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1.
Medicine (Baltimore) ; 99(9): e19295, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118743

RESUMO

BACKGROUND: Preoperative chemoradiotherapy (CRT) is one standard option for localized esophageal or gastroesophageal junction (GEJ) cancer patients but an optimal concurrent chemotherapy combination is not established. METHODS: 412 patients with resectable (cT1N1M0 or cT2-4N0-3M0) esophageal or GEJ cancer treated at the MDACC between October 2002 and June 2016 were analyzed. Exposures: CRT with DF or FOX followed by surgery (trimodality; TMT). Main outcomes and measures: Primary endpoints were overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox analyses were performed. RESULTS: Of the 412 patients analyzed, 264 (64%) received DF and 148 (36%) FOX. The median age was 60 years, and 95% had adenocarcinoma. The clinical complete response, positron-emission tomography response, and pathologic complete response rates were 73%, 73%, and 30%, respectively. Median follow-up was 60.4 months. Median OS for the entire cohort was 81.6 months (95% confidence interval [CI], 56.3-122.0); 81.6 months (95% CI, 55.9-not estimable) for the DF group and 67.7 months (95% CI, 41.6-not estimable) for the FOX group (P = .24). The median DFS was 45.6 months (95% CI, 33.1-61.7) for the entire cohort; 49.5 months (95% CI, 38.6-70.3) for DF and 33.0 months (95% CI, 18.1-70.4; P = .38) for FOX. Higher tumor location (unfavorable) and clinical complete response (favorable) were prognostic for both OS and DFS in the multivariate analysis. CONCLUSION: At our high-volume center, the outcome of 412 TMT esophageal cancer patients was excellent. Taxane-based chemotherapy produces nonsignificant favorable trend.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Compostos de Platina/uso terapêutico , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Hidrocarbonetos Aromáticos com Pontes/normas , Quimiorradioterapia/normas , Quimiorradioterapia/estatística & dados numéricos , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Quimioterapia Combinada/estatística & dados numéricos , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Platina/normas , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Sobrevida , Taxoides/normas , Texas , Resultado do Tratamento
2.
Int J Cancer ; 146(2): 487-495, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31119730

RESUMO

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15-4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41-5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26-9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prevalência , Taxoides/uso terapêutico , Adulto Jovem
3.
BMC Cancer ; 19(1): 962, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619197

RESUMO

BACKGROUND: We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. METHODS: Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). RESULTS: This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). CONCLUSIONS: The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. TRIAL REGISTRATION: Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Adulto , Idoso , Antraciclinas/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Taxoides/uso terapêutico , Tegafur/administração & dosagem , Tegafur/efeitos adversos
4.
Zhonghua Zhong Liu Za Zhi ; 41(8): 587-593, 2019 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-31434449

RESUMO

Objective: To assess the association of single nucleotide polymorphisms (SNPs) in SLCO1B3 gene with prognosis of breast cancer (BC) patients treated with neoadjuvant chemotherapy of TA regimen (taxane and antharcycline drugs). Methods: 439 female BC patients were recruited and treated with neoadjuvant chemotherapy of TA regimen. A blood sample (2 ml) of peripheral blood was collected from each patient before chemotherapy. Tagging SNPs (tag-SNPs) were selected. We investigated the association of tag-SNPs with prognosis, by Sequenom Mass ARRAY system platform, characterizing tag-SNPs. The hazard ratio (HR) and 95% confidence interval (CI) for progression or death were calculated by multivariable-adjusted Cox regression model. Results: Seven tag-SNPs (rs11045689, rs200104106, rs3764006, rs3834935, rs4149117, rs7305323 and rs73241801) were selected for study. Compared with individuals carrying the rs11045689 GG genotype, individuals carrying rs11045689 AA genotype performed worse PFS and OS, with the HR (95% CI) for progression being 1.39 (1.11~1.75) and the HR (95% CI) for death being 1.38 (1.04~1.83). Compared with individuals carrying the rs73241801 CC genotype, individuals carrying rs73241801 TT genotype performed better OS (P=0.041), with the HR (95% CI) for death being 0.65 (0.44~0.94). The number of risk allele was significantly associated with PFS (P=0.012) and OS (P=0.017) of BC patients by accumulation analysis. Compared with individuals carrying one or less than one risk allele, individuals carrying four risk alleles performed worse PFS and OS, with the HR (95% CI) for progression being 1.37 (1.09~1.72) and the HR (95% CI) for death being 1.36 (1.02~1.81). Conclusion: The variations of rs11045689 and rs73241801 in SLCO1B3 gene were significantly associated with prognosis of BC patients treated with neoadjuvant chemotherapy of TA regimen, which might serve as biomarkers for predicting prognosis of BC patients treated with neoadjuvant chemotherapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Genótipo , Humanos , Terapia Neoadjuvante , Polimorfismo de Nucleotídeo Único , Prognóstico , Taxoides/uso terapêutico
5.
Asia Pac J Clin Oncol ; 15(6): 377-382, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31321873

RESUMO

BACKGROUND: Pertuzumab, when combined with trastuzumab and chemotherapy, is a highly active human epidermal growth factor receptor 2 (HER2), targeting agent in the neoadjuvant, adjuvant and first-line metastatic HER2-positive breast cancer setting. The efficacy of late-line (after first/second-line) pertuzumab in combination with trastuzumab and chemotherapy is unknown. AIMS: To establish pertuzumab efficacy by performing an audit of patients who received pertuzumab after first-line HER2 directed therapy. We sought to establish whether efficacy differed by clinicopathological factors. METHODS: The primary endpoint was progression-free survival (PFS) and the secondary endpoint, overall survival (OS). Clinicopathological factors, PFS and OS data were collated and clinicopathological factors associated with PFS were evaluated using Cox regression models. RESULTS: Fourteen women were identified. Six (43%) had hormone receptor (HR) negative and eight (57%) had HR-positive, metastatic HER2-positive breast cancer. Median follow up was 22.8 months, median prior lines of therapy were 5 (range: 1-9). Median time from diagnosis of metastatic disease to receiving pertuzumab was 4.5 years (range: 4.2-5.8). All patients received initial chemotherapy with pertuzumab and trastuzumab (taxane-based 71%). Median PFS was 9 months (95% confidence interval [CI]: 7-not estimable [NE]) and median OS was not reached (95% CI, 16 months-NE). Univariable analysis demonstrated that HR-negative patients had a significantly longer PFS than HR-positive patients (hazard ratio = 0.11; 95% CI, 0.01-0.88; P = 0.04). CONCLUSION: This small cases series reports a favorable PFS and OS for pertuzumab with trastuzumab and chemotherapy in the later line metastatic setting. This finding warrants further study.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Austrália , Neoplasias da Mama/mortalidade , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2 , Estudos Retrospectivos , Taxoides/uso terapêutico , Trastuzumab/administração & dosagem
6.
Drugs ; 79(11): 1231-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267481

RESUMO

For more than 20 years, the combination of a platinum agent and a taxane has served as the primary chemotherapy strategy for epithelial ovarian cancer. Alternative approaches employing these drugs (intraperitoneal drug delivery, neoadjuvant therapy) have favorably impacted outcomes in selected patient populations. Multiple single agent and combination therapy strategies have been delivered in the second-line (or later) setting with the goal to prolong survival and optimize quality-of-life. The anti-angiogenic agent bevacizumab has been shown to be clinically active when added to chemotherapy and delivered as a "maintenance" strategy in the front-line, platinum-sensitive recurrent and platinum-resistant settings. Several poly-(ADP-ribose) polymerase (PARP) inhibitors are currently utilized as single-agent "second-line" treatment options or in the maintenance setting. Recent clinical research efforts in ovarian cancer have focused on the potential role of checkpoint inhibitors used alone or in combination with PARP inhibitors or anti-angiogenic agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Terapia Neoadjuvante , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Taxoides/uso terapêutico
7.
Prostate ; 79(14): 1597-1603, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31361358

RESUMO

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies. METHODS: A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory. RESULTS: From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with 177 Lu-PSMA-617. Serum PSA declines were seen in 7 of 8 (88%) of the treatment periods where PSMA decreased. CONCLUSIONS: PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.


Assuntos
Antígenos de Superfície/sangue , Glutamato Carboxipeptidase II/sangue , Recidiva Local de Neoplasia/terapia , Células Neoplásicas Circulantes/química , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Dipeptídeos/uso terapêutico , Glutamato Carboxipeptidase II/genética , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Projetos Piloto , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/genética , Neoplasias de Próstata Resistentes à Castração/sangue , RNA Mensageiro/sangue , Receptores Androgênicos/efeitos dos fármacos , Estudos Retrospectivos , Taxoides/uso terapêutico , Resultado do Tratamento
8.
Breast Cancer ; 26(6): 826-834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31254201

RESUMO

BACKGROUND: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. METHODS: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. RESULTS: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. CONCLUSIONS: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autopsia , Índice de Massa Corporal , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Comorbidade , Feminino , Alemanha , Insuficiência Cardíaca/complicações , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Pneumonia/complicações , Estudos Prospectivos , Embolia Pulmonar/complicações , Fatores de Risco , Sepse/complicações , Taxoides/efeitos adversos , Taxoides/uso terapêutico
9.
BMC Cancer ; 19(1): 517, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31146717

RESUMO

BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Humanos , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Proteínas de Membrana/metabolismo , Mutação , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , RNA Mensageiro/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Análise de Sobrevida , Taxoides/uso terapêutico , Trastuzumab/uso terapêutico
10.
Medicine (Baltimore) ; 98(19): e15608, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083254

RESUMO

BACKGROUND: androgen receptor variant 7 (AR-V7) has been suggested as potential marker for treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). The aim of the present review is to critically analyze: frequency of the AR-V7 expression in mCRPC cases-impact of AR-V7 expression on abiraterone, enzalutamide, and taxane therapy. METHODS: we searched in the Medline and Cochrane Library database from the literature of the past 10 years. We critically evaluated the level of evidence according to the European Association of Urology (EAU) guidelines. RESULTS: 12 clinical trials were selected. The determination of AR-V7 in peripheral blood using circulating tumor cells mRNA seems to be the preferred method. At baseline, the mean percentage of cases with AR-V7 positivity was 18.3% (range 17.8%-28.8%). All data on mCRPC submitted to enzalutamide or abiraterone reported a significantly (P <.05) lower clinical progression-free survival (CPFS) and overall survival (OS) in AR-V7+ than AR-V7- cases (CPFS hazard ratio [HR]: 2.3; 95% CI 1.1-4.9; OS HR: 3.0; 95% CI 1.4-6.3). In mCRPC cases submitted to chemotherapies data are not homogeneous and some studies showed no association between CPFS or OS and AR-V7 status (OS HR 1.6; 95% CI 0.6-4.4; P = .40). CONCLUSIONS: the suggestion is that taxane therapy is more efficacious than abiraterone or enzalutamide for men with AR-V7+ CRPC. On the contrary, clinical outcomes did not seem to differ significantly on the basis of the type of therapy used among AR-V7- cases.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Androstenos/uso terapêutico , Biomarcadores Tumorais/genética , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Variação Genética , Humanos , Masculino , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Taxoides/uso terapêutico
11.
J Obstet Gynaecol Res ; 45(7): 1423-1428, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31060113

RESUMO

Sex cord tumor with annular tubules (SCTAT) is rare, and 20% of SCTAT cases, excluding those associated with Peutz-Jeghers syndrome, are clinically malignant. Limited data is available regarding the role of chemotherapy in the management of SCTAT. We encountered a 44-year-old woman with recurrent SCTAT complicated by peritoneal dissemination following a right adnexectomy. The surgical resection could not be performed completely due to the wide extension of the tumor. Considering the potential of becoming malignant, we chose a combination of bleomycin, etoposide and cisplatin (BEP) as postoperative chemotherapy treatment. However, the patient showed partial response following a complete BEP regimen. The patient received three courses of chemotherapy with docetaxel and carboplatin plus bevacizumab. After the combination chemotherapy, positron emission tomography-computed tomography scan confirmed a complete response, and is currently continuing bevacizumab treatment without relapsing and having no major adverse effects from complications. This case proved the potential of a combination of taxane and bevacizumab in patients with recurrent SCTAT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Tumores do Estroma Gonadal e dos Cordões Sexuais/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Feminino , Humanos , Neoplasias Ovarianas/patologia , Ovário/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia
12.
Nat Biomed Eng ; 3(4): 264-280, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952988

RESUMO

Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas/uso terapêutico , Receptor EphA2/metabolismo , Animais , Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Docetaxel/sangue , Docetaxel/química , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Humanos , Lipossomos , Camundongos Endogâmicos NOD , Camundongos SCID , Taxoides/farmacologia , Taxoides/uso terapêutico , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Lung Cancer ; 131: 122-127, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31027688

RESUMO

INTRODUCTION: Median survival of small-cell lung cancer (SCLC) patients is usually around 1 year. The advent of new drugs may have slightly improved their prognosis. We aimed to assess whether SCLC response to chemotherapy and survival had changed over time. METHODS: Consecutive SCLC patients were included at Grenoble University Hospital, France. We compared the patients' characteristics, response to chemotherapy and survival between 1997-2009 (period 1) and 2010-2017 (period 2). RESULTS: A total of 529 patients were identified, of whom 498 received a first line of chemotherapy and 279 a second line. The majority (n = 290, 58%) had extensive disease. The objective response rate (ORR) to first-line chemotherapy in metastatic patients was 63% in period 1 and 62% in period 2; the ORRs to second-line chemotherapy were 39% and 29%, respectively. Median overall survival from first-line chemotherapy was 13.2 months (interquartile range [IQR] 7.4-24.4) in period 1 and 11.2 months (IQR 7.1-21.2) in period 2. Mortality in these two periods did not differ significantly even after adjustment for prognostic factors (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.66-1.00). The factors independently associated with death were cardiovascular comorbidities (HR = 1.28 [95%CI 1.05-1.55]), liver comorbidities (HR = 1.31 [95%CI 1.03-1.65]), poor ECOG performance status (3-4vs. 0-1, HR = 2.45 [95%CI 1.83-3.30]) and extensive disease (HR = 2.69 [95%CI 2.18-3.33]). CONCLUSIONS: Since 1997, there has been no improvement in the survival or response rate to chemotherapy of SCLC patients. There is a desperate need for new approaches in this setting.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Etoposídeo/uso terapêutico , Hepatopatias/epidemiologia , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Feminino , França/epidemiologia , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida
14.
Future Oncol ; 15(12): 1323-1334, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30942088

RESUMO

Aim: Investigate the effectiveness of chemotherapy for first-line (1L) treatment of metastatic bladder cancer (mBC). Methods: Retrospective cohort study evaluating treatment patterns/outcomes in 1155 mBC patients receiving initial treatment in the community practice setting from January 2010 to June 2014, and followed through July 2016. Results: The most commonly utilized 1L and second-line (2L) regimens were platinum-based and taxane-based, respectively. Median (95% CI) OS for all patients from 1L initiation was 12.8 months (11.7-14.6), and median OS for all 2L regimens was 9.4 months (8.2-11.1). Conclusion: mBC patients eligible for and who received cis-based regimens experienced better OS results. Poor renal function was a key driver of cis-ineligibility. The various monotherapy and combination chemotherapy regimens in 2L produced relatively short OS outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Registros Eletrônicos de Saúde/estatística & dados numéricos , Neoplasias da Bexiga Urinária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Taxoides/uso terapêutico , Estados Unidos/epidemiologia , Neoplasias da Bexiga Urinária/tratamento farmacológico
15.
BMC Cancer ; 19(1): 236, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30935371

RESUMO

BACKGROUND: Triple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options. METHODS: NUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated. RESULTS: We have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy. CONCLUSIONS: We have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients.


Assuntos
Antraciclinas/uso terapêutico , Antineoplásicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Antraciclinas/farmacologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
16.
Breast Cancer Res Treat ; 175(3): 627-635, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30900137

RESUMO

PURPOSE: In high-risk early breast cancer, adjuvant taxane-Gemcitabine combinations result in a recurrence-free survival similar to single-agent taxanes. However, haematologic toxicities and need for dose reductions are more frequent in combinations. Which option ultimately provides a better quality of life (QoL) is unknown. We compared the QoL curves before, during, and up to one year after three cycles of Fluorouracil-epirubicin-cyclophosphamide followed by three cycles of Docetaxel-Gemcitabine or Docetaxel. METHODS: Overall, 3691 women with recent R0-resection of a primary epithelial breast cancer participated in the nationwide SUCCESS A clinical trial. The centres sent QoL questionnaires of the European Organisation for Research and Treatment of Cancer before and up to 15 months after randomisation to Docetaxel-Gemcitabine versus Docetaxel. Multilevel analysis by chemotherapy arm estimated the QoL time curves, questionnaire return, and dropout. RESULTS: The combination caused one-point higher global QoL (95% confidence ±1; p = 0.05) and 1.1 lower odds of adherence to the outcome (95% confidence 1.0-1.1; p = 0.23) than the monotherapy. In both groups, a 10-point decrease during therapy preceded a 16-point increase after chemotherapy (p < 0.001). The secondary QoL outcomes showed transient superiority of the combination at the end of chemotherapy. Discontinuation from chemotherapy and its reasons were equal in both groups. CONCLUSIONS: While patients perceive a one-point QoL difference as meaningless, a six-point increase is clinically relevant for them. That is, both regimens cause the same relevant long-term QoL improvement. With the similar recurrence-free survival, the lower toxicity, and the shorter chemotherapy duration in mind, taxanes without Gemcitabine are the preference. This challenges previous recommendations supporting combinations.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Desoxicitidina/análogos & derivados , Qualidade de Vida/psicologia , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/urina , Neoplasias da Mama/psicologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
17.
Support Care Cancer ; 27(10): 3905-3912, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30770977

RESUMO

PURPOSE: While older adults with cancer are more likely to develop chemotherapy-induced peripheral neuropathy (CIPN), the study aimed to determine if patient-reported and objective measures of CIPN differ by age among cancer survivors. METHODS: Cancer survivors with persistent CIPN after completion of platinum and/or taxane chemotherapy completed CIPN questionnaires (severity, interference with activities, sensory, and motor symptoms) and objective testing (light touch, vibration, pain, cold sensation). CIPN measures were compared by age group (< 65 n = 260 versus ≥ 65 n = 165) using parametric and nonparametric tests. RESULTS: Among 425 cancer survivors with CIPN, mean age was 60.9 (SD 10.5). CIPN location did not differ by age (overall 68% hands and feet, 27% only feet, 5% only hands). For patient-reported measures, older survivors reported less severe pain in the hands and feet than younger survivors. In addition, older survivors reported lower interference with general activity, routine activities, normal work, enjoyment of life, sleep, mood, relations with other people, and sexual activity. No age differences in sensory and motor symptom scores were found. In contrast, for objective measures, older survivors had worse light touch and cold sensations in their feet and worse vibration detection in their hands and feet. CONCLUSIONS: Despite having worse light touch, cold, and vibration sensations, older cancer survivors with CIPN reported less severe pain and interference with activities. This discordance highlights the importance of including both patient-reported and objective measures to assess CIPN in cancer survivors to better evaluate this clinical condition.


Assuntos
Antineoplásicos/efeitos adversos , Sobreviventes de Câncer/estatística & dados numéricos , Dor/diagnóstico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Autorrelato/estatística & dados numéricos , Idoso , Antineoplásicos/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Platina/efeitos adversos , Platina/uso terapêutico , Inquéritos e Questionários , Taxoides/efeitos adversos , Taxoides/uso terapêutico
18.
Integr Cancer Ther ; 18: 1534735419828823, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30741022

RESUMO

Individuals diagnosed with chemotherapy-induced peripheral neuropathy (CIPN) demonstrate impaired balance and carry an increased risk of falling. However, prior investigations of postural instability have only compared these individuals against healthy controls, limiting the understanding of impairments associated with CIPN. Therefore, the purpose of this study was to better isolate postural control impairments that are associated with CIPN. Twenty cancer survivors previously diagnosed with breast or colorectal cancer participated. Participants were separated into 3 groups: no prior chemotherapy exposure (CON, n = 6), and recent treatment with taxane- or oxaliplatin-based chemotherapy with no/mild symptoms of CIPN (-CIPN, n = 8) or moderate/severe symptoms of CIPN (+CIPN, n = 6). Postural control was assessed by measuring center of pressure during standing balance conditions that systematically interfered with somatosensory, visual, and/or vestibular information. The presence of CIPN sensory symptoms was associated with impaired postural control, particularly during eyes-closed balance conditions ( P < .05). Additionally, medial-lateral postural instability was more pronounced in the +CIPN group compared with the -CIPN group and CON participants ( P < .05). Greater postural instability during eyes-closed balance in individuals with CIPN is consistent with impaired peripheral sensation. Balance impairments in cancer survivors with CIPN demonstrate the unique challenges in this population and motivate the need for targeted efforts to mitigate postural control deficits that have previously been associated with fall risk.


Assuntos
Antineoplásicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/etiologia , Equilíbrio Postural/fisiologia , Acidentes por Quedas , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Sobreviventes de Câncer , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Taxoides/efeitos adversos , Taxoides/uso terapêutico
19.
Breast Cancer Res Treat ; 175(2): 267-276, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30806923

RESUMO

PURPOSE: Chemotherapy-induced alopecia (CIA) remains a distressing adverse event of cancer treatment but may be prevented by scalp cooling. The effectiveness of scalp cooling, however, is dependent on the chemotherapy regimen with successful hair preservation (i.e., < 50% hair loss) in 41-59% of women on taxane-based therapies in comparison to 16-36% on anthracycline-based therapies. Despite the potential utility, use of scalp cooling has shown a more equivocal impact on quality of life (QoL). In this review, we aim to evaluate the use of scalp cooling for CIA and quantitative QoL measures. METHODS: A systematic review of PubMed, Embase, Web of Science, and Cochrane databases for clinical studies on scalp cooling to prevent CIA published before October 29, 2018 was performed. Clinical studies with 5 or more patients that reported on a quantitative QoL measure were included and graded according to a modified five-point scale from the Oxford Centre for Evidence-Based Medicine. RESULTS: Studies meeting inclusion criteria included 4 randomized clinical trials (RCT), 8 cohort studies, and 1 cross-sectional study with 1282 unique patients. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30: 46%) and Breast Cancer Module (QLQ-BR23: 46%) represented the most commonly used QoL assessments. Overall, 4 (31%) of the 13 studies concluded that scalp cooling was associated with significant improvements in QoL measures; 8 (62%) determined that there was either non-significant or no improvements; and 1 (7.7%) provided a mixed conclusion. Although 2 (50%) RCT demonstrated that scalp cooling can effectively prevent CIA depending on the chemotherapy regimen, these studies did not show that successful hair preservation was associated with improved QoL measures. CONCLUSIONS: This review demonstrates that scalp cooling is not consistently associated with significant QoL improvements as assessed by EORTC QLQ-C30 and -BR23. Representing a critical limitation, more than one-third of the studies did not subcategorize QoL outcomes for successfully or unsuccessfully scalp-cooled patients but rather reported on QoL measures for all scalp-cooled patients in general. Failure to prevent hair loss in patients undergoing an expensive and potentially uncomfortable treatment likely contributes to decreased well-being, impacting the overall distribution of QoL measures in scalp cooling patients compared to controls. Future studies should incorporate validated QoL instruments specific to hair disease and classify QoL outcomes for scalp-cooled patients based on the degree of hair preservation.


Assuntos
Alopecia/prevenção & controle , Neoplasias da Mama/tratamento farmacológico , Crioterapia , Quimioterapia de Indução/efeitos adversos , Alopecia/induzido quimicamente , Alopecia/patologia , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Feminino , Humanos , Qualidade de Vida , Couro Cabeludo/patologia , Taxoides/efeitos adversos , Taxoides/uso terapêutico
20.
J Neurooncol ; 142(3): 455-462, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30726533

RESUMO

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. METHODS: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m2 i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. RESULTS: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. CONCLUSION: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01989884.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida
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