Dermatomyositis in a young patient: A rare paraneoplastic syndrome of renal cell carcinoma.

Introduction: Paraneoplastic syndromes are frequent in patients with renal cell carcinoma. Dermatomyositis is an idiopathic inflammatory myopathy that may be associated with neoplasms. This case aims to describe the rare association of dermatomyositis with renal cell carcinoma and to increase clinical suspicion of this neoplasm when systemic rheumatologic symptoms are present. Case presentation: A 35-year-old female developed severe rheumatologic symptoms (progressive muscle weakness, heliotrope rash, and Gottron's papules). Clinical and laboratory findings indicated dermatomyositis. During the investigation, computed tomography revealed a left kidney solid mass. She underwent a left radical nephrectomy, and histology confirmed renal cell carcinoma. After 3 months, dermatomyositis manifestations disappeared and the patient withdrawn steroid therapy. Conclusion: Most paraneoplastic syndromes associated with renal cell carcinoma are only cured with nephrectomy. We highlight the potential role of surgery in dermatomyositis caused by renal cell carcinoma. The recurrence of symptoms related to the syndrome should alert for disease progression.

20-year follow-up of rheumatic mitral stenosis patients after percutaneous mitral commissurotomy: invasive transmitral gradient differential as a predictor of events.

Percutaneous mitral valve commissurotomy (PMC) is a viable alternative to mitral valve (MV) surgery in the treatment of patients with rheumatic mitral stenosis (RMS). In this single-center retrospective study of consecutive patients with RMS submitted to PMC from 1991 to 2008, we analyzed clinical, echocardiographic, and hemodynamic data and events during follow-up (FUP) until December 2021. Major adverse cardiovascular events (MACE) were a combined endpoint of all-cause death, cardiovascular hospitalization, and MV re-intervention. A total of 124 patients were enrolled: 108 (87.1%) were female, with a mean age at PMC of 46 [standard deviation (SD) 11] years. PMC was successful in 91.1%, with a mean reduction in invasive transmitral pressure gradient (TMPG) of 8 (SD 7) mmHg at PMC time. During the mean FUP of 20 (SD 6) years, 51 (41.1%) patients had MV re-intervention (86.3% surgery and 13.7% redo-PMC), 37 (29.8%) were hospitalized, and 30 (24.2%) died. Approximately 75% of patients remained MACE-free after 10 years, and this percentage decreased to around 40% after 20 years; at this time mark, about 8 in 10 patients were alive. A reduction of <5 mmHg in TMPG at PMC time was associated with a 2.7-fold greater rate of MACE compared to a reduction of ≥5 mmHg, independent of MV regurgitation after PMC and moderate disease of other valves (adjusted hazard ratio 2,7; 95% confidence interval 1.395-5.298, p=0.003). In this cohort with favorable long-term results after PMC, a reduction of <5 mmHg in TMPG at PMC time was associated with MACE during FUP. More studies are needed to validate this independent predictor.

Cultural Translation and Validation of the Bariatric Quality of Life Index to European Portuguese.

INTRODUCTION: Obesity is a chronic noncommunicable disease, defined by a body mass index over 30 kg/m2. Its impact is not restricted to its association with higher risks of mortality and morbidity from other noncommunicable diseases, but also with a decrease in quality of life (QoL). There are several tools to assess QoL, from generic health-related tools to obesity-related specific ones. However, to assess QoL in patients undergoing bariatric surgery, only the Bariatric Analysis and Reporting Outcome System was available, which presented some significant problems. Therefore, the Bariatric Quality of Life (BQL) Index was developed. The aim of this study was the validation and cultural adaptation of the BQL Index for European Portuguese. METHODS: A cross-sectional study was conducted, with the presentation of two questionnaires to the participants: BQL Index and EQ-5D-3L (European Quality of Life 5 Dimensions and 3 Level) Index. Direct translation followed reviewing, back-translation, comparison, and pilot testing were performed. Retest was done six months after the baseline. The following psychometric properties were assessed: convergent validity using the Spearman r correlation coefficient between BQL Index and EQ-5D-3L Index; internal consistency based on Cronbach alpha coefficient; and reproducibility between test and retest through Spearman r correlation coefficient and intraclass correlation coefficient (ICC). RESULTS: A total of 260 participants were included, the mean age was 45 ± 10 years old, the mean body mass index was 44 ± 6.5 kg/m2 and 78% were females. The most frequent obesity-related comorbidities were osteoarticular disease (69%), anxiety/depression (60%), and hypertension (54%). The most common eating patterns were volume eater (67%) and sweet eater (62%). Quality of Life scores were 41.3 ± 9.3 for the BQL Index, 0.35 ± 0.19 for the EQ-5D-3L Index and 55.7 ± 19.8 for the EQ-5D-3L VAS. The translation yielded good convergent validity (r = 0.62), good internal consistency (alpha = 0.94), and good reproducibility (r = 0.62 and ICC = 0.79). CONCLUSION: Our translation exhibited good parametric properties, with validity within the original BQL values, higher internal consistency, and good reproducibility.

Comparative analysis of antioxidant and fatty acid composition in avocado (Persea americana Mill.) fruits: Exploring regional and commercial varieties.

On Madeira Island, Portugal, the avocado crop benefits from a Mediterranean climate, exhibiting exceptional phytochemical and biochemical properties. Aiming to evaluate the antioxidant quality and fatty acid composition with a commercial avocado, flours were obtained from five varieties (four regional and one commercial Hass) across different tissues (pulp and by-products) and cycles (years and on-tree maturation stages). Results showed that a regional variety with thin purple skin had the highest antioxidant qualities and lipid content, surpassing the other regional and commercial Hass varieties. Oleic acid prevailed in all samples, with regional avocados containing arachidonic acid which is an uncommon occurrence among higher plants. Variations in fatty acid content were influenced by the timing of harvest. These outcomes highlight the promising potential of avocados from Madeira Island.

Development of a perioperative thermal insulation system: Testing comfort properties for different textile sets.

The poorly physical and psychological conditions of the patients make the body thermal protection crucial in the perioperative context, due to the risk of hypothermia. The lack of evidence regarding the effectiveness of textile coverings in protecting patients in the operating room, underscores the recommendation of the forced warming system using non-woven fabric for ensuring the best thermal protection in the perioperative context. This study is part of a development process of a three-layered thermal insulation system, a blanket for use in the perioperative context. After previous selection of two fabrics for the mid and outer layers, in this study three fabric samples for the inner layer with same soft tactile sensation and different textile compositions were tested to find its effect on increasing the thermal insulation of the whole set, using a thermal manikin. The serial method was used to calculate the thermal insulation properties of the sets. The best thermal insulation and thermal comfort performance was obtained by the set using an inner layer composed of polypropylene, polyamide, and elastane whose results were the highest thermal conductivity and thickness and the lowest maximum stationary heat flow density. The results indicated that this fabric influenced positively the values of the whole set once increased its thermal protection effectiveness when compared to the other tested sets. This set is more suitable for future testing in patients during their stay in the perioperative setting.

Is dyslipidemia a risk factor for trastuzumab-induced cardiotoxicity in breast cancer patients? A systematic review and meta-analysis.

INTRODUCTION: Breast cancer patients undergoing trastuzumab therapy have greater risk of cardiovascular disease. Risk factors for this effect have been proposed. However, the role of dyslipidemia is not completely understood. This systematic review aimed to explore the role of dyslipidemia in trastuzumab-induced cardiotoxicity. METHODS: The investigators searched MEDLINE, Scopus, and Web of Science up to October 25, 2020. A random-effects model was used to determine pooled estimates of the results. The primary endpoint was trastuzumab-induced cardiotoxicity in patients with and without dyslipidemia. RESULTS: A total of 39 studies were selected for inclusion in our systematic review assessing 21079 patients. One study demonstrated a statistically significant association between dyslipidemia and cardiotoxicity (OR=2.28, 95% CI 1.22-4.26, p=0.01). In all other studies, no such association was observed. Twenty-one studies including 6135 patients were eligible for meta-analysis. In this meta-analysis of unadjusted data, dyslipidemia was significantly associated with cardiotoxicity (OR=1.25, 95% CI 1.01-1.53, p=0.04, I2=0%), however, a subgroup analysis of studies reporting adjusted measures did not demonstrate a significant association (OR=0.89, 95% CI 0.73-1.10, p=0.28, I2=0%). CONCLUSION: This systematic review and meta-analysis did not demonstrate a significant association between dyslipidemia alone and the development of cardiotoxicity. In the absence of other relevant cardiovascular risk factors, review of lipid profile may not be obligatory, and management of patients could be performed without referral for cardio-oncology assessment. Further investigation of risk factors for trastuzumab-induced cardiotoxicity is required to confirm these results.

The world upside down - after 20 years of follow-up of dextro-transposition of the great arteries.

Dextro-transposition of the great arteries (D-TGA) is a congenital heart disease (CHD) classically palliated with atrial switch (ATR-S) and nowadays corrected with arterial switch (ART-S). Our aim was to observe a group of D-TGA patients followed in an adult CHD outpatient clinic. We analyzed a group of D-TGA patients born between 1974 and 2001. Adverse events were defined as a composite of death, stroke, myocardial infarction or coronary revascularization, arrhythmia, and ventricular, baffle, or significative valvular dysfunction. A total of 79 patients were enrolled, 46% of whom were female, with a mean follow-up of 27±6 years after surgery. ATR-S was performed in 54% and ART-S in 46%; the median age at procedure was 13 months and 10 days, respectively. During follow-up, almost all ART-S remained in sinus rhythm versus 64% of ATR-S (p=0.002). The latter group had a higher incidence of arrhythmias (41% versus 3%, p<0.001), mostly atrial flutter or fibrillation; the median time to first arrhythmia was 23 years. Systemic ventricle systolic dysfunction (SVSD) was more frequent in ATR-S (41% versus 0%, p<0.001); the mean time to SVSD was 25 years. In ART-S, the most frequent complication was significant valvular regurgitation (14%). Regarding time-to-event analysis, 80% and 40% of ATR-S maintained adverse events-free after 20 and 30 years, respectively; the time-to-first adverse event was 23 years, and there was no difference compared to ART-S (Log-rank=0.596). ART-S tended to maintain more preserved biventricular function than ATR-S (Log-rank=0.055). After a long term free of adverse events, ATR-S patients experienced more arrhythmias and SVSD. ART-S complications were predominantly anastomosis-related; SVSD or arrhythmias were rare.

Cardiovascular toxicity in breast cancer patients - contributors and role of cardioprotective drugs.

Breast cancer (BC) patients treated with anthracyclines and/or anti-HER2-targeted therapies (AHT) are highly associated with cardiovascular toxicity (CVT). Our objective was to evaluate the risk of CVT secondary to cancer treatment and the role of cardioprotective-drugs (CPD) in BC patients. We collected a retrospective cohort of females with BC treated with chemotherapy and/or AHT from 2017 to 2019. CVT was defined as LVEF<50% or decline ≥10% during follow-up. As CPD, we considered renin-angiotensin-aldosterone-system inhibitors and beta-blockers. A subgroup analysis of the AHT patients was also performed. A total of 203 women were enrolled. The majority had high or very-high CVT risk score and normal cardiac function at presentation. As for CPD, 35.5% were medicated pre-chemotherapy. All patients were submitted to chemotherapy; AHT were applied to 41.7%. During a 16 months follow-up, 8.5% developed CVT. There was a significant decrease of GLS and LVEF at 12-months (decrease of 1.1% and 2.2%, p<0.001). AHT and combined therapy were significantly associated with CVT. In the AHT sub-group analysis (n=85), 15.7% developed CVT. Patients previously medicated with CPD had a significative lower incidence of CVT (2.9% vs 25.0%, p=0.006). Patients already on CPD presented a higher LVEF at 6-months follow-up (62.5% vs 59.2%, p=0.017). Patients submitted to AHT and anthracycline therapy had higher risk of developing CVT. In the AHT sub-group, pre-treatment with CPD was significantly associated with a lower prevalence of CVT. These results highlight the importance of cardio-oncology evaluation and strengthen the value of primary prevention.

Prostate-specific antigen response after Abiraterone treatment in mCRPC: PSA as a predictor of overall survival.

OBJECTIVES: Abiraterone Acetate (AA) is an important agent in the treatment of advanced prostate cancer. It was primarily approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) after failure of androgen deprivation therapy. There is still no available strong data regarding the impact of early decline of prostate-specific antigen (PSA) in the overall survival. The aim of this study was to evaluate the clinical efficacy of an early prostate-specific antigen response as a predictor of overall survival (OS) in metastatic castration-resistant prostate cancer when treated with Abiraterone Acetate. MATERIALS AND METHODS: A dual center, retrospective, cohort study on patients diagnosed with mCRPC treated with abiraterone between 2013 and 2020 was performed. Primary end-point was to demonstrate the efficacy of AA, with the analysis of PSA decline, and the correlation with overall survival. RESULTS: The cohort analysis consisted of 84 patients with a median age of 71 ± 9 years. A PSA response of > 30% and > 50% at 60 and 90 days was associated with improved OS. Multivariate analysis revealed that a 60 day PSA decline of > 30% was predictive of overall survival. Median OS of diag-nosed mCRPC patients was 28 months. Docetaxel pre-treatment was not associated with longer OS. The median duration of drug exposure for patients submitted to AA was found to be 14 months. CONCLUSIONS: Early PSA response rate can offer clinically meaningful information and can be considered a surrogate of longer OS. A > 30% or > 50% prostate-specific antigen decline at 60 and 90 days provided an important low-cost clinical tool to predict subsequent events in mCRPC patients treated with abiraterone.

Wernicke encephalopathy and beriberi disease presenting as STEMI-equivalent.

Thiamine deficiency is commonly associated with malnutrition, alcoholism and bariatric surgery. Thiamine deficiency can manifest in different ways, especially in developing countries: as peripheric neuropathy, as Wernicke encephalopathy or as beriberi disease. The authors present the case of a 72-year-old male, with a hiatal hernia that led to thiamine deficiency due to malnutrition. The initial clinical manifestation was an ST-elevation myocardial infarct equivalent, an ECG with a shark-fin pattern that evolved to a Wellens type B pattern. The patient evolved with severe altered mental status. A Wernicke encephalopathy diagnosis was confirmed by MRI; the patient was medicated with high-dose thiamine, with quick recovery, both neurologic and cardiac. The clinical history and response to treatment confirm the diagnosis of Wernicke encephalopathy and beriberi disease.

Dependência de Pacing a Longo-Prazo e Preditores de Implante de Pacemaker após Implante Percutâneo de Prótese Valvular Aórtica - 1 Ano de Seguimento / Long-Term Ventricular Pacing Dependency and Pacemaker Implantation Predictors after Transcatheter Aortic Valve Replacement - A 1-Year Follow-Up

Resumo Fundamento Os distúrbios de condução (DC) são a complicação mais frequente após a substituição da válvula aórtica transcateter (TAVR) e ainda não há consenso sobre seu tratamento. Objetivo Avaliar novos DC e implante de marca-passo definitivo (MPD) após a TAVR e avaliar a porcentagem de estimulação ventricular (EV) até 1 ano de acompanhamento. Métodos Pacientes submetidos a TAVR de outubro de 2014 a novembro de 2019 foram cadastrados; pacientes com MPD anterior foram excluídos. Dados clínicos, do procedimento, do ECG e do MPD foram coletados até 1 ano após o implante. O nível de significância adotado para a análise estatística foi 0,05%. Resultados Um total de 340 indivíduos foram submetidos a TAVR. O DC mais comum foi bloqueio de ramo esquerdo novo (BRE; 32,2%), sendo que 56% destes foram resolvidos após 6 meses. O bloqueio do ramo direito (BRD) foi o maior fator de risco para bloqueio atrioventricular avançado (BAV) [RC=8,46; p<0,001] e implante de MPD [RC=5,18; p<0,001], seguido de BAV de baixo grau prévio [RC=2,25; p=0,016 para implante de MPD]. Em relação às características do procedimento, válvulas de gerações mais recentes e procedimentos de válvula-em-válvula foram associados a menos DC. No total, 18,5% dos pacientes tiveram MPD implantado após a TAVR. Na primeira avaliação do MPD, pacientes com BAV avançado tinham uma porcentagem mediana de EV de 80%, e, após um ano, de 83%. Em relação aos pacientes com BRE e BAV de baixo grau, a EV mediana foi mais baixa (6% na primeira avaliação, p=0,036; 2% após um ano, p = 0,065). Conclusão O BRE foi o DC mais frequente após a TAVR, com mais da metade dos casos se resolvendo nos primeiros 6 meses. O BRD foi o principal fator de risco para BAV avançado e implante de MPD. O BAV avançado foi associado a uma porcentagem mais alta de EV no acompanhamento de 1 ano.

Abstract Background Conduction disturbances (CD) are the most frequent complication after transcatheter aortic valve replacement (TAVR), and there continues to be a lack of consensus on their management. Objective To assess new CD and permanent pacemaker (PPM) implantation after TAVR and to evaluate the ventricular pacing percentage (VP) up to 1 year of follow-up. Methods Patients who underwent TAVR from October 2014 to November 2019 were enrolled; patients with previous PPM were excluded. Clinical, procedure, ECG, and PPM data were collected up to 1 year after implantation. The significance level adopted in the statistical analysis was 0.05. Results A total of 340 patients underwent TAVR. The most frequent CD was the new left bundle branch block (LBBB; 32.2%), which 56% resolved after 6 months. Right bundle branch block (RBBB) was the biggest risk factor for advanced atrioventricular block (AVB) [OR=8.46; p<0.001] and PPM implantation [OR=5.18, p<0.001], followed by previous low-grade AVB [OR=2.25; p=0.016 for PPM implantation]. Regarding procedure characteristics, newer generation valves and valve-in-valve procedures were associated with fewer CDs. Overall, 18.5% of patients had a PPM implanted post-TAVR. At first PPM evaluation, patients with advanced AVB had a median percentage of VP of 80% and 83% at one year. Regarding patients with LBBB plus low-grade AVB, median VP was lower (6% at first assessment, p=0.036; 2% at one year, p = 0.065). Conclusion LBBB was the most frequent CD after TAVR, with more than half being resolved in the first six months. RBBB was the major risk factor for advanced AVB and PPM implantation. Advanced AVB was associated with a higher percentage of VP at 1 year of follow-up.

Long-Term Ventricular Pacing Dependency and Pacemaker Implantation Predictors after Transcatheter Aortic Valve Replacement - A 1-Year Follow-Up. / Dependência de Pacing a Longo-Prazo e Preditores de Implante de Pacemaker após Implante Percutâneo de Prótese Valvular Aórtica ­ 1 Ano de Seguimento.

BACKGROUND: Conduction disturbances (CD) are the most frequent complication after transcatheter aortic valve replacement (TAVR), and there continues to be a lack of consensus on their management. OBJECTIVE: To assess new CD and permanent pacemaker (PPM) implantation after TAVR and to evaluate the ventricular pacing percentage (VP) up to 1 year of follow-up. METHODS: Patients who underwent TAVR from October 2014 to November 2019 were enrolled; patients with previous PPM were excluded. Clinical, procedure, ECG, and PPM data were collected up to 1 year after implantation. The significance level adopted in the statistical analysis was 0.05. RESULTS: A total of 340 patients underwent TAVR. The most frequent CD was the new left bundle branch block (LBBB; 32.2%), which 56% resolved after 6 months. Right bundle branch block (RBBB) was the biggest risk factor for advanced atrioventricular block (AVB) [OR=8.46; p<0.001] and PPM implantation [OR=5.18, p<0.001], followed by previous low-grade AVB [OR=2.25; p=0.016 for PPM implantation]. Regarding procedure characteristics, newer generation valves and valve-in-valve procedures were associated with fewer CDs. Overall, 18.5% of patients had a PPM implanted post-TAVR. At first PPM evaluation, patients with advanced AVB had a median percentage of VP of 80% and 83% at one year. Regarding patients with LBBB plus low-grade AVB, median VP was lower (6% at first assessment, p=0.036; 2% at one year, p = 0.065). CONCLUSION: LBBB was the most frequent CD after TAVR, with more than half being resolved in the first six months. RBBB was the major risk factor for advanced AVB and PPM implantation. Advanced AVB was associated with a higher percentage of VP at 1 year of follow-up.

FUNDAMENTO: Os distúrbios de condução (DC) são a complicação mais frequente após a substituição da válvula aórtica transcateter (TAVR) e ainda não há consenso sobre seu tratamento. OBJETIVO: Avaliar novos DC e implante de marca-passo definitivo (MPD) após a TAVR e avaliar a porcentagem de estimulação ventricular (EV) até 1 ano de acompanhamento. MÉTODOS: Pacientes submetidos a TAVR de outubro de 2014 a novembro de 2019 foram cadastrados; pacientes com MPD anterior foram excluídos. Dados clínicos, do procedimento, do ECG e do MPD foram coletados até 1 ano após o implante. O nível de significância adotado para a análise estatística foi 0,05%. RESULTADOS: Um total de 340 indivíduos foram submetidos a TAVR. O DC mais comum foi bloqueio de ramo esquerdo novo (BRE; 32,2%), sendo que 56% destes foram resolvidos após 6 meses. O bloqueio do ramo direito (BRD) foi o maior fator de risco para bloqueio atrioventricular avançado (BAV) [RC=8,46; p<0,001] e implante de MPD [RC=5,18; p<0,001], seguido de BAV de baixo grau prévio [RC=2,25; p=0,016 para implante de MPD]. Em relação às características do procedimento, válvulas de gerações mais recentes e procedimentos de válvula-em-válvula foram associados a menos DC. No total, 18,5% dos pacientes tiveram MPD implantado após a TAVR. Na primeira avaliação do MPD, pacientes com BAV avançado tinham uma porcentagem mediana de EV de 80%, e, após um ano, de 83%. Em relação aos pacientes com BRE e BAV de baixo grau, a EV mediana foi mais baixa (6% na primeira avaliação, p=0,036; 2% após um ano, p = 0,065). CONCLUSÃO: O BRE foi o DC mais frequente após a TAVR, com mais da metade dos casos se resolvendo nos primeiros 6 meses. O BRD foi o principal fator de risco para BAV avançado e implante de MPD. O BAV avançado foi associado a uma porcentagem mais alta de EV no acompanhamento de 1 ano.

Robust and flexible inference for the covariate-specific receiver operating characteristic curve.

Diagnostic tests are of critical importance in health care and medical research. Motivated by the impact that atypical and outlying test outcomes might have on the assessment of the discriminatory ability of a diagnostic test, we develop a robust and flexible model for conducting inference about the covariate-specific receiver operating characteristic (ROC) curve that safeguards against outlying test results while also accommodating for possible nonlinear effects of the covariates. Specifically, we postulate a location-scale regression model for the test outcomes in both the diseased and nondiseased populations, combining additive regression B-splines and M-estimation for the regression function, while the distribution of the error term is estimated via a weighted empirical distribution function of the standardized residuals. The results of the simulation study show that our approach successfully recovers the true covariate-specific area under the ROC curve on a variety of conceivable test outcomes contamination scenarios. Our method is applied to a dataset derived from a prostate cancer study where we seek to assess the ability of the Prostate Health Index to discriminate between men with and without Gleason 7 or above prostate cancer, and if and how such discriminatory capacity changes with age.

Perineural invasion in prostate needle biopsy: Prognostic value on radical prostatectomy and active surveillance.

PURPOSE: The aim of this study was to evaluate the clinical impact of perineural invasion (PNI) in prostate biopsy in patients submitted to radical prostatectomy and on active surveillance (AS). MATERIALS AND METHODS: We performed a single center, retrospective, cohort study on patients diagnosed with clinically localized prostate cancer and submitted to radical prostatectomy between January 2010 and December 2016. We evaluated clinical and anatomopathological characteristics from the biopsy and radical prostatectomy specimen and correlated with biochemical recurrence (BCR) using a survival analysis. We also evaluated the impact of PNI in patients with criteria for active surveillance. RESULTS: The cohort analyzed consists of 107 patients, with a mean age of 63.1 years and a mean PSA prior to biopsy of 7.8 ng/ml. In prostate biopsy, 66.4% of the patients had a Gleason score of 6, 30.9% had a Gleason score of 7, and 2.7% had a Gleason score of 8 or higher, with PNI being detected in 57 (53.3%) of the patients. Regarding the anatomopathological characteristics of the surgical specimen, invasion of the seminal vesicles was observed in 6.5%, lymph nodes involvement in 9.3% and positive surgical margins in 27.1% of the cases. During follow-up, BCR was recorded in 24.3% of cases. Clinicopathological features were stratified according to the presence or absence of PNI, with statistical significance in relation to the Gleason Score (p = 0.001), pathologic T stage (p = 0.001), D'Amico risk (p = 0.002) and upstaging of the Gleason score (p = 0.045). The survival analysis revealed a relationship between PNI and BCR (hazard ratio = 2.98; 95% CI: 1.36-6.58; p = 0.007). Regarding the men potentially eligible for AS, the presence of PNI on the biopsy presented a significant relation with Gleason upgrade (p = 0.004) and extraprostatic extension (p = 0.017). CONCLUSIONS: The presence of PNI in prostate biopsy is related to adverse anatomopathological factors, being a potential predictor of BCR and have a possible role in the selection of patients for AS.

Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody.

Amplification and overexpression of HER2 (human epidermal growth factor receptor 2), an ErbB2 receptor tyrosine kinase, have been implicated in human cancer and metastasis. A bispecific tetravalent anti-HER2 antibody (anti-HER2-Bs), targeting two non-overlapping epitopes on HER2 in domain IV (trastuzumab) and domain II (39S), has been reported to induce rapid internalization and efficient degradation of HER2 receptors. In this study, we investigated the molecular mechanism of this antibody-induced rapid HER2 internalization and intracellular trafficking. Using quantitative fluorescent imaging, we compared the internalization kinetics of anti-HER2-Bs and its parental arm antibodies, alone or in combinations and under various internalization-promoting conditions. The results demonstrated that concurrent engagement of both epitopes was necessary for rapid anti-HER2-Bs internalization. Cellular uptake of anti-HER2-Bs and parental arm antibodies occurred via clathrin-dependent endocytosis; however, inside the cells antibodies directed different trafficking pathways. Trastuzumab dissociated from HER2 in 2 h, enabling the receptor to recycle, whereas anti-HER2-Bs stayed associated with the receptor throughout the entire endocytic pathway, promoting receptor ubiquitination, trafficking to the lysosomes, and efficient degradation. Consistent with routing HER2 to degradation, anti-HER2-Bs significantly reduced HER2 shedding and altered its exosomal export. Collectively, these results enable a better understanding of the mechanism of action of anti-Her2-Bs and can guide the rational design of anti-HER2 therapeutics as well as other bispecific molecules.

Ultra-Early Versus Early Aneurysm Surgery After Subarachnoid Hemorrhage: A Retrospective Outcome Analysis

Object The timing of definitive management of ruptured intracranial aneurysms has been the subject of considerable debate, although the benefits of early surgery (until 72 hours postictus) are widely accepted. The aim of the present study is to evaluate the potential benefit of ultra-early surgery (until 24 hours) when compared with early surgery, in those patients who were treated by surgical clipping at the Neurosurgery Department of the Coimbra Hospital and University Centre. Methods A 17-year database of consecutive ruptured and surgically treated intracranial aneurysms was analyzed. Outcome was measured by the Glasgow Outcome Scale (GOS). Baseline characteristics were analyzed by the Fisher exact test, the chi-squared and Mann-Whitney tests. Logistic regression was used to assess the impact of good grade according to the World Federation of Neurological Surgeons (WFNS) scale and ultra-early surgery in a good GOS outcome. Results 343 patients who were submitted to surgical clipping in the first 72 hours postictus were included, 165 of whom have undergone ultra-early surgery. Demographics and preoperative characteristics of ultra-early and early surgery patients were similar. Goodgrade patients according to the WFNS scale submitted to ultra-early surgery demonstrated an improvedGOS at discharge and at 6months. Poor-grade patients according to theWFNS scale submitted to ultra-early surgery demonstrated an improved GOS at discharge. Conclusions Ultra-early surgery for aneurysmal subarachnoid hemorrhage patients improves outcome mainly on good-grade patients. Efforts should be made on the logistics of emergency departments to consider achieving treatment on this timeframe as a standard of care.

Affinity-based measures of biomarker performance evaluation.

We propose new summary measures of biomarker accuracy which can be used as companions to existing diagnostic accuracy measures. Conceptually, our summary measures are tantamount to the so-called Hellinger affinity and we show that they can be regarded as measures of agreement constructed from similar geometrical principles as Pearson correlation. We develop a covariate-specific version of our summary index, which practitioners can use to assess the discrimination performance of a biomarker, conditionally on the value of a predictor. We devise nonparametric Bayes estimators for the proposed indexes, derive theoretical properties of the corresponding priors, and assess the performance of our methods through a simulation study. The proposed methods are illustrated using data from a prostate cancer diagnosis study.