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OBJECTIVE: Approximately 2 million women worldwide are infected with high-risk human papillomaviruses (HPV), resulting in a substantial risk for the development of invasive lower genital malignancies. This study was undertaken to determine the effects of vaccination with a protein encoding a bacterial heat shock protein fused to sequences from the oncogenic E7 protein of HPV-16 in women with high-grade cervical intraepithelial neoplasia. Endpoints included lesion regression, immune response, and viral clearance. METHODS: Twenty-one women were prospectively entered into an IRB-approved Phase II study. All women had biopsy-proven high-grade cervical intraepithelial neoplasia and persistent post-biopsy lesions visible by colposcopy. Four injections of HPV-16 Hsp E7 fusion protein at a dose of 500 mug were given 3 weeks apart after which Loop Electrosurgical Excision of the Transformation Zone (LLETZ) was performed. Immune parameters were evaluated pre-vaccine and at the time of LLETZ, and HPV testing was performed at intervals before and after LLETZ. Study subjects were followed for 1 year after LLETZ. RESULTS: Seven of 20 women (35%) evaluable for response had complete regression of their intraepithelial neoplasia at the time of LLETZ, 1 (5%) had regression to CIN I, 11 (55%) had stable disease and 1 (5%) had progression due to enlargement of her lesion. Immune responses were seen in 9 of the 17 women tested; 5 of the 7 complete responders had an immune response. Only 5 of 21 women had HPV-16 or -18. HPV clearance was not associated with lesion regression. CONCLUSION: Hsp-7 (SGN-00101), at this dose and schedule induced lesion regression in women with high-grade intraepithelial neoplasia. The fact that regression was correlated with immune response suggests that enhancing the immunogenicity of this vaccine may lead to improvement in the rate of lesion eradication.
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Proteínas Bacterianas/inmunología , Vacunas contra el Cáncer/uso terapéutico , Chaperoninas/inmunología , Proteínas Oncogénicas Virales/inmunología , Displasia del Cuello del Útero/terapia , Neoplasias del Cuello Uterino/terapia , Adulto , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Chaperonina 60 , Femenino , Humanos , Proteínas E7 de Papillomavirus , Infecciones por Papillomavirus/inmunología , Estudios Prospectivos , Proteínas Recombinantes de Fusión/inmunología , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Displasia del Cuello del Útero/inmunología , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
In this study, we examine the prevalence of finding isolated tumor cells (ITCs) in negative lymph nodes of endometrial cancer patients using immunohistochemistry. Seventy-six endometrial cancer patients with lymph nodes histologically negative for metastatic disease were examined. Nodal tissue sections were stained with anticytokeratin antibodies AE-1 and CAM 5.2. Nodes with single or groups of cells (two to four cells) < or =0.2 mm and showing cytokeratin reactivity were positive for ITCs. Findings were compared to features of the primary tumor and patient outcome. ITCs were present in 31 of 1712 lymph nodes. Fifteen (19.7%) patients had ITC-positive nodes. ITCs involved only pelvic nodes in nine cases, only para-aortic nodes in five cases, and pelvic and para-aortic in one case. Tumor in adnexa was the only pathologic feature associated with nodal ITCs (P= 0.0485). All 15 patients with nodal ITCs were alive at follow-up. One (6.7%) patient suffered recurrent disease but was alive at last encounter. Disease recurred in 5 (8.8%) of 57 patients without nodal ITCs. Two are alive without disease, two alive with disease, and one died from her cancer. In summary, a significant proportion of endometrial cancer patients have ITCs detected by immunohistochemistry in histologically negative regional lymph nodes.
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Neoplasias Endometriales/patología , Inmunohistoquímica , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico , Metástasis Linfática/patología , Adulto , Anciano , Carcinoma/patología , Estudios Transversales , Diagnóstico Diferencial , Femenino , Humanos , Queratinas/análisis , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Estudios RetrospectivosRESUMEN
Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.
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Papillomaviridae/inmunología , Infecciones por Papillomavirus/prevención & control , Neoplasias del Cuello Uterino/prevención & control , Vacunas Virales/uso terapéutico , Femenino , Humanos , Incidencia , Tamizaje Masivo , Enfermedades del Cuello del Útero/prevención & control , Neoplasias del Cuello Uterino/epidemiologíaRESUMEN
OBJECTIVE: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. METHODS: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV-seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T-cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. RESULTS: At least one abnormal smear was found during all of follow-up among 73.0% of HIV-seropositive patients and 42.3% of seronegatives (p <.001). Only 5.9% of seropositives ever developed high-grade lesions, and the proportion with high-grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV-seropositive patients and seronegative patients was 26.4 and 11.0/100 woman-years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9-3.0), whereas that of at least low-grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6-6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p <.05); HPV detection and HIV RNA level predicted progression (p <.01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p <.001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm(3) and HIV RNA levels <4000/ml of similar HPV status. CONCLUSIONS: Although HIV infected women were at high risk for abnormal cytology, high-grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.
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Infecciones por VIH/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Enfermedades del Cuello del Útero/epidemiología , Displasia del Cuello del Útero/epidemiología , Frotis Vaginal , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , VIH-1/aislamiento & purificación , Humanos , Incidencia , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Vigilancia de la Población , Pronóstico , Estudios Prospectivos , ARN Viral/sangre , Factores de Riesgo , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/diagnóstico , Enfermedades del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/complicaciones , Displasia del Cuello del Útero/diagnósticoRESUMEN
OBJECTIVE: The toxicity and activity of intravenous topotecan were assessed in a multicenter Phase II study (GOG 76-U) in patients with advanced, recurrent, or persistent squamous cell carcinoma of the uterine cervix. METHODS: Intravenous topotecan was administered at 1.5 mg/m2 per day for 5 consecutive days every 4 weeks in patients without prior chemotherapy, aside from chemosensitizing agents used in conjunction with radiotherapy. The study required histologic confirmation of primary diagnosis, adequate performance status, and measurable disease to assess response. A two-stage design for accrual was used to allow for early termination of the study should inadequate response or excessive toxicity be an issue. Modifications of dose were based on hematologic toxicity. Treatment was continued until progression of disease was documented or adverse effects prohibited further therapy. RESULTS: A total of 49 patients were entered on study: of these 5 were never treated, and 1 was not evaluable for response. More than 88% (38 of 43 patients) had received prior radiotherapy. A median of two courses were administered per patient with a range of 1 to 14 cycles. Grade 4 neutropenia occurred in 68% and grade 4 thrombocytopenia in 18% of patients. Nonhematologic toxic effects were infrequent and not dose-limiting. The overall response rate (complete and partial) was 18.6%. The median progression-free survival was 2.4 months. CONCLUSIONS: Topotecan administered at this dose and schedule demonstrated moderate activity albeit at a cost of substantial hematologic toxicity in patients with advanced, recurrent, or persistent squamous cell carcinoma of the cervix.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Topotecan/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana EdadRESUMEN
OBJECTIVE: To determine associations among cervical cytology, colposcopy, and biopsy in HIV-seropositive women. MATERIALS AND METHODS: HIV-seropositive women and uninfected comparison women in a multicenter prospective cohort study underwent colposcopy for protocol indications. Women were eligible if they had a cervix, satisfactory cytology, and colposcopy between October 1994 and September 1999. Cytology, colposcopic impression, and biopsy were compared using equivalent categorizations. Kappa statistics with bootstrap sampling assessed strength of associations. RESULTS: Colposcopy was performed in 978/1370 HIV-seropositive women and in 154/224 seronegative women. Biopsies were performed on 603 (44%) seropositive women at least once during 1015 colposcopy visits and on 82 (37%) seronegative women at 116 visits. The positive predictive value of cytology was 72% for seropositive women and 60% for seronegative women. The positive predictive value of colposcopy was 71% for seropositive women and 55% for seronegative women. CONCLUSION: The correlation between either cervical cytology or colposcopic impression and colposcopic biopsy was poor.
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OBJECTIVE: The goal of this study was to develop a device which will elevate the small intestine out of the pelvic cavity during radiation after radical surgery. METHODS: A prosthetic device of silicone plastic was designed which conforms to the pelvis. This device is filled with saline and renograffin for X-ray visualization. The capacity of the device is between 750 and 1500 cc. A small bowel contrast radiograph is performed prior to radiation to document exclusion from the radiation field. The device remains in place throughout radiation therapy and is then removed through a small incision after draining the contents of the prosthesis. RESULTS: Seven devices have been placed to date. The patients' age ranged from 35 to 65 years. All women had stage Ib1 carcinoma of the cervix and all underwent a type III radical hysterectomy with bilateral pelvic and common iliac lymphadenectomy. The indication for placement of the device was deep invasion of tumor in five patients, close margin in one patient, and positive pelvic lymph nodes in one patient. The amount of fluid instilled in the device ranged from 960 to 1200 cc. All patients had a return to normal bowel function within 3 days of surgery. All had radiologically documented exclusion of the small intestine from the radiation field prior to beginning radiation. In the postoperative period there was one major complication: a pulmonary embolism documented by pulmonary angiogram on postoperative day 2. All seven patients completed planned radiotherapy. The devices have been removed, with no adhesions to the prosthesis. CONCLUSIONS: The results of this study determine that the feasibility, safety, and efficacy of a prosthetic device in displacing the small bowel from the radiation field following radical surgery are sufficient to warrant a large-scale study. The device should be applicable to any and all tumors that require high dose pelvic radiation. It is expected that displacement of the small intestine from the radiation field will diminish overall complications and may allow delivery of radiation doses that approach colon and bladder tolerance.
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Histerectomía , Intestino Delgado/efectos de la radiación , Traumatismos por Radiación/prevención & control , Protección Radiológica/instrumentación , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Braquiterapia , Terapia Combinada , Femenino , Humanos , Intestino Delgado/anatomía & histología , Persona de Mediana Edad , Proyectos Piloto , Protección Radiológica/métodos , Dosificación Radioterapéutica , Neoplasias del Cuello Uterino/cirugíaRESUMEN
OBJECTIVE: The aim of this study was to determine the response rate and toxicity of cis-platinum and gemcitabine in advanced, recurrent, or persistent squamous cell carcinoma of the cervix. METHODS: From July 1997 to January 1999, we conducted a Phase II trial in patients with advanced, persistent, or recurrent carcinoma of the cervix. The schedule employed 1250 mg/m(2) of gemcitabine on days 1 and 8 and 50 mg/m(2) of cis-platinum on day 1 in a 21-day cycle. Eligibility criteria were a GOG performance status of 0-2, adequate bone marrow reserve, serum creatinine less than 1.8 mg%, and a lesion which could be measured in two dimensions. None of the patients had received prior chemotherapy other than radiation sensitizers. Standard GOG toxicity and response criteria were used. RESULTS: Nineteen patients were enrolled into the trial. Two patients were inevaluable because of inadequate trial of drug. Seventeen patients were evaluable for response and toxicity. The median age of the patients was 47 years (range 24-72). The median number of cycles delivered was 5 (range 2-8). The incidence of grade 4 neutropenia and anemia was 2.4 and 1.2%, respectively. Two patients developed a single episode of grade 3 gastrointestinal toxicity. The overall response rate was 41% (7/17). There was 1 complete response of 14 months duration and 6 partial responses. Among those patients not previously irradiated, the response rate was 57% (4/7). Among the radiated patients, the response rate was 30% (3/10) with all responses occurring in the radiation field. CONCLUSION: This combination of cis-platinum and gemcitabine is a well-tolerated regimen which exhibits high activity in advanced, recurrent, or persistent squamous cell cervical cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patología , GemcitabinaRESUMEN
BACKGROUND: Cervical neoplasia occurs with increased frequency among women infected with HIV-1. OBJECTIVE: To characterize prevalence of and risk factors for abnormal cervical cytology among women with HIV and to compare them to uninfected women. METHODS: Baseline cervical cytology was obtained from 1713 women seropositive for HIV and 482 at-risk control women who were enrolled in the Women's Interagency HIV Study, a multicenter prospective cohort study conducted in six U.S. cities. Associations with sociodemographic, medical, and sexual variables were assessed by Fisher's exact test, Mantel extension test, and logistic regression analysis. RESULTS: Cervical cytology was abnormal in 38.3% of HIV-infected women (atypical squamous cells of uncertain significance [ASCUS] 20.9%, low-grade squamous cells of uncertain significance [LSIL] 14.9%, high-grade squamous cells of uncertain significance [HSIL] 2.3%, cancer 0.2%) and 16.2% of HIV-uninfected women (ASCUS 12.7%, LSIL 2.3%, HSIL 1.2%, cancer 0.0%). Risk factors for any abnormal cytology in multivariate analysis included HIV infection, CD4 cell count, HIV RNA level, detection of human papillomavirus (HPV), a prior history of abnormal cytology, employment, and number of male sex partners within 6 months of enrollment. Prior abortion was associated with a decreased risk of cytologic abnormality. CONCLUSIONS: Cervical cytologic abnormalities were frequent among women infected with HIV, although high-grade changes were found in only 2.5%. Factors linked to sexual and reproductive history, HPV infection, and HIV disease all influenced risk.
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Carcinoma de Células Escamosas/epidemiología , Seropositividad para VIH/patología , VIH-1 , Prueba de Papanicolaou , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Frotis Vaginal , Adulto , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Estudios de Cohortes , Sondas de ADN de HPV , Femenino , Seronegatividad para VIH , Seropositividad para VIH/complicaciones , VIH-1/genética , Humanos , Papillomaviridae/aislamiento & purificación , Prevalencia , Estudios Prospectivos , ARN Viral/análisis , Factores de Riesgo , Estados Unidos/epidemiología , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/etiología , Displasia del Cuello del Útero/patologíaRESUMEN
OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.
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Histerectomía , Escisión del Ganglio Linfático , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/epidemiología , Estadificación de Neoplasias , Pelvis , Estudios Prospectivos , Radioterapia/efectos adversos , Radioterapia Adyuvante , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS: Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS: The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.
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Antineoplásicos/uso terapéutico , Carcinoma/terapia , Cisplatino/uso terapéutico , Histerectomía , Neoplasias del Cuello Uterino/terapia , Adulto , Anciano , Anciano de 80 o más Años , Braquiterapia , Carcinoma/patología , Carcinoma/radioterapia , Terapia Combinada/efectos adversos , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/radioterapiaRESUMEN
OBJECTIVE: The objective of this study was to evaluate the expression of bcl-2, a regulatory protein in programmed cell death, in endometrial hyperplasia before and after progestational therapy. METHODS: Pre- and posttreatment paraffin-embedded endometrial tissue samples from 20 women with an initial diagnosis of endometrial hyperplasia were obtained from archived files. Cases were evaluated and classified as either complete resolution of hyperplasia or persistent hyperplasia in response to progestin treatment. Sections were examined for bcl-2, estrogen receptor, and progesterone receptor expression using immunohistochemistry and compared within the treatment response groups. RESULTS: Among the 20 women studied, 13 had complete regression of their hyperplasia with progestin treatment and 7 had evidence of persistent disease after therapy. Bcl-2 expression was significantly decreased after treatment from a mean reactivity score of 2.08 to 0.31 (P = 0.0005) in the group of patients whose hyperplasia completely regressed with progestin administration. Among the women who had persistent hyperplasia after therapy, no significant change was observed between pre- and posttreatment bcl-2 expression, with a mean reactivity of 1.86 to 1. 29, respectively (P = 0.075). Progestational therapy significantly decreased the status of estrogen receptors from a mean score of 2.08 to 0.46 (P = 0.0005) in completely resolved cases of hyperplasia and from 2.00 to 0.43 (P = 0.0025) in persistent hyperplasias. Treatment also significantly decreased the status of progesterone receptors from a mean reactivity score of 1.92 to 0.31 (P = 0.0005) in cases of regressed hyperplasia and from a mean reactivity of 1.86 to 0.29 (P = 0.005) in persistent cases of hyperplasia. CONCLUSIONS: Bcl-2 expression decreases following successful progestin treatment of endometrial hyperplasias, whereas it remains expressed in hyperplasias which persist despite progestational therapy. This suggests that bcl-2 expression may represent a component of the therapeutic effects exerted in the endometium during progestational therapy in the treatment of hyperplasia. The activity of the oncoprotein may be a potential measure of the progress of treatment.
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Regulación hacia Abajo , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/metabolismo , Progestinas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Adulto , Biomarcadores , Hiperplasia Endometrial/patología , Femenino , Humanos , Persona de Mediana Edad , Receptores de Estrógenos/fisiología , Receptores de Progesterona/fisiología , Inducción de RemisiónRESUMEN
OBJECTIVE: Our purpose was to compare the diagnostic ability and treatment efficacy of conization by the loop electrosurgical excision procedure with cold-knife conization. STUDY DESIGN: One hundred eighty women who required conization for diagnosis and treatment of cervical dysplasia or microinvasive cervical carcinoma were prospectively enrolled in a randomized clinical trial to receive either cold-knife conization or conization by the loop electrosurgical excision procedure. Conization complications, rate of lesion clearance, and therapeutic outcome were assessed for the 2 study groups. RESULTS: There were no statistically significant differences in the complication rate (P = 1.00), the rate of lesion clearance (P =.18), or the rate of disease recurrence (P =.13) between the 2 study groups. The mean follow-up was 11.2 months in the cold-knife conization group and 10.4 months in the loop-excision conization group. CONCLUSION: Cold-knife conization and loop-excision conization yield similar diagnostic and therapeutic results.
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Conización/métodos , Electrocirugia , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirugía , Biopsia , Femenino , Humanos , Recurrencia Local de Neoplasia , Complicaciones Posoperatorias , Estudios Prospectivos , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/cirugía , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/cirugíaRESUMEN
OBJECTIVE: The aim of this study was to test the hypothesis that DNA methylation is important for silencing the p16 tumor suppressor gene in ovarian epithelial tumors and to compare the prevalence of this mechanism among different ovarian epithelial tumor subtypes. METHOD: Methylation-specific PCR was used to analyze the p16 gene for DNA methylation in 20 ovarian cystadenomas, 15 low malignant potential (LMP) tumors, and 37 carcinomas. p16 expression was determined immunohistochemically in 58 of these tumors (16 cystadenomas, 13 LMP tumors, 29 carcinomas). Differences in methylation or expression rates between specific tumor subgroups were examined by Fisher's exact test. RESULTS: Fragments from the distal promoter and beginning of the first exon of the p16 gene were both methylated in 5 of 15 (33%) LMP tumors compared to 2 of 37 (5%) carcinomas (P = 0. 02). Those sites were also methylated in 5 of 20 (25%) cystadenomas. Lack of p16 expression was present in 7 of 16 cystadenomas, 4 of 13 LMP tumors, and 22 of 29 carcinomas (P [LMPs versus carcinomas] = 0. 01) and correlated with methylation changes in LMP tumors (P = 0.05). p16 expression was correlated with mucinous differentiation in cystadenomas (P = 0.001). CONCLUSION: p16 silencing may be important for the development of ovarian carcinomas and a subset of LMP tumors. Changes in DNA methylation may be more important for inactivation of this gene (and perhaps other tumor suppressor genes) in LMP tumors, which lack many of the alternative mechanisms present in carcinomas. p16 expression is primarily related to mucinous differentiation in cystadenomas.
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Carcinoma/genética , Cistoadenoma/genética , Metilación de ADN , Regulación Neoplásica de la Expresión Génica/genética , Genes p16/genética , Neoplasias Ováricas/genética , Femenino , HumanosRESUMEN
OBJECTIVE: To determine the usefulness of serum carcinoembryonic antigen (CEA) determination in predicting the nature of an isolated pelvic mass. STUDY DESIGN: Two hundred twenty-six women with an isolated pelvic mass had a serum CEA determination preoperatively. The results were correlated with the histopathologic findings. RESULTS: CEA was elevated in 19 of the 226 women. Twelve of the 183 (7%) women with benign masses, 2 of the 17 (12%) women with tumors of low malignant potential and 5 of the 15 (33%) women with a frankly invasive epithelial ovarian cancer had elevated CEA. None of the women with a malignant germ cell or stromal tumor had elevated CEA (P = .06 for prediction of malignancy.) There were no cases of metastatic gastrointestinal malignancies in the study group. The sensitivity, specificity, positive predictive value and negative predictive value of serum CEA were 16%, 93%, 37% and 83%, respectively. The corresponding figures for serum CA-125 were 67%, 71%, 35% and 90%. There was no statistically significant correlation between elevated CEA and mucinous histology. CONCLUSION: Preoperative serum CEA determination in women with isolated pelvic masses is not useful.
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Antígeno Carcinoembrionario/sangre , Neoplasias Pélvicas/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígeno Ca-125/análisis , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Neoplasias Pélvicas/patología , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To determine if the quantity of lymph-vascular space invasion influences the risk of pelvic nodal metastases in women with early-stage cervical squamous carcinoma. METHODS: Between 1991 and 1997, 105 women with stages IA2, Ib, and IIa squamous carcinoma of the cervix underwent radical hysterectomy and pelvic lymphadenectomy. The histopathology slides were prospectively reviewed. If lymph-vascular space invasion (LVSI) was present, the amount was quantified in four ways: percentage of cervical histopathologic sections containing LVSI, percentage of sections with tumor containing LVSI, total number of foci of LVSI, and maximal number of foci of LVSI in 10 high-powered fields. These measures of LVSI were correlated with the risk of nodal metastases. RESULTS: Seventy-three (70%) women had tumors with LVSI. Of these, 23 had pelvic nodal metastases. All women with nodal metastases had tumors with LVSI. Using logistic regession, independent predictors of nodal metastases were depth of cervical stromal invasion (P = 0.01) and tumor size (P = 0.04). LVSI was also a significant predictor of nodal metastases based on the Mantel-Haenszel test (P = 0.01). In women whose tumors contained LVSI, logistic regression identified tumor size (P = 0.004) and LVSI in > 45% of all cervical histopathologic sections (P = 0.002) as significant predictors of nodal metastases. CONCLUSION: The quantity of LVSI, as defined by the percentage of all cervical histopathologic sections containing LVSI, correlates significantly with the risk of nodal metastases in women with early-stage squamous carcinoma of the cervix.
Asunto(s)
Carcinoma de Células Escamosas/patología , Sistema Linfático/patología , Neoplasias del Cuello Uterino/patología , Adulto , Anciano , Biopsia , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Histerectomía , Escisión del Ganglio Linfático , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Estudios Prospectivos , Análisis de Regresión , Factores de Riesgo , Neoplasias del Cuello Uterino/cirugíaRESUMEN
BACKGROUND: Telomerase is an enzyme essential for the normal replication of chromosomes. Telomerase activity is absent in most somatic cells in adults, but it is usually expressed in cancer cells, including ovarian carcinoma cells. Our principal goal was to compare the sensitivity of a telomerase assay, i.e., the telomeric repeat amplification protocol (TRAP) assay, with that of cytologic examination in detecting cancer cells in the peritoneal cavity of patients with ovarian carcinoma. METHODS: TRAP assays and cytologic examinations were performed on peritoneal washings and ascitic fluids from 42 patients with active ovarian carcinoma. Control specimens included washings from 29 patients with benign ovarian diseases and ascitic fluids from 14 patients with liver failure. We also evaluated the stability of telomerase in ascitic fluids left unprocessed at room temperature as well as the ability of the TRAP assay to detect cancer cells in mixtures containing large numbers of normal cells. RESULTS: Specimens from 37 (88%) of the 42 patients with ovarian carcinoma tested positive for telomerase. Cytologic examination detected cancer cells in only 27 of the telomerase-positive specimens (i.e., in specimens from 64% of the 42 patients). This difference of 24% (95% confidence interval = 17%-30%) in sensitivity between the two tests was statistically significant (two-sided P = .002). Specimens from five of the patients with ovarian carcinoma were cytologically negative and telomerase negative. All 43 control specimens were cytologically negative, but the TRAP assay detected telomerase in two of them. Telomerase activity was detected in unprocessed samples left at room temperature for 5 days and in mixtures containing a small number of cancer cells and a 2000- to 10000-fold excess of normal cells. CONCLUSIONS: Assaying for telomerase is more sensitive than cytologic examination in detecting cancer cells in the peritoneal cavity of patients with ovarian carcinoma.
Asunto(s)
Líquido Ascítico/patología , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Cavidad Peritoneal/patología , Telomerasa/metabolismo , Femenino , Amplificación de Genes , Humanos , Sensibilidad y Especificidad , Telomerasa/genéticaRESUMEN
OBJECTIVE: To quantify the risk of residual invasion when cervical conization reveals microinvasive squamous carcinoma and to determine whether any factors affect this risk. METHODS: We reviewed the charts and histopathology slides of 87 women who underwent a conization that contained microinvasive squamous carcinoma, followed by either a repeat conization or hysterectomy. Depth of invasion, number of invasive foci, and status of the internal margin and post-conization endocervical curettage (ECC) were assessed. The findings were correlated with the presence of residual invasion. RESULTS: Significant predictors of residual invasion included status of the internal margin (residual invasion present in 22% of women with an involved margin versus 3% with a negative margin; P < .03) and the combined status of the internal margin and post-conization ECC (residual invasion in 4% of patients if both negative, 13% if one positive, and 33% if both positive; P < .015). Depth of invasion and number of invasive foci in the conization specimen were not significant. The power of this study to detect a 25% difference in the risk of residual invasion was 73% for depth of invasion and 75% for number of invasive foci. CONCLUSION: Women with microinvasive squamous carcinoma in a conization specimen in which both the internal conization margin and post-conization ECC are negative have a low risk of residual invasion and are candidates for follow-up or simple hysterectomy. If either the internal margin or the post-conization ECC contains dysplasia or carcinoma, the risk of residual invasion is high and warrants repeat conization before definitive treatment planning.
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Carcinoma de Células Escamosas/patología , Conización , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/patología , Carcinoma de Células Escamosas/cirugía , Cuello del Útero/patología , Cuello del Útero/cirugía , Femenino , Humanos , Histerectomía , Persona de Mediana Edad , Neoplasia Residual , Estudios Retrospectivos , Factores de Riesgo , Neoplasias del Cuello Uterino/cirugía , Displasia del Cuello del Útero/cirugíaRESUMEN
Radiation therapy is the mainstay in treatment of locally advanced cervical carcinoma. Several chemotherapeutic agents have been used as radiation sensitizers in the treatment of cervical cancer in an effort to improve local response and survival. A prospective study was designed to evaluate carboplatin as a radiosensitizer in advanced cervical cancer. Standard radiotherapy techniques were used to treat patients with Stage IIA-IIIB cervical cancer. Intravenous carboplatin was administered twice weekly concurrent with external beam radiation. Of 22 evaluable patients, there were 19 complete responders of whom 15 remain alive: 11 patients were alive and disease free at last visit for a median duration of 15 months follow-up (range, 4-43 months) and 4 patients remain alive with disease for a median duration of 17 months (range, 3-55 months). Seven have died, one of whom was without evidence of disease. There were no treatment-related deaths and no grade 4 toxicity. The most significant adverse effect was hematologic resulting in four patients with grade 3 neutropenia or anemia. There were no fistulae or late gastrointestinal or genitourinary complications. This pilot study suggests that carboplatin administered with standard radiation is safe, well-tolerated, and thus may be useful as a radiation sensitizer in the treatment of locally advanced cervical cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Terapia Combinada , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patologíaRESUMEN
OBJECTIVE: To determine the ability of pelvic examination, tumor marker assessment, and transvaginal ultrasonography, with selected use of Doppler ultrasonography, to predict pelvic malignancy. METHODS: Two hundred twenty-six women scheduled for operative removal of a pelvic mass were entered in the study prospectively. Each woman underwent pelvic examination, tumor marker assessment, and transvaginal ultrasonography preoperatively. Women whose gray-scale findings were suspicious for malignancy underwent Doppler ultrasonography. Suspicious findings included masses that were fixed or irregular on pelvic examination; CA 125 level greater than 35 U/mL; elevations in serum lactic dehydrogenase, alpha-fetoprotein, or hCG; and the presence of a substantial solid component on gray-scale ultrasonography. Suspicious Doppler findings included intratumoral color flow, pulsatility index less than 1.0, or resistance index 0.4 or lower. The findings were correlated with the presence of malignancy. RESULTS: If all three indicators (examination, tumor marker assessment, and gray-scale ultrasound findings) were nonsuspicious, 99% of premenopausal women and 100% of postmenopausal women had benign masses. If all three indicators were suspicious, 77% of premenopausal women and 83% of postmenopausal women had malignant tumors. Logistic regression identified ultrasound impression and tumor size to be significant predictors of malignancy in premenopausal women, whereas CA 125 level and ultrasound impression were significant in postmenopausal women. In patients with suspicious gray-scale findings, recategorization based on Doppler findings resulted in inferior diagnostic indices. CONCLUSIONS: Ultrasonographic tumor size and appearance are the best predictors of pelvic malignancy in premenopausal women, whereas CA 125 level and ultrasonographic appearance are the best predictors in postmenopausal women. Neither color nor spectral Doppler is useful in this setting.