome measures by means of a set of robot measured parameters.

Development of a progressive task regulation algorithm for robot-aided rehabilitation.

Patient motivation is an important factor in rehabilitation. The difficulty level of the motor task, the awareness of the performance obtained, and the quantity and quality of feedbacks presented to the patient can influence patient motivation and produce different ways of acting and different performances. This study presents a Progressive Task Regulation algorithm able to evaluate the patient's performance during training and automatically change the features of the reaching movement, so as to adapt automatically the difficulty level of the motor task to the patient's ability. Use of the progressive task regulation algorithm should promote patient motivation throughout the course of treatment.

Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.

BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.