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1.
Anticancer Res ; 40(2): 929-938, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014937

RESUMO

BACKGROUND/AIM: The efficacy of gemcitabine-based chemotherapy in locally advanced/metastatic biliary tract carcinoma is limited. The aim of this trial was to assess the activity of a novel gemcitabine-pazopanib combination in such patients. PATIENTS AND METHODS: In this phase II, multicenter trial, patients with histologically/cytologically confirmed biliary tract carcinoma, previously untreated for advanced disease, received 1000 mg/m2 of gemcitabine on days 1 and 8 every 21 days and 800 mg of pazopanib once daily continuously for 8 cycles, followed by pazopanib maintenance. The primary endpoint was objective response rate (ORR). RESULTS: A total of 29 patients (median age; 69 years) were enrolled between June 2013 and March 2018. The ORR was 13.8% in the intent-to-treat and 19.1% in the per protocol population. The median progression-free and overall survival were 6.3 and 10.4 months, respectively. CONCLUSION: The low response rate precludes further testing of the combination in patients with biliary tract carcinoma.

2.
JAMA Netw Open ; 3(1): e1918939, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31922558

RESUMO

Importance: The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. Objective: To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. Data Sources: In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Study Selection: Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Data Extraction and Synthesis: Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Main Outcomes and Measures: Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. Results: In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. Conclusions and Relevance: This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

3.
Anticancer Res ; 40(1): 305-313, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892581

RESUMO

BACKGROUND: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines. PATIENTS AND METHODS: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months. RESULTS: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m2), trauma history, renal insufficiency and bevacizumab use. CONCLUSION: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning.


Assuntos
Neoplasias/complicações , Trombose/etiologia , Trombose/terapia , Feminino , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Fatores de Risco
4.
Anticancer Res ; 40(1): 435-441, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892598

RESUMO

AIM: The purpose of the Imadje study was to confirm the efficacy and safety of imatinib, following resection of kit-positive gastrointestinal stromal tumour (GIST), in the adjuvant setting in the Greek population. PATIENTS AND METHODS: A total of 34 adult patients already receiving imatinib were enrolled. Recurrence-free (RFS) and overall survival, as well as time to treatment failure and safety were assessed. RESULTS: Overall survival could not be estimated in the present study, as no death occurred. Overall, 91.2% of patients were recurrence-free at 36 months, while the median time to treatment failure was 35 months. No new or unexpected safety findings were observed. Mutation analysis in 14 patients showed that the most frequent mutations were located in KIT exon 11 (64.3%) and exon 9 (28.6%). Univariate analysis showed that only surgical resection with a margin classification of R0 was associated with better RFS. CONCLUSION: Adjuvant treatment with imatinib for 3 years in patients with intermediate to high risk of recurrence was proven to prolong RFS, while being well-tolerated and not exhibiting a negative impact on patient compliance with therapy.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/patologia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Grécia , Humanos , Mesilato de Imatinib/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
5.
PLoS One ; 14(12): e0226853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31860648

RESUMO

BACKGROUND: Analysis of circulating tumor nucleic acids in plasma of Non-Small Cell Lung Cancer (NSCLC) patients is the most widespread and documented form of "liquid biopsy" and provides real-time information on the molecular profile of the tumor without an invasive tissue biopsy. METHODS: Liquid biopsy analysis was requested by the referral physician in 121 NSCLC patients at diagnosis and was performed using a sensitive Next Generation Sequencing assay. Additionally, a comparative analysis of NSCLC patients at relapse following EGFR Tyrosine Kinase Inhibitor (TKIs) treatment was performed in 50 patients by both the cobas and NGS platforms. RESULTS: At least one mutation was identified in almost 49% of the cases by the NGS approach in NSCLC patients analyzed at diagnosis. In 36 cases with paired tissue available a high concordance of 86.11% was observed for clinically relevant mutations, with a Positive Predictive Value (PPV) of 88.89%. Furthermore, a concordance rate of 82% between cobas and the NGS approach for the EGFR sensitizing mutations (in exons 18, 19, 21) was observed in patients with acquired resistance to EGFR TKIs, while this concordance was 94% for the p.T790M mutation, with NGS being able to detect this mutation in three 3 additional patients. CONCLUSIONS: This study indicates the feasibility of circulating tumor nucleic acids (ctNA) analysis as a tumor biopsy surrogate in clinical practice for NSCLC personalized treatment decision making. The use of new sensitive NGS techniques can reliably detect tumor-derived mutations in liquid biopsy and provide clinically relevant information both before and after targeted treatment in patients with NSCLC. Thus, it could aid physicians in treatment decision making in clinical practice.

6.
Cutan Ocul Toxicol ; : 1-3, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31648558

RESUMO

Immune checkpoint inhibitors have demonstrated durable responses in some patient groups and gained regulatory approval for various cancer indications since 2011. Autoimmune and autoinflammatory adverse events, secondary to the use of such agents are known as "immune-related adverse events" (irAEs) and their incidence, severity and tolerability may vary among the classes of the checkpoint inhibitors. This short review provides an update and summarises the clinical manifestations and management of cutaneous irAEs induced by checkpoint inhibitors that are currently in use.

7.
Int J Colorectal Dis ; 34(11): 1871-1877, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31598748

RESUMO

PURPOSE: Colorectal cancer is the fourth cause of cancer-related death. Drug toxicity and resistance remain concerns of major importance. miR-100 and miR-218 are micro-RNAs that regulate cellular proliferation, differentiation and apoptosis acting as oncogenes and tumour suppressors; their functions and have been linked with toxicity development and drug resistance. METHODS: We investigated the correlation between rs11134527 miR-218 and rs1834306 miR-100 polymorphisms and irinotecan-based regimens with regard to drug efficacy and toxicity. A total of 105 mCRC patients receiving irinotecan-based regimens were included in our study and assessed in terms of toxicity development and response to treatment. Rs11134527 miR-218 and rs1834306 miR-100 polymorphism genotyping in the peripheral blood was performed with PCR-RFLP. RESULTS: Neither rs11134527 miR-218 nor rs1834306 miR-100 are associated with toxicity risk to treatment regimens. GA/AA genotypes of rs11134527 and CT/TT genotypes of rs1834306 were associated with a significantly reduced time-to-progression (TTP) and overall survival (OS). CONCLUSIONS: GA/AA genotypes of rs11134527 miR-218 and CT/TT genotypes of rs1834306 miR-100 polymorphisms could serve as prognostic biomarkers of TTP and OS. Carriers of the A allele of the miR-218 rs11134527 and T allele of the miR-100 rs1834306 polymorphisms are more likely not to respond to irinotecan-based therapies. However, further studies in larger patient populations are required.

8.
J Oncol Pharm Pract ; : 1078155219865597, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382864

RESUMO

Fluoropyrimidine-based regimens are among the most commonly used chemotherapy combinations for the treatment of solid tumors. Several genetic polymorphisms that are implicated with fluoropyrimidine anabolism and catabolism have been associated with the development of life-threatening toxicities. Uridine triacetate is an FDA-approved antidote for 5-fluorouracil or capecitabine overdose and early-onset, life-threatening toxicity within 96 h of last chemotherapy dose. To date, it is not accessible for Greek patients as per the current summary of product characteristic's time restrictions. We report and discuss the course and outcome of capecitabine toxicity in a 66-year-old female colorectal cancer patient with heterozygous dihydropyrimidine dehydrogenase deficiency. This paper highlights the difficulty in timely access of this lifesaving medication for Greek and possibly other European patients.

9.
ESMO Open ; 4(2): e000441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231556

RESUMO

Introduction: We sought to determine the level of activation of the critical components of the cyclin D1-mediated pathway and to evaluate their prognostic significance across the different molecular subtypes of advanced breast cancer. Patients and methods: The study population comprised 219 female patients with advanced breast cancer who had been found to have human epidermal growth factor receptor 2 (HER2)-positive disease by local testing and were all treated with trastuzumab-based regimens. For all tumours, central testing for HER2 was performed, and cyclin D1 gene (CCND1) amplification, mRNA and protein expression were assessed by FISH, quantitative real-time-PCR and immunohistochemistry, respectively. Prognostic impact on clinical endpoints was evaluated with Cox regression analyses. Results: After central testing, only 134 (61.2%) of 219 patients were confirmed to have HER2 gene amplification by FISH and/or 3+ HER2 protein expression by immunohistochemistry. After a median follow-up time of 136.0 months (95% CI 123.3 to 148.9), 105 (78.4%) HER2-positive patients and 76 (89.4%) HER2-negative patients had died, while 80% of the former and 87.1% of the latter had experienced a disease relapse. Patients with positive oestrogen receptor/progesterone receptor status presented with higher cyclin D1 mRNA expression. In the HER2-negative subgroup, patients with negative cyclin D1 protein expression were at higher risk of progression (HR= 1.66, 95%CI 1.01 to 2.72, Wald's p=0.045). Among de novo metastatic patients, the risk of progression was higher for patients with non-amplified CCND1 tumours (HR= 2.00, 95% CI 1.03 to 3.90, p=0.041). Conclusion: Aberrant activation of the cyclin D1-mediated pathway appears to reduce the risk of progression in HER2-negative tumours, but not in HER2-positive ones.

10.
Cancer Biomark ; 25(2): 213-221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31045514

RESUMO

BACKGROUND: Colorectal cancer is the fourth cause of cancer related death. Drug resistance and toxicity remain major clinical issues. HOTAIR and MALAT1 are long non-coding RNAS that affect cellular proliferation, apoptosis and drug resistance; their up-regulation has been linked with a poor prognosis. OBJECTIVE: Investigation of the association between rs4759314 HOTAIR and rs3200401 MALAT1 polymorphisms and irinotecan-based chemotherapy in terms of drug efficacy and toxicity. METHODS: Samples from 98 patients receiving different regimens of irinotecan-based therapy were included. Efficacy and toxicity were evaluated. KRAS mutation, rs3200401 HOTAIR and rs4759314 MALAT1 polymorphisms genotyping in the tumors and peripheral blood respectively were performed with PCR. RESULTS: Neither rs3200401 MALAT1 nor rs4759314 HOTAIR polymorphism are associated with response to treatment regimens. Rs4759314 was also not associated with increased toxicity in patients receiving irinotecan-based regimens. CT genotype of rs3200401 was associated with significantly reduced overall survival. An association between KRAS mutation and AG/GG genotypes in the rs4759314 was detected. CONCLUSIONS: CT genotype of rs3200401 MALAT1 polymorphism could serve as a toxicity biomarker. Carriers of the G allele of the rs4759314 HOTAIR are more likely to be carriers of KRAS mutations too. However, further studies in larger patient populations are required.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Irinotecano/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Irinotecano/farmacologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Razão de Chances , Inibidores da Topoisomerase I , Resultado do Tratamento
11.
Transl Oncol ; 12(5): 739-748, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877976

RESUMO

BACKGROUND: Src, CDKN1B, and JAK2 play a crucial role in the coordination of cell signaling pathways. In the present study, we aim to investigate the prognostic significance of these biomarkers in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab (T). METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 197 patients with HER2-positive MBC treated with T were retrospectively collected. All tissue samples were centrally assessed for ER, PgR, Ki67, HER2, and PTEN protein expression; EGFR gene amplification; PI3KCA mutational status; and tumor-infiltrating lympocytes density. Src, CDKN1B, and JAK2 mRNA expression was evaluated using quantitative reverse transcription-polymerase chain reaction. RESULTS: Only 133 of the 197 patients (67.5%) were found to be HER2-positive by central assessment. CDKN1B mRNA expression was strongly correlated with Src (rho = 0.71) and JAK2 (rho = 0.54). In HER2-positive patients, low CDKN1B conferred higher risk for progression [hazard ratio (HR) = 1.58, 95% confidence interval (CI) 1.08-2.32, P = .018]. In HER2-negative patients, low Src was associated with longer survival (HR = 0.56, 95% CI 0.32-0.99, P = .045). Upon multivariate analyses, only low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in de novo and relapsed (R)-MBC patients, respectively (HR = 2.36, 95% CI 1.01-5.48, P = .046 and HR = 1.76, 95% CI 1.01-3.06, P = .047, respectively). CONCLUSIONS: Low CDKN1B and JAK2 mRNA expressions were unfavorable prognosticators in a cohort of T-treated MBC patients. Our results suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T resistance, which seems to be associated with distinct pathways in de novo and R-MBC.

12.
Int J Clin Oncol ; 24(4): 411-419, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30374686

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) targeting represents the standard first-line therapy for metastatic renal-cell carcinoma (mRCC), while blocking the mammalian target of rapamycin (mTOR) is effective in relapsed disease. Since continuing blockade of VEGF may be of value, we studied the combination of bevacizumab with temsirolimus in mRCC patients relapsing after first-line treatment. METHODS: A prospective, phase II study of the combination of bevacizumab (10 mg/kg, every 2 weeks) with temsirolimus (25 mg weekly) in patients with mRCC who failed first-line anti-VEGF treatment. 6-month progression-free survival (PFS) rate was the primary end point. The association of VEGFa, VEGFR2, fibroblast growth factor (FGF) b, platelet-derived growth factor receptor (PDGFR) a and PDGFRb with prognostic factors and outcomes were also studied. RESULTS: 39 patients were enrolled. First-line therapy included: sunitinib (n = 16), bevacizumab/interferon (n = 12), pazopanib (n = 10), sorafenib (n = 1). After a median follow-up of 37 months, 6-month PFS rate was 50.9% [95% confidence interval (CI) 33.8-65.7], median time to progression 6.8 months (95% CI 5.5-9.2) and median overall survival (OS) 18.2 months (95% CI 12.9-27.2). Objective response rate was 27%. The most common AEs were metabolic (33%), renal (8%) and gastrointestinal (GI) (7%). The most common grade 3-5 AEs were GI (18%), infections (14%) and metabolic (25%). Toxicity was the most frequent cause of treatment discontinuation (40%). FGFb levels were associated with OS. CONCLUSIONS: In concert with recent data, our study confirms the efficacy of anti-VEGF/anti-mTOR combination in mRCC relapsing after anti-VEGF therapy. Toxicity was considerable leading to high rate of treatment discontinuations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01264341.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Prospectivos , Pirimidinas/administração & dosagem , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sorafenibe/administração & dosagem , Sulfonamidas/administração & dosagem , Sunitinibe/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
13.
Expert Rev Pharmacoecon Outcomes Res ; 19(4): 491-501, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30417707

RESUMO

Background:Metastatic RCC (mRCC) treatment has been revolutionized with 11 approved targeted agents. We report patterns of practice, outcomes and pharmacoeconomic analyses after the introduction of targeted therapy. Patients and methods: CRISIS was a retrospective multicenter study of mRCCpatients who received targeted therapy . Results were related to the start of 1st-line therapy, with a cut off at 1 January 2011 in order to depict the impact of increased availability of effective options. Results: 164 patients, were included. 70.1% and 44.5% received 2nd and 3rd-line therapy, respectively. More patients were treated in 2nd-line after 1 January 2011. After a median follow-up of 55.1 months, median progression-free (PFS) and overall survival (OS) were 10.7 (95% confidence intervals [CI]: 8.3-13.7), 7.3 (95% CI: 5.1-8.6), 5.8 (95% CI: 3.8-7.8) and 34 (95% CI: 28.5-39.8), 22.4 (95% CI: 16-32.1), 18.3 (95% CI: 12.4-26.4) months for first, second and third line, respectively. Efficacy of sunitinib and pazopanib in 1st-line were similar. The mean total cost/patient was 35,012.2 Euros (standard deviation [SD]: 28,971.5). Conclusions: Our study confirms previous real-world data suggesting that continuing advances in the treatment of mRCC produce favorable outcomes in everyday practice. Pharmacoeconomic analyses are important for cost-effective utilization of emerging novel therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Farmacoeconomia , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/economia , Carcinoma de Células Renais/economia , Análise Custo-Benefício , Intervalo Livre de Doença , Feminino , Seguimentos , Grécia , Humanos , Neoplasias Renais/economia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/economia , Metástase Neoplásica , Padrões de Prática Médica/estatística & dados numéricos , Pirimidinas/administração & dosagem , Pirimidinas/economia , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Sulfonamidas/economia , Sunitinibe/administração & dosagem , Sunitinibe/economia , Taxa de Sobrevida
14.
Oncotarget ; 9(86): 35623-35638, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30479693

RESUMO

Background: We explored the clinical significance of tumor genotypes and immunophenotypes in non-metastatic colorectal cancer (CRC). Methods: In primary tumors (paraffin blocks) from 412 CRC patients treated with adjuvant chemotherapy, we examined pathogenic mutations (panel NGS; 347 informative); mismatch repair (MMR) immunophenotype (360 informative); and CD8+ lymphocyte density (high - low; 412 informative). The primary outcome measure was disease-free survival (DFS). Results: We evaluated 1713 pathogenic mutations (median: 3 per tumor; range 0-49); 118/412 (28.6%) tumors exhibited high CD8+ density; and, 40/360 (11.1%) were MMR-deficient. Compared to MMR-proficient, MMR-deficient tumors exhibited higher CD8+ density (chi-square, p<0.001) and higher pathogenic mutation numbers (p=0.003). High CD8+ density was an independent favorable prognosticator (HR=0.49, 95%CI 0.29-0.84, Wald's p=0.010). Pathogenic BRCA1 and ARID1A mutations were inversely associated with each other (p<0.001), were not associated with MMR-deficiency or CD8+ density, but both independently predicted for unfavorable DFS (HR=1.98, 95%CI 1.12-3.48, p=0.018 and HR=1.99, 95%CI 1.11-3.54, p=0.020, respectively). Conclusion: In non-metastatic CRC, high CD8+ lymphocyte density confers a favorable prognosis and may be developed as a single marker in routine diagnostics. The unfavorable prognostic effect of pathogenic BRCA1 and ARID1A mutations is a novel observation that, if further validated, may improve treatment selection.

15.
Clin Colorectal Cancer ; 17(4): e631-e637, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29980490

RESUMO

BACKGROUND: The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity. RESULTS: Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of < 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]). CONCLUSION: The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Prognóstico , Estudos Prospectivos , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Taxa de Sobrevida , Adulto Jovem
16.
Clin Breast Cancer ; 18(1): 53-62.e3, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28870680

RESUMO

BACKGROUND: The prognostic/predictive value of aberrant MYC gene copies and protein expression is not clear in breast cancer. PATIENTS AND METHODS: Early breast cancer patients were treated with anthracycline-containing chemotherapy within 2 randomized adjuvant trials. MYC gene and centromere-8 status, as well as Myc protein expression were investigated on 1060 paraffin tumors with fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: MYC amplification was present in 45% and polysomy-8 in 23% of the tumors. Cytoplasmic staining was observed in 60% and nuclear staining in 26% of the tumors, strongly correlating with each other but not with MYC gene status. MYC gene amplification in the absence of polysomy-8 was associated with adverse disease-free survival (DFS) and overall survival (OS), and remained as an independent unfavorable prognostic factor in multivariate analysis (Wald P = .022 for DFS; P = .032 for OS), whereas patients with MYC amplification and polysomy-8, with polysomy-8 only, and with normal MYC without polysomy-8 performed significantly better compared with those with MYC gene amplification only. Nuclear Myc protein expression benefitted patients treated with paclitaxel (interaction P = .052 for DFS; P = .049 for OS). This interaction remained independently significant in multivariate analysis for OS (overall P = .028). CONCLUSION: The effect of MYC gene status on breast cancer patient outcome seems to depend on the underlying chromosomal instability and appears unfavorable for tumors with MYC amplification without polysomy. Nuclear Myc protein expression seems predictive for benefit from adjuvant paclitaxel. These data might aid in the interpretation of relevant findings from large clinical trials.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Amplificação de Genes , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Antraciclinas/uso terapêutico , Mama/citologia , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Núcleo Celular/metabolismo , Quimioterapia Adjuvante/métodos , Instabilidade Cromossômica , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adulto Jovem
17.
Curr Probl Cancer ; 41(6): 407-412, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29096940

RESUMO

BACKGROUND: Immune checkpoint inhibitors are novel agents approved for the treatment of late-stage malignancies. Despite its important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects known as immune-related adverse events. Skin toxicities are the most frequent immune-related adverse events during anti-PD1 blockade therapies. Among them, rare cases of psoriasis exacerbation have been reported. METHODS: We present the clinical characteristics of exacerbated psoriasis in 5 patients under anti-PD1/PDL1 therapy. RESULTS: A total of 5 patients were overall included (4 males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1 (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a strong related family history (3/5 siblings). Four out of 5 patients experienced guttate lesions, though the most severe exacerbation was noted in the durvalumab group. Four out of 5 patients managed to continue treatment after close dermatologic monitoring, whereas 1 patient under durvalumab was forced to treatment delays owing to the severity of the skin reactions. Skin rashes appeared in all patients after the fourth cycle of immunotherapy. CONCLUSIONS: Both anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although more severe flares were noted in patients treated with durvalumab. Not only personal but also related family history of psoriasis are significant risk factors and need to be outlined before treatment initiation. If such related history exists, strict skin surveillance can lead to the early diagnosis and treatment of any psoriatic exacerbations that could otherwise severely affect quality of life or even compromise therapeutic protocols and final prognosis.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/terapia , Psoríase/imunologia , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Progressão da Doença , Feminino , Humanos , Imunoterapia/métodos , Masculino , Anamnese , Pessoa de Meia-Idade , Neoplasias/imunologia , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Psoríase/diagnóstico , Psoríase/prevenção & controle , Qualidade de Vida , Medição de Risco , Fatores de Risco
18.
PLoS One ; 12(8): e0180489, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28797035

RESUMO

BACKGROUND-AIM: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. METHODS: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. RESULTS: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively. CONCLUSIONS: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Ciclina D1/análise , Ciclina E/análise , Inibidor de Quinase Dependente de Ciclina p21/análise , Inibidor de Quinase Dependente de Ciclina p27/análise , Proteínas Oncogênicas/análise , Proteína Supressora de Tumor p53/análise , Adulto , Idoso , Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
19.
Transl Oncol ; 10(4): 589-598, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28666187

RESUMO

BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription-polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P=.002 and P<.001, respectively). In the univariate analysis, low RANKL mRNA expression was found to be an unfavorable factor for DFS [hazard ratio (HR)=1.33, 95% confidence interval (CI) 1.05-1.68, Wald's P=.018] and bone metastasis-free survival (HR=1.67, 95% CI 1.09-2.56, P=.018), although it did not retain its significance in the multivariate analysis. CONCLUSIONS: Low RANKL mRNA expression in early breast cancer patients is of prognostic significance for increased risk for relapse and bone metastases and might potentially guide clinical decision-making for the use of anti-RANKL agents in the treatment of early breast cancer patients at high risk for metastatic spread, provided that our findings are validated in independent cohorts.

20.
Anticancer Res ; 37(5): 2323-2334, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28476798

RESUMO

BACKGROUND: The Notch pathway has been implicated in triple-negative breast cancer (TNBC). Herein, we studied the subcellular localization of the less investigated Notch2 and Notch3 and that of the Jagged1 (Jag1) ligand in patients with operable TNBC. PATIENTS AND METHODS: We applied immunohistochemistry for Notch2, Notch3 and Jag1 in 333 tumors from TNBC patients treated with adjuvant anthracycline-based chemotherapy. We evaluated cytoplasmic (c), membranous (m) and nuclear (n) protein localization. RESULTS: c-Notch2 (35% positive tumors), c-Notch3 (63%), c-Jag1 (43%), m-Notch3 (23%) and n-Jag1 (17%) were analyzed individually and by using hierarchical clustering for prognostic evaluation. Upon multivariate analysis, compared to high m-Notch3 in the absence of n-Jag1 (cluster 4), all other marker combinations (clusters 1, 2, 3) conferred significantly higher risk for relapse (p<0.05). CONCLUSION: Specific Notch3 and Jag1 subcellular localization patterns may provide clues for the behavior of the tumors and potentially for Jag1 targeting in TNBC patients.


Assuntos
Proteína Jagged-1/metabolismo , Receptor Notch2/metabolismo , Receptor Notch3/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
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