Synthetic Lethality by Co-Inhibition of Androgen Receptor and Polyadenosine Diphosphate-Ribose in Metastatic Prostate Cancer.

Androgen receptor pathway inhibitors (ARPI) and polyadenosine diphosphate-ribose inhibitors (PARPi) are part of the standard of care in patients with metastatic castration-resistant prostate cancer (mCRPC). There is biological evidence that the association of ARPI and PARPi could have a synergistic effect; therefore, several ongoing clinical trials are investigating the efficacy of this combination with preliminary results that are not perfectly concordant in identifying patients who can obtain the most benefit from this therapeutic option. The purpose of this review is to describe the PARPi mechanisms of action and to analyze the biological mechanisms behind the interplay between the androgen receptor and the PARPi system to better understand the rationale of the ARPI + PARPi combinations. Furthermore, we will summarize the preliminary results of the ongoing studies on these combinations, trying to understand in which patients to apply. Finally, we will discuss the clinical implications of this combination and its possible future perspectives.

Is There a Place for De-escalating Therapy in Patients with Metastatic Hormone-sensitive Prostate Cancer?

Although intermittent androgen deprivation therapy was often recommended for metastatic hormone-sensitive cancer therapy in the past, we do not know whether its use can be extrapolated to combination therapy. Trials evaluating intermittent therapy are necessary as this strategy could improve patient quality of life and reduce adverse events and costs.

Navigating the ICI Combination Treatment Journey: Patterns of Response and Progression to First-Line ICI-Based Combination Treatment in Metastatic Renal Cell Carcinoma.

The use of immune checkpoint inhibitors (ICIs) in combination with tyrosine kinase inhibitors or other ICIs has significantly improved the prognosis for patients with mccRCC. This marks a major milestone in the treatment of mccRCC. Nonetheless, most patients will discontinue first-line therapy. In this narrative review, we analyze the different patterns of treatment discontinuation in the four pivotal phase III trials that have shown an improvement in overall survival in mccRCC first-line therapy, starting from 1 January 2017 to 1 June 2023. We highlight the different discontinuation scenarios and their influences on subsequent treatment options, aiming to provide more data to clinicians to navigate a complex decision-making process through a narrative review approach. We have identified several causes for discontinuations for patients treated with ICI-based combinations, such as interruption for drug-related adverse events, ICI treatment completion, treatment discontinuation due to complete response or maximum clinical benefit, or due to progression (pseudoprogression, systemic progression, and oligoprogression); for each case, an extensive analysis of the trials and current medical review has been conducted.

EORTC 2238 "De-Escalate": a pragmatic trial to revisit intermittent androgen deprivation therapy in the era of new androgen receptor pathway inhibitors.

The landscape of treating metastatic prostate cancer has evolved with the addition of Androgen Receptor pathway inhibitor (ARPI) to Androgen Deprivation Therapy (ADT), significantly improving survival rates. However, prolonged use of these therapies introduces notable side effects, prompting a need to revisit intermittent treatment duration. The EORTC 2238 De-Escalate trial is a pragmatic trial seeking to reassess the role of intermittent therapy in patients undergoing maximal androgen blockade (MAB) for metastatic hormone naïve prostate cancer (mHNPC), i.e., the combination of ADT with an ARPI, with the aims of reducing side effects, enhancing Quality of Life (QoL) and optimizing resource usage, while maintaining oncological benefits.

Treatment options in first-line metastatic renal carcinoma: A meta-analysis of 2556 patients treated with immune checkpoint inhibitors-based combinations in randomised controlled trials.

BACKGROUND & AIMS: The average five-year survival of metastatic renal cell carcinoma (mRCC) is 71%. However, there is significant variability in patient prognosis. Immune checkpoint inhibitors (ICIs) have been introduced into the treatment landscape of mRCC. This meta-analysis aimed to estimate progression-free and overall survival probabilities and identify possible outcome predictors of mRCC patients treated with ICI combination as first-line treatment. METHODS: Studies comparing the combination of ICI combinations versus standard of therapy for first-line treatment of advanced renal-cell carcinoma were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through September 2023. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using the DerSimonian and Laird methods. RESULTS: Six studies met the inclusion criteria. Globally, 5121 patients were included in this meta-analysis: 2556 patients treated with immune checkpoint inhibitors and 2565 with sunitinib as control. The ICI combination was associated with improved PFS (hazard ratio (HR) 0.68; 95 % confidence interval (CI), 0.56-0.81, p < 0.0001). Furthermore, ICI combination was also associated with OS improvement (HR 0.85; 95 % CI, 0.78-0.92, p = 0.001). There is no statistical increase in adverse events. CONCLUSIONS: Our findings show that PFS and OS are statistically increased in mRCC with ICI combination treatment by 32% and 15%, respectively.

Safety profile of darolutamide versus placebo: a systematic review and meta-analysis.

BACKGROUND: Darolutamide is an androgen receptor pathway inhibitor (ARPI) used in patients with prostate cancer (PC). In pivotal trials, it has demonstrated a favorable toxicity profile. There are no head-to-head comparison studies between the different ARPIs, but the efficacy of these drugs seems to be similar making the toxicity profile a key element for treatment selection. METHODS: We conducted a systematic review of all clinical trials assessing treatment with darolutamide for patients with PC using placebo as the control using the PubMed/Medline and Cochrane library databases. We also performed a meta-analysis to compare the safety of darolutamide versus placebo evaluating adverse events (AE) leading to treatment discontinuation and the rate of the AE reported as "AE of interest" in the ARAMIS trial. The comparison among darolutamide and the placebo group in terms of safety and tolerability was performed using odds ratio (OR) as meta-analytic outcome. RESULTS: We identified three articles comprising 2902 patients for the systematic review and meta-analysis (1652 treated with darolutamide and 1250 with placebo). Darolutamide did not increase AE leading to treatment discontinuation compared to placebo (pooled OR: 1.176, 95% CI 0.918-1.507, p = 0.633). Regarding the "AE of interest" there was no difference between darolutamide and placebo in terms of asthenia, cardiac arrhythmia, cardiac disorder, coronary artery disorder, depression mood disorder, falls, fatigue, heart failure, hot flushes, hypertension, mental-impairment disorder, rash, seizure and weight loss. The only "AE of interest" with a statistically significant difference in favor of placebo was bone fractures (pooled OR: 1.523, 95% CI 1.081-2.146). CONCLUSIONS: In our systematic review and meta-analysis, darolutamide showed a toxicity profile comparable to placebo with the exception of bone fractures. In the absence of head-to-head comparison studies between the different ARPIs, the results of our research suggest a preferred use of darolutamide in the approved settings.

Prognostic and Predictive Role of SPOP Mutations in Prostate Cancer: A Systematic Review and Meta-analysis.

CONTEXT: Mutations in the speckle-type POZ (SPOP) gene are frequently identified in prostate cancer (PC); yet, prognostic implications for affected patients remain unclear. Limited consensus exists regarding tailored treatments for SPOP-mutant (SPOPmut) PC. OBJECTIVE: To elucidate the prognostic and predictive significance of SPOP mutations across distinct PC stages and treatments. EVIDENCE ACQUISITION: A systematic literature search of PubMed, Embase, and Scopus was conducted up to January 29, 2024. The meta-analysis included studies comparing survival outcomes between SPOPmut and SPOP wild-type (SPOPwt) PC. EVIDENCE SYNTHESIS: From 669 records, 26 studies (including five abstracts) were analyzed. A meta-analysis of metastasis-free survival in localized (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.59-0.88; p < 0.01) and overall survival (OS) in metastatic PC (HR: 0.64, 95% CI: 0.53-0.76; p < 0.01) showed a favorable prognosis for patients with SPOPmut PC. In metastatic settings, SPOP mutations correlated with improved progression-free survival (PFS) and OS in patients undergoing androgen deprivation therapy ± androgen receptor signaling inhibitor (HR: 0.51, 95% CI: 0.35-0.76, p < 0.01, and HR: 0.60, 95% CI:0.46-0.79, p < 0.01, respectively). In metastatic castration-resistant PC, only abiraterone provided improved PFS and OS to patients with SPOP mutations compared with patients with SPOPwt, but data were limited. SPOP mutations did not correlate with improved PFS (p = 0.80) or OS (p = 0.27) for docetaxel. CONCLUSIONS: Patients with SPOPmut PC seem to exhibit superior oncological outcomes compared with patients with SPOPwt. Tailored risk stratification and treatment approaches should be explored in such patients. PATIENT SUMMARY: Speckle-type POZ (SPOP) mutations could be a favorable prognostic factor in patients with prostate cancer (PC) and may also predict better progression-free and overall survival than treatment with hormonal agents. Therefore, less intensified treatments omitting chemotherapy for patients with SPOP-mutant PC should be explored in clinical trials.

Hormonal Agents in Localized and Advanced Prostate Cancer: Current Use and Future Perspectives.

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

Análise da segurança e dos preditores de arritmias durante o ecocardiograma sob estresse com Dobutamina em um ambiente não hospitalar / Analyzing the safety and predictors of arrhythmias during dobutamine-atropine estress echocardiography in a non-hospital setting

Fundamento: O ecocardiograma sob estresse com dobutamina-atropina (EEDA) é um exame acessível e importante, principalmente em pacientes sob investigação de doença coronariana. Contudo, faz-se necessário a avaliação de sua segurança, devido ao seu emprego em pacientes com patologias cada vez mais complexas, graves e idosos.Objetivo: Confirmar segurança do EEDA e avaliar os preditores de arritmias em ambiente não hospitalar.Métodos: EEDA foi realizado com o objetivo de avaliar isquemia utilizando o protocolo padrão de infusão de dobutamina de 5 a 40 mcg/kg/min associado a atropina.Resultados: Foram avaliados de forma prospectiva 2227 pacientes no período de setembro a novembro de 2010. Idade média foi de 60,7 +/- 12,5 anos e 60,8% eram mulheres. A fração de ejeção média foi de 67,9% +/- 9. Dentre dos eventos adversos, 12 pacientes apresentaram resposta hipertensiva, 466 arritmias, 58 cefaleias e 57 dores precordial. Nenhum paciente apresentou infarto agudo do miocárdio, fibrilação ventricular, ruptura cardíaca, assistolia ou morte. Quanto ao surgimento das arritmias significativas, 3 pacientes apresentaram fibrilação atrial,16 taquicardias supraventricular sustentada, 19 taquicardias ventricular não sustentada e 2 taquicardias ventricular sustentada. Nestes pacientes, idade (OR = 1,0559, p = 0,0002) e o índice de escore de contração segmentar (IECS) em repouso > 1 (OR 2,5039, p = 0,0354) foram preditores independentes para o surgimento de arritmias significativas durante o exame.Conclusão: O EEDA mostrou-se seguro nesse grupo de pacientes em ambiente não hospitalar. Idade e IECS em repouso > 1 foram preditores independentes para o surgimento de arritmias significativas durante o exame

Background: Dobutamine-atropine stress echocardiography (DASE) is an accessible and important test, especially in patients under investigation for coronary artery disease. However, it is necessary to evaluate its safety, as it is used in patients with increasingly complex and serious conditions and in seniors.Objective: To confirm the safety of DASE and evaluate the predictors of arrhythmias in a non-hospital setting. Methods: DASE was performed to evaluate ischemia using the standard protocol of dobutamine infusion of 5 to 40 mcg/kg/min associated with atropine. Results: From September to November 2010, 227 patients were evaluated prospectively. The mean age was 60.7 +/- 12.5 years old and 60.8% were females. Mean ejection fraction was 67.9 +/- 9. Among the adverse events, 12 patients presented hypertensive response, 466 had arrhythmia, 58 had headaches and 57 had precordial pain. No patient had acute myocardial infarction, ventricular fibrillation, cardiac rupture, asystole or death. As for the onset of significant arrhythmia, three patients had atrial fibrillation, 16 had sustained supraventricular tachycardia, 19 had non-sustained ventricular tachycardia and 2 had sustained ventricular tachycardia. In these patients, age (OR = 1.0559, p = 0.0002) and segmental contractility index at rest (SCIr) > 1 (OR 2.5039, p = 0.0354) were independent predictors for the onset significant arrhythmia during the test. Conclusion: DASE was proven safe in this group of patients in a non-hospital setting. Age and SCIr > 1 were independent predictors for the onset of significant arrhythmia during the test

Dobutamine Stress Echocardiography Safety in Chagas Disease Patients / Segurança do Ecocardiograma sob Estresse com Dobutamina-Atropina em Pacientes com Doença de Chagas

Abstract Background: A few decades ago, patients with Chagas disease were predominantly rural workers, with a low risk profile for obstructive coronary artery disease (CAD). As urbanization has increased, they became exposed to the same risk factors for CAD of uninfected individuals. Dobutamine stress echocardiography (DSE) has proven to be an important tool in CAD diagnosis. Despite being a potentially arrhythmogenic method, it is safe for coronary patients without Chagas disease. For Chagas disease patients, however, the indication of DSE in clinical practice is uncertain, because of the arrhythmogenic potential of that heart disease. Objectives: To assess DSE safety in Chagas disease patients with clinical suspicion of CAD, as well as the incidence of arrhythmias and adverse events during the exam. Methods: Retrospective analysis of a database of patients referred for DSE from May/2012 to February/2015. This study assessed 205 consecutive patients with Chagas disease suspected of having CAD. All of them had their serology for Chagas disease confirmed. Results: Their mean age was 64±10 years and most patients were females (65.4%). No patient had significant adverse events, such as acute myocardial infarction, ventricular fibrillation, asystole, stroke, cardiac rupture and death. Regarding arrhythmias, ventricular extrasystoles occurred in 48% of patients, and non-sustained ventricular tachycardia in 7.3%. Conclusion: DSE proved to be safe in this population of Chagas disease patients, in which no potentially life-threatening outcome was found.

Resumo Fundamento: Até poucas décadas atrás, os pacientes chagásicos eram predominantemente trabalhadores rurais, com baixo perfil de risco para doença obstrutiva coronária. Com a crescente urbanização, passaram a ter os mesmos fatores de risco para doença aterosclerótica que indivíduos não infectados. O ecocardiograma sob estresse com dobutamina (EED) é uma importante ferramenta no diagnóstico de coronariopatia. É referido, porém, como um método potencialmente arritmogênico, mas seguro, em pacientes coronarianos não chagásicos. Entretanto, há insegurança na prática clínica de indicá-lo no paciente chagásico, devido ao potencial arritmogênico já intrínseco nesta cardiopatia. Objetivos: Analisar a segurança do EED em uma população de chagásicos com suspeita clínica de coronariopatia. Métodos: Análise retrospectiva de um banco de dados de pacientes encaminhados para a realização do EED entre maio/2012 e fevereiro/2015. Avaliou-se pacientes consecutivos portadores de doença de Chagas e com suspeita de coronariopatia. Confirmou-se a sorologia para doença de Chagas em todos os pacientes. Resultados: A média etária dos 205 pacientes analisados foi de 64 ± 10 anos, sendo a maioria do sexo feminino (65,4%). Nenhum paciente apresentou eventos adversos significativos, como infarto agudo do miocárdio, fibrilação ventricular, assistolia, acidente vascular encefálico, ruptura cardíaca ou morte. Quanto às arritmias, extrassístoles ventriculares frequentes ocorreram em 48% dos pacientes, taquicardia ventricular não sustentada em 7,3%, bigeminismo em 4,4%, taquicardia supraventricular e taquicardia ventricular sustentada em 1% e fibrilação atrial em 0,5%. Conclusão: O EED mostrou ser um exame seguro nessa população de pacientes chagásicos, onde nenhum desfecho grave foi encontrado.

Placa de aterosclerose em aorta: revisão sobre aterogênese, formação de placa, significado clínico, métodos de imagens e tratamento / Plaque of atherosclerosis in aorta: review on atherogenesis, formation of plaque, clinical significance, methods of imaging and treatment

Há consenso na literatura de que o estagio mais precoce da aterogênese é caracterizado por acúmulo de células espumosas na região da íntima arterial. Fatores de risco como hipertensão arterial, tabagismo, diabetes mellitus, dislipidemias (hipercolesterolemia), sexo masculino e idade avançada predispõem à maior formação de placas em coronárias e aorta, nas quais tem sido observado maior número de eventos coronarianos agudos e acidentes vasculares cerebrais. Acidentes vasculares cerebrais são a terceira causa de mortes nos EUA, com aproximadamente 40 por cento dos casos de origem criptogênica. Desde 1989, as placas de ateroma, que se desenvolvem na aorta torácica, têm sido responsabilizadas por acidentes vasculares cerebrais e periféricos...

Avaliaçäo da assistência médica prestada no ambulatório da Liga de Combate às DST/AIDS - Centro de Saúde, S.P., 1994-1997 / Evaluation of the care provided by the outpatient clinic of the league of combat against STD/AIDS, Health Center, S.P., 1994-1997

Este trabalho analisou a assistência médica prestada pelos alunos da Liga de Combate a DST/AIDS, da Faculdade de Medicina de Ribeiräo Preto - USP, no curso de três anos e meio, junto ao Programa de Prevençäo e Controle de Aids do Centro de Saúde Escola. Foi utilizada a metodologia de avaliaçäo em saúde (processo e resultados), que contemplou o estudo da assistência médica em um período contínuo de seguimento, sendo analisados os diagnósticos formulados, os exames laboratoriais e complementares prescritos, as medidas curativas e de promoçäo da saúde e prevençäo de doenças. Foram estudados sessenta e seis (66) indivíduos, sendo 48,5 por cento comunicantes de portadores do Vírus da Imunodeficiência Humana ou de doentes de aids, 27,3 por cento, portadores do HIV e 24,2 por cento de doentes de aids. Houve maioria de pacientes masculinos, embora a relaçäo homem:mulher cresça de 1:1, 2:1 e 3,5:1 no sentido comunicantes, portadores e doentes, com uma freqüência modal de 40,9 por cento na faixa etária de trinta (30) e trinta e nove (39) anos, o grau de escolaridade e as ocupações foram características de nível socio-econômico baixo. Formularam-se diagnósticos de deficiência da imunidade celular, exposiçäo a doenças transmissíveis (aids, tuberculose e outras doenças infecciosas), infecções respiratórias agudas, doenças sexualmente transmissíveis, parasitoses, entre as principais. Em média, a clientela permaneceu 3,2 meses em seguimento, recebeu 2,4 consultas e 47,7 por cento dela abandonou o atendimento. Os alunos participaram ativamente da pesquisa; a metodologia e as informações quantitativas contribuíram para a avaliçäo da qualidade da assistência médica, tendo o serviço de saúde correspondido como alternativa institucional para formaçäo e assistência mais próxima da comunidade