HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer.

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16% of the cases with uterine serous papillary and clear cell type histology, respectively. In contrast, EGFR expression was significantly lower in type II compared with type I EC (34 vs 46%, P=0.041). EGFR expression but not HER2 gene amplification was significantly associated with poor overall survival in patients with type II EC, (EGFR, median survival 20 vs 33 months, P=0.028; HER2, median survival 18 vs 29 months, P=0.113) and EGFR expression retained prognostic independence when adjusting for histology, stage, grade, and age (EGFR, P=0.0197; HER2, P=0.7855). We conclude that assessment of HER2 gene amplification and/or EGFR expression may help to select type II EC patients who could benefit from therapeutic strategies targeting both HER2 and EGFR.

Microsatellite instability in sporadic endometrial carcinoma.

BACKGROUND: Recent studies have demonstrated ubiquitous somatic microsatellite mutations in some cancers of the colon, endometrium, stomach, and pancreas. PURPOSE: Our purpose was to characterize the frequency and nature of this replication error (RER) or mutator phenotype in sporadic endometrial carcinoma. METHODS: Formalin-fixed, paraffin-embedded normal and tumor tissues from 45 patients with sporadic endometrial cancer were screened for the RER phenotype at three microsatellite loci. To further characterize when these alterations were acquired relative to clonal expansion, the sizes of the altered microsatellites in different tumor and normal regions were determined using selective UV radiation fractionation. Approximately 150-300 histologically defined cells on stained tissue sections were covered with small ink dots, and UV irradiation was used to destroy the DNA of cells not covered by ink. Undamaged DNA from seven to 25 spots per section were extracted, then analyzed at the Mfd27, Mfd41, and Mfd47 microsatellite loci and also at the c-K-ras gene locus with individual polymerase chain reactions. Radioactively labeled amplified DNAs were analyzed by electrophoresis and autoradiography. Fisher's exact test and the logrank test were used for statistical analysis. RESULTS: The RER positive (RER+) phenotype was detected in nine (20%) of 45 sporadic endometrial carcinomas. The topographic tissue distributions of the altered microsatellites revealed clues to their pathogenesis. The RER+ phenotype was homogeneously present in the primary tumors and their metastases and was absent from adjacent normal and hyperplastic endometrium. The altered microsatellites were predominantly the same sizes throughout five tumors but demonstrated greater intratumor heterogeneity in three tumors. In one case, the primary tumor was stable but its metastasis was unstable. Mutant c-K-ras alleles were significantly more frequent in RER+ (56%) than in RER negative (RER-) (14%) tumors (P = .0165) and appeared to be acquired after the RER+ phenotype in one tumor. There were no significant clinical differences between the RER+ and RER- tumors. CONCLUSIONS AND IMPLICATIONS: The RER+ phenotype is frequently present in sporadic endometrial cancers and is expressed before and during clonal expansion. The underlying mutator mutations are probably heterogeneous, since the RER+ phenotypes were diverse. The absence of altered microsatellites in adjacent normal endometrium demonstrates that the expression of the RER+ phenotype is limited to neoplastic tissue. The bulk of the microsatellite alterations appeared to be acquired prior to clonal expansion, suggesting that expression of the underlying genomic instability contributes to, and is not a consequence of, transformation.

Detection of ovarian cancer cells: comparison of a telomerase assay and cytologic examination.

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.

Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma.

Endometrial carcinoma is theorized to arise from a series of somatic mutations which alter benign endometrium to progressively less differentiated histological lesions. One genetic alteration implicated in the carcinogenesis of endometrial cancer is the mutational activation of the c-Ki-ras oncogene. This study characterizes the frequency and the topographical distribution of activated c-Ki-ras alleles in endometrial carcinoma. Sixty formalin-fixed, paraffin-embedded endometrial cancer specimens were screened for point mutations at codons 12 and 13 of the c-Ki-ras oncogene by polymerase chain reaction and allelic specific oligomer dot-blot hybridization. c-Ki-ras mutations were identified in nine of 60 (15%) tumor specimens. Five cases resulted in G to A transitions, three in G to T transversions, and one in a G to C transversion. These nine mutant tumors were analyzed by selective UV radiation fractionation and polymerase chain reaction for the presence of activated c-Ki-ras alleles in cell populations of various histological phenotype. In eight tumors, c-Ki-ras mutations were uniformly present in the carcinoma cells. One tumor exhibited heterogeneous mutational activation, with mutant c-Ki-ras alleles detected in only grade 2 carcinoma cells but not grade 1 carcinoma cells. c-Ki-ras mutations were present in adjacent hyperplasia with atypia but absent from hyperplasia without atypia. With rare exception, c-Ki-ras activation appears to be an early oncogenic event since it is homogeneously present in premalignant and malignant endometrial tissues.

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

PURPOSE: A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS: Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS: Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION: Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients.

A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive.

Eighteen women with high-grade cervical or vulvar intraepithelial neoplasia who were positive for human papillomavirus (HPV) 16 and were HLA-A2 positive were treated with escalating doses of a vaccine consisting of a 9-amino acid peptide from amino acids 12-20 encoded by the E7 gene emulsified with incomplete Freund's adjuvant. Starting with the eleventh patient, an 8-amino acid peptide 86-93 linked to a helper T-cell epitope peptide with a covalently linked lipid tail was added. Patients with colposcopically and biopsy-proven cervical intraepithelial neoplasia/vulvar intraepithelial neoplasia II/III received four immunizations of increasing doses of the vaccine each 3 weeks apart, followed by a repeat colposcopy and definitive removal of dysplastic tissue 3 weeks after the fourth immunization. Patients were skin tested with the E7 12-20 peptide as well as control candida, mumps, and saline prior to and after the series of immunizations. Peripheral blood mononuclear cells were obtained by leucopheresis prior to and after the series of immunizations for analyses of CTL reactivity to the E7 12-20 and 86-93 epitope sequences. The presence of HPV 16 was assessed by DNA PCR on cervical scrapings and the biopsy specimens after vaccination. Pathology specimens were analyzed before and after vaccination for the presence of dysplasia, and the intralesional infiltrate of CD4/CD8 T-cells and dendritic cells was measured by immunohistochemical staining. Only 3 of 18 patients cleared their dysplasia after vaccine, but an increased S100+ dendritic cell infiltrate was observed in 6 of 6 patients tested. Cytokine release and cytolysis assays to measure E7-specific reactivity revealed increases in 10 of 16 patients tested. No positive delayed type hypersensitivity skin test reactivity was shown in any patient to HPV E7 12-20 before or after vaccinations. Virological assays showed that 12 of 18 patients cleared the virus from cervical scrapings by the fourth vaccine injection, but all biopsy samples were still positive by in situ RNA hybridization after vaccination. Six patients had partial colposcopically measured regression of their cervical intraepithelial neoplastic lesions in addition to the three complete responders. The data establish that a HPV-16 peptide vaccine may have important biological and clinical effects and suggest that future refinements of an HPV vaccine strategy to boost antigen-specific immunity should be explored.

Digital camera assessment for detection of cervical intraepithelial neoplasia in rural El Salvador.

OBJECTIVE: To explore the feasibility of digital photography for primary cervical cancer screening in a low-resource setting in El Salvador. METHODS: Three independent examiners performed Pap test, visual inspection, digital camera assessment and colposcopy on each subject. RESULTS: Lesions were detected in 99 of 504 patients (20%) by visual inspection, 72/504 (14%) by DART and 90/504 (18%) by colposcopic impression. Seven of 504 patients (1.3%) had CIN on histology. Pap detected 2 of 7 subjects (29% sensitivity) (C.I. 4%, 56%), visual inspection detected 5 of 7 (71% sensitivity, C.I. 34%, 95%), digital assessment detected 6 of 7 (86% sensitivity C. I. 45%, 99%), and colposcopic impression detected 5 of 7 (71% sensitivity, C.I. 34%, 95%). CONCLUSION: This small pilot trial demonstrates the potential value and feasibility of performing digital camera assessment of the reproductive tract on women in a developing country setting.

The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management.

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.

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women.

OBJECTIVE: Cervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DESIGN: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). METHODS: HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participant's consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. RESULTS: Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4-81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52-0.88) to demonstrate progression CONCLUSIONS: HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

Second-look laparotomy for stage III epithelial ovarian cancer: rationale and current issues.

During the past two decades, the initial treatment of an advanced ovarian malignancy has been generally uniform: it begins with an exploratory laparotomy surgically to remove as much tumor as possible (1) and to stage the cancer (2). For the 70% of patients classified as stages III and IV, surgery is then followed by combination chemotherapy. Although opinions differ as to the optimal regimen, the standard involves a platinum-based program (3), recently also including paclitaxel (4). A second-look laparotomy is often performed in all patients who achieve a clinical complete remission, that is the inability to detect disease by physical examination and non-invasive laboratory tests. This surgical procedure is able to detect clinical disease not apparent on computerized axial tomography (CT scan), ultrasound, magnetic resonance imaging (MRI), serum CA-125 levels or physical examination (5-7). Major questions, however, have arisen around the need for such a procedure, and whether one can justify it in terms of an improved outcome or merely as an assessment of prognosis (8-14). We shall review: (i) the technique; (ii) the rationale; (iii) the results that have been reported from its routine application; and (iv) controversial issues, particularly as they relate to the evolution of therapeutic strategies.

Platinum compounds in cervical and endometrial cancers: focus on carboplatin.

Drug therapy for cervical cancer is slowly undergoing evaluation in early disease stages, in which it is more likely to make an impact. Cisplatin has been the principal drug used in systemic therapy for all stages, with the possible exception of the radiosensitizer hydroxyurea. Nevertheless, current studies use cisplatin in this role as well. To a limited extent, substitution of carboplatin for cisplatin also has been explored. Conflicting interpretations of carboplatin trials nonetheless support continued study of this drug; its activity is reproducible and it can be combined with radiation therapy in practical dose schedules. The major question in the systemic nonendocrine treatment of endometrial cancer revolves around whether cisplatin adds to results achievable with doxorubicin. Carboplatin, documented as active against this neoplasm, represents a potentially advantageous cisplatin substitute for elderly patients. Moreover, if combination chemotherapy should prove disappointing, single-agent carboplatin may provide the best strategy for palliative therapy.

The significance of positive margins in loop electrosurgical cone biopsies.

OBJECTIVE: To determine the interpretability and significance of the endocervical margins of cervical cone biopsy specimens removed by the loop electrosurgical excision procedure (LEEP). METHODS: Loop electrosurgical cervical conization was performed on 57 women with biopsy-confirmed, high-grade dysplasias in whom the extent of the lesion could not be determined by colposcopic visualization. Internal endocervical margins of the resected specimens were marked with ink by the operating physician and evaluated microscopically by the pathologist. Endocervical curettage (ECC) was done in all instances, and all subjects were followed for 1 year after the procedure. RESULTS: Histologic evaluation of the inked endocervical margins was possible for all 57 resected specimens and was in no instance hindered by thermal artifact. In 19 patients, dysplasia was present in the inked core margin, the ECC, or both. Each patient had re-excisions of the endocervical area; 12 of the 19 (63%) had dysplasia in the specimen. Of 12 cases in which dysplasia was present in both the endocervical margin and the ECC, nine had residual dysplasia. Two of four patients with positive margins but a negative ECC had residual dysplasia, but only one of three patients with a negative endocervical margin and a positive ECC showed residual dysplasia. In the 38 patients with negative inked margins and a negative ECC, there was only one instance of dysplasia demonstrated during the 1-year follow-up period. CONCLUSION: Endocervical margins of cone biopsies removed by LEEP can be accurately assessed pathologically and can help predict the presence of persistent dysplasia.

Risk of residual invasive disease in women with microinvasive squamous cancer in a conization specimen.

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.

Cervical cancer in pregnancy: reporting on planned delay in therapy.

OBJECTIVE: To report our experience with invasive carcinoma of the cervix during pregnancy, assessing maternal morbidity due to treatment delay and reporting maternal and fetal outcome. METHODS: Twenty-seven patients with invasive cervical cancer, who were pregnant at the time of diagnosis or treatment, were identified from review of morbidity and mortality statistics between January 1, 1980 and December 31, 1991. All medical records were examined retrospectively. RESULTS: The incidence of cervical carcinoma in our population was 1.2 cases per 10,000 pregnancies. Most patients had stage I lesions. The predominant histologic cell type was squamous cell carcinoma, followed by adenosquamous carcinoma and adenocarcinoma. Eight patients with stage Ia or Ib cervical cancer postponed therapy to optimize fetal outcome, with a mean diagnosis-to-treatment interval of 144 days (range 53-212). Nineteen patients elected immediate treatment, with a mean diagnosis-to-treatment interval of 17 days (range 2-42). Fetal outcome was uniformly good for the delayed-treatment group. Nine fetal deaths and two neonatal deaths occurred in the immediate-treatment group. All patients who delayed therapy are free of disease after a median follow-up of 23 months. CONCLUSION: Deliberate delay of therapy to achieve fetal maturity appears to be a reasonable option for patients with stage I cervical cancer complicating pregnancy.

Pelvic examination, tumor marker level, and gray-scale and Doppler sonography in the prediction of pelvic cancer.

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.

The role of endocervical curettage at cervical conization for high-grade dysplasia.

OBJECTIVE: To quantify the risk of invasive cancer above the location where the conization specimen was taken in patients with an endocervical curettage (ECC) positive for dysplasia at conization for high-grade cervical intraepithelial neoplasia (CIN), and to determine if any pathologic features may influence this risk. METHODS: The charts of 104 patients who underwent cervical conization for high-grade dysplasia followed by repeat conization or hysterectomy at Los Angeles County + University of Southern California Women's Hospital between January 1986 and December 1992 were reviewed retrospectively. Patients with invasive cancer or glandular dysplasia on the initial conization were excluded. The ECC performed immediately after conization biopsy (conization ECC) was benign in 63 patients and contained dysplasia in 41. All available conization ECC specimens that contained dysplasia were evaluated for volume of dysplasia and degree of cytologic atypia. Fisher exact test was used for statistical comparison between and within groups. RESULTS: Invasive cancer was not present in any patients in the benign ECC group but was present in nine (22%) patients in the dysplasia group (P < .0001); five of these patients had microinvasion (no more than 3 mm of stromal invasion and no lymph-vascular space involvement) and four had frank invasion. Comparison of patients with involved endocervical margins revealed that none of 37 patients in the benign ECC group versus eight of 27 patients in the dysplasia group had invasive cancer (P < .0005). All patients with invasion were 35 years or older and all patients with frank invasion were 50 years or older. Neither volume nor cytologic grade of dysplasia in the ECC was predictive of invasion in the residual cervix. CONCLUSIONS: An ECC at conization positive for dysplasia is an important predictor of invasion in the residual cervix of patients whose conization reveals high-grade intraepithelial neoplasia and should be routinely performed. Women 50 years or older with both a positive endocervical margin and conization ECC should undergo repeat conization before further therapy. Women under 50 years of age should undergo repeat conization if fertility is not desired; otherwise, close follow-up is necessary to exclude the presence of an invasive lesion in the residual cervix.

Risk factors for trichomoniasis among women with human immunodeficiency virus (HIV) infection at a public clinic in Los Angeles County, California: implications for HIV prevention.

Persons with human immunodeficiency virus (HIV) infection who subsequently develop an acute sexually transmitted disease have an increased probability of transmitting HIV. Therefore, characterizing such persons can help direct prevention efforts to a group who are likely to be continuing sources of HIV transmission. We assessed the incidence and factors associated with trichomoniasis in a cohort of HIV-infected women receiving care at a public clinic in Los Angeles County, California from 1992 through 1995. Demographic, clinical, and behavioral data were available from medical records and from patient interviews. Trichomonas infection was the most frequently identified sexually transmitted disease and was found in 37 (17.4%) of 212 women representing a crude incidence rate of 14.1 per 100 person-years experience. The crude rate of trichomoniasis was highest in black women (69.0 per 100 person-years), women with a history of trading sex for drugs or money (51.0 per 100 person-years), those using crack or cocaine (35.5 per 100 person-years), women with four or more sex partners (43.0 per 100 person years), and those born in the United States (23.3 per 100 person-years). Among women with severe immunosuppression (CD4+ count < 200), 18.4% (18 of 98) were diagnosed with trichomoniasis. After multivariate analysis using a Cox proportional hazards approach, black race (adjusted rate ratio [RR] = 5.6, 95% confidence interval [CI] = 2.3, 13.3) continued to be strongly associated with Trichomonas infection. Trading sex for money or drugs (adjusted RR = 25.2, 95% CI = 4.3, 148.6) and single marital status (adjusted RR = 3.7, 95% CI = 1.1, 13.0) were independent risk factors for trichomoniasis in nonblack women but not among black women. Data from this study indicate that Trichomonas may be a frequently acquired infection in HIV-positive women. Our findings suggest that HIV-infected women who are black, and nonblack women who trade sex for money or drugs or are unmarried, are at increased risk of trichomoniasis and therefore may be more likely to transmit HIV infection. Local HIV prevention strategies should target such women for intervention efforts.

Concurrent interstitial radiotherapy and infusional chemotherapy for recurrent gynecologic malignancies.

Patients with unresectable locally recurrent gynecologic malignancies pose a difficult therapeutic challenge. Conventional therapies are frequently unsuccessful and offer only marginal palliation. In this study, interstitial 192iridium-needle implants and concomitant infusional 5-fluorouracil (5FU) and cisplatin (CDDP) or carboplatin (CBDCA) chemotherapy were used to treat 14 women with recurrent pelvic tumors. Malignancies of the cervix, endometrium ovary, tube and vulva are represented; all patients were heavily pretreated. Twenty interstitial implants were performed in these 14 patients. Needle distributions and doses were individualized to accommodate the recurrent tumor volumes. Tumor responses were seen in 12 patients (six complete and six partial responses). Four women remain clinically free of disease and four are alive with disease at 18-34 months of follow-up. There were no severe acute toxicities, however, four patients have subsequently developed fistulae associated with tumor progression. Although longer follow-up is required, the high response rate, wide applicability and acceptable toxicity observed in this heavily pretreated patient population warrant further study of combined interstitial radiation and chemotherapy.

Residual disease in the uterus after preoperative radiotherapy and hysterectomy in stage IB cervical carcinoma.

Sixty-one patients with FIGO IB cervical cancer treated with planned preoperative radiotherapy (dose to point A: 52-93 Gy, mean 73 Gy) and hysterectomy from 1969 to 1993 were retrospectively reviewed. Patient characteristics and treatment parameters and their association with residual tumor in the hysterectomy specimen were analyzed. Glandular (adenocarcinoma and adenosquamous) tumors were smaller than squamous tumors: 6/11 (55%) were < 6 cm in diameter, versus 12/50 (24%) squamous tumors (p = 0.03). Glandular tumors had a higher incidence of residual disease: 10/11 (91%) versus 24/50 (48%) (p = 0.01). There was no association between presence of pathologic residual disease in the hysterectomy specimen and tumor size, morphology (endophytic vs. exophytic), patient age, dose to point A, time to deliver radiotherapy, or interval between radiotherapy and hysterectomy. Overall 34/61 (56%) patients had residual disease in their hysterectomy specimens after planned preoperative radiotherapy. There were significantly more glandular tumors than squamous tumors with residual disease, even though glandular tumors were a group of smaller tumors.

Carcinoembryonic antigen in women with isolated pelvic masses. Clinical utility?

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.