Valor preditivo de marcadores de transição epitelial - mesenquimatosa, PTEN, ERG, Ki-67 e de estudo mutacional, na recorrência bioquímica de carcinoma da próstata tratado com cirurgia

Valor Preditivo de Marcadores de Transição Epitelial-­‐Mesenquimatosa, PTEN, ERG, Ki67 e de Estudo Genético na Recorrência Bioquímica de Carcinoma da Próstata tratado com cirurgia Introdução: O carcinoma da próstata apresenta uma elevada incidência e prevalência. A maioria dos carcinomas da próstata localizados são curáveis, com as opções terapêuticas disponíveis. Contudo, a recorrência da doença está associada a morbilidade, a mortalidade e a custos elevados. Como tal, é importante otimizar o tratamento da doença localizada. Uma das possibilidades para o fazer, passa por uma melhoria do nosso conhecimento, acerca dos factores preditivos. Um reconhecimento precoce de uma maior probabilidade de recorrência poderia levar a uma otimização da abordagem terapêutica dos tumores primários, nomeadamente através de estratégias que incluam intensificação terapêutica. Material e Métodos: Numa amostra populacional constituída por doentes, com carcinoma da próstata localizado, e tratados com prostatectomia radical de intuito curativo, avaliámos o valor preditivo de factores clínicos, anatomopatológicos, imunohistoquímicos e genéticos. Utilizámos como “endpoint” a recorrência bioquímica (RBQ). Resultados: Em 147 doentes, e após um seguimento, cuja mediana foi de 20 meses (4-­‐55 meses), ocorreu RBQ em 15,6% dos casos. Na nossa amostra, o PSA pré-­‐ operatório (p=0,02); o tipo de cirurgia (p=0,01); o score de Gleason da biópsia (p=0,004) e da lesão índice (P<0,001); a classificação de Epstein da biópsia (p=0,005), da peça (p=0,006), e da lesão índice (p<0,001); o número de fragmentos de biópsia envolvidos por tumor (p=0,05), a extensão do envolvimento tumoral nos fragmentos de biópsia, em milímetros (p=0,01) e percentualmente (p=0,02); a existência de áreas de diferenciação intraductal (p=0,003); a presença de padrão de terciário (p<0,001); a dimensão linear da lesão índice (p=0,005); a existência de margem cirúrgica positiva (p=0,05); a existência de extensão extraprostática (p=0,02); a invasão vascular (p=0,002); a invasão das vesículas seminais (p=0,01); o número de gânglios isolados em doentes submetidos a linfadenectomia (p=0,01); o estádio patológico referente ao tumor primário (p=0,02) e a pErda de expressão da caderina E (p<0,001), mostraram significância estatística relativamente à ocorrência de recorrência bioquímica. Por análise multivariável, apenas a existência de áreas de diferenciação intraductal (p=0,01), a classificação de Epstein da lesão índice (p<0,001), a invasão vascular (p=0,02) e o número de gânglios isolados em doentes submetidos a linfadenectomia (p=0,05), mantiveram a significância estatística, após ajuste para as outras variáveis. Os restantes biomarcadores associados à transição epitelial-­‐mesenquimatosa (caderina N e vimentina), o PTEN, o Ki-­‐67 e o ERG, na nossa amostra, e por análise univariável, não estão associados à ocorrência de RBQ. A expressão de SChLAP1, quer em tecido tumoral, quer em tecido não tumoral, também não está associado à ocorrência de RBQ. Conclusões: O nosso trabalho confirma, na nossa população, o interesse preditivo de factores clínicos e anatomopatológicos normalmente associados a um comportamento biológico mais agressivo. Também sugere o interesse preditivo de alguns factores anatomopatológicos menos estudados. Por fim aponta para a possibilidade, de associação entre o fenómeno de transição epitelial e a ocorrência de RBQ.Predictive value of epithelial-­‐mesenchymal transition markers, PTEN, ERG, Ki67, and genetic analysis in biochemical recurrence of prostate cancer treated with surgery Introduction: Prostate cancer is a contemporary health issue. It has a very high incidence and prevalence. The majority of patients with localized disease are cured with current standard therapeutic options. Nevertheless, disease recurrence is associated with morbidity, mortality and significant costs. It is, therefore, important to optimize therapeutic efficacy. One of the possibilities to achieve it, is through better understanding of predictive factors. Pinpointing in advance, the cases with worse prognosis, could allow a therapeutic adjustment, by adding adjuvant treatment. Methods: In a clinical cohort study, we evaluated the predictive impact of several clinical, pathological and molecular factors in the development of biochemical recurrence (BCR), in patients with localized prostate cancer treated with radical prostatectomy. Results: A total of 147 patients were included in our study. The median follow-­‐up time was 20 months. BCR occurred in 15.6% of the patients. In univariate analysis, pre-­‐operative PSA (p=0.02); the type of surgery (p=0.01); the Gleason score both in biopsy (p=0.004) and in the index lesion (p<0.001); the Epstein grading system in the biopsy (p=0.005), in the entire tumor (p=0.006), and in the index lesion (p<0.001); the number of positive cores in the biopsy (p=0.05), the maximum length of cancer in any one biopsy core (p=0.01) and the greatest percentage of cancer in any biopsy core (p=0.02); the presence of intraductal differentiation in the prostatic specimen (p=0.003); the presence of a minor high-­‐grade pattern (p<0.001); the index lesion dimension (p=0.005); positive surgical margin (p=0.05); the existence of extra prostatic extension (p=0.02); vascular invasion (p=0.002); seminal vesicle invasion (p=0.01); the total number of lymph nodes retrieved in patients submitted to lymphadenectomy (p=0.01); T stage (p=0.02) and loss of E-­‐Cadherine, were all predictive factors for BCR. In multivariate analysis, only the presence of intraductal differentiation (p=0.01), Epstein grading system in the index lesion (p<0.001), vascular invasion (p=0.02) and the total number of lymph nodes (p=0.05) remained independently predictive of BCR. The remaining epithelial-­‐mesenchymal transition markers (N-­‐Cadherine and Vimentine), PTEN, Ki-­‐67 and ERG, were not predictive factors for BCR. Neither was SChLAP1 expression, both in tumoral and non-­‐tumoral tissue. Conclusions: Our study, in this population, confirms the predictive impact of many well-­‐established predictive factors. It also implies, that other less known pathological factors might also have predictive importance. Finally, it suggest the existence of a link between epithelial-­‐mesenchymal transition and BCR

Predicting biochemical recurrence after radical prostatectomy: the role of prognostic grade group and index tumor nodule

The aim of the current study was to test whether the grade group assessed in the index tumor nodule predicts biochemical recurrence after surgery. The study cohort series included 144 consecutive patients treated by laparoscopic radical prostatectomy. The following parameters were evaluated in each case: type of radical prostatectomy (with/without lymphadenectomy), pT and pN status, histologic type of prostate carcinoma (acinar versus mixed histology), surgical margin resection status, perineural invasion, lymphovascular invasion, biochemical recurrence status, presence of tertiary Gleason 5 pattern, and grade group that was assessed both in overall prostate cancer and in index (dominant) tumor nodule. Twenty patients (13.9%) experienced postoperative biochemical recurrence at a mean follow-up time of 12.2 months. The univariate survival analysis selected type of radical prostatectomy, histological subtype, lymphovascular invasion, American Joint Committee on Cancer pT and pN classification, tertiary Gleason 5 pattern, preoperative serum prostate specific antigen level, and the grade group assessed in both the overall prostate and index tumor nodule as significant for biochemical recurrence-free survival. Type of radical prostatectomy (P = .020), histological subtype (P = .002), lymphovascular invasion (P = .023), tertiary Gleason pattern 5 (P = .016), and grade group classification in index tumor nodule (P ≤ .0001) were selected as independent predictors of biochemical recurrence-free survival. In conclusion, our results validate grade group in the index tumor nodule as an independent predictor of biochemical recurrence-free survival, thus emphasizing the value of reporting grade group in index tumor nodule. The main limitation of our study is the relatively low number of cases in the current series, suggesting the need of large confirmatory studies

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed

Lípidos e Síndroma Nefrótico na Criança

Fazendo parte da sua definição, só recentemente se tem vindo a demonstrar a verdadeira extensão e fisiopatologia das alterações do metabolismo lipídicoobservadas nos doentes com sindroma nefrótico.A importância destas alterações deve-se à relação conhecida entre o nível sérico de lípidos e doençacardiovascular aterosclerótica e, mais recentemente, sua implicação no desencadear ou agravar de lesões renais.São revistas as indicações terapêuticas bemcomo os meios ao nosso dispôr para o tratamento da hiperlipidémia nas crianças com sindroma nefrótico

Tp53 and its potential therapeutic role as a target in bladder cancer

Despite more than 30\ua0years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer. Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords 'p53, Tp53, p53 and bladder cancer, p53 and therapeutic target'. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer. Expert opinion: Novel strategies developed to restore the function of mutants with chemical chaperones or by using compounds to improved pharmacokinetic properties are in development with potential to be applied in the oncology clinic. Other strategies targeting aberrantly overexpressed p53 regulators with wild-type p53 are also an active area of research. In particular, studies inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 are an important field in drug discovery. Small molecules for inhibition of MDM2 are now in clinical trials process. However, personalized anticancer therapy might eventually advance through analyses of p53 status in cancer patients

Emerging Immunotargets in Bladder Cancer

Bladder cancer treatment, namely systemic therapy, was dominated in the last three decades due to the absence of newer therapeutic options other than chemotherapy regimens. Chemotherapy, by itself, both in first and second-line seems to have achieved the modest plateau of its possibilities at the cost of non-negligible toxicity. Targeted therapies, which changed the therapy of many different tumors, seem rather ineffective in bladder cancer. More recently, a new generation of Immunotherapy based regimens represent the most promising avenue for the future systemic treatment of bladder cancer. Checkpoint inhibition, namely PD1/PD-L1 pathway inhibition, showed impressive results in many other tumor types and are expected to become a major player in the treatment of bladder cancer. Other immunotherapy strategies such as fusion proteins represent distant, although promising, options. A brief overview of the current status of bladder cancer immunotherapy is presented

Emerging immunotargets in bladder cancer

Bladder cancer treatment, namely systemic therapy, was dominated in the last three decades due to the absence of newer therapeutic options other than chemotherapy regimens. Chemotherapy, by itself, both in first and second-line seems to have achieved the modest plateau of its possibilities at the cost of non-negligible toxicity. Targeted therapies, which changed the therapy of many different tumors, seem rather ineffective in bladder cancer. More recently, a new generation of Immunotherapy based regimens represent the most promising avenue for the future systemic treatment of bladder cancer. Checkpoint inhibition, namely PD1/PD-L1 pathway inhibition, showed impressive results in many other tumor types and are expected to become a major player in the treatment of bladder cancer. Other immunotherapy strategies such as fusion proteins represent distant, although promising, options. A brief overview of the current status of bladder cancer immunotherapy is presented

Body mass index in patients treated with cabozantinib for advanced renal cell carcinoma: A new prognostic factor?

We analyzed the clinical and pathological features of renal cell carcinoma (RCC) patients treated with cabozantinib stratified by body mass index (BMI). We retrospectively collected data from 16 worldwide centers involved in the treatment of RCC. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. We collected data from 224 patients with advanced RCC receiving cabozantinib as second- (113, 5%) or third-line (111, 5%) therapy. The median PFS was significantly higher in patients with BMI ≥ 25 (9.9 vs. 7.6 months, p &lt; 0.001). The median OS was higher in the BMI ≥ 25 subgroup (30.7 vs. 11.0 months, p = 0.003). As third-line therapy, both median PFS (9.2 months vs. 3.9 months, p = 0.029) and OS (39.4 months vs. 11.5 months, p = 0.039) were longer in patients with BMI ≥ 25. BMI was a significant predictor for both PFS and OS at multivariate analysis. We showed that a BMI ≥ 25 correlates with longer survival in patients receiving cabozantinib. BMI can be easily assessed and should be included in current prognostic criteria for advanced RCC.</p

Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study

Background: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial. METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy. RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P &lt; .001), better PFS (20.8 vs. 8.5 months, P &lt; .001), and higher overall response rate (52 vs. 37%, P = .033). Conclusion: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice