RESUMEN

BACKGROUND: In certain cancers, expression of CXCL16 and its receptor CXCR6 associate with lymphocyte infiltration, possibly aiding anti-tumour immune response. In other cancers, CXCL16 and CXCR6 associate with pro-metastatic activity. In the current study, we aimed to characterise the role of CXCL16, sCXCL16, and CXCR6 in ovarian cancer (OC). METHODS: CXCL16/CXCR6 expression was analysed on tissue microarray containing 306 OC patient samples. Pre-treatment serum sCXCL16 was determined in 118 patients using ELISA. In vitro, (primary) OC cells were treated with an ADAM-10/ADAM-17 inhibitor (TAPI-2) and an ADAM-10-specific inhibitor (GI254023x), whereupon CXCL16 levels were evaluated on the cell membrane (immunofluorescent analysis, western blots) and in culture supernatants (ELISA). In addition, cell migration was assessed using scratch assays. RESULTS: sCXCL16 independently predicted for poor survival (hazard ratio=2.28, 95% confidence interval=1.29-4.02, P=0.005), whereas neither CXCL16 nor CXCR6 expression correlated with survival. Further, CXCL16/CXCR6 expression and serum sCXCL16 levels did not associate with lymphocyte infiltration. In vitro inhibition of both ADAM-17 and ADAM-10, but especially the latter, decreased CXCL16 membrane shedding and strongly reduced cell migration of A2780 and cultured primary OC-derived malignant cells. CONCLUSIONS: High serum sCXCL16 is a prognostic marker for poor survival of OC patients, possibly reflecting ADAM-10 and ADAM-17 pro-metastatic activity. Therefore, serum sCXCL16 levels may be a pseudomarker that identifies patients with highly metastatic tumours.

Asunto(s)

Proteínas ADAM/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Quimiocinas CXC/sangre , Proteínas de la Membrana/metabolismo , Neoplasias Ováricas/sangre , Receptores Depuradores/sangre , Proteína ADAM10 , Proteína ADAM17 , Quimiocina CXCL16 , Quimiocinas CXC/biosíntesis , Femenino , Humanos , Inmunohistoquímica , Metástasis de la Neoplasia , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Pronóstico , Estudios Prospectivos , Receptores CXCR6 , Receptores de Quimiocina/biosíntesis , Receptores de Quimiocina/sangre , Receptores Depuradores/biosíntesis , Receptores Virales/biosíntesis , Receptores Virales/sangre , Análisis de Supervivencia , Análisis de Matrices Tisulares

RESUMEN

BACKGROUND: Tumour cell-selective activation of apoptosis by recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL) is enhanced through co-activation of p53 by chemotherapeutic drugs. The novel anticancer agent nutlin-3 provides a promising alternative for p53 activation by disrupting the interaction between p53 and its negative feedback regulator MDM2. METHODS: We examined whether nutlin-3 enhances apoptosis induction by rhTRAIL and the DR5-selective TRAIL variant D269H/E195R in wild-type p53-expressing ovarian, colon and lung cancer cell lines and in an ex vivo model of human ovarian cancer. RESULTS: Nutlin-3 enhanced p53, p21, MDM2 and DR5 surface expression. Although nutlin-3 did not induce apoptosis, it preferentially enhanced D269H/E195R-induced apoptosis over rhTRAIL. Combination treatment potentiated the cleavage of caspases 8, 9, 3 and PARP. P53 and MDM2 siRNA experiments showed that this enhanced apoptotic effect was mediated by wild-type p53. Indeed, nutlin-3 did not enhance rhTRAIL-induced apoptosis in OVCAR-3 cells harbouring mutant p53. Addition of the chemotherapeutic drug cisplatin to the combination further increased p53 and DR5 levels and rhTRAIL- and D269H/E195R-induced apoptosis. As a proof of concept, we show that the combination of D269H/E195R, nutlin-3 and cisplatin induced massive apoptosis in ex vivo tissue slices of primary human ovarian cancers. CONCLUSION: Nutlin-3 is a potent enhancer of D269H/E195R-induced apoptosis in wild-type p53-expressing cancer cells. Addition of DNA-damaging agents such as cisplatin further enhances DR5-mediated apoptosis.

Asunto(s)

Apoptosis/efectos de los fármacos , Imidazoles/farmacología , Neoplasias/patología , Piperazinas/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Proteínas Recombinantes/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Sustitución de Aminoácidos , Apoptosis/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Genes p53 , Humanos , Neoplasias/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Proteínas Recombinantes/genética , Especificidad por Sustrato , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Células Tumorales Cultivadas

RESUMEN

OBJECTIVE: It is generally recognized that the immune system has an important role in regulating cancer development. Evidence indicating a prognostic role of the immune system in vulvar carcinoma is scarce. This study investigated the presence and prognostic significance of several aspects of the immune system in vulvar squamous carcinoma. METHODS: The number of intratumoral CD8(+) and Foxp3(+) T-lymphocytes, next to HLA class I (HLA-A, HLA-B/C and ß(2)-m) and indoleamine 2,3-dioxygenase (IDO) expression was determined by immunohistochemistry in a consecutively selected cohort of 286 vulvar squamous carcinoma patients, all treated in the University Medical Center Groningen, the Netherlands. Associations between immunohistochemistry expression and the influence on survival were determined. RESULTS: The number of tumor-infiltrating CD8(+) T-lymphocytes was significantly lower in tumors with loss of HLA-A (p=0.004), HLA-B/C (p=0.024) or ß(2)-m (p=0.025) expression compared with tumors with expression of HLA class I. No association was found between the number of intratumoral CD8(+) T-lymphocytes and Foxp3(+) T-lymphocytes, HLA class I and IDO expression and survival of vulvar squamous carcinoma patients. CONCLUSION: Our results indicate that the immune system does not seem to have a major influence on prognosis of patients with vulvar squamous carcinoma.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/inmunología , Inmunidad Celular , Neoplasias de la Vulva/inmunología , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Células Escamosas/mortalidad , Femenino , Factores de Transcripción Forkhead/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inmunohistoquímica , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Neoplasias de la Vulva/mortalidad

RESUMEN

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are predictors of disease-specific survival (DSS) in ovarian cancer. It is largely unknown what factors contribute to lymphocyte recruitment. Our aim was to evaluate genes and pathways contributing to infiltration of cytotoxic T lymphocytes (CTLs) in advanced-stage serous ovarian cancer. METHODS: For this study global gene expression was compared between low TIL (n=25) and high TIL tumours (n=24). The differences in gene expression were evaluated using parametric T-testing. Selectively enriched biological pathways were identified with gene set enrichment analysis. Prognostic influence was validated in 157 late-stage serous ovarian cancer patients. Using immunohistochemistry, association of selected genes from identified pathways with CTL was validated. RESULTS: The presence of CTL was associated with 320 genes and 23 pathways (P<0.05). In addition, 54 genes and 8 pathways were also associated with DSS in our validation cohort. Immunohistochemical evaluation showed strong correlations between MHC class I and II membrane expression, parts of the antigen processing and presentation pathway, and CTL recruitment. CONCLUSION: Gene expression profiling and pathway analyses are valuable tools to obtain more understanding of tumour characteristics influencing lymphocyte recruitment in advanced-stage serous ovarian cancer. Identified genes and pathways need to be further investigated for suitability as therapeutic targets.

Asunto(s)

Perfilación de la Expresión Génica , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Quísticas, Mucinosas y Serosas/economía , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Linfocitos T Citotóxicos/inmunología , Niño , Femenino , Antígenos HLA/análisis , Humanos , Persona de Mediana Edad , Pronóstico , Transducción de Señal

RESUMEN

OBJECTIVE: Presence of tumor-infiltrating lymphocytes (TIL) is of prognostic importance in a variety of malignancies. This study aims to determine the prognostic value of CD8(+) cytotoxic T-lymphocytes (CTL), FoxP3(+) regulatory T-lymphocytes (Treg) and CD45R0(+) memory T-lymphocytes in endometrial cancer. METHODS: The number of tumor-infiltrating CD8(+), FoxP3(+), and CD45R0(+) T-lymphocytes was determined by immunohistochemistry on tissue microarrays containing tumor material from 368 FIGO stage I-IV endometrial cancer patients. Results from immunohistochemistry were correlated with clinicopathological parameters and survival. RESULTS: High numbers of intra-tumoral CD8(+) T-lymphocytes, a high CD8(+)/FoxP3(+) ratio and the presence of CD45R0(+) T-lymphocytes were strongly associated with well-known favorable prognostic factors in endometrial cancer. Furthermore, high numbers of CD8(+) T-lymphocytes and a high CD8(+)/FoxP3(+) ratio were associated with a better disease free survival (DFS). High numbers of CD8(+) T-lymphocytes and the presence of CD45R0(+) T-lymphocytes were associated with a prolonged overall survival (OS). In multivariate analysis, high numbers of CD8(+) T-lymphocytes had an independent prognostic impact for overall survival in the entire cohort (HR 0.48, 95% C.I. 0.26-0.89, p=0.019) and in type II endometrial cancer (HR 0.17, 95% C.I. 0.08-0.36, p<0.001). A high CD8(+)/FoxP3(+) ratio was independently associated with improved survival in type I endometrial cancer (HR 0.44, 95% C.I. 0.23-0.84, p=0.013). CD45R0(+) lymphocytes were an independent factor for improved OS (HR 0.42, 95% C.I. 0.19-0.93, p=0.033). CONCLUSION: This study shows that the presence of TIL is an independent prognostic factor in endometrial cancer and indicates an important role for the immune system in endometrial cancer.

Asunto(s)

Neoplasias Endometriales/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Linfocitos T/inmunología , Antígenos CD/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/cirugía , Femenino , Factores de Transcripción Forkhead/análisis , Humanos , Inmunohistoquímica , Antígenos Comunes de Leucocito/inmunología , Escisión del Ganglio Linfático , Análisis por Micromatrices , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Sobrevivientes , Linfocitos T/patología

RESUMEN

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT-PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.

Asunto(s)

Receptores ErbB/metabolismo , Neoplasias Ováricas/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Células Epiteliales/patología , Receptores ErbB/biosíntesis , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Proteína Oncogénica v-akt/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Fosfohidrolasa PTEN/metabolismo , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Resultado del Tratamiento

RESUMEN

Three amino-acid loop extension (TALE) homeobox proteins MEIS and PBX are cofactors for HOX-class homeobox proteins, which control growth and differentiation during embryogenesis and homeostasis. We showed that MEIS and PBX expression are related to cisplatin resistance in ovarian cancer cell lines. Therefore, MEIS1, MEIS2 and PBX expression were investigated immunohistochemically in a tissue microarray (N=232) of ovarian cancers and ovarian surface epithelium (N=15). Results were related to clinicopathologic characteristics and survival. All cancers expressed MEIS1, MEIS2 and PBX in nucleus and cytoplasm. MEIS1 and 2 only stained nuclear in surface epithelium. Nuclear MEIS2 was negatively related to stage, grade and overall survival in univariate analyses. Additionally, MEIS and PBX RNA expression in ovarian surface epithelium and other normal tissues and ovarian cancer versus other tumour types using public array data sets were studied. In ovarian cancer, MEIS1 is highly expressed compared to other cancer types. In conclusion, MEIS and PBX are extensively expressed in ovarian carcinomas and may play a role in ovarian carcinogenesis.

Asunto(s)

Proteínas de Homeodominio/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Neoplasias Ováricas/mortalidad , Factores de Transcripción/metabolismo

RESUMEN

BACKGROUND: Loss of mismatch repair (MMR) gene expression has been associated with fewer metastases and improved prognosis in various tumour types. AIMS: To evaluate the predictive and prognostic significance of loss of MMR protein MSH2 in early stage cervical cancer. METHODS: Specimens from 218 consecutive patients with early stage, surgically treated cervical cancer were analysed. Median age was 42 years (interquartile range 35-53). International Federation of Gynecology and Obstetrics (FIGO) stages were IB1 (57%), IB2 (25%) and IIA (18%). Histology was 70% squamous cell, 6% adenosquamous and 24% adenocarcinoma. Pelvic lymph node metastasis was present in 66 (30%) patients. Median follow-up was 5.2 years (interquartile range 2.5-7.9). Tissue microarrays (TMAs) were constructed containing three cores of paraffin-embedded tumour per case. MSH2 expression was assessed by immunohistochemistry on TMAs and full sections. RESULTS: In TMAs MSH2 expression could be analysed in 184/218 (84%) tumours. Loss of MSH2 was observed in 58/184 (32%) tumours, with a moderately strong concordance between TMAs and full sections (kappa = 0.47). In tumours with loss of MSH2, pelvic lymph node metastasis and cancer invasion beyond 10 mm were more frequent (48% vs 25%, and 59% vs 37%, respectively). However, loss of MSH2 expression was not related to recurrence or survival. CONCLUSION: TMAs are powerful tools for high throughput screening of biological markers for prognostic value in cervical cancer. Absence of MSH2 expression is associated with a high-risk profile in early stage cervical cancer, but does not predict lymph node status with sufficient accuracy to be used in the clinic.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Adulto , Femenino , Humanos , Metástasis Linfática , Inestabilidad de Microsatélites , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Análisis por Matrices de Proteínas/métodos , Factores de Riesgo , Análisis de Supervivencia , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología

RESUMEN

OBJECTIVES: In patients with a granulosa cell tumor of the ovary, the value of serum inhibin A and B concentrations for the assessment of disease status was investigated. METHODS: In 30 consecutive patients with a stage I-III granulosa cell tumor, inhibin A and B concentrations were measured in pre- and post-treatment serum samples. Clinical data concerning diagnosis, treatment and follow-up of these patients were related to serum inhibin A and B concentrations. Serum samples from 41 premenopausal females with cervical dysplasia served as controls. RESULTS: In 30 patients, 13 (43%) recurrences were observed during a median follow-up of 10 years (range 1-31 years). Serum inhibin A and B concentrations were elevated in respectively 67% and 89% of the patients at diagnosis, and in 58% and 85% at recurrence. Inhibin A and B concentrations were normal in all controls. Sensitivity of inhibin A testing for the diagnosis of granulosa cell tumor was 67% with a specificity of 100%, compared to 89% and 100% respectively for inhibin B (ns). Elevations in serum inhibin B concentrations predated recurrences by a median of 11 months. None of the patients in remission showed increased concentrations of inhibin A and B. CONCLUSION: Inhibin B seems to be the predominant form of inhibin secreted by granulosa cell tumors and appears to reflect disease status more accurately than inhibin A. Measurement of serum inhibin B concentrations may be preferred for the follow-up of granulosa cell tumors.

Asunto(s)

Tumor de Células de la Granulosa/sangre , Inhibinas/sangre , Neoplasias Ováricas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Tumor de Células de la Granulosa/terapia , Humanos , Periodo Intraoperatorio , Persona de Mediana Edad , Neoplasias Ováricas/terapia , Radioterapia Adyuvante , Displasia del Cuello del Útero/sangre

RESUMEN

OBJECTIVES: High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immunohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated. RESULTS: EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (p=0.07). CONCLUSIONS: EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome.

Asunto(s)

Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Receptores ErbB/biosíntesis , Neoplasias de la Vulva/metabolismo , Neoplasias de la Vulva/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Femenino , Humanos , Inmunohistoquímica , Conducto Inguinal , Escisión del Ganglio Linfático , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas

RESUMEN

The prognostic impact of p53 immunostaining in a large series of tumours from epithelial ovarian cancer patients in a two-centre study was analysed. The study population (n=476) comprised of a retrospective series of 188 patients (Dutch cohort) and a prospective series of 288 patients (Scottish cohort) enrolled in clinical trials. P53 expression was determined by immunohistochemistry on tissue microarrays. Association with progression-free survival (PFS) and overall survival (OS) was analysed by univariate and multivariate Cox regression analysis. Aberrant p53 overexpression was significantly associated with PFS in the Dutch and Scottish cohorts (P=0.001 and 0.038, respectively), but not with OS in univariate analysis. In multivariate analysis, when the two groups were combined and account taken of clinical factors and country of origin of the cohort, p53 expression was not an independent prognostic predictor of PFS or OS. In this well-powered study with minimal methodological variability, p53 immunostaining is not an independent prognostic marker of clinical outcome in epithelial ovarian cancer. The data demonstrate the importance of methodological standardisation, particularly defining patient characteristics and survival end-point data, if biomarker data from multicentre studies are to be combined.

Asunto(s)

Genes p53 , Neoplasias Ováricas/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores de Tumor , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Resultado del Tratamiento

RESUMEN

OBJECTIVE: Increasing imbalance between proliferation and apoptosis is important in cervical carcinogenesis. The death ligands FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis by binding to their cognate cell-surface death receptors Fas or death receptor (DR) 4 and DR5. This study aims to examine if changes in death ligand and death receptor expression during different stages of cervical carcinogenesis are related to an imbalance between proliferation and apoptosis. METHODS: The immunohistochemical expression and localization of Fas/FasL and DR4/DR5/TRAIL were assessed in 11 normal cervices, 15 cervical intraepithelial neoplasia (CIN) grade I, 15 CIN II, 13 CIN III, and 25 (microinvasive) squamous cell cervical cancers. The number of apoptotic cells was determined by morphological criteria and the number of proliferating cells by counting Ki-67-positive cells. RESULTS: A marked increase in proliferation as well as apoptosis percentage was found with increasing severity of neoplasia. In normal cervix and CIN I samples, FasL, DR4, DR5, and TRAIL staining was mainly observed in the basal/parabasal layer, whereas Fas staining was localized in the superficial, more differentiated epithelial layer. Frequency of Fas-positive staining decreased with increasing severity of CIN. In contrast, homogeneous FasL, DR4, DR5, and TRAIL expression throughout the lesions was more frequently observed in CIN III and cervical cancer. FasL, DR4, DR5, and TRAIL staining patterns were correlated, although TRAIL expression was more intense in low-grade lesions. No association was found between death receptor or ligand expression with the percentage of apoptosis or proliferation. CONCLUSION: The loss of Fas and the deregulation of FasL, DR4, DR5, and TRAIL in the CIN-cervical cancer sequence suggest a possible functional role of these death ligands and receptors during cervical carcinogenesis. The frequent expression of DR4 and DR5 presents these receptors as promising targets for innovative therapy modalities in cervical cancer.

Asunto(s)

Carcinoma de Células Escamosas/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Displasia del Cuello del Útero/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Receptor fas/metabolismo , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Procesos de Crecimiento Celular/fisiología , Cuello del Útero/metabolismo , Proteína Ligando Fas , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Glicoproteínas de Membrana/biosíntesis , Estadificación de Neoplasias , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Receptor fas/biosíntesis , Displasia del Cuello del Útero/patología

RESUMEN

AIM: To study the effects of tamoxifen on the proliferation index and oestrogen receptor (ER) and progesterone receptor (PR) expression in postmenopausal endometrium. METHODS: A total of 125 endometrial specimens of postmenopausal women, comprising benign endometria from tamoxifen users (n = 35) and non-users (n = 24), and endometrial cancer from tamoxifen users (n = 15) and non-users (n = 51), were immunohistochemically examined using MIB-1, anti-ER, and anti-PR antibodies in endometrial epithelium and stroma. RESULTS: In benign endometrium the mean MIB-1 index in the epithelium was higher in tamoxifen users than in non-users (mean, 13% (SD, 13%) v mean, 2% (SD, 2%); p < 0.05), whereas in endometrial cancer the MIB-1 index was higher, but similar in tamoxifen users and non-users (mean, 32% (SD, 24%) and mean, 35% (SD, 18%)). The expression of ER was comparably high in benign epithelium from tamoxifen users and non-users (97% and 92%, respectively), but in endometrial cancer it was lower in tamoxifen users (60% and 88%; p < 0.05). The expression of PR in stromal cells was higher in tamoxifen users, both in benign (84% v 54%) and in malignant endometrium (33% v 10%; p < 0.05). CONCLUSION: The proliferation index (as measured by MIB-1) in benign endometrial epithelium is higher in tamoxifen users than in non-users, and this might play a role in the reported higher incidence of endometrial cancer in postmenopausal tamoxifen users. The increased expression of PR in stroma from tamoxifen users with both benign and malignant endometrium demonstrates an additional oestrogenic effect of tamoxifen on the endometrial stroma.

Asunto(s)

Antineoplásicos Hormonales/farmacología , Neoplasias Endometriales/patología , Endometrio/efectos de los fármacos , Posmenopausia , Tamoxifeno/farmacología , Anciano , Anciano de 80 o más Años , División Celular/efectos de los fármacos , Neoplasias Endometriales/metabolismo , Endometrio/metabolismo , Endometrio/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Receptores de Estrógenos/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/efectos de los fármacos , Receptores de Progesterona/metabolismo

RESUMEN

To evaluate the impact of tamoxifen on subjective and psychosexual well-being in breast cancer patients in relation to type of prior chemotherapy and menopausal status. Longitudinal interview study in breast cancer patients during and after adjuvant tamoxifen use. Menopausal status was defined by last menstrual period and serum oestradiol and FSH levels. Gynaecology outpatient clinic, Tertiary Referral Hospital, January 1995 to September 1999. Breast cancer patients <56 years of age, participating in a randomised trial comparing adjuvant high-dose (n=45) and standard-dose (n=53) chemotherapy, followed by radiotherapy and tamoxifen. Relative incidence and correlation of subjective and psychosexual symptoms during and after tamoxifen. During tamoxifen the most frequent complaints were hot flushes (85%), disturbed sleep (55%), vaginal dryness and/or dyspareunia (47%), decreased sexual desire (44%) and musculo-skeletal symptoms (43%). Disturbed sleep correlated with hot flushes (P<0.0005) and concentration problems (P<0.05). Decreased sexual interest correlated with vaginal dryness (P<0.0005) and/or dyspareunia (P<0.0005). In the high-dose group more patients became postmenopausal (95% vs 33%) and more patients reported symptoms than in the standard-dose group (P<0.05). After discontinuation of tamoxifen, symptoms decreased significantly. However, hot flushes, disturbed sleep and vaginal dryness persisted more often in patients who remained postmenopausal after high-dose chemotherapy (P<0.05). Overall, during tamoxifen patients reported many symptoms. More patients become postmenopausal after high-dose chemotherapy, and they remain often symptomatic after tamoxifen.

Asunto(s)

Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/psicología , Moduladores de los Receptores de Estrógeno/efectos adversos , Trastornos Mentales/inducido químicamente , Disfunciones Sexuales Psicológicas/inducido químicamente , Tamoxifeno/efectos adversos , Adulto , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/psicología , Neoplasias de la Mama/terapia , Terapia Combinada , Dispareunia/inducido químicamente , Edema/inducido químicamente , Moduladores de los Receptores de Estrógeno/administración & dosificación , Moduladores de los Receptores de Estrógeno/uso terapéutico , Femenino , Sofocos/inducido químicamente , Humanos , Incidencia , Menopausia , Persona de Mediana Edad , Trastornos del Humor/inducido químicamente , Enfermedades Musculoesqueléticas/inducido químicamente , Calidad de Vida , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Tamoxifeno/administración & dosificación , Tamoxifeno/uso terapéutico

RESUMEN

Tamoxifen increases endometrial cell proliferation and the incidence of endometrial cancer in postmenopausal women. The purpose of this study was to evaluate apoptosis and apoptosis-related factors in endometrium in relation to tamoxifen exposure. We analyzed benign postmenopausal endometrium from breast cancer patients receiving tamoxifen (n = 35) and from controls (n = 24), and endometrial cancer tissue from tamoxifen-treated breast cancer patients (n = 15) and endometrial cancer from women without tamoxifen exposure (n = 51). Apoptosis was examined morphologically, and the percentage of apoptotic epithelial cells was defined as the apoptotic index. In the benign samples, the presence of apoptotic cells was also evaluated immunohistochemically by the expression of caspase-3 and the monoclonal antibody M30. The expression of Fas, FasL, and Bcl-2 was analyzed in all tissue samples. No differences were observed in the mean apoptotic index in benign endometrium in tamoxifen users (0.17%) versus controls (0.08%), or in tamoxifen-exposed (2.46%) versus nonexposed endometrial cancer (2.28%). However, the ratio of the apoptotic index with the previously reported proliferation index was lower in benign endometrium from tamoxifen users than in controls (0.02 +/- 0.026 vs. 0.05 +/- 0.03, Mann-Whitney U <0.005). In benign endometrium FasL was more frequently expressed in tamoxifen-users than in controls (chi(2) <0.05). We conclude that the apoptosis/proliferation ratio in benign endometrium from tamoxifen users is lower than in controls, indicating that the tamoxifen-induced higher proliferation is not compensated for by increased apoptosis. An imbalance between cell proliferation and apoptosis, and possibly suppression of the antitumor immune response by FasL overexpression in tamoxifen-exposed endometrium might play a role in the development of endometrial cancer in tamoxifen users.

Asunto(s)

Antineoplásicos Hormonales/efectos adversos , Apoptosis/efectos de los fármacos , Endometrio/efectos de los fármacos , Posmenopausia , Tamoxifeno/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Apoptosis/fisiología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Caspasa 3 , Caspasas/metabolismo , División Celular/efectos de los fármacos , Neoplasias Endometriales/etiología , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Endometrio/metabolismo , Endometrio/patología , Proteína Ligando Fas , Femenino , Humanos , Inmunohistoquímica , Glicoproteínas de Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Tamoxifeno/uso terapéutico , Receptor fas/metabolismo

RESUMEN

OBJECTIVE: To review the literature on tamoxifen side effects on the female genital tract and psychosexual function in premenopausal and postmenopausal women. DATA SOURCES: We used the English-language literature in MEDLINE and reference lists from selected articles. Search terms included: "tamoxifen and estrogen receptor," "transcription activation," "premenopause," "postmenopause," "vaginal epithelium," "uterus," "endometrial hyperplasia," "polyps," "endometrial cancer," "sonography," "sonohysterography," "hysteroscopy," "myometrium," "myoma," "sarcoma," "endometriosis," "ovarian cysts," "hot flushes," "concentration problems," "sleep disturbance," "vaginal dryness," "sexual function," "libido," "dyspareunia," and "quality of life." No study-type restrictions were imposed. METHODS OF STUDY SELECTION: With respect to clinical studies we included case cohort studies, observational studies; if no trials were available on a subject, case reports published in peer-reviewed journals were selected. For the discussion on endometrial surveillance of tamoxifen users, letters and editorials published in peer-reviewed journals also were used. Subjects of interest were mechanism of action of tamoxifen, tamoxifen and the vaginal epithelium, endometrium, mesenchymal tumors of the uterus, ovaries, sexual function, and vasomotor instability. TABULATION, INTEGRATION, AND RESULTS: Eligible studies were analyzed to determine their usefulness in this review. Data from trials that evaluated tamoxifen side effects on specific genital tissues were combined, with special interest in differentiation of side effects in premenopausal and postmenopausal women. Weighted estimates of severity and extent of side effects were usually not possible because of lack of randomized trials. Only the risk of endometrial cancer in relation to tamoxifen treatment could be estimated. CONCLUSION: The gynecologic side effects of tamoxifen are diverse and reflect the complexity of its mechanism of action, with agonistic and antagonistic effects on various tissues, depending on the ambient estradiol concentration and hence menopausal status of the patient. The most frequently reported side effect was hot flushes, and the most worrisome gynecologic side effect was a two- to three-fold increased risk of endometrial cancer in postmenopausal women. Despite its side effects, the benefits of tamoxifen in controlling breast cancer or prevention of its relapse are still without debate.

Asunto(s)

Neoplasias de la Mama/prevención & control , Neoplasias Endometriales/inducido químicamente , Antagonistas de Estrógenos/efectos adversos , Tamoxifeno/efectos adversos , Femenino , Sofocos/diagnóstico , Humanos , Menopausia , Disfunciones Sexuales Psicológicas/inducido químicamente

RESUMEN

The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre-screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis.

Asunto(s)

Biomarcadores de Tumor/biosíntesis , Proteínas de Unión al ADN , Hiperplasia Endometrial/metabolismo , Neoplasias Endometriales/metabolismo , Proteínas de Neoplasias/biosíntesis , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Adaptadoras Transductoras de Señales , Adulto , Proteínas Portadoras , Análisis Mutacional de ADN , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/genética , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Femenino , Mutación de Línea Germinal , Humanos , Inmunohistoquímica , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS , Proteínas Nucleares , Pronóstico

RESUMEN

OBJECTIVES: The goals of this study were to analyze preoperative serum levels of CA 125, carcinoembryonic antigen (CEA), and CA 19-9 in patients with borderline ovarian tumors and to investigate if routine assessment of these markers in follow-up may lead to earlier detection of recurrence. METHODS: For patient identification a database was used, in which data from all patients treated for gynecologic malignancies in the Department of Gynecologic Oncology, University Hospital Groningen, The Netherlands, are compiled. Between 1982 and 1997, 44 patients with borderline ovarian tumors were identified. Clinical data and serum CA-125 and CEA levels were retrieved from the database. CA 19-9 levels were determined in retrospect in available stored preoperative (24 patients) and follow-up (43 patients) serum samples. RESULTS: Preoperative CA 125 levels were elevated in 8 of 33 (24%), CEA levels in 3 of 32 (9%), and CA 19-9 levels in 11 of 24 (46%) cases. In patients with mucinous tumors preoperative CA 19-9 was more frequently elevated (8/14, 57%) than CA 125 (3/20, 15%) (P = 0.02) or CEA (2/18, 11%) (P = 0.02). Complete follow-up serum CA 125, CEA, and CA 19-9 levels were available for 43 of 44 patients. Median follow-up was 84 months (range, 22-204). During follow-up two patients (5%) had recurrent disease. In one patient CA 125 became elevated at the time of recurrence; in the other patient (in retrospect) the CA 19-9 level did not return to normal after surgery, but kept rising, preceding clinical symptoms of recurrence for 13 months. CONCLUSIONS: If one chooses to use serum markers in follow-up of mucinous borderline ovarian tumors CA 19-9 should be included. Measurement of serum tumor markers in the follow-up of patients with borderline ovarian tumors may lead to earlier detection of recurrence in only a very small proportion of patients, while the clinical value of earlier detection of recurrence remains to be established.

Asunto(s)

Adenocarcinoma Mucinoso/patología , Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Antígeno CA-19-9/sangre , Antígeno Carcinoembrionario/sangre , Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/patología , Adenocarcinoma Mucinoso/inmunología , Adenocarcinoma Mucinoso/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Cistadenocarcinoma Seroso/inmunología , Cistadenocarcinoma Seroso/cirugía , Bases de Datos Factuales , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos

RESUMEN

Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l(-1); P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l(-1) and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Estrógenos/efectos adversos , Quistes Ováricos/inducido químicamente , Tamoxifeno/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/complicaciones , Estudios Transversales , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Persona de Mediana Edad

RESUMEN

BACKGROUND: The increased risk of endometrial carcinoma following the use of tamoxifen has stimulated studies on endometrial diagnostic screening methods. In tamoxifen users the endometrial thickening observed with transvaginal ultrasonography (TVU) frequently cannot be confirmed by hysteroscopy or histology. OBJECTIVE: The aim was to investigate the relationship between TVU and hysteroscopic and histologic endometrial findings in postmenopausal patients using tamoxifen. METHODS: Fifty-three asymptomatic postmenopausal tamoxifen-using breast cancer patients underwent a gynecological examination combined with TVU. Patients with an endometrial thickness of >5 mm were offered hysteroscopy and endometrial biopsy. FINDINGS: Thirty-one patients (58%) had an endometrial thickness of >5 mm with enhanced, inhomogeneous echogenicity. Hysteroscopy was performed in 22 patients and 3 underwent hysterectomy. Seven of 22 patients had endometrial polyps, histologically characterized by cystically dilated glands lined with atrophic epithelium and periglandular stromal condensation. Histology of the three hysterectomy specimens showed a similar picture of atrophic luminal epithelium, covering dilated glands lined with atrophic epithelium and surrounded by dense stroma, which resembled the histology of the endometrial polyps. In all three specimens the histologically measured endometrial thickness corresponded with that on TVU. INTERPRETATION: Tamoxifen can induce specific endometrial changes consisting of cystically dilated glands with periglandular stromal condensation while the overlying epithelium remains atrophic. The changes occur either in the endometrium itself or as a protrusion of the endometrium, i.e., as endometrial polyps. These findings explain the discrepancy between ultrasound, hysteroscopy, and histology. Due to the high number of false-positive findings, TVU is not an effective screening instrument in these patients.

Asunto(s)

Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Endometrio/diagnóstico por imagen , Endometrio/patología , Histeroscopía , Posmenopausia , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Endometrio/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Ultrasonografía