RESUMEN
Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.
Asunto(s)
Carcinoma/genética , Carcinoma/patología , Hemangiosarcoma/genética , Hemangiosarcoma/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cervical cancer cells often express Epidermal Growth Factor Receptor (EGFR). Cetuximab (CET), an anti-EGFR antibody, can be safely combined with carboplatin (C) and paclitaxel (P), a standard treatment for advanced/recurrent cervical cancer (ARCC) patients. PATIENTS AND METHODS: ARCC patients, ECOG PSâ¯≤â¯1, were randomized to CP for 6â¯cycles with or without CET (400â¯mg/m2 one week before starting CP, then 250â¯mg/m2 weekly) until disease progression or unacceptable toxicity. Event-free survival (EFS) was the primary endpoint. With a 4.5â¯months expected median EFS and a 6.4â¯months predicted EFS (HR 0.70), 0.20 one-tailed α and 80% power, 89 events were required for the final intent-to-treat analysis. RESULTS: 108 patients were assigned to CP (nâ¯=â¯53) or CP-CET (nâ¯=â¯55). Median age was 50, 69% were PS0, 76% had recurrent disease, 91% had distant metastasis and 57% had received previous chemotherapy. After a median follow-up of 23â¯months, 102 patients had an event, 97 progressed and 61 died. Median EFS was 4.7 and 6.0â¯months (one-tail Pâ¯=â¯0.43), median PFS was 5.2 and 7.6â¯months (one-tail Pâ¯=â¯0.20) and median OS was 17.7 and 17â¯months (one-tail Pâ¯=â¯0.27), with CP and CP-CET, respectively. There was no difference in the occurrence of severe adverse events, except for skin toxicity. Biomarker analysis, in a small subgroup of patients, suggests that PIK3CA mutation might be predictive of CET resistance. CONCLUSION: CP-CET was not more active than CP alone in unselected ARCC patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Cetuximab/administración & dosificación , Fosfatidilinositol 3-Quinasa Clase I/genética , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Paclitaxel/administración & dosificación , Supervivencia sin Progresión , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias del Cuello Uterino/genéticaRESUMEN
Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Mutación , Telomerasa/genética , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/enzimología , Displasia del Cuello del Útero/patologíaRESUMEN
BACKGROUND: Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer. METHODS: We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model. FINDINGS: We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months [95% CI 15-22]) and a low-risk group (90 patients; median progression-free survival 38 months [24-not estimable]; hazard ratio [HR] 1·85 [1·29-2·64], p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33-4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11-1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03-2·13, p=0·036; OC263: adjusted HR 3·09 [2·24-4·28], p<0·0001; and OC452: HR 1·41 [1·11-1·79], p=0·0047). INTERPRETATION: MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay. FUNDING: AIRC and CARIPLO Foundation.
Asunto(s)
Adenocarcinoma de Células Claras/patología , Adenocarcinoma Mucinoso/patología , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/patología , MicroARNs/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/cirugía , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Estudios de Cohortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirugía , Progresión de la Enfermedad , Neoplasias Endometriales/genética , Neoplasias Endometriales/cirugía , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVE: This study aimed to analyze the long-term oncologic and reproductive outcomes in endometrial cancer (EC) in young patients conservatively treated by combined hysteroscopic resection (HR) and levonorgestrel intrauterine device (LNG-IUD). METHODS: Twenty-one patients (age ≤ 40 years; Stage IA, G1-2 endometrioid EC), wishing to preserve their fertility, were enrolled into this prospective study. The HR was used to resect (1) the tumor lesion, (2) the endometrium adjacent to the tumor, and (3) the myometrium underlying the tumor. Hormonal therapy consisted of LNG-IUD (52 mg) for at least 6 months. RESULTS: The median follow-up time is 85 months (range, 30-114). After 3 months from the progestin start date, 18 patients (85.7%) showed a complete regression (CR), 2 (9.5%) showed persistent disease, whereas 1 patient (4.8%) presented with progressive disease and underwent definitive surgery (Stage IA, G3 endometrioid). At 6 months, 1 of the 2 persistences underwent definitive surgery (Stage IA, G1 endometrioid), whereas the other was successfully re-treated. Two recurrences (10.5%) were observed, both involving the endometrium and synchronous ovarian cancer (OC) (atypical hyperplasia and Stage IIB G1 endometrioid OC; Stage IA endometrioid G1 EC, and Stage IA G1 endometrioid OC). The median duration of complete response was 85 months (range, 8-117). Sixty-three percent of complete responders attempted to conceive with 92% and 83% pregnancy and live birth rates, respectively. To date, all patients are alive and have no evidence of disease. CONCLUSIONS: After a long follow-up, combined HR and LNG-IUD would seem to improve the efficacy of progestin alone. High pregnancy and live birth rates were observed in women attempting to conceive. This approach is still experimental and should be offered only in the framework of scientific protocols conducted in cancer centers.
Asunto(s)
Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/cirugía , Fertilidad , Tratamientos Conservadores del Órgano , Embarazo , Adulto , Femenino , Humanos , Histeroscopía , Dispositivos Intrauterinos Medicados , Levonorgestrel/administración & dosificación , Estudios ProspectivosRESUMEN
Epithelial ovarian cancer is the most lethal gynecologic malignancy; it is highly aggressive and causes almost 125,000 deaths yearly. Despite advances in detection and cytotoxic therapies, a low percentage of patients with advanced stage disease survive 5 y after the initial diagnosis. The high mortality of this disease is mainly caused by resistance to the available therapies. Here, we profiled microRNA (miR) expression in serous epithelial ovarian carcinomas to assess the possibility of a miR signature associated with chemoresistance. We analyzed tumor samples from 198 patients (86 patients as a training set and 112 patients as a validation set) for human miRs. A signature of 23 miRs associated with chemoresistance was generated by array analysis in the training set. Quantitative RT-PCR in the validation set confirmed that three miRs (miR-484, -642, and -217) were able to predict chemoresistance of these tumors. Additional analysis of miR-484 revealed that the sensitive phenotype is caused by a modulation of tumor vasculature through the regulation of the VEGFB and VEGFR2 pathways. We present compelling evidence that three miRs can classify the response to chemotherapy of ovarian cancer patients in a large multicenter cohort and that one of these three miRs is involved in the control of tumor angiogenesis, indicating an option in the treatment of these patients. Our results suggest, in fact, that blockage of VEGF through the use of an anti-VEGFA antibody may not be sufficient to improve survival in ovarian cancer patients unless VEGFB signaling is also blocked.
Asunto(s)
Resistencia a Antineoplásicos/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neovascularización Patológica/genética , Neoplasias Ováricas/genética , Antineoplásicos/farmacología , Western Blotting , Carboplatino/farmacología , Carcinoma Epitelial de Ovario , Línea Celular Tumoral , Técnicas de Cocultivo , Cistadenocarcinoma Seroso/irrigación sanguínea , Cistadenocarcinoma Seroso/genética , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Neoplasias Glandulares y Epiteliales/irrigación sanguínea , Neoplasias Glandulares y Epiteliales/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/irrigación sanguínea , Paclitaxel/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Factor B de Crecimiento Endotelial Vascular/genética , Factor B de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Mutations in the tumor suppressor gene TP53 and proto-oncogene PIK3CA and alterations of p53 and PIK3CA AKT mTOR pathways are common events in several human cancers. We focused on the analysis of TP53 and PIK3CA gene variations in adenocarcinoma, squamous cell carcinoma as well as in intraepithelial neoplasia grade 3 of the cervix. METHODS: DNA samples from 28 cervical adenocarcinoma, 55 squamous cell carcinoma and 31 intraepithelial neoplasia grade 3 (CIN3), previously characterized in terms of human papillomavirus (HPV) prevalence and genotype distribution, were analyzed for TP53 and PIK3CA mutations in the exons 4-9 and exon 9, respectively. RESULTS: Single nucleotide substitutions in TP53 and PIK3CA genes were detected in 36% and 11% of adenocarcinoma, in 16% and in 5% of squamous cell carcinoma, and in 13% and none of CIN 3, respectively. Nucleotide changes in TP53 were significantly more frequent in adenocarcinoma cases than in squamous cell carcinoma and CIN3 (P = 0.035) and were independent from HPV infection status. CONCLUSIONS: Mutations in the TP53 gene and to lesser extent in the PIK3CA gene seem more frequent in cervical adenocarcinoma than in squamous cell carcinoma and CIN3. Whether TP53 and PIK3CA gene mutations have an impact on prognosis and response to molecularly targeted therapies as well as in cytotoxic drugs in different cervical cancer histotypes needs to be analyzed in investigative clinical trials.
Asunto(s)
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Proteína p53 Supresora de Tumor/genética , Displasia del Cuello del Útero/genética , Neoplasias del Cuello Uterino/genética , Adulto , Fosfatidilinositol 3-Quinasa Clase I , Femenino , Humanos , Persona de Mediana Edad , Proto-Oncogenes MasRESUMEN
Aim of this work is to provide a detailed comparison of clinical-pathologic features between well-differentiated and poorly differentiated tumors according to their BRAF and RASSF1A status. We analyzed RASSF1A methylation by MSP and BRAF mutation by LCRT-PCR with LightMix® kit BRAF V600E in neoplastic thyroid tissues. Immunohistochemical evaluation of RASSF1A expression was also performed by standard automated LSAB-HRP technique. An overall higher degree of RASSF1A over-expression than normal thyroid parenchyma surrounding tumors (P < 0.05) has been found in all malignant well-differentiated lesions. Moreover, statistically significant higher levels of RASSF1A expression were observed in differentiated cancers associated to an inflammatory autoimmune background (P = 0.01). Amplifiable DNA for LC PCR with LightMix® kit BRAF V600E was obtained in nine PTCs, four FVPTCs, five ATCs, and one control. The V600E mutation was found in 13 of 18 (72%) tumors. BRAF was mutated in 6 of 9 (66%) classical PTC, in 2 of 4 (50%) follicular variant PTC and in all ACs (100%). The overall frequency of RASSF1A promoter methylation observed was 20.5% (9 cases out 44). Hypermethylation of RASSF1A in primary tumors was variable according to histotypes ranging from100% (5/5) in ACs to only 12.5% (4/32) in PTCs. We show a correlation between RASSF1A methylation status and RASSF1A protein expression. Finally, we conclude that BRAF V600E mutation and RASSF1A methylation were pathogenetic event restricted to a subgroup of PTC/FVPTCs in early stage and to clinically aggressive ATCs.
Asunto(s)
Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Metilación de ADN/genética , Demografía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Italia , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estadificación de Neoplasias , Desnaturalización de Ácido Nucleico , Regiones Promotoras Genéticas/genética , Glándula Tiroides/metabolismo , Glándula Tiroides/patologíaRESUMEN
Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have shown that HOX genes play a role in neoplastic transformation of several human tissues. In particular, the genes belonging to HOX paralogous group 13 seem to hold a relevant role in both tumor development and progression. We have identified a significant prognostic role of HOX D13 in pancreatic cancer and we have recently showed the strong and progressive over-expression of HOX C13 in melanoma metastases and deregulation of HOX B13 expression in bladder cancers. In this study we have investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX paralogous group 13 genes/proteins expression in thyroid cancer evolution and progression, also evaluating its ability to discriminate between main histotypes. Our results showed an aberrant expression, both at gene and protein level, of all members belonging to paralogous group 13 (HOX A13, HOX B13, HOX C13 and HOX D13) in adenoma, papillary and follicular thyroid cancers samples. The data suggest a potential role of HOX paralogous group 13 genes in pathogenesis and differential diagnosis of thyroid cancers.
Asunto(s)
Diferenciación Celular , Proteínas de Homeodominio/biosíntesis , Pronóstico , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Anciano , Carcinogénesis/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patologíaRESUMEN
The presence of lymph node metastases is one of the most important prognostic indicators in head and neck squamous cell carcinomas (HNSCCs). An alteration of the E-cadherin-catenins complex and EGFR is essential for the invasiveness of cancer cells. Caveolin-1, the major structural protein of the caveolae, represents a scaffolding molecule for several signaling proteins including EGFR. Although caveolin-1 has been shown to play a role in inducing the invasive phenotype of cancer cells, its role appears to be cell-type specific and for some tumors it has not been defined yet. In this study we used 57 HNSCC specimens to investigate whether the abnormal expression of caveolin-1 was associated with the derangement of the E-cadherin-catenins complex and with the overexpression of ErbB receptors. We demonstrate that in HNSCCs caveolin-1 overexpression is associated with the simultaneous abnormal expression of at least one member of the E-cadherin/α-ß catenins complex and multiple ErbB receptors as well as with lymph node metastases. We also demonstrate that chronic stimulation of a human hypopharyngeal carcinoma cell line (FaDu) with EGF induced the internalization of ß-catenin and caveolin-1 and their co-localization with EGFR. Moreover, EGF treatment induced an increased physical interaction between EGFR/ß-catenin/caveolin-1 and between E-cadherin/ß-catenin/caveolin-1. These molecular events were associated with an increased directional motility of FaDu cells in vitro. These findings may provide new insight into the biology of HNSCC progression and help to identify subgroups of primary HNSCCs with a more aggressive behavior.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Factor de Crecimiento Epidérmico/administración & dosificación , Neoplasias de Cabeza y Cuello/metabolismo , Receptor ErbB-2/metabolismo , beta Catenina/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Hipofaríngeas/metabolismo , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Invasividad Neoplásica/genética , Metástasis de la Neoplasia , Receptor ErbB-2/genética , alfa Catenina/genética , alfa Catenina/metabolismo , beta Catenina/genéticaRESUMEN
Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma.
Asunto(s)
Antineoplásicos , Neoplasias Óseas , Cisplatino , Osteosarcoma , Neoplasias Ováricas , Antineoplásicos/uso terapéutico , Autofagia/genética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Línea Celular Tumoral , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
OBJECTIVE: This study evaluated the feasibility and efficacy of combined operative hysteroscopy (HSC) and hormone therapy as fertility-preserving treatment in a cohort of selected young women with early endometrial carcinoma (EC). METHODS: Fourteen patients (median age 38 years, range 26-40) with FIGO stage IA (intramucous) EC wishing to preserve fertility were enrolled with the following inclusion criteria: age ≤40 years; no evidence of Lynch II syndrome; well-differentiated estrogen/progesterone receptor positive (ER+/PR+) endometrioid EC; no evidence of myoinvasion, multifocal tumor, node metastasis, ovarian mass; normal serum CA 125. Treatment consisted of hysteroscopic ablation of the lesion and the myometrial tissue below, followed by oral megestrol acetate (MA) 160 mg/day for 6 months (6 pts) or 52 mg levonorgestrel-medicated intrauterine device (LNG-IUD) for 12 months (8 pts). RESULTS: With a median follow-up of 40 months (range 13-79), one patient recurred after 5 months from operative HSC and underwent definitive surgery, one patient showed an endometrial hyperplasia without atypia at the 3 and 6 month HSC control, with negative controls thereafter. Three patients have attempted to conceive and one of them conceived and term delivered a healthy baby. CONCLUSIONS: Combined operative HSC and progestin therapy may have a role for safe and effective conservative management of early EC in selected patients wishing to preserve fertility.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/cirugía , Levonorgestrel/administración & dosificación , Acetato de Megestrol/administración & dosificación , Adulto , Terapia Combinada , Neoplasias Endometriales/patología , Femenino , Fertilidad , Humanos , Histeroscopía/métodos , Dispositivos Intrauterinos Medicados , Estadificación de Neoplasias , Proyectos Piloto , Estudios ProspectivosRESUMEN
INTRODUCTION: Uterine papillary serous and clear cell carcinomas (UPSCs/CCs) show a different spreading from that of poorly differentiated endometrioid carcinomas (PDECs) and are usually thought to be prognostically more aggressive than PDECs. On the contrary, it has been recently claimed that UPSC/CC and PDEC have a similar prognosis. In this retrospective study on 2 institutional databases, the surgical-pathological data and survival have been compared in patients with UPSC/CC and PDEC. METHODS: A total of 139 surgically staged consecutive patients, 63 with UPSC/CC (37 UPSC; 26 CC) and 76 with PDEC clinically limited to the uterine corpus, have been compared for nuclear ploidy, myometrial invasion, (occult) cervical extension, peritoneal, and lymph node metastasis. Prognostic factors have been correlated through multivariate analysis with survival (disease-specific [DSS] and disease-free [DFS]). RESULTS: Peritoneal metastases and aneuploidy were found to be the only parameters significantly different in the 2 groups: peritoneal metastases 28.6% in UPSC/CC (extrapelvic 19%) and 7.9% in PDEC (extrapelvic 2.6%) (P = 0.001), aneuploidy 48.6% in UPSC/CC and 30.6% in PDEC (P = 0.05). Five-year DSS was 57.9% versus 75.2% (P = 0.02), and DFS was 52.3% versus 71.4% (P = 0.04) for UPSC/CC and PDEC, respectively. All but cervical and lymph node involvement were significant predictors of survival. After multivariate analysis, histotype (DSS: hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.02-3.86; P = 0.04; DFS: HR, 1.94; 95% CI, 1.04-3.63; P = 0.04), stage (DSS: HR, 2.26; 95% CI, 1.10-4.65; P = 0.03; DFS: HR, 2.21; 95% CI, 1.12-4.38; P = 0.02), and myometrial invasion (DSS: HR, 2.86; 95% CI, 1.22-6.69; P = 0.01; DFS: HR, 3.96; 95% CI, 1.63-9.62; P = 0.002) were independent risk factors for survival. CONCLUSIONS: Uterine papillary serous and clear cell carcinomas spread to abdominal peritoneum more frequently than PDEC; multivariate analysis confirms UPSC/CC as an independent, unfavorable predictor of outcome.
Asunto(s)
Adenocarcinoma de Células Claras/diagnóstico , Carcinoma Endometrioide/diagnóstico , Cistadenocarcinoma Papilar/diagnóstico , Cistadenocarcinoma Seroso/diagnóstico , Neoplasias Uterinas/diagnóstico , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/patología , Diferenciación Celular/fisiología , Cistadenocarcinoma Papilar/patología , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Progresión de la Enfermedad , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patologíaRESUMEN
Vaginal melanoma (VM) is a rare disease comprising <1% of all melanomas among women, and about 3% of all vaginal malignancies. Patients experience a poor prognosis, showing <15% 5-year survival. The report concerns two premenopausal patients with VM treated by surgery with radical intent. The first patient presented with a large lesion also infiltrating the proximal paracolpium and the bladder. The second patient had a persistent lesion of the lower third of the vagina. However, in the absence of any evidence-based guidelines or even clear suggestions from the literature, it is reasonable to believe that an appropriate management of primary malignant VM should address the radical tumor resection with wide tumor-free surgical margins and symptom relief.
Asunto(s)
Melanoma/cirugía , Neoplasias Vaginales/cirugía , Adulto , Resultado Fatal , Femenino , Humanos , Melanoma/patología , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Exenteración Pélvica , Pronóstico , Neoplasias Vaginales/patologíaRESUMEN
The treatment approach to cervix cancer has remained unchanged for several decades and new therapeutic strategies are now required to improve outcomes, as the prognosis is still poor. In the last years, a better understanding of HPV tumor-host immune system interactions and the development of new therapeutics targeting immune checkpoints generated interest in the use of immunotherapy in cervix cancer. Preliminary phase I-II trials demonstrated the efficacy, the duration of responses and the manageable safety of this approach. Currently, many phase II and III studies are ongoing in both locally advanced and metastatic cervical cancer, assessing immunotherapy as a single agent or in combination with chemotherapy and radiotherapy. We reviewed the published data and the therapeutic implications of the most promising novel immunotherapeutic agents under investigation in cervix cancer.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: The anatomical complexity of the oropharynx and the difficulty in reaching its distal portion have always conditioned the surgical accessibility.Robotic surgery represents an excellent alternative in the treatment of cervico-facial oncological diseases. METHODS: This series comprises all patients managed for head and neck cancer by Trans Oral Robotic Surgery TORS.The staging assessment, including neck ultrasound and total body PET/CT scan, was performed in each patient according to the TNM classification.All charts were recorded with the following data: name and surname, age, gender, date of surgery intra or post-operative hemorragia, tumor site, histology, TNM stage, robot set-up time, tumor resection time, whether or not tracheotomy was performed, whether or not neck dissection was performed, insertion of a nasogastric tube or gastrostomy, time to resumption of oral feeding, surgical margins, mean length of hospital stay, adjuvant treatment and follow-up. RESULTS: From February 2013 to February 2018, TORS was performed in 67 consecutive patients affected by head and neck tumours.We divided, our sample, in 3 subsites: supraglottic larynx, parapharyngeal space and oropharynx.Pathology reports confimed malignancy in 44 cases: 8 cases lymphomas, 36 cases of Squamous cell carcinoma (SCC), 5 cases of benign salivary glands tumors and 18 miscellaneous cases. Neck dissection was performed in 12 cases.Tracheotomy was perfomed in 3/67 cases for respiratory failures. A nasogastric tube was inserted at the end of the surgical procedure in 21 patients. The mean length of hospital stay was 10 days .Major complications included post-operative bleeding in 3 patients, 1 exitus for massive bleeding 20 days post-surgery and 1 respiratory failure treated with tracheotomy and monitoring in the Intensive Care Unit (ICU) for 3 days. CONCLUSIONS: Robotic surgery has been considered a valid alternative to traditional open treatment in many specializations with the advantages of an endoscopic procedure, with the same oncological and functional results and with fewer complications. The advantages of this type of surgical technique have been discussed, it is mandatory to focus on the indications and contraindications.
RESUMEN
Resistance to platinum-based chemotherapy is a common event in patients with cancer, generally associated with tumor dissemination and metastasis. Whether platinum treatment per se activates molecular pathways linked to tumor spreading is not known. Here, we report that the ubiquitin-specific protease 1 (USP1) mediates ovarian cancer cell resistance to platinum, by regulating the stability of Snail, which, in turn, promotes tumor dissemination. At the molecular level, we observed that upon platinum treatment, USP1 is phosphorylated by ATM and ATR and binds to Snail. Then, USP1 de-ubiquitinates and stabilizes Snail expression, conferring resistance to platinum, increased stem cell-like features, and metastatic ability. Consistently, knockout or pharmacological inhibition of USP1 increased platinum sensitivity and decreased metastatic dissemination in a Snail-dependent manner. Our findings identify Snail as a USP1 target and open the way to a novel strategy to overcome platinum resistance and more successfully treat patients with ovarian cancer.
Asunto(s)
Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Platino (Metal)/química , Factores de Transcripción de la Familia Snail/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Complejos de Coordinación/uso terapéutico , Resistencia a Antineoplásicos , Femenino , Edición Génica , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Factores de Transcripción de la Familia Snail/antagonistas & inhibidores , Factores de Transcripción de la Familia Snail/genética , Proteasas Ubiquitina-Específicas/antagonistas & inhibidores , Proteasas Ubiquitina-Específicas/genética , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The causative role of human papillomaviruses (HPV) and HPV16 variants has been extensively studied in uterine cervix dysplastic lesions and invasive carcinoma; few such studies, however, have been performed in penile tumors. We have investigated HPV genotype and HPV16 variant distribution on 41 penile cancer biopsies from Italian patients. Cases were extracted from the respective pathology departments databases of National Cancer Institutes in Naples and Milan. HPV sequences were detected by PCR and characterized by direct sequence analysis. Among the 19 HPV-positive cases (46.3%) 2 viral genotypes were identified (HPV16 and 18) with HPV16 accounting for 94.7% (18 out of 19) of the infections. Sequence analysis of E6, E7 genes and long control region (LCR) of 18 HPV16 isolates allowed the identification of European (E-G-350) and non-European (AA and Af-1) variants in 44.4% and in 55.6% of the samples, respectively. The AA variant alone represented 44.4% of all HPV16 infections, a significantly higher frequency of that observed in cervical carcinoma from Italian women (Tornesello et al., J Med Virol 2004;74:117-26). Our results suggest that HPV16 has a very high prevalence among penile cancer patients in Italy and the increased frequency of HPV16 non-European classes, particularly the AA, suggests that they are more oncogenic than European variants in penile tissue.
Asunto(s)
Variación Genética , Papillomavirus Humano 16/genética , Infecciones por Papillomavirus/virología , Neoplasias del Pene/genética , Anciano , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , ADN Viral/genética , ADN Viral/metabolismo , Genotipo , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 16/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas Virales/genética , Proteínas Oncogénicas Virales/metabolismo , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/genética , Neoplasias del Pene/virología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: High risk human papillomaviruses (HPVs) have been unequivocally recognised as the necessary cause of squamous intraepithelial lesions (SIL) and invasive carcinoma of the cervix. The distribution and the role of unclassified risk HPV genotypes in cervical neoplasia has not been fully elucidated. METHODS: Liquid-based cytological samples were collected from 337 women referred for colposcopy following an abnormal cytological diagnosis. HPV DNA was detected by broad-spectrum PCR and genotypes identified by nucleotide sequencing analysis and reverse line blot (RLB). RESULTS: The overall frequency of HPV infection was 36.5% (35 out of 96) in samples negative for intraepithelial lesions or malignancy (NILM), 80% (181 out of 226) in low grade SIL and 93.3% (14 out of 15) in high grade SIL (P < 0.001). Thirty-five different genotypes were identified among the 230 HPV-positive cases. The Group 1 oncogenic viruses (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) were found in 21.9, 46.5, and 86.7% of NILM, low grade SIL and high grade SIL, respectively. The Group 2A, including the probably oncogenic virus HPV68, was found in 1 and 0.8% of NILM and low grade SIL, respectively. The Group 2b possibly oncogenic HPVs (HPV34, 53, 66, 67, 70, 73, 82 and 85) were found in 4.2, 21.7 and 26.7% of NILM, low grade SIL and high grade SIL, respectively. The unclassified viruses (HPV12, 42, 54, 55, 61, 62, 81, 83, 84, 89, 90, 91) were detected in 8.3 and 14.6% of NILM and low grade SIL, respectively, and never in high grade SIL. CONCLUSIONS: Group 1 HPVs were mainly prevalent in high grade SIL and low grade SIL while Group 2B were equally distributed among the two groups. The dominant frequency of unclassified HPVs in low grade SIL and NILM and their rarity in high grade SIL suggests their marginal role in cervical neoplasia of the studied population.