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1.
Gynecol Oncol ; 167(1): 3-10, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36085090

RESUMEN

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.


Asunto(s)
Carcinoma de Células Escamosas , Linfadenopatía , Ganglio Linfático Centinela , Neoplasias de la Vulva , Carcinoma de Células Escamosas/patología , Femenino , Ingle , Humanos , Escisión del Ganglio Linfático/efectos adversos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Linfadenopatía/patología , Metástasis Linfática/patología , Recurrencia Local de Neoplasia/patología , Ganglio Linfático Centinela/patología , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Neoplasias de la Vulva/patología
2.
Ultrasound Obstet Gynecol ; 51(6): 829-835, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28976616

RESUMEN

OBJECTIVE: To determine whether International Ovarian Tumor Analysis (IOTA) logistic regression models LR1 and LR2 developed for the preoperative diagnosis of ovarian cancer could also be used to differentiate between benign and malignant adnexal tumors in the population of women attending gynecology outpatient clinics. METHODS: This was a single-center prospective observational study of consecutive women attending our gynecological diagnostic outpatient unit, recruited between May 2009 and January 2012. All the women were first examined by a Level-II ultrasound operator. In those diagnosed with adnexal tumors, the IOTA-LR1/2 protocol was used to evaluate the masses. The LR1 and LR2 models were then used to assess the risk of malignancy. Subsequently, the women were also examined by a Level-III examiner, who used pattern recognition to differentiate between benign and malignant tumors. Women with an ultrasound diagnosis of malignancy were offered surgery, while asymptomatic women with presumed benign lesions were offered conservative management with a minimum follow-up of 12 months. The initial diagnosis was compared with two reference standards: histological findings and/or a comparative assessment of tumor morphology on follow-up ultrasound scans. All women for whom the tumor classification on follow-up changed from benign to malignant were offered surgery. RESULTS: In the final analysis, 489 women who had either or both of the reference standards were included. Their mean age was 50 years (range, 16-91 years) and 45% were postmenopausal. Of the included women, 342/489 (69.9%) had surgery and 147/489 (30.1%) were managed conservatively. The malignancy rate was 137/489 (28.0%). Overall, sensitivities of LR1 and LR2 for the diagnosis of malignancy were 97.1% (95% CI, 92.7-99.2%) and 94.9% (95% CI, 89.8-97.9%) and specificities were 77.3% (95% CI, 72.5-81.5%) and 76.7% (95% CI, 71.9-81.0%), respectively (P > 0.05). In comparison with pattern recognition (sensitivity 94.2% (95% CI, 88.8-97.4%), specificity 96.3% (95% CI, 93.8-98.0%)), the specificities of the IOTA models were significantly lower (P < 0.0001). A significantly higher number of women would have been offered surgery for suspected cancer if the women had been assessed using the IOTA models instead of pattern recognition (213/489 (43.6%) vs 142/489 (29.0%); P < 0.001). CONCLUSIONS: The IOTA models maintained their high sensitivity when used in an outpatient setting. Specificity was relatively low, which indicates that a significant proportion of the women would have been offered unnecessary surgery for suspected ovarian cancer. These findings show that the IOTA models could be used as a first-stage test to diagnose ovarian cancer in an outpatient setting, but a different second-stage test is required to minimize the number of false-positive findings. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.


Asunto(s)
Modelos Logísticos , Pacientes Ambulatorios , Neoplasias Ováricas/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Londres , Persona de Mediana Edad , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/diagnóstico , Guías de Práctica Clínica como Asunto , Estudios Prospectivos , Sensibilidad y Especificidad , Ultrasonografía/normas , Adulto Joven
3.
Hum Reprod ; 32(2): 340-345, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27994000

RESUMEN

STUDY QUESTION: What is the natural history of endometrial polyps in women who are managed expectantly? SUMMARY ANSWER: The growth rates of expectantly managed polyps vary considerably and cannot be accurately predicted. WHAT IS KNOWN ALREADY: The majority of polyps detected on ultrasound are treated surgically, and therefore little is known about their natural history. Some polyps have been reported to regress spontaneously without the need for treatment; however, the factors predictive of regression are unknown. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study conducted at the Department of Gynaecology, University College London Hospitals. We searched our ultrasound clinic database between July 1997 and September 2015, to identify women aged 18 years or older with endometrial polyps that were managed expectantly for ≥6 months. All women attended for a minimum of two ultrasound scans. PARTICIPANTS/MATERIALS, SETTING, METHODS: A single expert operator performed all ultrasound scans. Those with <6-month follow-up and those who were taking hormonal contraception, HRT or tamoxifen were excluded from the study. The mean diameter of each polyp was calculated from the measurements in three perpendicular planes. The polyp growth rate was expressed as annual percentage change in the mean diameter. Non-parametric tests and the Fisher's exact test were used to compare differences in polyp mean diameters and growth rates between women of different demographic characteristics. To correct for multiple significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0029 (as 17 tests were undertaken). MAIN RESULTS AND THE ROLE OF CHANCE: We included 112 women with endometrial polyps, which were expectantly managed over a median period of 22.5 months (range, 6-136). The annual endometrial polyp growth rate varied with a median of 1.0% (interquartile range, -6.5 to 14.3). There was no association between women's demographic characteristics or polyps' morphology and their growth rates. Eleven out of 75 (15% (95% CI, 6.9%-23.1%)) women who initially did not have abnormal uterine bleeding subsequently developed abnormal bleeding during the follow-up period. Polyp growth rate was not associated with the subsequent development of abnormal uterine bleeding (P = 0.397). Seven out of 112 (6.3% (95% CI, 1.8%-10.8%)) women had complete regression of their polyps without treatment during a median follow-up period of 28 months (range, 9-56). Spontaneous regression appeared to occur more frequently in premenopausal women (P = 0.016) and in those who presented with abnormal uterine bleeding at diagnosis (P = 0.004); however, the differences did not reach statistical significance after correction for multiple comparisons. LIMITATIONS, REASONS FOR CAUTION: This study was retrospective and therefore may be prone to selection and information biases. The lack of histological confirmation on all ultrasound diagnoses may also be considered as a limitation. WIDER IMPLICATIONS OF THE FINDINGS: Women should be advised that the growth pattern of an individual polyp cannot be accurately predicted; however, a small proportion of polyps do regress spontaneously. There was no correlation between polyps' growth rate and the subsequent development of abnormal uterine bleeding. In view of that, routine monitoring of asymptomatic polyps by ultrasound is not helpful and encouraging women to report clinical symptoms is more useful in deciding whether treatment is required. In contrast to previous studies, we found that polyps may regress more frequently in premenopausal women and in those who presented with abnormal uterine bleeding; a larger sample size would give us greater power to detect a difference in these subgroups of women. STUDY FUNDING/COMPETING INTERESTS: No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: N/A.


Asunto(s)
Neoplasias Endometriales/patología , Pólipos/patología , Ultrasonografía , Enfermedades Uterinas/patología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Neoplasias Endometriales/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Pólipos/diagnóstico por imagen , Estudios Retrospectivos , Enfermedades Uterinas/diagnóstico por imagen
4.
BJOG ; 123(6): 1012-20, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26032603

RESUMEN

OBJECTIVE: To compare time to diagnosis of the typically slow-growing Type I (low-grade serous, low-grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high-grade serous, high-grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC). DESIGN: Multicentre observational study. SETTING: Ten UK gynaecological oncology centres. POPULATION: Women diagnosed with primary EOC between 2006 and 2008. METHODS: Symptom data were collected before diagnosis using patient questionnaire and primary-care records. We estimated patient interval (first symptom to presentation) using questionnaire data and diagnostic interval (presentation to diagnosis) using primary-care records. We considered the impact of first symptom, referral and stage on intervals for Type I and Type II iEOC. MAIN OUTCOME MEASURES: Patient and diagnostic intervals. RESULTS: In all, 78% of 60 Type I and 21% of 134 Type II iEOC were early-stage. Intervals were comparable and independent of stage [e.g. median patient interval for Type I: early-stage 0.3 months (interquartile range 0.3-3.0) versus late-stage 0.3 months (interquartile range 0.3-4.5), P = 0.8]. Twenty-seven percent of women with Type I and Type II had diagnostic intervals of at least 9 months. First symptom (questionnaire) was also similar, except for the infrequent abnormal bleeding (Type I 15% versus Type II 4%, P = 0.01). More women with Type I disease (57% versus 41%, P = 0.04) had been referred for suspected gynaecological cancer. Median time from referral to diagnosis was 1.4 months for women with iEOC referred via a 2-week cancer referral to any specialty compared with 2.6 months (interquartile range 2.0-3.7) for women who were referred routinely to gynaecology. CONCLUSION: Overall, shorter diagnostic delays were seen when a cancer was suspected, even if the primary tumour site was not recognised to be ovarian. Despite differences in carcinogenesis and stage for Type I and Type II iEOC, time to diagnosis and symptoms were similar. Referral patterns were different, implying subtle symptom differences. If symptom-based interventions are to impact on ovarian cancer survival, it is likely to be through reduced volume rather than stage-shift. Further research on histological subtypes is needed. TWEETABLE ABSTRACT: No difference in time to diagnosis for Type I versus Type II invasive epithelial ovarian cancers.


Asunto(s)
Neoplasias Glandulares y Epiteliales/patología , Neoplasias Ováricas/patología , Atención Primaria de Salud , Derivación y Consulta , Anciano , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario , Diagnóstico Tardío , Detección Precoz del Cáncer , Femenino , Humanos , Registros Médicos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Ováricas/diagnóstico , Estudios Retrospectivos , Encuestas y Cuestionarios , Evaluación de Síntomas , Factores de Tiempo
5.
Br J Cancer ; 111(12): 2297-307, 2014 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-25349970

RESUMEN

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.


Asunto(s)
Biomarcadores de Tumor/biosíntesis , Receptor 1 de Folato/biosíntesis , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Carcinoma Epitelial de Ovario , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis de Supervivencia , Análisis de Matrices Tisulares
6.
Ultrasound Obstet Gynecol ; 44(5): 503-14, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24920435

RESUMEN

OBJECTIVES: To present data on prospective evaluation of the International Ovarian Tumor Analysis (IOTA) 'simple-rules' tool for the diagnosis of ovarian cancer and to perform a meta-analysis of studies that utilized the same diagnostic method. METHODS: In the present study a level-II ultrasound operator systematically assessed the tumors of women with an ultrasound diagnosis of adnexal tumor(s) according to the IOTA simple-rules protocol to determine the risk of the tumor being malignant. The results of simple rules were compared with the 'pattern recognition' method and with histological findings. This validation study was included in the subsequent meta-analysis, for which we searched MEDLINE, EMBASE and Cochrane from the publication of the first study in 2008. The terms used were 'simple rules', 'simple rules ovarian', 'ovar tumor' and 'ultrasound'. Quality assessment was performed using the modified Quality Assessment of the Diagnostic Accuracy of Studies (QUADAS-2) checklist. Random effects meta-analysis was used to calculate pooled estimates of sensitivity and specificity for the simple-rules tool, and meta-regression was used to investigate heterogeneity across the studies. RESULTS: Three hundred and three women were included in the validation study with 168 (55.4%) benign, 19 (6.3%) borderline and 116 (38.3%) malignant tumors on histological examination. The rules were applicable in 237 (78.2%) of the tumors and for these tumors, sensitivity was 96.2% (95% CI, 90.5-99.0%) and specificity was 88.6% (95% CI, 82.0-93.5%). Six of the 88 discovered studies were included in the meta-analysis along with the current validation study, which resulted in inclusion of a total of 3568 patients. When the meta-analysis was performed the pooled sensitivity (when the rules were applicable) was 93% (95% CI, 90-96%) (I(2) = 32.1%) and the pooled specificity was 95% (95% CI, 93-97%) (I(2) = 78.1%). Heterogeneity was observed across the studies. Sensitivity was higher and specificity lower in the study populations in which the prevalence of malignant tumors was greatest. CONCLUSION: The simple rules protocol could be used in 76-89% of tumors and is an accurate test for the diagnosis of ovarian cancer. Assessment by an ultrasound expert is required when the protocol cannot be applied.


Asunto(s)
Neoplasias Ováricas/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Lista de Verificación , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Garantía de la Calidad de Atención de Salud , Sensibilidad y Especificidad , Ultrasonografía , Adulto Joven
7.
Br J Cancer ; 106(12): 1910-6, 2012 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-22596242

RESUMEN

BACKGROUND: In research studies, accurate information of cancer diagnosis is crucial. In women with breast cancer (BC), we compare cancer registration (CR) in England/Wales and self-reporting with independent confirmation. METHODS: In the UK Collaborative Trial of Ovarian Cancer Screening, notification of BC diagnosed between randomisation and 31 December 2009 was obtained through (1) CR (17 October 2011) and (2) self-reporting using postal-questionnaire. Breast cancer was confirmed using a detailed questionnaire (BC questionnaire BCQ) completed by the treating clinician (gold standard). Apparent sensitivity and positive-predictive value of CR/self-reporting vs BCQ were calculated. RESULTS: Of 1065 women with possible BC notification, diagnosis was confirmed in 932 (87.5%). A total of 3.1% (28 out of 918) of BC CR and 12.4% (128 out of 1032) of women with self-reported BC only had in-situ carcinoma on BCQ. Another 4.6% (43 out of 932) of BCQ-confirmed cancer did not have a BC registration, and 3.6% (34 out of 932) did not self-report BC. Apparent sensitivity of CR and self-reporting vs BCQ were 95.4 and 96.4%, respectively. Positive-predictive value of self-reporting (87.1%) was significantly lower than that of CR (96.8%). Women aged<65 were more likely to over report in-situ carcinoma as BC. Overall, 73 (6.8%) women would have been misclassified/missed if CR, and 167 (15.6%) if self-reporting data alone was used. CONCLUSION: This study confirms the reliability of BC registration in England/Wales and highlights the fact that 1 in 10 women self-reporting BC might only have in-situ breast carcinoma.


Asunto(s)
Neoplasias de la Mama/epidemiología , Sistema de Registros , Autoinforme , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/patología , Estudios de Cohortes , Inglaterra , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Encuestas y Cuestionarios , Gales
8.
Br J Cancer ; 106(1): 189-98, 2012 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-22108517

RESUMEN

BACKGROUND: The role of CHAC1 (cation transport regulator-like protein 1), a recently identified component of the unfolded protein response (UPR) pathway, in gynaecological cancers has not yet been characterised. Now, this work illustrates CHAC1 mRNA expression and associated clinical outcome in breast and ovarian cancer. METHODS: The prognostic value of CHAC1 and its two transcript variants was investigated in 116 breast and 133 ovarian tissues using quantitative real-time reverse-transcriptase PCR. Subsequently, we conducted functional studies using short-interfering RNA-mediated knockdown and plasmid-mediated overexpression of CHAC1 in breast and ovarian cancer cells. RESULTS: Poorly differentiated tumours exhibited higher CHAC1 mRNA expression (breast cancer: P=0.004; ovarian cancer: P=0.024). Hormone receptor-negative breast tumours and advanced-staged ovarian cancers demonstrated elevated CHAC1 mRNA expression levels (P<0.001 and P=0.026, respectively). The multivariate survival analysis showed a prognostic value of both transcript variants in breast cancer (transcript variant 1: RR(death) 6.7 (2.4-18.9); P<0.001), RR(relapse) 6.7 (2.1-21.3); P=0.001); (transcript variant 2: RR(death) 4.9 (2.0-12.4); P<0.001), RR(relapse) 8.0 (2.4-26.8); P<0.001). Ovarian cancer patients aged younger than 62.6 years with high CHAC1 mRNA expression showed poorer relapse-free- and overall-survival (P=0.030 and P=0.012, respectively). In functional studies CHAC1 knockdown suppressed cell migration, whereas ectopic overexpression opposed these effects. CONCLUSION: High CHAC1 mRNA expression could be an independent indicator for elevated risk of cancer recurrence in breast and ovarian cancer.


Asunto(s)
Neoplasias de la Mama/patología , Proteínas de Transporte de Catión/genética , Neoplasias Ováricas/patología , Empalme del ARN , ARN Mensajero/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Western Blotting , Neoplasias de la Mama/genética , Línea Celular Tumoral , Cartilla de ADN , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genética
9.
Br J Cancer ; 101(1): 160-5, 2009 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-19491898

RESUMEN

BACKGROUND: Oestrogens play a crucial role in breast carcinogenesis. Earlier studies have analysed the serum levels of endogenous hormones measured by conventional assays. In this study, we analysed the capacity of serum from breast cancer cases and controls to transactivate the oestrogen receptor alpha (ER-alpha) and beta (ER-beta). METHODS: We used a receptor oestrogen-responsive element (ERE) -- the green fluorescent protein (GFP)-reporter test system in Saccharomyces cerevisiae. Oestrogen receptor-alpha or ER-beta bioactivity was determined in serum from 182 randomly chosen postmenopausal women with breast cancer and from 188 age-matched controls. RESULTS: High serum ER-alpha and ER-beta bioactivity were independently associated with the presence of breast cancer. Women whose levels of serum ER-alpha and ER-beta bioactivity were in the highest quintile among controls had a 7.57-(95% confidence interval (CI): 2.46-23.32; P=0.0004) and a 10.14 (95% CI: 3.19-32.23; P<0.0001)-fold risk for general and oestrogen receptor-positive breast cancer, respectively. CONCLUSION: The use of serum ER-alpha and ER-beta bioactivity assays as clinical tools in the management of breast cancer warrants further research. Future studies will dictate whether surrogate markers of ER-alpha and ER-beta bioactivity will provide a means to monitor the efficacy of anti-endocrine, adjuvant and chemopreventive strategies.


Asunto(s)
Neoplasias de la Mama/sangre , Receptor alfa de Estrógeno/sangre , Receptor beta de Estrógeno/sangre , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Estradiol/sangre , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia/sangre , Valor Predictivo de las Pruebas , Elementos de Respuesta , Factores de Riesgo , Activación Transcripcional
10.
J Natl Cancer Inst ; 92(10): 826-32, 2000 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-10814678

RESUMEN

BACKGROUND: A growing body of evidence supports the hypotheses that the retinoic acid receptor beta2 (RAR-beta2) gene is a tumor suppressor gene and that the chemopreventive effects of retinoids are due to induction of RAR-beta2. RAR-beta2 expression is reduced in many malignant tumors, and we examined whether methylation of RAR-beta2 could be responsible for this silencing. METHODS: RAR-beta2 expression was studied by reverse transcription-polymerase chain reaction (RT-PCR) analysis in eight breast cancer cell lines that were either treated with the demethylating agent 5-aza-2'-deoxycytidine and subsequently with all-trans-retinoic acid (ATRA) or left untreated. Sodium bisulfite genomic sequencing was used to determine the locations of 5-methylcytosines in the RAR-beta2 genes of three of these cell lines. In 16 breast cancer biopsy specimens and non-neoplastic breast tissue, methylation-specific PCR was used to determine the methylation status of RAR-beta2, and, in 13 of the specimens, RT-PCR analysis was used to detect RAR-beta2 expression. RESULTS: Cell lines SK-BR-3, T-47D, ZR-75-1, and MCF7 exhibited expression of RAR-beta2 only after demethylation and treatment with ATRA. The first exon expressed in the RAR-beta2 transcript was methylated in cell lines ZR-75-1 and SK-BR-3. Six breast cancer specimens showed methylation in the same region of the gene. No expression of RAR-beta2 was found in any grade III lesion. An inverse association between methylation and gene expression was found in all grade II lesions. The RAR-beta2 gene from non-neoplastic breast tissue was unmethylated and expressed. CONCLUSIONS: Methylation of the RAR-beta2 gene may be an initial step in breast carcinogenesis; treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality.


Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Metilación de ADN , Receptores de Ácido Retinoico/genética , Secuencia de Bases , Western Blotting , Regulación Neoplásica de la Expresión Génica , Genes Supresores , Humanos , Reacción en Cadena de la Polimerasa , Células Tumorales Cultivadas
11.
Cancer Res ; 55(10): 2135-9, 1995 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-7743514

RESUMEN

Retinoids and gamma-interferon (IFN-gamma) have been demonstrated to synergistically amplify growth inhibition in cultured breast cancer cells. Since IFN-gamma enhances effects mediated by retinoids more than vice versa, we focused our investigations on the mRNA expression of cellular retinoic acid-binding proteins (CRABPs) and retinoic acid receptors (RARs), since these are the key molecules that mediate retinoid action. Synergistic inhibition of cell proliferation under treatment with 9-cis-retinoic acid and IFN-gamma was detected in the three breast cancer cell lines MCF-7, SKBR-3, and even in the RA-resistant BT-20 cells. RAR-alpha and RAR-gamma mRNA were observed in all cell lines, whereas RAR-beta was not detectable. CRABP I message was expressed in MCF-7 cells only, but CRABP II was found in all three breast cancer cell lines. IFN-gamma (10 ng/ml) increased RAR-gamma expression but had no influence on RAR-alpha, whereas RAR-beta was not detectable in any of the cell lines. RA (1 microM)-mediated CRABP II increase was suppressed by IFN-gamma (10 ng/ml). These observations indicate that IFN-gamma-mediated increase in RAR-gamma and suppression of RA-mediated CRABP II activation may play a role in synergistic inhibition of proliferation in breast cancer cell lines.


Asunto(s)
Neoplasias de la Mama/metabolismo , Interferón gamma/farmacología , Receptores de Ácido Retinoico/metabolismo , Tretinoina/farmacología , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Cicloheximida/farmacología , Sinergismo Farmacológico , Humanos , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Ácido Retinoico/efectos de los fármacos , Células Tumorales Cultivadas
12.
Cancer Res ; 57(17): 3818-22, 1997 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-9288793

RESUMEN

Taxanes represent a new class of antineoplastic agents that are being evaluated in several malignant tumors; they have been shown to induce a high remission rate and to prolong survival in ovarian cancer patients. However, CA-125 has been suggested to be an unreliable marker for monitoring response to paclitaxel therapy. Therefore, we were interested in whether taxanes may directly modulate CA-125 expression. Human ovarian carcinoma cell lines OVCAR-3, HOC-7, SKOV-6, 2780, 2774, and HTB-77 were treated with paclitaxel or docetaxel. Secreted, surface-associated, and cytosolic CA-125 were estimated by means of a sandwich solid-phase RIA or by immuno-flow cytometry. In addition to in vitro antiproliferative activity, paclitaxel and docetaxel augmented the expression of the tumor marker CA-125 in the three ovarian carcinoma cell lines, OVCAR-3, HOC-7, and SKOV-6, constitutively expressing this tumor marker. The three CA-125-negative cell lines, 2780, 2774, and HTB-77, did not respond to taxane treatment by expressing this tumor marker, although their proliferation was markedly inhibited. The taxane-mediated induction of CA-125 was found to be dependent on intact protein and RNA biosynthesis. However, CA-125 concentration was increased in the supernatant medium only and not on cell surface or cytosol. Our results demonstrate an in vitro activation of ovarian carcinoma cells in terms of CA-125 secretion by taxanes. This may explain the CA-125 fluctuations observed in vivo under paclitaxel treatment and may indicate that CA-125 is not a reliable tumor marker during taxane chemotherapy.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antígeno Ca-125/efectos de los fármacos , Proteínas de Neoplasias/efectos de los fármacos , Neoplasias Ováricas/inmunología , Paclitaxel/análogos & derivados , Paclitaxel/farmacología , Taxoides , Antígeno Ca-125/metabolismo , División Celular/efectos de los fármacos , Citosol/inmunología , Docetaxel , Femenino , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias Ováricas/patología , Células Tumorales Cultivadas/efectos de los fármacos
13.
Cancer Res ; 57(19): 4158-61, 1997 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-9331065

RESUMEN

Retinoids and their receptors [retinoic acid receptors (RARs) and retinoid X receptors] play an important role in maintaining the balance between proliferation and apoptosis. Recently, Deng et al. [Science (Washington DC), 274: 2057-2059, 1996] reported a loss of heterozygosity on chromosome 3p24 in breast cancer specimens and the morphologically normal appearing adjacent tissue. The 3p24 locus includes, among other genes, the region coding for RAR-beta. This study was designed to determine whether there are abnormalities in the expression of retinoid receptors in surgical specimens of patients with breast cancer. In 14 patients, transcripts of nuclear retinoid receptors were detected by in situ hybridization in formalin-fixed, paraffin-embedded specimens by means of digoxigenin-labeled riboprobes specific for RAR-alpha, -beta and -gamma. We found RAR-alpha expressed in all specimens, whereas RAR-gamma was expressed in 100% of normal breast tissue but in only 11 of 14 tumorous lesions. RAR-beta was found in all cases of normal breast tissue localized distant from the tumor, but in 13 of 14 cases it was completely absent in the tumor and the morphologically normal appearing tissue adjacent to the tumor. One possibility to explain the suppression of RAR-beta is a mutation in the promoter region. Sequencing the DNA extracted from paraffin-embedded tumor tissue of the corresponding breast cancer specimens, we were not able to detect any mutation in the retinoic acid-responsive element. Our results clearly indicate a crucial role of RAR-beta in the carcinogenesis of breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/biosíntesis , Receptores de Ácido Retinoico/deficiencia , Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Transformación Celular Neoplásica , Análisis Mutacional de ADN , Estrógenos , Femenino , Humanos , Hibridación in Situ , Proteínas de Neoplasias/genética , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/metabolismo , Receptores de Ácido Retinoico/biosíntesis , Receptores de Ácido Retinoico/genética
14.
J Clin Oncol ; 16(5): 1861-8, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9586902

RESUMEN

PURPOSE: The clinical impact of endogenous cytokines supplied with deterministic properties in the generation of either T helper (Th)1 -type or Th2-type immune response was investigated in patients with ovarian cancer. Whereas interleukin (IL)- 12 initiates the differentiation of naive Th0 cells toward Th1 phenotype, IL-4 and IL-10 mediate the development of Th2-type immunity. PATIENTS AND METHODS: Cytokines were determined before treatment by means of enzyme-linked immunosorbent assay (ELISA) in ascites fluid and serum of 76 patients with ovarian cancer. Cytokine levels were compared with each other and with standard clinicopathologic parameters. A stepwise logistic regression was calculated to rule out interdependence in the associations of the various variables. Survival analyses were performed with the Kaplan-Meier method and differences in survival were examined according to Mantel and Breslow. Cox proportional hazards analysis was used to identify independent prognostic factors. RESULTS: Whereas IL-10 and IL-12 were detectable in all ascites-fluid samples, IL-4 was measurable in only 43% of the specimens. With the exception of neopterin, macrophage colony-stimulating factor (M-CSF), and IL-4, determined cytokine levels were significantly elevated in ascites fluid compared with serum (P < .01). In univariate analyses, high ascitic-fluid concentrations of either neopterin, tumor necrosis factor-alpha (TNF-alpha), or IL-12 were associated with poor disease-free (P < .005) and overall (P < .01) survival. Multivariate Cox regression analysis showed ascitic-fluid IL-12 levels to be the only immunologic variable that retained independent prognostic significance (P < .03 for disease-free and P < .01 for overall survival), together with residual disease, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO)-stage, and patient age. CONCLUSION: In ovarian cancer, high ascitic-fluid IL-12 levels, which may indicate a local Th1-generated immune response, are associated with disease progression.


Asunto(s)
Líquido Ascítico/química , Biomarcadores de Tumor/análisis , Interleucina-12/análisis , Neoplasias Ováricas/diagnóstico , Adulto , Anciano , Supervivencia sin Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Interleucina-10/análisis , Interleucina-10/sangre , Interleucina-12/sangre , Interleucina-4/análisis , Factor Estimulante de Colonias de Macrófagos/análisis , Persona de Mediana Edad , Neopterin/análisis , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/mortalidad , Pronóstico , Tasa de Supervivencia , Factor de Necrosis Tumoral alfa/análisis
15.
Methods Inf Med ; 44(4): 516-9, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16342918

RESUMEN

OBJECTIVES: Changes in the status of DNA methylation, known as epigenetic alterations, are among the most common molecular alterations in human neoplasia. For the first time, we reported on the analysis of fecal DNA from patients with CRC to determine the feasibility, sensitivity and specificity of this approach. We want to present basic information about DNA methylation analysis in the context of bioinformatics, the study design and several statistical experiences with gene methylation data. Additionally we outline chances and new research questions in the field of DNA methylation. METHODS: We present current approaches to DNA methylation analysis based on one reference study. Its study design and the statistical analysis is reflected in the context of biomarker development. Finally we outline perspectives and research questions for statisticians and bioinformaticians. RESULTS: Identification of at least three genes as potential DNA methylation-based tumor marker genes (SFRP2, SFRP5, PGR). CONCLUSIONS: DNA methylation analysis is a rising topic in molecular genetics. Gene methylation will push the extension of biobanks to include new types of genetic data. Study design and statistical methods for the detection of methylation biomarkers must be improved. For the purpose of establishing methylation analysis as a new diagnostic/prognostic tool the adaptation of several approaches has become a challenging field of research activity.


Asunto(s)
Neoplasias del Colon/genética , Biología Computacional , Metilación de ADN , Epigénesis Genética , Biomarcadores de Tumor , Estudios de Factibilidad , Humanos , Sensibilidad y Especificidad
16.
Oncogene ; 34(15): 1961-7, 2015 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-24858038

RESUMEN

Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Quinasas Ciclina-Dependientes/biosíntesis , Daño del ADN , Fluorouracilo/farmacología , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Replicación del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Transplantation ; 71(12): 1821-7, 2001 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-11455264

RESUMEN

BACKGROUND: Calcium represents a key mediator of cold ischemia/reperfusion (CIR) injury presumably by affecting mitochondrial function. In this study, we investigated cellular and mitochondrial changes of calcium homeostasis in sublethally damaged human endothelial cells. METHODS: Changes in cellular and mitochondrial calcium concentrations were studied after cold ischemia in University of Wisconsin solution for 12 hr and reperfusion in ringer solution. Cytosolic-free calcium concentration ([Ca2+]c) and mitochondrial-free calcium content ([Ca2+]m) were analyzed by fura-2 and rhod-2 fluorescence, respectively. Pretreatment of cells with ruthenium red (RR) or a H+-ionophore was used to inhibit mitochondrial calcium uptake. Mitochondrial membrane potential (DeltaPsim) was measured by 5,5',6,6'-tetrachloro- 1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide and 3,3'-dihexyloxacarbocyanine iodide fluorescence. RESULTS: Twelve-hr cold ischemia did not induce apoptosis in endothelial cells. In such sublethally damaged cells, [Ca2+]c rose from approximately 20 nmol/L after cold ischemia to approximately 120 nmol/L during reperfusion. Pretreatment with RR leads to an approximately 5-fold rise in [Ca2+]c. Image analysis revealed a significant increase of [Ca2+]m in a subpopulation of mitochondria during reperfusion. This was not the case in RR-pretreated cells. DeltaPsim decreased significantly during cold ischemia and was sustained during reperfusion. The loss of DeltaPsim can be related to a reduced portion of mitochondria exhibiting high DeltaPsim. CONCLUSIONS: Our results suggest that cytosolic calcium influx during CIR is buffered by a selective portion of mitochondria in human umbilical vein endothelial cells. These mitochondria protect cells against cytosolic calcium overload and probably against subsequent cell injury.


Asunto(s)
Calcio/metabolismo , Frío , Citosol/metabolismo , Endotelio Vascular/metabolismo , Isquemia/metabolismo , Mitocondrias/fisiología , Daño por Reperfusión , Daño por Reperfusión/metabolismo , Células Cultivadas , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Homeostasis , Humanos , Isquemia/fisiopatología , Potenciales de la Membrana , Concentración Osmolar , Daño por Reperfusión/fisiopatología , Venas Umbilicales
18.
Biochem Pharmacol ; 60(8): 1153-63, 2000 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11007953

RESUMEN

Due to its critical involvement in cell cycle control and apoptotic signaling, the transcription factor p53 has become the most important tumor suppressor currently under investigation. TP53 is the most frequently mutated gene in human cancers and is thought to play a crucial role in malignant transformation. Therefore, p53 appears to be an appealing target for gene therapy. Adenoviral-based p53 gene transfection is now being introduced in large clinical trials. Viral cell entry was found to be the rate-limiting step of gene delivery and thus of therapeutic efficiency. Attachment of adenoviruses to the target cell surface is mediated through the coxsackie-adenovirus receptor, and internalization is achieved via interactions with integrins of the alpha v beta(3) and alpha v beta(5) class. The assumption that the restitution of the p53-dependent apoptotic pathway results in a higher responsiveness of solid tumors to cytostatic agents remains a major matter of debate. Combinations of p53-based gene therapy with other components involved in apoptosis, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO2L, or agents neutralizing tumor-promoting antiapoptotic signals, such as humanized anti-growth factor antibodies, should further improve the effectiveness of cancer treatment in the future.


Asunto(s)
Regulación de la Expresión Génica , Terapia Genética , Neoplasias Ováricas/terapia , Proteína p53 Supresora de Tumor/genética , Resistencia a Antineoplásicos , Femenino , Técnicas de Transferencia de Gen , Terapia Genética/tendencias , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Tolerancia a Radiación , Proteína p53 Supresora de Tumor/fisiología , Proteína p53 Supresora de Tumor/uso terapéutico
19.
J Steroid Biochem Mol Biol ; 47(1-6): 123-6, 1993 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8274426

RESUMEN

Combination of all-trans-retinoic acid (RA) with either interferon-alpha or -gamma resulted in a synergistic amplification of the anti-proliferative effect on cultured breast cancer cells. RA could be replaced by other biologically active retinoids. The synergism was also observed for the induction of 2'-5'-oligoadenylate synthetase, an enzyme which is involved in anti-viral activity of interferons and possibly in growth regulation of tumor cells. Combination of RA with interferon-gamma increased the down-regulation of specific binding sites for [125I]interferon-gamma. On the other hand interferons had no effect on the cytoplasmic binding protein for RA. Comparing all-trans- with 9-cis-RA, the latter was more effective in inhibiting tumor cell growth and in inducing synergism with interferon-gamma. This would indicate that retinoic X receptors are more important in mediating these effects than the RA receptors (RARs). This assumption is also supported by the failure of Ro-415253, a specific RAR-alpha antagonist, to reduce the synergistic interaction of RA with interferon with respect to growth inhibition.


Asunto(s)
Neoplasias de la Mama/patología , Interferón gamma/farmacología , Factores de Transcripción , Tretinoina/farmacología , Neoplasias de la Mama/tratamiento farmacológico , División Celular/efectos de los fármacos , Resistencia a Medicamentos , Sinergismo Farmacológico , Humanos , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores de Ácido Retinoico/fisiología , Proteínas Recombinantes , Receptores X Retinoide , Estereoisomerismo , Tretinoina/metabolismo , Células Tumorales Cultivadas
20.
Anticancer Res ; 18(3A): 1777-86, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9673404

RESUMEN

Retinoids modulate several cell functions and especially inhibit the growth of tumor cells. Their biological activity is mediated by retinoic acid receptors (RARs), of which three subtypes (alpha, beta, gamma) have been identified. In human neuroblastoma (NB) reduced endogenous RAR-gamma expression was suggested to diminish the sensitivity for retinoids, to promote proliferation, and to contribute to the malignant phenotype. To correlate receptor selectivity with in vitro activity, we analysed the effect of six synthetic retinoids with selectivity for human RAR-alpha/beta/gamma on the human LAN-5 NB cell line and compared it with the natural compound all-trans-retinoic acid (ATRA). Apoptosis was determined by flow-cytometry using terminal-deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. The antagonist for RAR-beta/gamma CD2665 as well as the selective agonists for RAR-alpha CD336 and RAR-beta CD2019 were less effective in growth inhibition than ATRA. In contrast, the synthetic RAR-gamma selective agonists CD437 and CD2325 induced a concentration- and time-dependent antiproliferative effect, which was similar or even more pronounced than ATRA. In contrast to ATRA, the adition of CD437 and CD2325 did not induce morphological changes typical of NB cell maturation but resulted in morphological features consistent with the occurrence of programmed cell death. Flow-cytometric analysis showed that in contrast to ATRA the addition of CD 437 and CD 2325 results in progressive time-dependent increase of apoptotic cells (25.9% and 57.7% after 72 hours). In conclusion, our study demonstrates RAR-gamma selectively binding retinoids dramatically suppress NB cell growth, primarily by inducing programmed cell death rather than by cell differentiation. Since advanced or disseminated NB tumors endogenously express low levels of RAR-gamma and lack of apoptosis is involved in tumor progression, RAR-gamma selectively binding retinoids may be more appropriate retinoids for clinical trials in NB.


Asunto(s)
Receptores de Ácido Retinoico/metabolismo , Retinoides/metabolismo , Retinoides/toxicidad , Tretinoina/toxicidad , Apoptosis/efectos de los fármacos , Unión Competitiva , División Celular/efectos de los fármacos , Humanos , Cinética , Neuroblastoma , Receptores de Ácido Retinoico/biosíntesis , Receptores de Ácido Retinoico/efectos de los fármacos , Receptor alfa de Ácido Retinoico , Relación Estructura-Actividad , Células Tumorales Cultivadas , Receptor de Ácido Retinoico gamma
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