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1.
Immunotherapy ; 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34806404

RESUMO

Background: Combinations based on immune checkpoint inhibitors are the new first-line standard treatment for metastatic renal cell carcinoma. Sarcomatoid renal cell carcinoma (sRCC) has a dismal prognosis but good immunogenicity. Methods: The authors performed a network meta-analysis of Phase III randomized trials of immune checkpoint inhibitor-based combinations versus standard tyrosine kinase inhibitor monotherapy reporting data for sRCC. The endpoints were overall survival, progression-free survival and objective response rate. Results: Five trials comprising 569 sRCC patients (out of a total of 4409 metastatic renal cell carcinoma patients) were included. Nivolumab-cabozantinib was the highest ranking treatment for overall survival (p-value = 88%) and progression-free survival (p-value = 81%). Atezolizumab-bevacizumab had the highest rank for objective response rate (p-value = 80%). Conclusion: Despite some limitations, nivolumab-cabozantinib might be the preferred first-line option for sRCC in terms of efficacy.

2.
Ther Adv Urol ; 13: 17562872211053189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34733356

RESUMO

Background: In recent years, new therapeutic combinations based on immunotherapy provided significant benefits as a first-line treatment for patients with advanced renal cell carcinoma (mRCC). Objective: This work aims to address the lack of head-to-head comparisons and the uncertainty of the benefit from immunotherapy-based combinations in all the International Metastatic RCC Database Consortium (IMDC) subgroups. Design setting and participants: A systematic review and a network meta-analysis were performed. Overall survival (OS) in the intention-to-treat (ITT) population was the primary endpoint. OS according to IMDC subgroups (favorable, intermediate, poor), PD-L1 expression, and grade ⩾3 adverse events (AEs) were secondary endpoints. A SUCRA analysis was performed. Results and limitations: Six randomized phase III trials with 5121 patients were included. There was a high likelihood (82%) that nivolumab-cabozantinib was the preferred treatment in OS. The benefit of ICI-based combinations over sunitinib was unclear in the favorable-risk subgroup. Nivolumab-ipilimumab had the best risk/benefit ratio among all the ICI-based combinations. The limitations were the lack of individual patient data; the heterogeneity of patients' characteristics, trial designs, and follow-up times; and a limited number of studies for indirect comparisons. Conclusions: A customized approach for the first-line treatment of patients with mRCC should consider the risk/benefit profile of each treatment option, especially considering the likeliness of long-term survival finally reached in this setting.

3.
Ther Adv Urol ; 13: 17562872211054302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707691

RESUMO

Background: Considering the growing genitourinary (GU) cancer population undergoing systemic treatment with immune checkpoint inhibitors (ICIs) in the context of the COVID-19 pandemic, we planned a clinical audit in 24 Italian institutions treating GU malignancies. Objective: The primary objective was investigating the clinical impact of COVID-19 in GU cancer patients undergoing ICI-based therapy during the first outbreak of SARS-CoV-2 contagion in Italy. Design setting and participants: The included centers were 24 Oncology Departments. Two online forms were completed by the responsible Oncology Consultants, respectively, for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC) patients receiving at least one administration of ICIs between 31 January 2020 and 30 June 2020. Results and limitation: In total, 287 mRCC patients and 130 mUC patients were included. The COVID-19 incidence was, respectively, 3.5%, with mortality 1%, in mRCC patients and 7.7%, with mortality 3.1%, in mUC patients. In both groups, 40% of patients developing COVID-19 permanently discontinued anticancer treatment. The pre-test SARS-CoV-2 probability in the subgroup of patients who underwent nasal/pharyngeal swab ranged from 14% in mRCC to 26% in mUC. The main limitation of the work was its nature of audit: data were not recorded at the single-patient level. Conclusion: GU cancer patients undergoing active treatment with ICIs have meaningful risk factors for developing severe events from COVID-19 and permanent discontinuation of therapy after the infection. Treatment delays due to organizational issues during the pandemic were unlikely to affect the treatment outcome in this population.

4.
Cancers (Basel) ; 13(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34572748

RESUMO

The treatment landscape of advanced prostate cancer has completely changed during the last decades. Chemotherapy (docetaxel, cabazitaxel), androgen-receptor signaling inhibitors (ARSi) (abiraterone acetate, enzalutamide), and radium-223 have revolutionized the management of metastatic castration-resistant prostate cancer (mCRPC). Lutetium-177-PSMA-617 is also going to become another treatment option for these patients. In addition, docetaxel, abiraterone acetate, apalutamide, enzalutamide, and radiotherapy to primary tumor have demonstrated the ability to significantly prolong the survival of patients with metastatic hormone-sensitive prostate cancer (mHSPC). Finally, apalutamide, enzalutamide, and darolutamide have recently provided impactful data in patients with nonmetastatic castration-resistant disease (nmCRPC). However, which is the best treatment sequence for patients with advanced prostate cancer? This comprehensive review aims at discussing the available literature data to identify the optimal sequencing approaches in patients with prostate cancer at different disease stages. Our work also highlights the potential impact of predictive biomarkers in treatment sequencing and exploring the role of specific agents (i.e., olaparib, rucaparib, talazoparib, niraparib, and ipatasertib) in biomarker-selected populations of patients with prostate cancer (i.e., those harboring alterations in DNA damage and response genes or PTEN).

7.
Biomolecules ; 11(1)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477996

RESUMO

BACKGROUND: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness. METHODS: In the present review, the interaction between BC, host metabolism, and patients' prognosis has been reviewed across available literature evidence. CONCLUSIONS: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis.


Assuntos
Insulina/metabolismo , Somatomedinas/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
8.
Br J Cancer ; 124(3): 552-563, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33106584

RESUMO

Over the past years, several studies have demonstrated that defects in DNA damage response and repair (DDR) genes are present in a significant proportion of patients with prostate cancer. These alterations, particularly mutations in BRCA2, are known to be associated with an increased risk of developing prostate cancer and more aggressive forms of the disease. There is growing evidence that certain DDR gene aberrations confer sensitivity to poly-(ADP ribose) polymerase inhibitors and/or platinum chemotherapy, while other defects might identify cases that are more likely to benefit from immune checkpoint inhibition. The potential prognostic impact and relevance for treatment selection together with the decreasing costs and broader accessibility to next-generation sequencing have already resulted in the increased frequency of genetic profiling of prostate tumours. Remarkably, almost half of all DDR genetic defects can occur in the germline, and prostate cancer patients identified as mutation carriers, as well as their families, will require appropriate genetic counselling. In this review, we summarise the current knowledge regarding the biology and clinical implications of DDR defects in prostate cancer, and outline how this evidence is prompting a change in the treatment landscape of the disease.


Assuntos
Dano ao DNA/genética , Reparo do DNA/genética , Medicina de Precisão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Ensaios Clínicos como Assunto , Dano ao DNA/fisiologia , Reparo do DNA/fisiologia , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Indazóis/uso terapêutico , Indóis/uso terapêutico , Masculino , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Compostos de Platina/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico
11.
Semin Oncol ; 47(6): 361-366, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33168323

RESUMO

The treatment landscape of metastatic renal cell carcinoma (mRCC), a chemotherapy-resistant disease, has dramatically changed in the last decade after the introduction of small molecule inhibitors targeting the vascular endothelial growth factor receptor and mammalian target of rapamycin kinases. The CheckMate 025 phase III trial in second line mRCC also introduced immunotherapy with immune-checkpoint inhibitors as an option in the management of mRCC. Both small molecules and immunotherapy are used as single agents and they are associated with different toxicities. Recent data demonstrated that the combination of 2 immunotherapies, nivolumab and ipilimumab, is more effective than tyrosine kinase inhibitors (TKI) monotherapy as first line treatment in intermediate and poor risk mRCC. Furthermore, combination of immunotherapies and TKI has been tested in several trials to evaluate if the combo with agents presenting a different mechanism of action is more effective than monotherapy with TKI. During the past several years, combined therapy of cytokines doublets or cytokines and bevacizumab doublets demonstrated little improvement in clinical outcomes and a relevant toxicity profile. Conversely, the combination of new agents has been recently shown to improve survival in patients with metastatic disease, thus changing the treatment landscape of mRCC. This comprehensive review aims at summarizing the recent advances in the treatment of mRCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Humanos
12.
Cancer Treat Res Commun ; 25: 100221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33091733

RESUMO

BACKGROUND: Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC. METHODS: Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal. RESULTS: VP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients' prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss. CONCLUSIONS: Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/análogos & derivados , Compostos Organofosforados/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores da Topoisomerase II/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Humanos , Masculino , Compostos Organofosforados/farmacologia , Inibidores da Topoisomerase II/farmacologia
13.
Cancers (Basel) ; 12(10)2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33022939

RESUMO

The real-world outcomes of patients with metastatic prostate cancer (mPCa) are largely unexplored. We investigated the trends in overall survival (OS) and cancer-specific survival (CSS) in patients with de novo mPCa according to distinct time periods. The U.S. Surveillance, Epidemiology, and End Results (SEER) Research Data (2000-2017) were analyzed using the SEER*Stat software. The Kaplan-Meier method and Cox regression were used. Patients with de novo mPCa were allocated to three cohorts based on the year of diagnosis: A (2000-2003), B (2004-2010), and C (2011-2014). The maximum follow-up was fixed to 5 years. Overall, 26,434 patients were included. Age, race, and metastatic stage (M1) significantly affected OS and CSS. After adjustment for age and race, patients in Cohort C showed a 9% reduced risk of death (hazard ratio (HR): 0.91 (95% confidence interval [CI] 0.87-0.95), p < 0.001) and an 8% reduced risk of cancer-specific death (HR: 0.92 (95% CI 0.88-0.96), p < 0.001) compared with those in Cohort A. After adjustment for age, race, and metastatic stage, patients in Cohort C showed an improvement in OS and CSS compared with Cohort B (HR: 0.94 (95% CI 0.91-0.97), p = 0.001; HR: 0.89 (95% CI 0.85-0.92), p < 0.001). Patients with M1c disease had a more pronounced improvement in OS and CSS compared with the other stages. No differences were found between Cohorts B and C. In conclusion, the real-world survival of de novo mPCa remains poor, with a median OS and CSS improvement of only 4 months in the latest years.

14.
J Oncol ; 2020: 4986365, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32963528

RESUMO

Despite chemotherapy and novel androgen-receptor signalling inhibitors (ARSi) have been approved during the last decades, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease with poor clinical outcomes. Several studies found that germline or acquired DNA damage repair (DDR) defects affect a high percentage of mCRPC patients. Among DDR defects, BRCA mutations show relevant clinical implications. BRCA mutations are associated with adverse clinical features in primary tumors and with poor outcomes in patients with mCRPC. In addition, BRCA mutations predict good response to poly-ADP ribose polymerase (PARP) inhibitors, such as olaparib, rucaparib, and niraparib. However, concerns still remain on the role of extensive mutational testing in prostate cancer patients, given the implications for patients and for their progeny. The present comprehensive review attempts to provide an overview of BRCA mutations in prostate cancer, focusing on their prognostic and predictive roles.

15.
Cancers (Basel) ; 12(8)2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32824674

RESUMO

The novel coronavirus disease 2019 (COVID-19) shows a wide spectrum of clinical presentations, severity, and fatality rates. The reason older patients and males show increased risk of severe disease and death remains uncertain. Sex hormones, such as estradiol, progesterone, and testosterone, might be implicated in the age-dependent and sex-specific severity of COVID-19. High testosterone levels could upregulate transmembrane serine protease 2 (TMPRSS2), facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells via angiotensin-converting enzyme 2 (ACE2). Data from patients with prostate cancer treated with androgen-deprivation therapy seem to confirm this hypothesis. Clinical studies on TMPRSS2 inhibitors, such as camostat, nafamostat, and bromhexine, are ongoing. Antiandrogens, such as bicalutamide and enzalutamide, are also under investigation. Conversely, other studies suggest that the immune modulating properties of androgens could protect from the unfavorable cytokine storm, and that low testosterone levels might be associated with a worse prognosis in patients with COVID-19. Some evidence also supports the notion that estrogens and progesterone might exert a protective effect on females, through direct antiviral activity or immune-mediated mechanisms, thus explaining the higher COVID-19 severity in post-menopausal women. In this perspective, we discuss the available evidence on sex hormones and hormone therapy in patients infected with SARS-CoV-2, and we highlight the possible implications for cancer patients, who can receive hormonal therapies during their treatment plans.

16.
Transl Oncol ; 13(7): 100789, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32416542

RESUMO

Periostin (POSTN) is an extracellular matrix protein associated with tumor progression and shorter survival in prostate cancer (PCa). Here, we performed an integrative analysis of POSTN's role in patients with PCa. Clinical and POSTN data from large-scale datasets were analyzed. POSTN cutoffs were identified with X-Tile, and STRING was used for protein-protein interaction analysis. In a cohort of 48 patients with metastatic castration-resistant prostate cancer (mCRPC), we used the AdnaTest platform to isolate circulating tumor cells and extract POSTN mRNA. Plasma samples were also tested for POSTN protein expression by dot blot assay. Data from large-scale datasets did not reveal any association between POSTN genetic alterations and outcome. In primary tumors, we found a significant correlation between POSTN mRNA overexpression, worse baseline prognostic features, and shorter disease-free survival. POSTN was overexpressed in mCRPC and correlated with aggressive features. In our cohort of mCRPC patients, we found a positive correlation between POSTN plasma levels and androgen-receptor variant 7 positivity and an association with shorter overall survival. Our integrative analysis shows that POSTN is associated with poor clinical features and worse outcome in patients with PCa. Further studies are warranted to uncover the function of POSTN in PCa progression and to validate the prognostic significance of POSTN in mCRPC.

18.
Front Public Health ; 8: 602988, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33392140

RESUMO

Background: The COVID-19 outbreak rapidly became a public health emergency affecting particularly the frail category as cancer patients. This led oncologists to radical changes in patient management, facing the unprecedent issue whether treatments in oncology could be postponed without compromising their efficacy. Purpose: To discuss legal implications in oncology practice during the COVID-19 pandemic. Perspective: Treatment delay is not always feasible in oncology where the timing often plays a key role and may impact significantly in prognosis. During the COVID-19 pandemic, the oncologists were found between the anvil and the hammer, on the one hand the need to treat cancer patients aiming to improve clinical benefits, and on the other hand the goal to reduce the risk of COVID-19 infection avoiding or delaying immunosuppressive treatments and hospital exposure. Therefore, two rising scenarios with possible implications in both criminal and civil law are emerging. Firstly, oncologists may be "accused" of having delayed or omitted the diagnosis and/or treatments with consequent worsening of patients' outcome. Secondly, oncologists can be blamed for having exposed patients to hospital environment considered at risk for COVID-19 transmission. Conclusions: During the COVID-19 pandemic, clinical decision making should be well-balanced through a careful examination between clinical performance status, age, comorbidities, aim of the treatment, and the potential risk of COVID-19 infection in order to avoid the risk of suboptimal cancer care with potential legal repercussion. Moreover, all cases should be discussed in the oncology team or in the tumor board in order to share the best strategy to adopt case by case.


Assuntos
COVID-19/economia , Responsabilidade Legal/economia , Imperícia/economia , Neoplasias/economia , Neoplasias/terapia , Oncologistas/economia , Pandemias/economia , Adulto , Feminino , Culpa , Humanos , Masculino , Pessoa de Meia-Idade , Oncologistas/estatística & dados numéricos , SARS-CoV-2
19.
Cancers (Basel) ; 11(9)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540293

RESUMO

BACKGROUND: Circulating tumor cells (CTC), androgen receptor full-length (AR-FL), and androgen receptor splice variant 7 (AR-V7) are prognostic in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). AR-V7 seems to predict resistance to androgen-receptor signaling inhibitors (ARSi). METHODS: We assessed the association of CTC, AR-FL, and AR-V7 with prostate-specific antigen (PSA) response and overall survival (OS). We used a modified AdnaTest CTC-based AR-FL and AR-V7 mRNA assay. Chi-square test, Fisher Exact test, Kaplan-Meier method, log-rank test, Cox proportional hazards models were used as appropriate. RESULTS: We enrolled 39 mCRPC pts, of those 24 started a first-line treatment for mCRPC (1L subgroup) and 15 had received at least two lines for mCRPC (>2L subgroup). CTC, AR-FL, and AR-V7 were enriched in >2L compared to 1L subgroup. Detection of these biomarkers was associated with a lower percentage of biochemical responses. Only 1/7 AR-V7+ pts had a PSA response and received cabazitaxel. Median OS was 4.7 months (95% CI 0.6-8.9) in AR-V7+ pts and not reached in AR-V7- pts. AR-V7 was the only variable with prognostic significance in the Cox model. CONCLUSION: AR-V7, CTC, and AR-FL are associated with advanced mCRPC and AR-V7+ predicts for shorter OS.

20.
Cancers (Basel) ; 11(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547436

RESUMO

The possible treatments options for metastatic hormone-sensitive prostate cancer (mHSPC) have dramatically increased during the last years. The old backbone, which androgen-deprivation therapy (ADT) is the exclusive approach for hormone-naïve patients, has been disrupted. Despite the fact that several high-quality, randomized, controlled phase 3 trials have been conducted in this setting, no direct comparison is currently available among the different strategies. Inadequate power, absence of preplanning and small sample size frequently affect the subgroup analyses according to disease volume or patient's risk. The choice between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide, apalutamide or radiotherapy to the primary tumor remains challenging. Factors that are related to the tumor, patient or drug side effects, currently guide these clinical decisions. This comprehensive review aims to indirectly compare the phase 3 trials in the mHSPC setting, in order to extrapolate data useful for treatment selection, providing also perspectives on future biomarkers.

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