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1.
Front Cardiovasc Med ; 9: 867867, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35498037

RESUMO

Cardiovascular toxicity in cancer patients receiving chemotherapy remains one of the most undesirable side effects, limiting the choice of the most efficient therapeutic regimen, including combinations of different anticancer agents. Anthracyclines (doxorubicin) and antimetabolites (5-fluorouracil (5-FU), capecitabine) are among the most known agents used in breast cancer and other neoplasms and are associated with cardiotoxic effects. Extra-virgin olive oil (EVOO) is rich in polyphenols endowed with antioxidant cardioprotective activities. Olive mill wastewater (OMWW), a waste product generated by EVOO processing, has been reported to be enriched in polyphenols. In this study, we investigated the activities of polyphenol-rich extract from OMWW, A009, in cooperation with chemotherapy on two breast cancer cell lines, namely, BT459 and MDA-MB-231, in a cardio-oncology perspective. The effects of A009 on cardiac cells were also investigated with and without chemotherapeutic agents. Cell viability was determined on BT459 and MDA-MB-231 (i.e., breast cancer cells) and H9C2 (i.e., rat cardiomyocytes) cells, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A spheroids assay was used as a 3D in vitro model on BT459 and MDA-MB-231 cells. For in vivo studies, the murine sponge assay of angiogenesis was used as a model of breast cancer-associated vascularization. The embryo of Danio rerio (zebrafish) was used to detect the cardioprotective activities of the OMWW. We found that the A009 extract exhibited antiangiogenic activities induced by breast cancer cell supernatants and increased T-cell recruitment in vivo. The combination of the OMWW extracts with doxorubicin or 5-FU limited BT459 and MDA-MB-231 cell viability and the diameter of 3D spheroids, while mitigating their toxic effects on the rat H9C2 cardiomyocytes. Cardioprotective effects were observed by the combination of OMWW extracts with doxorubicin in zebrafish embryos. Finally, in human cardio myocytes, we observed 5-FU-induced upregulation of the inflammatory, senescence-associated cytokine IL6 and p16 genes, which expression was reduced by OMWW treatment. Our study demonstrates that the polyphenol-rich purified OMWW extract A009 combined with cancer chemotherapy could represent a potential candidate for cardiovascular protection in breast cancer patients, while increasing the effects of breast cancer chemotherapy.

2.
Front Oncol ; 11: 769158, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868998

RESUMO

Reliable liquid biopsy-based tools able to accurately discriminate prostate cancer (PCa) from benign prostatic hyperplasia (BPH), when PSA is within the "gray zone" (PSA 4-10), are still urgent. We analyzed plasma samples from a cohort of 102 consecutively recruited patients with PSA levels between 4 and 16 ng/ml, using the SANIST-Cloud Ion Mobility Metabolomic Mass Spectrometry platform, combined with the analysis of a panel of circulating microRNAs (miR). By coupling CIMS ion mobility technology with SANIST, we were able to reveal three new structures among the most differentially expressed metabolites in PCa vs. BPH. In particular, two were classified as polyunsaturated ceramide ester-like and one as polysaturated glycerol ester-like. Penalized logistic regression was applied to build a model to predict PCa, using six circulating miR, seven circulating metabolites, and demographic/clinical variables, as covariates. Four circulating metabolites, miR-5100, and age were selected by the model, and the corresponding prediction score gave an AUC of 0.76 (C.I. = 0.66-0.85). At a specified cut-off, no high-risk tumor was misclassified, and 22 out of 53 BPH were correctly identified, reducing by 40% the false positives of PSA. We developed and applied a novel, minimally invasive, liquid biopsy-based powerful tool to characterize novel metabolites and identified new potential non-invasive biomarkers to better predict PCa, when PSA is uninformative as a tool for precision medicine in genitourinary cancers.

3.
Cancers (Basel) ; 13(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34638439

RESUMO

Natural Killer (NK) cells have been found to be anergic, exhausted and pro-angiogenic in cancers. NK cell from healthy donors, exposed to TGFß, acquire the CD56brightCD9+CD49a+ decidual-like-phenotype, together with decreased levels of NKG2D activation marker, increased levels of TIM-3 exhaustion marker, similar to cancer-associated NK cells. Tissue inhibitors of metalloproteases (TIMPs) exert dual roles in cancer. The role of TIMPs in modulating immune cells is a very novel concept, and the present is the first report studying their ability to contrast TGFß action on NK cells. Here, we investigated the effects of TIMP1 and TIMP2 recombinant proteins in hindering decidual-like markers in NK cells, generated by polarizing cytolytic NK cells with TGFß. The effects of TIMP1 or TIMP2 on NK cell surface antigens were determined by multicolor flow cytometry. We found that TIMP1 and TIMP2 were effective in interfering with TGFß induced NK cell polarization towards a decidual-like-phenotype. TIMP1 and TIMP2 counteracted the effect of TGFß in increasing the percentage of CD56bright, CD16-, CD9+ and CD49a+, and restoring normal levels for TIMP 1 and 2 also inhibited decrease levels of the activation marker NKG2D induced by TGFß and decreased the TGFß upregulated exhaustion marker TIM-3. NK cell degranulation capabilities against K562 cells were also decreased by TGFß and not by TIMP1 or TIMP2. TIMP1 treatment could partially restore degranulation marker CD107a expression. Treatment with recombinant TIMP-1 or TIMP-2 showed a trend, although not statistically significant, to decrease CD49a+ and TIM-3+ expression and increase NKG2D in peripheral blood NK cells exposed to conditioned media from colon cancer cell lines. Our results suggest a potential role of TIMPs in controlling the tumor-associated cytokine TGFß-induced NK cell polarization. Given the heterogeneity of released factors within the TME, it is clear that TGFß stimulation represents a model to prove TIMP's new properties, but it cannot be envisaged as a soloist NK cell polarizing agent. Therefore, further studies from the scientific community will help defining TIMPs immunomodulatory activities of NK cells in cancer, and their possible future diagnostic-therapeutic roles.

4.
Ther Adv Urol ; 13: 17562872211022870, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211586

RESUMO

Currently, conventional treatments for metastatic RCC (mRCC) include immune-based combination regimens and/or targeted therapies, the latter mainly acting on angiogenesis, a key element of the process of tumor growth and spread. Although these agents proved able to improve patients' outcomes, drug resistance and disease progression are still experienced by a substantial number of VEGFR-TKIs-treated mRCC patients. Following the inhibition of the VEGF/VEGFRs axis, two strategies have emerged: either specifically targeting resistance pathways, at the same time continuing to inhibit angiogenesis, or using a completely different approach aimed at re-activating the immune system through the use of inhibitors of specific negative immune checkpoints. These two approaches, practically represented by the use of either cabozantinib or nivolumab, seem to remain a rational therapeutic approach also when first-line immune-based combinations are used. The objective of this study is to design a preferential therapeutic pathway for the second-line treatment of mRCC. The procedure applied in this project was a group discussion, based on the Nominal Group Technique (NGT) method in a meeting session, aimed at defining the therapeutic choice for the second-line treatment of mRCC. The NGT process defined the most relevant parameters that, according to the interviewed panelists, clinicians should consider for the selection of the second-line therapy in the context of advanced renal cell carcinoma of mRCC. The algorithm developed for the treatment selection as a result of this process should thus be considered by clinicians as reference for therapy selection. PLAIN LANGUAGE SUMMARY: The result of this paper was the definition of an algorithm intended to suggest a preferential therapeutic pathway considering both the outputs of the Nominal Group Technique (NGT) process and the actual clinical practice and the experience of selected panelists. During the NGT process and the discussion phase, panelists defined the most important parameters to be included in the algorithm that are important for the treatment definition. Cabozantinib and nivolumab are identified as the most reasonable therapeutic options for patients progressing after first-line treatment and are the medication options included in the algorithm for therapy selection.

5.
Ther Adv Med Oncol ; 13: 17588359211019642, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046089

RESUMO

BACKGROUND: Despite the survival advantage, not all metastatic renal cell carcinoma (mRCC) patients achieve a long-term benefit from immunotherapy. Moreover, the identification of prognostic biomarkers is still an unmet clinical need. METHODS: This multicenter retrospective study investigated the prognostic role of peripheral-blood inflammatory indices and clinical factors to develop a novel prognostic score in mRCC patients receiving at least second-line nivolumab. The complete blood count before the first cycle of therapy was assessed by calculating neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI). Clinical factors included pre-treatment International Metastatic RCC Database Consortium (IMDC) score, line of therapy, and metastatic sites. RESULTS: From October 2015 to November 2019, 571 mRCC patients received nivolumab as second- and further-line treatment in 69% and 31% of cases. In univariable and multivariable analyses all inflammatory indices, IMDC score, and bone metastases significantly correlated with overall survival (OS). The multivariable model with NLR, IMDC score, and bone metastases had the highest c-index (0.697) and was chosen for the developing of the score (Schneeweiss scoring system). After internal validation (bootstrap re-sampling), the final index (Meet-URO score) composed by NLR, IMDC score, and bone metastases had a c-index of 0.691. It identified five categories with distinctive OSs: group 1 (median OS - mOS = not reached), group 2 (mOS = 43.9 months), group 3 (mOS = 22.4 months), group 4 (mOS = 10.3 months), and group 5 (mOS = 3.2 months). Moreover, the Meet-URO score allowed for a fine risk-stratification across all three IMDC groups. CONCLUSION: The Meet-URO score allowed for the accurate stratification of pretreated mRCC patients receiving nivolumab and is easily applicable for clinical practice at no additional cost. Future steps include its external validation, the assessment of its predictivity, and its application to first-line combinations.

7.
Target Oncol ; 15(4): 495-501, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32671807

RESUMO

BACKGROUND: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy. OBJECTIVE: To describe the outcome of cabozantinib in patients previously treated with immunotherapy. PATIENTS AND METHODS: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity. RESULTS: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up. CONCLUSIONS: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.


Assuntos
Anilidas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Receptores Proteína Tirosina Quinases/uso terapêutico , Idoso , Anilidas/farmacologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/farmacologia
8.
Front Oncol ; 10: 533, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32457826

RESUMO

Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.

9.
Urol Oncol ; 37(8): 529.e1-529.e7, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30935843

RESUMO

OBJECTIVES: To investigate if a first-line treatment delay (TD) can negatively affect the outcomes of patients affected by metastatic renal cancer. PATIENTS AND METHODS: Patients with a diagnosis of metastatic renal cancer who were ineligible for active surveillance were included in the sample. A TD was defined as the time from the diagnosis of metastatic disease to the start of first-line therapy with tyrosine kinase inhibitors. RESULTS: A total of 835 patients were assessed and 635 were included in the final analysis. The median TD was 6.3 weeks. No significant differences were found in baseline characteristics between patients experiencing a TD below/equal to or above the median value, with the exceptions being the rate of bone metastases (25.3% vs. 35.9%) and advanced disease at diagnosis (34.7% vs. 54.9%). In patients who had received a previous nephrectomy for localized disease, the TD was 5.3 compared to 8.0 weeks for those with metastatic disease at diagnosis (P = 0.001). Among this latter group, 68.7% had received a cytoreductive nephrectomy. In patients with a TD below/equal to and above the median value, the median progression-free survival was 10.3 and 11.2 months, respectively (hazard ratio = 1.03; 95% confidence intervals, 0.86-1.22; P = 0.78); the median overall survival was 27.3 and 28.2 months, respectively (hazard ratio = 1.04; 95% confidence intervals, 0.86-1.27; P = 0.68). The lack of differences was confirmed when adjusted for prognostic factors and baseline characteristics. CONCLUSIONS: This study reports that patients with bone metastases and advanced disease at diagnosis have a significant probability of experiencing delayed first-line therapy of more than 6 weeks from the time of diagnosis. However, a TD does not significantly affect outcomes and survival.


Assuntos
Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Análise de Sobrevida , Tempo para o Tratamento
10.
Cancers (Basel) ; 12(1)2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31905816

RESUMO

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second- or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second- or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51-10.88) and 11.57 months (95% CI 10.90-not reached (NR)) as second-line and 11.38 months (95% CI 5.79-NR) and NR (95% CI 11.51-NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib-nivolumab and 25.64 months and NR with nivolumab-cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39; 95% CI 1.24-4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04-2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33; 95%CI, 1.16-4.69, p = 0.018) and Hb levels (HR = 3.12; 95%CI 1.18-8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72; 95%CI 1.04-7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.

11.
Clin Genitourin Cancer ; 16(4): e945-e951, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753637

RESUMO

BACKGROUND: The randomized phase 3 METEOR study confirmed a survival benefit of cabozantinib over everolimus in patients with metastatic renal-cell carcinoma (mRCC) with disease that progressed after treatment with at least one previous antiangiogenic inhibitor. The aim of this analysis was to evaluate the safety and activity of cabozantinib in an unselected population. METHODS: Data were collected across 24 Italian centers. Cabozantinib therapy was initiated at physician request between September and December 2016. Patients with mRCC with disease that progressed after one or more prior systemic treatment were evaluated. Cabozantinib 60 mg was administered orally once daily. Doses were reduced to 40 mg or 20 mg in patients experiencing grade 3 or intolerable grade 2 adverse events (AEs). RESULTS: Data from 96 patients were evaluated. Cabozantinib was administered as second-line therapy in 28 patients (29%) and as third-line therapy in 18 patients (19%), while the remaining 50 patients (52%) received cabozantinib in further treatment lines. Sixty-six patients began therapy with the full dose of 60 mg. Because of poor performance status, 29 patients began therapy with a reduced dose of 40 mg and 1 patient with 20 mg. At the time of our analysis, grade 3/4 AEs were observed in 35 patients (36%). Only 5 patients discontinued treatment as a result of AEs. Partial response was observed in 35 patients (36%), whereas 33 (34%) had stable disease and 28 (30%) progressive disease. Median progression-free survival was 8.0 months. CONCLUSION: Cabozantinib showed acceptable tolerability and activity in a large unselected population treated according to everyday clinical practice.


Assuntos
Anilidas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Piridinas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
12.
Clin Genitourin Cancer ; 16(5): 355-359.e1, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29803346

RESUMO

BACKGROUND: The International mRCC (metastatic renal cell carcinoma) Database Consortium (IMDC) is the standard classification for mRCC. We aimed to evaluate the outcomes of a large cohort of patients with an intermediate or a poor prognosis treated with sunitinib using a different cutoff point for IMDC to improve the classification. PATIENTS AND METHODS: Patients with an intermediate or a poor prognosis according to the IMDC criteria and treated with sunitinib were included in the present study. A new cutoff point was used to categorize the patients. The new score was validated in an independent cohort of patients. RESULTS: A total of 457 patients were included in the present study. Significant differences in overall survival (OS) were highlighted regarding the number of prognostic factors. Three categories were identified according to the presence of 1 (ie, favorable-intermediate group), 2 (ie, real-intermediate group), and > 2 (ie, poor group) factors. The corresponding median OS periods were 32.9, 20.0, and 8.9 months, with significant differences among the groups. The validation cohort included 389 patients. The median OS period for the favorable-intermediate group, real-intermediate group, and poor group was 34.3, 19.4, and 9.0 months, respectively, with confirmed significant differences among the groups. CONCLUSION: Our analysis revealed significant differences among patients with an intermediate prognosis using the IMDC prognostic factors. Further investigations to optimize the use of available and upcoming therapies are required.


Assuntos
Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/classificação , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
13.
Anticancer Drugs ; 29(7): 705-709, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29846246

RESUMO

We aimed to investigate the different outcomes in patients with metastatic renal cell carcinoma treated with second-line axitinib or everolimus after sunitinib. Patients treated in 16 oncological centres in Italy were included, and those receiving axitinib or everolimus from January 2013 onwards were analysed for outcomes. Descriptive statistical tests were used to highlight differences between groups. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Data on 634 patients with metastatic renal cell carcinoma treated with first-line sunitinib have been obtained. A total of 182 patients received a second-line therapy with everolimus (79 patients, 43%) or axitinib (103 patients, 57%), respectively. The median PFS was 4.6 [95% confidence (CI): 2.6-6.5] months for patients treated with everolimus and 5.5 (95% CI: 4.3-6.7) months for patients treated with axitinib (P=0.7). The median OS was 13.9 (95% CI: 10.4-17.4) months for patients treated with everolimus and 12.0 (95% CI: 7.9-16.2) months for patients treated with axitinib (P=0.3). No differences were found based on length of first-line treatment. Major limitations are the retrospective nature of the study and the lack of a prospective evaluation of the progression. This study reports no significantly differences between everolimus and axitinib in terms of both PFS and OS. Furthermore, the length of first-line treatment cannot be used as such a predictive factor and cannot suggest the use of a molecule compared with another.


Assuntos
Antineoplásicos/uso terapêutico , Axitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Antineoplásicos/administração & dosagem , Axitinibe/administração & dosagem , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Esquema de Medicação , Everolimo/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Sunitinibe/administração & dosagem
14.
Target Oncol ; 12(4): 525-533, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28669023

RESUMO

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos
15.
Oncotarget ; 7(26): 40085-40094, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-27223078

RESUMO

We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies.


Assuntos
Androstenos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Docetaxel , Seguimentos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Modelos de Riscos Proporcionais , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxoides/uso terapêutico
16.
Oncotarget ; 7(22): 33381-90, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27027342

RESUMO

PURPOSE: We retrospectively analyzed the risk of recurrence and conditional Disease-Free Survival (cDFS) in 63 patients with complete remission during treatment with tirosin kinase inhibitor (TKI), alone or with local treatment in metastatic renal cell carcinoma. RESULTS: 37% patients achieve CR with TKI alone, while 63% with additional loco-regional treatments. 49% patients recurred after CR, with a median Disease free survival of 28.2 months. Patients treated with multimodal approaches present lower rate of recurrence (40% vs 61%) and longer Disease free survival compared to patient treated with TKI alone (16.5 vs 41.9 months, p=0.039).Furthermore the rate of recurrence was higher in patients with brain (88%), pancreatic (71%) and bone metastasis (50%). Patients who continued TKI therapy after complete response had a longer disease free survival than patients who stopped therapy, although the difference was not significant (42.1 vs 25.1 months, p=0.254). 2y-cDFS was better in patients treated with multimodal treatment and who continued TKIs than the other patient arms. CONCLUSIONS: The prognostic value of CR depends on the site where was obtained and how was obtained (with or without locoregional treatment). Cessation of TKI should be carefully considered in complete responder patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/enzimologia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Itália , Estimativa de Kaplan-Meier , Neoplasias Renais/enzimologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Análise Multivariada , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
17.
ESMO Open ; 1(6): e000111, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28848658

RESUMO

OBJECTIVE: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC). METHODS: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (ΔSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p <0.0001) and ΔSTL (HR 1.16, 95% CI 1.06 to 1.27, p=0.002) predicted OS. We found an increase of 9% of diameter as the best threshold for discriminating OS (HR 2.64, 95% CI 1.61 to 4.34, p <0.001). In the multivariate analysis, baseline and week 8 cavitation remained significant PFS predictors. Baseline cavitation, RECIST 1.1 and ΔSTL remained predictors of OS in exploratory multivariable models. Assessment of liver metastases density did not predict clinical outcome. CONCLUSIONS: RECIST 1.1 and ΔSTL predict favourable outcome to regorafenib. In contrast to liver metastases density that failed to be a predictor, lung metastases cavitation represents a novel radiological marker of favourable outcome that deserves consideration.

18.
Am J Hypertens ; 29(2): 158-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26031304

RESUMO

BACKGROUND: In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs. METHODS: Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment. RESULTS: Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped. CONCLUSIONS: All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.


Assuntos
Antineoplásicos/efeitos adversos , Artérias/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Indazóis , Indóis/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Compostos de Fenilureia/efeitos adversos , Análise de Onda de Pulso , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Sorafenibe , Sulfonamidas/efeitos adversos , Sunitinibe , Neoplasias da Glândula Tireoide/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos
19.
Epidemiol Prev ; 39(1): 45-51, 2015.
Artigo em Italiano | MEDLINE | ID: mdl-25855546

RESUMO

OBJECTIVES: to identify the typologies of facial and dental asymmetries in a sample of children aged between 3 and 6 years and to correlate these asymmetries with possible morphological and functional situations. DESIGN: cross-sectional observational study. SETTING AND PARTICIPANTS: sample of 95 subjects aged between 3 and 6 years. Clinical data were collected in 10 sessions conducted during school hours in April 2013 by a doctor of Dentistry at two preschools in the city of Sanremo (Liguria Region, Northern Italy) and a kindergarten in the city of Pavia (Lombardy Region, Northern Italy). To collect the data, a weighted clinical questionnaire was used. MAIN OUTCOME MEASURES: presence and type of bad habit, type of breathing, presence and type of facial asymmetry, dental formula, presence of diastema, presence and type of occlusal asymmetries, presence and type of dental malocclusions. RESULTS: analysed sample consisted of 53.7% (51/95) of males and 46.3 % (44/95) females; the mean age was 4.3 ± 0.9 years. Most frequent facial asymmetry is orbits asymmetry (35%, 33/95); dental malocclusions are detected in 70%(67/95) of cases. High percentage of subjects (69.5%, 66/95) presents displacement between superior dental midline (SDM) and inferior dental midline (IDM). Several statistically significant associations are observed: in particular, asymmetry of molar ratios is linked to asymmetry of the cheekbones and displacement of the SDM; facial midline has statistical association with asymmetry of the cheekbones (p <0.001). CONCLUSIONS: the results of this study agree with scientific literature, in particular as regards the prevalence of compromising habits observed and the close correlation between: the presence of dental malocclusions and the presence of compromising habits, the presence of dental malocclusions and the presence of oral breathing.


Assuntos
Assimetria Facial/epidemiologia , Má Oclusão/epidemiologia , Criança , Pré-Escolar , Estudos Transversais , Diastema/epidemiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Respiração Bucal , Inquéritos e Questionários , Hábitos Linguais , Dente Decíduo
20.
Eur Urol ; 68(1): 147-53, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25457020

RESUMO

BACKGROUND: The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. OBJECTIVE: To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. RESULTS AND LIMITATIONS: We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. CONCLUSIONS: We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. PATIENT SUMMARY: It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.


Assuntos
Acetato de Abiraterona/uso terapêutico , Antineoplásicos/uso terapêutico , Feniltioidantoína/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Benzamidas , Estudos de Coortes , Intervalo Livre de Doença , Docetaxel , Humanos , Itália , Masculino , Análise Multivariada , Nitrilas , Feniltioidantoína/uso terapêutico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento
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