Chlamydia trachomatis and Pap testing from a single, fluid-based sample. A multicenter study.

OBJECTIVE: To determine the potential for both Pap testing and the Chlamydia direct fluorescence assay (DFA) from a single sample using the fluid-based ThinPrep Pap Test method (Cytyc Corporation, Boxborough, Massachusetts). STUDY DESIGN: Conventional DFA was compared to ThinPrep DFA in a direct-to-vial, double-blinded, multicenter protocol. Cervical scrapings were collected for the ThinPrep Pap Test, and then a second swab was used to collect an endocervical sample for a conventional DFA test. The DFA slide prepared from the ThinPrep Test and the conventional DFA sample prepared from the endocervical swab were evaluated independently. Discrepant cases were adjudicated by testing residual specimens using a Chlamydia direct DNA method. RESULTS: Combining 636 adequate cases (94% of the total collected), 582 (91.5%) were negative on both slides, 43 (6.8%) positive by both and 11 (1.7%) discrepant. The prevalence of Chlamydia was 7.9% based on the conventional DFA method (range, 4.3-10.9%). McNemar's two-tailed test indicated the results not to be statistically different (P > .05). Adjudication favored ThinPrep 45% of the time and conventional 55%. Specimen adequacy favored ThinPrep with high statistical significance (McNemar's test, P > .01). CONCLUSION: A second slide prepared from the same vial of cells as that used for the ThinPrep Pap Test can be used for Chlamydia testing by DFA. Fluid-based collection could allow multiple tests from a single sample.

Wilms' tumor of the cervix: a case report and review of the literature.

INTRODUCTION: Extrarenal Wilms' tumors are rare, with only 55 well-documented cases in the literature and only 4 confined to the uterus. A fifth case along with review of the current literature is presented. CASE: A 13-year-old girl presented with a 2-month history of irregular vaginal spotting. A 6.5 x 4.5 x 2.5-cm polypoid mass meeting criteria for an extrarenal Wilms tumor was removed from the superior aspect of the cervix, but recurred 8 months later on the posterior lip. The patient underwent a Schauta procedure, lymph node dissection, and bilateral oophoropexy. The surgery was followed by typical renal Wilms' tumor chemotherapy. The patient is without evidence of disease 5 years after surgery. DISCUSSION: This case uniquely suggests that limited excision of the original tumor has inherent risks for relapse. Oophoropexy appears to be reasonable when fertility preservation is desired and reconfirms that treatment mimicking renal nephroblastomas offers good long-term survival.

In vitro phase II comparison of the cytotoxicity of a novel platinum analog, nedaplatin (254-S), with that of cisplatin and carboplatin against fresh, human cervical cancers.

OBJECTIVE: To compare the in vitro cytotoxicity of nedaplatin, an investigational platinum analog, with that of cisplatin and carboplatin against fresh cervical cancers from untreated patients. METHODS: Specimens were obtained prior to irradiation or radical surgery from 20 patients with locally invasive cervical carcinoma. Cytotoxicity was measured after single cell suspensions were grown in agar using colony counts and incorporation of [3H]thymidine. Nedaplatin and cisplatin were tested at 1 and 10 micrograms/ml dose levels while carboplatin was tested at 10 and 100 micrograms/ml dose levels continuously. When single hour exposures were used, drug doses were increased by 10-fold. RESULTS: The median drug concentrations associated with a 50% inhibition of growth (IC50) for nedaplatin, cisplatin, and carboplatin were 0.435, 0.73, and 18.6 micrograms/ml, respectively. At 10 micrograms/ml for both cisplatin and nedaplatin and 100 micrograms/ml for carboplatin, cisplatin was the most active drug with 70% of tumors sensitive (

Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases.

Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer (cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha-tocopherol, gamma-tocopherol, and retinol). The results indicated that: (a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; however, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: (a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.

Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study.

OBJECTIVE: Our purpose was to evaluate the risk factors and prognosis in patients with stage IA squamous cell carcinoma of the cervix and 3 to 5 mm of invasion. STUDY DESIGN: From 1981 to 1984 the Gynecologic Oncology Group conducted a prospective clinicopathologic study of patients with stage I carcinoma of the cervix. A selective study group that was previously defined and reported included patients with squamous cell carcinoma of the cervix who were treated with radical hysterectomy and pelvic lymphadenectomy and who had disease confined to the uterus, with or without microscopically positive lymph nodes. RESULTS: One hundred eighty-eight patients had invasion of 3, 4, or 5 mm as determined by central pathology review. Patients who satisfied the 3 to 5 mm invasion definition of the current stage IA2 classification of the International Federation of Gynecology and Obstetrics (1995) are the subject of this report. CONCLUSIONS: Patients with stage IA2 carcinoma of the cervix who have 3 to 5 mm of invasion present on conization with no invasion in the hysterectomy specimen are at very low risk for lymph node metastases, recurrences, or death caused by cancer.

Tamoxifen in platinum-refractory ovarian cancer: a Gynecologic Oncology Group Ancillary Report.

There is a critical need to find additional effective therapies in the management of ovarian cancer. A previously reported Gynecologic Oncology Group trial demonstrated that tamoxifen is an active drug when used in the salvage setting in this malignancy. Unfortunately, this original report did not specifically examine the utility of tamoxifen in patients with clinically defined platinum-refractory disease. In this reanalysis of the results of treatment of 102 evaluable patients entered into this multi-institutional trial, an objective response rate of 13% (95% confidence interval, 6.4-22.6%) was observed in patients with cisplatin-refractory ovarian cancer. The median response duration in this patient population was 4.4 months (range 1.2-9.2 months). Although the response rate is modest, this well-tolerated hormonal agent is a reasonable therapeutic option in selected patients with ovarian cancer when salvage therapy is to be considered. A possible role for this hormonal agent in other clinical settings in ovarian cancer will need to be defined through the conduct of carefully designed randomized clinical trials.

New surgical approaches to treatment of cervical cancer.

PURPOSE: Our goal was to evaluate laparoscopic pelvic lymph node dissection, para-aortic lymph node sampling, and laparoscopic radical vaginal hysterectomy (Schauta) in the treatment of early stage cervical cancer. MATERIALS AND METHODS: In a retrospective study of 37 patients treated in the period between October 1993 and February 1996, we evaluated operative time, blood loss, length of hospital stay, lymph node count, and morbidity. Radical abdominal hysterectomy was compared with laparoscopic pelvic lymph node dissection and para-aortic lymph node sampling. Improvement over time was analyzed. RESULTS: Mean operative time was 225 minutes, blood loss was 525 mL, and the average hospital stay was 3 days. This information was compared with a radical abdominal hysterectomy and pelvic and para-aortic lymph node dissection, where the operative time was 210 minutes, blood loss was 1500 mL, and the hospital stay was 9.7 days. Blood transfusion was required in 11% of patients compared with a range of 35%-95% reported in the literature for radical abdominal hysterectomy. The mean pelvic lymph node count was 35; the mean para-aortic lymph node count was 11. Two patients had cystotomies repaired at surgery without lengthening hospital stay or subsequent complication. Two patients had ureteral vaginal fistulae treated by a ureteral stent, which was removed 6 weeks later without further operative procedures or urinary damage. When the data were correlated with the length of experience using the analysis of variance test and linear regression, operative time, blood loss, and hospital costs significantly improved over time. Patient charges averaged $14,868.00 and estimated hospital costs averaged $6449.00. CONCLUSION: Laparoscopic pelvic lymph node dissection and para-aortic lymph node sampling can be performed with adequate lymph node counts and lower morbidity. Laparoscopic Schauta allows shorter hospital stay than radical abdominal hysterectomy, with significantly less blood loss and markedly fewer blood transfusions. Morbidity is higher early in the surgeon's experience but decreases over time.

The role of laparoscopy in gynecologic oncology.

The use of laparoscopy in the management of gynecologic malignancies has significantly increased over the last 5 years. The safety and adequacy of pelvic and para-aortic lymphadenectomy has been established by several investigators. Patients with early carcinoma of the cervix are now undergoing Schauta (radical vaginal) hysterectomy after laparoscopic lymphadenectomy. Patients with carcinoma of the endometrium are treated by laparoscopically assisted vaginal hysterectomy in conjunction with laparoscopic pelvic and para-aortic lymphadenectomy. Staging and second-look procedures are now being performed laparoscopically in patients with carcinoma of the ovary. The Gynecologic Oncology Group is currently investigating the role of laparoscopic surgery for patients with carcinoma of the cervix, endometrium, and ovary in four Phase II trials. A randomized Phase III trial comparing laparoscopy to laparotomy for patients with carcinoma of the endometrium will begin soon.

Laparoscopic surgical staging of ovarian cancer.

The feasibility of laparoscopic staging in patients with ovarian cancer was undertaken prospectively to determine the ability to adequately evaluate both the intraperitoneal cavity and the retroperitoneal lymph nodes. Two groups of ovarian cancer patients were evaluated: those with optimally debulked advanced disease undergoing second-look procedures and those with presumed stage I disease undergoing surgical staging. Twenty-four of the 44 laparoscopic second-look procedures (56%) were positive for persistent disease. Five of these patients had microscopic disease only, in the omentum, washings, pelvic peritoneum, and in para-aortic lymph nodes (2 patients). In the group of 14 patients undergoing staging for presumed early ovarian carcinoma, metastatic disease was discovered in 8 (57%) patients. Two patients had peritoneal washings positive for adenocarcinoma; 3 had pelvic disease, 1 confined to a fallopian tube and 2 to the pelvic peritoneum; and 3 patients had para-aortic lymph nodes positive for metastatic adenocarcinoma. There were no serious complications in this category. The average hospital stay was 1.6 days. Laparoscopic staging appears to be an accurate staging technique, and further investigation into the validity of this approach is warranted.

An evaluation of human papillomavirus testing for intermediate- and high-risk types as triage before colposcopy.

OBJECTIVE: Our purpose was to evaluate the role of testing for intermediate- and high-risk human papillomavirus by use of a hybrid capture technique for predicting which patients with abnormal Papanicolaou smears are most likely to have squamous intraepithelial lesions or cancer. STUDY DESIGN: Cervical cytologic studies, hybrid capture tests, and colposcopically directed biopsies were performed on 311 women referred to the colposcopy clinics with abnormal cytologic study results. RESULTS: There was a highly significant correlation (p < 0.0001) between a positive human papillomavirus test and the finding of squamous intraepithelial lesions or invasive cancer. The sensitivity of human papillomavirus testing to detect high-grade squamous intraepithelial lesions was 74% when it was used alone and increased to 91% when coupled with abnormal cytologic study results of low- or high-grade squamous intraepithelial lesions or cancer. In 44 women with atypical squamous cells of undetermined significance on cytologic study, human papillomavirus testing identified six of 10 who had high-grade squamous intraepithelial lesions. For the 96 patients with low-grade squamous intraepithelial lesions, human papillomavirus testing was successful in identifying 29 of the 37 with high-grade squamous intraepithelial lesions (sensitivity 0.76). CONCLUSION: Testing for intermediate- and high-risk human papillomavirus types by hybrid capture improves the detection of high-grade squamous intraepithelial lesions in women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions over cytologic study used alone.

Phase II study of 13-cis-retinoic acid plus interferon-alpha 2a in heavily pretreated squamous carcinoma of the cervix.

The combination of 13-cis-retinoic acid (13-cRA) and interferon (IFN)-alpha 2a has been reported to be highly active in previously untreated squamous carcinoma of the cervix. In this phase II study, 13-cRA was given at a dose of 1 mg/kg/day and IFN-alpha 2a was given subcutaneously at a dose of 3 million units/m2/day. Thirteen of 14 patients enrolled in this study are evaluable for response and toxicity. There were no complete or partial responses. Ten patients had progressive disease and the remaining three had stable disease. Principle toxicities were fatigue, nausea, and vomiting. This regimen appears cross-resistant with radiotherapy and/or platinum-based cytotoxic therapy in heavily pretreated patients with squamous carcinoma of the cervix.

Cryotherapy.

Cryotherapy is as effective as any other therapy for CIN 1 and CIN 2. It can be performed with a minimum of side-effects and long-term sequelae. It is more cost-efficient than other methods since the equipment is inexpensive and it requires little technical training.

Abdominal-wall tumor implantation after laparoscopy for malignant conditions.

OBJECTIVE: To determine the incidence of abdominal-wall tumor implantation after laparoscopic procedures in patients with known malignancies. METHODS: We reviewed 557 laparoscopic procedures performed by the Gynecologic Oncology Service between November 1990 and February 1994. In 105 procedures, malignancy was documented cytologically or histologically, 88 with intraperitoneal disease and 17 with retroperitoneal disease. Ovarian cancer represented 80% (70 of 88) of the procedures with intraperitoneal malignancy, and the remaining cases consisted of carcinoma of the fallopian tube (two), endometrium (11), cervix (one), breast (three), and stomach (one). Histologically, ovarian carcinomas ranged from low malignant potential to poorly differentiated. Among 88 patients with intraperitoneal disease, 77 had gross disease and 11 had microscopic disease. Four hundred thirty-seven different abdominal-wall puncture sites were used (38 Veress needle sites and 399 laparoscopic ports). RESULTS: One of the 437 (0.2%) abdominal-wall puncture sites developed implantation, a frequency of 1.0% (one in 105) per procedure; this developed after a second-look laparoscopic procedure for ovarian carcinoma in which only microscopic disease was present. If only intraperitoneal disease is considered, the incidence of implantation was 0.3% (one in 363) per abdominal puncture and 1.1% (one in 88) per procedure. CONCLUSION: Tumor implantation at the abdominal-wall puncture site is an infrequent occurrence after laparoscopy in patients with intraperitoneal and retroperitoneal carcinoma.

Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma.

BACKGROUND: Global DNA hypomethylation has been observed in some human neoplasms and has been implicated as an important factor in carcinogenesis. The current study was designed to assess whether DNA hypomethylation occurs in cervical dysplasia and cancer, and to determine the relationship between the degree of DNA hypomethylation and the grade of neoplasia. METHODS: Cervical biopsy specimens were obtained from colposcopically identifiable lesions in 41 patients with abnormal Pap smear results. The extent of global DNA methylation was assessed by incubating the extracted DNA with [3H]-S-adenosylmethionine and Sss1 methyltransferase, an enzyme that specifically catalyzes the transfer of methyl groups to cytosine residues in the cytosine-guanine doublet. The degree of exogenous 3H-methyl group incorporation into the DNA therefore is related reciprocally to the extent of endogenous DNA methylation. These data were compared with the histopathologic classification of the lesions. RESULTS: The extent of 3H-methyl group incorporation was increased threefold and sevenfold in the DNA from cervical dysplasia and cancer, respectively, compared with the DNA from normal cervical tissue (P = 0.006, analysis of variance). Significant incremental increases in DNA hypomethylation were observed in the progression from normal and low grade squamous intraepithelial lesions (SIL) to high grade SIL and to cancer (P < 0.0001, trend). CONCLUSIONS: These data show that global DNA hypomethylation is a significant epigenetic event in cervical carcinogenesis and that the degree of DNA hypomethylation increases with the grade of cervical neoplasia. These data suggest that global DNA methylation may serve as a biochemical marker of cervical neoplasia.

Anti-tumor antibody produced by human tumor-infiltrating and peripheral blood B lymphocytes.

Cell suspensions from 69 human tumor biopsies and malignant effusions depleted of infiltrating T cells were incubated for 10-14 days with mitomycin-C-treated cells of the transformed T cell line MOT as feeder cells. B lymphocytes proliferated and differentiated as indicated by immunoglobulin (Ig) secretion in the culture supernatants (B cell expansion). Ig was present in culture supernatants of tumor cell suspensions incubated without MOT feeder cells (non-expanded cells), but the addition of MOT feeder cells to these cultures invariably resulted in a significant increase in Ig concentration. While IgG, IgA, and IgM isotypes were all detected in supernatants of both expanded- and non-expanded tumor cell suspensions, the increase in total Ig induced by MOT feeder cells was mainly due to an increase in IgG. Peripheral blood B lymphocytes (PBBL) from 15 cancer patients and 4 healthy individuals were also successfully expanded by the same method. In these it was shown that IgA was the predominant Ig isotype. Using a modified enzyme-linked immunosorbent assay, IgG of 25/36 expansions from tumor cell suspensions showed reactivity with autologous tumor targets, and that from 10/13 expansions reacted with allogeneic tumor targets of the same histological diagnosis. No reactivity was found against tumor targets of different histology. IgG of 4/10 expansions of PBBL from cancer patients showed reactivity with allogeneic tumor targets of the same histology, while no reactivity was demonstrated against tumor targets of different histology. IgG of expanded PBBL from healthy individuals showed no reactivity against tumor targets. This method allows detailed study of the specific humoral antitumor immune response of intratumoral and peripheral blood B lymphocytes in cancer.