RESUMO
High-grade serous epithelial ovarian cancer (HGS-EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS-EOC and their route toward malignancy. In our study, -omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS-EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region ß, 495 kb long). Analysis in two external databases confirmed regions α and ß are features of HGS-EOC. The MECOM gene is located in region α, and 15 genes are in region ß. No functional data are yet available for the genes in the ß region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS-EOC, opening up a potential biological role in its etiopathogenesis.
Assuntos
Carcinoma Epitelial do Ovário/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Neoplasias Ovarianas/genética , Biópsia , Carcinoma Epitelial do Ovário/patologia , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Feminino , Genômica , Humanos , Gradação de Tumores , Neoplasias Ovarianas/patologia , Ovário/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC). METHODS: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS). RESULTS: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P<0.001) and shorter CSS (P=0.001). The type of treatment did not influence CSS or RFI in any grade group. We also found a significant association between low-grade tumours and younger age. CONCLUSIONS: Fertility-sparing surgery is an adequate treatment for patients with stage I EOC. The clinical outcome of patients with G3 tumours, which is confirmed to be the most important prognostic factor, is not determined by the type of treatment received.
Assuntos
Carcinoma/cirurgia , Preservação da Fertilidade , Neoplasias Ovarianas/cirurgia , Ovariectomia/métodos , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Carcinoma/mortalidade , Terapia Combinada , Intervalo Livre de Doença , Feminino , Preservação da Fertilidade/efeitos adversos , Preservação da Fertilidade/métodos , Seguimentos , Humanos , Histerectomia/efeitos adversos , Infertilidade Feminina/etiologia , Excisão de Linfonodo , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Omento/cirurgia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Ovariectomia/efeitos adversos , Peritônio/cirurgia , Reoperação , Estudos Retrospectivos , Salpingectomia/efeitos adversosRESUMO
Objective To evaluate the safety, local tumor efficacy and relief of symptoms of electrochemotherapy (ECT) treatment in patients affected by recurrence of vulvar cancer (VC), unsuitable for standard treatments. Methods Ten patients were recruited with histological diagnosis of recurrence of VC. Intravenous bleomycin was injected, after an accurate mapping of all lesions and ECT was performed. Response to therapy was evaluated and quality of life (QoL) was evaluated via questionnaires. Results Diagnosis stage of primary tumors, according to the FIGO system, was: four patients respectively at stage IB (40%), and at stage II (40%), one patient at stage IIIA (10%), one patient with Paget cancer (10%). Mean age was 76 years (SD ± 7) at time of enrollment. Eight patients (80%) were previously submitted to surgery and/or radio-chemotherapy. Mean treatment time was 20 (range 10-20) min. After a median follow-up of 12 (3-22) months, six patients (60%) were alive. Conclusions Objective responses (ORs) with local control of the tumor were obtained in 80%. After a mean follow-up of 12 (3-22) months six patients (60%) were alive. The favorable outcome of this study, indicates that ECT is a reliable treatment option that may improve their functioning, thus enhancing the care provided in the palliative setting.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Bleomicina/uso terapêutico , Eletroquimioterapia/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Cuidados Paliativos/métodos , Neoplasias Vulvares/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Eletroquimioterapia/efeitos adversos , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Neoplasias Vulvares/cirurgiaRESUMO
OBJECTIVE: Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed. MATERIALS AND METHODS: Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease. RESULTS: Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol-containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival. CONCLUSIONS: Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Neoadjuvante , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Adolescente , Adulto , Idoso , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Systematic aortic and pelvic lymphadenectomy (SAPL) is a milestone procedure in the treatment of early stage ovarian cancer. It defines staging and prognosis and helps in tailoring adjuvant chemotherapy. Only limited data are available about SAPL at second look surgery in patients with apparent early stage ovarian cancer who underwent inadequate surgical staging and adjuvant platinum based chemotherapy. METHODS: From January 1991 through January 2013, 66 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA-IIA epithelial ovarian carcinoma suboptimally surgically staged and treated with adjuvant chemotherapy, were referred to our center and underwent second look surgery including SAPL. RESULTS: Twenty-two women underwent bilateral and 44 unilateral SAPL. A total of 2168 nodes were removed and analyzed. The median number of lymph nodes dissected was 29 (range 14-73); in particular it was 29 (range 14-60) in case of unilateral and 37 (range 17-73) in case of bilateral SAPL. Only one woman had nodal metastasis (1.5%). After a median follow-up of 78 months, 10 women (15.2%) relapsed and 5 (7.6%) died of progressive disease. The 5-year disease-free survival and overall survival are 91.7% and 96%. CONCLUSION: The risk of nodal metastases in stage I-IIA unstaged ovarian cancer after adjuvant chemotherapy is negligible. Our study suggests that SAPL at second look is not indicated in this subset of women.
Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Pelve/patologia , Adulto , Idoso , Aorta , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Pelve/cirurgia , Prognóstico , Estudos Retrospectivos , Cirurgia de Second-LookRESUMO
OBJECTIVE: The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. STUDY DESIGN: Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. RESULTS: Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients (P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients (P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. CONCLUSION: Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.
Assuntos
Carcinoma/mortalidade , Neoplasias do Endométrio/mortalidade , Fatores Etários , Idoso , Índice de Massa Corporal , Carcinoma/patologia , Carcinoma/terapia , Terapia Combinada , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Excisão de Linfonodo , Metástase Linfática , Análise Multivariada , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Obesidade Abdominal/epidemiologia , PrognósticoRESUMO
OBJECTIVE: Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached. METHODS: Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy. RESULTS: FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70 mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16 weeks. Between 30 and 36 weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40 days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression. CONCLUSION: During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.
Assuntos
Complicações Neoplásicas na Gravidez/tratamento farmacológico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Quimioterapia Adjuvante , Terapia Combinada , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Terapia Neoadjuvante , Gravidez , Complicações Neoplásicas na Gravidez/patologia , Complicações Neoplásicas na Gravidez/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgiaRESUMO
BACKGROUND: International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer (EOC) has a significantly better prognosis than stage III/IV EOC, with about 80% of patients surviving at 5 years (compared with about 20% of those with stage III/IV EOC). However, 20% of patients with stage I EOC relapse within 5 years. It is therefore crucial that the biological properties of stage I EOCs are further elucidated. MicroRNAs (miRNAs) have shown diagnostic and prognostic potential in stage III and IV EOCs, but the small number of patients diagnosed with stage I EOC has so far prevented an investigation of its molecular features. We profiled miRNA expression in stage I EOC tumours to assess whether there is a miRNA signature associated with overall and progression-free survival (PFS) in stage I EOC. METHODS: We analysed tumour samples from 144 patients (29 of whom relapsed) with stage I EOC gathered from two independent tumour tissue collections (A and B), both with a median follow-up of 9 years. 89 samples from tumour tissue collection A were stratified into a training set (51 samples, 15 of which were from patients who relapsed) for miRNA signature generation, and into a validation set (38 samples, seven of which were from patients who relapsed) for signature validation. Tumour tissue collection B (55 samples, seven of which were from patients who relapsed) was used as an independent test set. The Cox proportional hazards model and the log-rank test were used to assess the correlation of quantitative reverse transcription PCR (qRT-PCR)-validated miRNAs with overall survival and PFS. FINDINGS: A signature of 34 miRNAs associated with survival was generated by microarray analysis in the training set. In both the training set and validation set, qRT-PCR analysis confirmed that 11 miRNAs (miR-214, miR-199a-3p, miR-199a-5p, miR-145, miR-200b, miR-30a, miR-30a*, miR-30d, miR-200c, miR-20a, and miR-143) were expressed differently in relapsers compared with non-relapsers. Three of these miRNAs (miR-200c, miR-199a-3p, miR-199a-5p) were associated with PFS, overall survival, or both in multivariate analysis. qRT-PCR analysis in the test set confirmed the downregulation of miR-200c in relapsers compared with non-relapsers, but not the upregulation of miR-199a-3p and miR-199a-5p. Multivariate analysis confirmed that downregulation of miR-200c in the test set was associated with overall survival (HR 0·094, 95% CI 0·012-0·766, p=0·0272) and PFS (0·035, 0·004-0·311; p=0·0026), independent of clinical covariates. INTERPRETATION: miR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC. FUNDING: Nerina and Mario Mattioli Foundation, Cariplo Foundation (Grant Number 2010-0744), and the Italian Association for Cancer Research.
Assuntos
Biomarcadores Tumorais , MicroRNAs , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Feminino , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Estudos RetrospectivosRESUMO
A cross-sectional study was carried out in a population of North Italy to determine the prevalence of eight oncogenic human papillomavirus (HPV) types most commonly found in cervical carcinoma and to study the relationship between HPV DNA loads and severity of disease. A total of 597 cervical samples obtained from patients with pathological findings (n = 472) and from women with normal cytology (n = 125) were analyzed by means of normalized Real-time PCR assays to quantify HPV-16, -18, -31, -45, and -33 group (including -33, -52, -58, -67); the normalization of oncogenic HPV viral load was carried out by quantitation of a single copy gene. The two most common oncogenic HPV types found were 16 and 31 (24.3% and 22.9% of pathological samples, respectively); multiple infections were demonstrated in 22% of pathological samples. Overall, the HPV total viral load was found to increase with increasing severity of associated lesions, although a stronger association was observed only for HPV-31 and HPV-16 (gamma = 0.49 and 0.41, respectively) as compared to HPV-18 and -33 group (gamma = 0.19 and 0.02, respectively). However, we found that high levels of HPV-31 or 33 group DNA could be prognostic of minor oncogenic risk for high-grade squamous intraepithelial lesions (H-SIL) (age adjusted odds ratio [AORs] = 1.57 and 1.26, respectively) than HPV-16 and HPV-18 (AORs = 30 and 8, respectively). The AORs also increased with HPV total viral load and reached a maximum of AORs = 15.7. Thus, HPV load is a type-dependent risk marker for the development of H-SIL.
Assuntos
Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/virologia , Carga Viral , Adulto , Idoso , Estudos Transversais , DNA Viral/análise , DNA Viral/genética , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/genética , Prevalência , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
BACKGROUND: Five percent to 20% of stage I endometrial cancer patients undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop vaginal and pelvic recurrences. Adjuvant radiotherapy can improve locoregional control but not survival. This randomized trial aimed to determine whether a modified radical (Piver-Rutledge class II) hysterectomy can improve survival and locoregional control compared to the standard extrafascial (Piver-Rutledge class I) hysterectomy. METHODS: Eligible patients (n = 520) with stage I endometrial cancer were randomized to class I or class II hysterectomy. Primary endpoint was overall survival. RESULTS: The median length of parametria and vagina removed were 15 and 5 vs. 20 mm and 15 mm for class I and class II hysterectomy, respectively (P > 0.001). Operating time and blood loss were statistically significantly higher for class II hysterectomy. At a median follow-up of 70 months, 51 patients had died. Five-year disease-free and overall survival were similar between arms (87.7 and 88.9% in the class I arm and 89.7 and 92.2% in the class II arm, respectively). The unadjusted hazard ratios for recurrence was 0.91 (95% confidence interval, 0.55-1.51, P = 0.72), and the hazard ratio for death was 0.77 (95% confidence interval, 0.44-1.33, P = 0.35). CONCLUSIONS: Class II hysterectomy did not improve locoregional control and survival compared to class I hysterectomy, but when an adequate vaginal cuff transection is not feasible with class I hysterectomy, a modified radical hysterectomy allows to obtain an optimal vaginal and pelvic control of disease with a minimal increase in surgical morbidity.
Assuntos
Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/cirurgia , Carcinoma Adenoescamoso/cirurgia , Cistadenocarcinoma Seroso/cirurgia , Neoplasias do Endométrio/cirurgia , Histerectomia/métodos , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/patologia , Adolescente , Adulto , Idoso , Carcinoma Adenoescamoso/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To assess the effectiveness of chemo-surgical conservative therapy for stage IB1 cervical tumors in patients desiring to preserve fertility. METHODS: From 1995 to April 2007 51 nulliparous patients with tumor
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Conização , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Humanos , Histerectomia , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Excisão de Linfonodo , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
OBJECTIVE: To explore the clinicopathologic findings and oncological outcome of early-stage synchronous endometrial and ovarian malignancies. METHODS: A retrospective study of 93 women with synchronous stage I ovarian and stage I-II endometrial cancer treated between December 1981 and August 2005 in the gynecologic oncology department of San Gerardo Hospital, Italy. RESULTS: Fifty-one percent of the ovarian tumors were stage Ia and 71% of the endometrial cancers had minimal myometrial invasion. Endometrioid histology and grade 2 disease were prevalent in both sites. Hyperplasia and endometriosis coexisted in 71% and 22% of endometrial and ovarian cancers, respectively. The actuarial 5-year disease-free and overall survival rates were 83% and 96%, respectively. CONCLUSION: The incidence of synchronous endometrial and ovarian cancer is not negligible, especially among young women. Synchronous cancers show very favorable pathologic features and have an excellent oncologic outcome. Adjuvant therapy should be tailored according to surgical staging and histology.
Assuntos
Neoplasias do Endométrio/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Ovarianas/epidemiologia , Adulto , Comorbidade , Intervalo Livre de Doença , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Invasividade Neoplásica , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Análise de SobrevidaRESUMO
OBJECTIVE: Stage IB-IIA cervical carcinoma can be equally cured either by radical surgery or radiotherapy (RT). Albeit such policies show the same efficacy, they carry a different morbidity. This is an update after 20 years of a previously published randomized trial of RT vs. surgery in the treatment of stage IB-IIA cervical cancers to assess long-term survival and morbidity and the different pattern of relapse between the 2 modalities. METHODS: Between September 1986 and December 1991, women referred for a newly diagnosed stage IB and IIA cervical carcinoma were randomized to radical surgery or RT. The primary outcome measures were long-term survival and complications rate. The secondary outcome was recurrence of the disease. RESULTS: Three-hundred forty-three eligible women were randomized: 172 to radical surgery and 171 to external RT. Minimum follow-up was 19 years. Thirty-three patients (10%) died of intercurrent disease (31 cases) or fatal complications (2 cases). Twenty-year overall survival is 72% and 77% in the 2 treatment groups (p=0.280), respectively. As a whole, 94 recurrences (28%) were observed. Median time to relapse was 13.5 (surgery group) and 11.5 months (radiotherapy group) (p=0.100), respectively. Multivariate analysis confirms that risk factors for survival are histotype (p=0.020), tumor diameter (p=0.008), and lymph node status (p<0.001). CONCLUSION: The results of the present study seem to suggest that there is no treatment of choice for early stage cervical carcinoma in terms of survival. Long term follow-up confirms that the best treatment for the individual patient should take into account clinical factors such as menopausal status, comorbidities, histological type, and tumor diameter.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirurgia , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Histerectomia , Análise Multivariada , Recidiva Local de Neoplasia , Radioterapia de Alta Energia , Fatores de Tempo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologiaRESUMO
Purpose: Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC miR-200c-3p can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNA) to enable potential definition of a non-coding transcriptional signature with prognostic relevance for stage I EOC.Experimental Design: 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set (n = 73) and a validation set (n = 129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression-free survival (PFS).Results: The expression of lnc-SERTAD2-3, lnc-SOX4-1, lnc-HRCT1-1, and PVT1 was associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets (P < 0.001). Using the expression profiles of PVT1, lnc-SERTAD2-3, and miR-200c-3p simultaneously, it was possible to stratify patients into high and low risk. The OS for high- and low-risk individuals are 36 and 123 months, respectively (OR, 15.55; 95% confidence interval, 3.81-63.36).Conclusions: We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC. Clin Cancer Res; 23(9); 2356-66. ©2016 AACR.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Prognóstico , RNA Longo não Codificante/genética , Adulto , Idoso , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Estudos RetrospectivosRESUMO
PURPOSE: Neoadjuvant chemotherapy may represent an alternative to irradiation in locally advanced squamous cell cervical cancer. Aims of this study were to compare a three-drug (paclitaxel, ifosfamide, and cisplatin [TIP]) with a two-drug (ifosfamide and cisplatin [IP]) regimen and to assess the prognostic value of pathologic response on survival. PATIENTS AND METHODS: Patients (n = 219) were randomly assigned to ifosfamide 5 g/m(2) during 24 hours plus cisplatin 75 mg/m(2), or paclitaxel 175 mg/m(2) plus ifosfamide 5 g/m(2) during 24 hours and cisplatin 75 mg/m(2) every 3 weeks for three courses. RESULTS: Grades 3 to 4 neutropenia, anemia, and thrombocytopenia were more frequent with TIP. We recorded four deaths related to toxicity. The optimal pathologic response (OPT) rate (residual disease < 3 mm stromal invasion) was higher with TIP than with IP (48% v 23%; odds ratio, 3.22; 95% CI, 1.69 to 5.88; P = .0003). At a median follow-up of 43.4 months, 79 women experienced disease progression or died (46 in the IP arm, 33 in the TIP arm). Patients receiving TIP experienced a treatment failure rate 25% less than those receiving IP, but this difference was not statistically significant (hazard ratio [HR], 0.75; 95% CI, 0.48 to 1.17; P = .20). Sixty-one patients died (37 in the IP arm, 24 in the TIP arm), and the HR of death was in favor of TIP, although not significantly (HR, 0.66; 95% CI, 0.39 to 1.10; P = .11). In patients assessable for response (n = 189), the average death rates were higher in the group that did not achieve OPT (HR, 5.88; 95% CI, 2.50 to 13.84; P < .0001). CONCLUSION: The TIP regimen is associated with a higher response rate than the IP regimen, without a statistically significant effect on overall survival. OPT was a prognostic factor for survival.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/uso terapêutico , Ifosfamida/uso terapêutico , Taxoides/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adulto , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Itália , Modelos Logísticos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Análise de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. alpha(1)-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. PATIENTS AND METHODS: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. RESULTS: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C (max) and AUC(0-last) of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC(0-last) showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. CONCLUSION: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.
Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Clindamicina/farmacologia , Orosomucoide/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/farmacocinética , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Clindamicina/metabolismo , Esquema de Medicação , Interações Medicamentosas , Feminino , Humanos , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Ligação ProteicaRESUMO
PURPOSE: The PRL-3 phosphatase has been found expressed at higher levels in metastasis than in primary tumors of patients with colorectal cancer. In the present study, we evaluated the expression of PRL-3 in ovarian cancer tissue and its role in ovarian cancer cell growth. EXPERIMENTAL DESIGN: PRL-3 phosphatase expression was evaluated in 84 ovarian tumor samples. PRL-3 expression has been knocked down using specific small interfering RNAs to determine its role in ovarian cancer cell growth in vitro. RESULTS: In ovarian cancers, PRL-3 expression correlates with disease progression, being higher in advanced (stage III) than in early (stage I) tumors. In situ measurements of PRL-3 expression showed that it was confined to the epithelial neoplastic cells. The molecular mechanism underlying PRL-3 overexpression in ovarian cancers is independent from amplification of the corresponding genomic locus. Ovarian cancer cells growing in culture have high levels of expression of this phosphatase. PRL-3-specific knockdown using small interfering RNA severely impaired the growth of cells without affecting the expression of the closely related homologue PRL-1. Intriguingly, the growth of human colon carcinoma cells expressing lower levels of the PRL-3 was not affected by the PRL-3 knockdown. CONCLUSIONS: Altogether, these results show that PRL-3 expression is associated with ovarian cancer progression and point to a key role for this phosphatase in the control of ovarian cancer cells growth. This strongly suggests that PRL-3 should be considered as a target for the discovery of new anticancer agents to be tested against this malignancy.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Imediatamente Precoces/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Ovarianas/enzimologia , Proteínas Tirosina Fosfatases/fisiologia , Antineoplásicos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Células Epiteliais/metabolismo , Feminino , Humanos , Hibridização In Situ , RNA/química , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fatores de TempoRESUMO
PURPOSE: Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity. PATIENTS AND METHODS: Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B). RESULTS: Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS. CONCLUSION: Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Histerectomia , Excisão de Linfonodo , Terapia Neoadjuvante , Neoplasias do Colo do Útero/terapia , Adulto , Idoso , Análise de Variância , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Intervalo Livre de Doença , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Modelos de Riscos Proporcionais , Lesões por Radiação/epidemiologia , Taxa de Sobrevida , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/radioterapiaRESUMO
BACKGROUND: The present study is aimed to identify genetic pathways correlated with chemoresistance in epithelial ovarian cancer (EOC). METHODS: We compared the molecular profiles of 23 tumour biopsies of stage III-IV (training set) at primary surgery, before chemotherapy, to the profile from the same patients at second surgery, after several lines of platinum (Pt)-based chemotherapy when the tumours were resistant. In the hypothesis that identified markers were related to Pt-resistance and to prognosis, we validated this signature in 52 EOC taken at primary surgery (validation set) selected to be either very sensitive to the first line therapy, i.e. not relapsing before one year from the end of therapy, or resistant, i.e. relapsing within 6 months from the end of therapy. RESULTS: In the training set, we identified a resistance signature indicative of the activation of epithelial to mesenchymal transition (EMT) by transforming growth factor (TGF)-beta pathway. We then validated this signature in 52 EOC taken at primary surgery (validation set). Some genes involved in EMT, such as BMP and activin membrane-bound inhibitor (BAMBI), and mir-141 resulted in association with overall or progression free survival. CONCLUSION: Some genes involved in EMT were associated to overall or progression free survival, suggesting EMT as vital to the resistance mechanisms.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transição Epitelial-Mesenquimal/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Adulto , Idoso , Biópsia , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/genética , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/genética , Transdução de Sinais , Resultado do TratamentoRESUMO
PURPOSE: Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic diseases, with survival rate virtually unchanged for the past 30 years. EOC comprises different histotypes with molecular and clinical heterogeneity, but up till now the present gold standard platinum-based treatment has been conducted without any patient stratification. The aim of the present study is to generate microRNA (miRNA) profiles characteristic of each stage I EOC histotype, to identify subtype-specific biomarkers to improve our understanding underlying the tumor mechanisms. EXPERIMENTAL DESIGN: A collection of 257 snap-frozen stage I EOC tumor biopsies was gathered together from three tumor tissue collections and stratified into independent training (n = 183) and validation sets (n = 74). Microarray and quantitative real-time PCR (qRT-PCR) were used to generate and validate the histotype-specific markers. A novel dedicated resampling inferential strategy was developed and applied to identify the highest reproducible results. mRNA and miRNA profiles were integrated to identify novel regulatory circuits. RESULTS: Robust miRNA markers for clear cell and mucinous histotypes were found. Specifically, the clear cell histotype is characterized by a five-fold (log scale) higher expression of miR-30a and miR-30a*, whereas mucinous histotype has five-fold (log scale) higher levels of miR-192/194. Furthermore, a mucinous-specific regulatory loop involving miR-192/194 cluster and a differential regulation of E2F3 in clear cell histotype were identified. CONCLUSIONS: Our findings showed that stage I EOC histotypes have their own characteristic miRNA expression and specific regulatory circuits.