Oral contraceptives as risk factors for cervical adenocarcinomas and squamous cell carcinomas.

To assess the hypothesis that oral contraceptives (OCs) increase the risk of cervical adenocarcinomas, we conducted a six-center case-control study of 124 patients with adenocarcinomas, 139 with squamous cell carcinomas, and 307 population controls. Women between the ages of 18 and 69 who were newly diagnosed with cervical adenocarcinomas between 1992 and 1996 were eligible. Healthy female controls and a second case group of incident cervical squamous cell carcinomas were matched to the adenocarcinoma cases. All participants were interviewed regarding OCs, other risk factors for cervical carcinoma, and utilization of cytological screening, and a PCR-based test determined HPV genotype of cervical samples for both case groups and controls. Use of OCs was positively and significantly associated with adenocarcinomas and positively but weakly associated with squamous cell carcinomas. Associations between OCs and invasive adenocarcinomas (n = 91), squamous cell carcinoma in situ (n = 48), and invasive squamous cell carcinomas (n = 91) disappeared after accounting for HPV infection, sexual history, and cytological screening, but a positive association remained between current use of OCs and cervical adenocarcinoma in situ (n = 33). This association persisted after stratification by screening and sexual history and after restriction according to HPV status, but small numbers made it difficult to exclude detection bias, selection bias, or residual confounding by HPV as potential explanations Current OC use was associated with cervical adenocarcinomas in situ, but we saw no other evidence that OCs independently increase the risk of cervical carcinomas.

Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction.

As human papillomavirus (HPV) becomes accepted as the central cause of cervical cancer, longitudinal studies are shifting focus away from causality to a more detailed investigation of the natural history of HPV infections. These studies commonly require repeated samples for HPV testing over several years, usually collected during a pelvic exam, which is inconvenient to the participants and costly to the study. To alleviate the inconvenience and cost of repeated clinic visits, it has been proposed that women collect cervicovaginal cells themselves, hopefully increasing participation in the natural history studies. We evaluated the technical feasibility of self-collection of cervicovaginal cells using a Dacron swab for HPV DNA detection. We compared the self-collected swab sample and two clinician-administered swab samples (one from the endocervix and another from the ectocervix) from a total of 268 women participating in a case-control study of adenocarcinoma and squamous cell carcinomas of the uterine cervix (111 cases and 157 controls). HPV DNA was detected and genotyped using an L1 consensus PCR assay. The overall agreement between the clinician- and self-collected swabs was excellent [88.1%; kappa = 0.73 (95% confidence interval (CI), 0.61-0.85)]. The correlation was highest between the two clinician-administered swabs [kappa = 0.81 (95% CI, 0.69-0.93)] but was still excellent when comparing either clinician-administered swab to the self-administered sample [kappa = 0.75 (95% CI, 0.63-0.87) and 0.67 (95% CI, 0.55-0.79) for ectocervix and endocervix, respectively]. The type-specific agreement between samples was higher for high-risk, or cancer-associated, HPV genotypes than for low risk, noncancer-associated HPV genotypes when comparing the self-administered swab sample to the clinician-administered swab sample (kappa = 0.78 for high-risk versus 0.66 for low-risk HPV infections, t = -1.45, P = 0.15). The decrease in agreement for low risk types was largely attributable to an increased detection of these types in the self-administered sample (McNemar's chi2 = 6.25, P = 0.01 for clinician- versus self-administered swab comparisons). The agreement did not vary significantly by age, menopausal status, case status, or clinic center. We have demonstrated that a self-collected Dacron swab sample of cervicovaginal cells is a technically feasible alternative to clinician-administered cervical cell collection in natural history studies of HPV and cervical cancer.

Early management and decision making for the treatment of myelomeningocele.

A program for early selection and treatment of the infant with myelomeningocele was developed at the University of Oklahoma Health Sciences Center in 1977. Over a 5-year period, 69 babies were evaluated, 36 babies were recommended for early vigorous treatment. Of the 33 babies for whom only supportive care was recommended, five were initially treated at the parents' request, two underwent delayed vigorous treatment, one was subsequently treated by "crisis management," one moved and did not return for follow-up, and 24 received only supportive care. All 24 babies died between 1 to 189 days of age (mean 37 days). The involvement of several physicians and paramedical support personnel is considered essential for this approach of early selection and treatment. Continued support and regular follow-up is necessary for any baby who receives only supportive care. Parents retain legal custody. Although ethical concerns make any approach difficult, the method presented is considered to be the best alternative available at this time.

Radical hysterectomy morbidity in relation to age.

The complications of radical hysterectomy in patients 65 years and older were compared with those in women younger than 65. There was no statistical difference in complication rates between the two groups, although the older women had a significantly higher incidence of preoperative medical problems. No surgical deaths occurred in either group. Our data indicate that selected older women can tolerate radical hysterectomy as well as younger ones.

Human papillomaviruses: their clinical significance in the management of cervical carcinoma.

Studies have shown a strong association between certain human papillomaviruses and the development of cervical carcinoma and its precursor lesions. The oncogenic potential of papillomaviruses has been clearly demonstrated in both laboratory animals and cultured cells. Recent advances in our understanding of viral pathogenesis have provided insights into the natural history of papillomavirus infection and subsequent development of neoplasia. A more thorough understanding of the molecular mechanisms responsible for viral oncogenesis will facilitate the development of novel preventive and therapeutic strategies to prevent and treat papillomavirus-associated cervical neoplasias. Strategies under current investigation are focusing on the induction of effective humoral and cell-mediated immunity, the expression of HPV gene products, and cofactors that interact with HPV gene products to affect cell transformation. As a result of these investigative efforts, prophylactic HPV capsid vaccines and other gene therapies may soon become clinically available.

Ovarian cancer in pregnancy.

A pelvic mass in pregnancy is a relatively common entity, especially considering the increased use of ultrasound or early fetal evaluation. These masses can derive from multiple gynecologic and nongynecologic origin, and fortunately the majority will resolve with observation into the second trimester. Masses persisting into the second trimester should be surgically evaluated given the decreased risk to both mother and fetus at this time. For masses persisting into the third trimester, a 2% to 5% risk of malignancy is to be expected. Documentation of disease (FIGO stage) is critically important in defining need for adjuvant cytotoxic chemotherapy. Above all, potentially lifesaving therapy should not be withheld from patients because they are pregnant, especially considering that chemotherapy is apparently safe in the second and third trimesters.

Ineffectiveness of continuous 5-fluorouracil as salvage therapy for ovarian cancer.

5-Fluorouracil (5-FU) is an antimetabolite chemotherapy, which selectively functions at the S phase of the cell cycle. It is a short-acting agent with a serum half-life of approximately 11 minutes. Increased efficacy with this drug could theoretically be provided by sustained infusion over the doubling time of a tumor. Ovarian cancer that recurs or persists after treatment with platinum-based chemotherapy has a poor prognosis. This study examines the use of long-term infusional 5-FU as a salvage chemotherapy for ovarian cancer. 14 patients with epithelial ovarian cancer were studied. All were stage III or IV disease and all were initially treated with platinum-based chemotherapy with either persistence or recurrence of disease. Patients received 5-FU as 300 mg/m2/day via a continuous infusion for a 10-week cycle with discontinuation occurring for severe toxicity or documented progression. The average infusion per patient was 8 weeks (3-10). Three patients had drug discontinued secondary to toxicity (severe mucositis) and 4 patients had progression prior to the completion of 10 weeks. All patients had progression by the end of the first cycle. The average survival post-5-FU was 8.9 months (range: 0.75-22 months). The lack of response in 14 patients indicates that, statistically, the likelihood of an overall response rate of 20% is less than 0.05. Infusional 5-FU appears to be ineffective as salvage therapy for ovarian cancer.

Colonic surgery in gynecologic oncology. Risk factor analysis.

Colonic surgery is a critical part of gynecologic oncology care. A 12-year review of colonic surgery on a gynecologic oncology service was performed evaluating risk factors and their impact on postoperative morbidity. There were 124 procedures performed on 92 patients; 9 patients had no prior surgery, chemotherapy or radiation. Fifty-six percent of the patients were considered malnourished on the basis of a serum albumin level < 3.5 g/dL. The 124 procedures consisted of 57 colon resections with primary reanastomosis, 10 small bowel-colon bypass procedures and 57 colostomies. Of the 57 (67%) colostomy operations, 38 also had concomitant abdominal-pelvic procedures. There were 15 major bowel complications and 17 major systemic postoperative complications. Prior surgery and poor nutritional status significantly correlated with postoperative morbidity; however, prior radiation did not reveal an increased risk for postoperative complications.

An alternative approach to the vertical midline abdominal incision for staging in ovarian carcinoma.

The case report describes a situation that required staging laparotomy for ovarian cancer but the patient refused vertical incision for cosmetic reasons. The technique employed a low transverse skin incision with development of a skin flap and horizontal transection of the midabdominal wall near the level of the umbilicus. Operative exposure was adequate for standard staging procedures and the cosmetic requirements of the patient were satisfied.

Identification of H, K, and N-ras point mutations in stage IB cervical carcinoma.

OBJECTIVE: The ras oncogenes, Harvey (H), Kirsten (K), and neuroblastoma (N), are a family of genes coding for a membrane-associated protein (p21) which possesses inherent guanine triphosphatase (GTPase) activity. Point mutagenesis at codons 12, 13, and 61 has been implicated in ras activation and subsequent cellular transformation. Given the epidemiologic relationship of HPV infection with cervical carcinoma and the tumorigenic interaction of HPV and mutated ras oncogenes, this study was undertaken to identify if mutated ras oncogenes were present in early invasive cervical carcinomas. METHODS: A combination of polymerase chain reaction (PCR) and dot-blot hybridization was used to determine the frequency and types of ras point mutants occurring in cervical carcinoma. Thirty-three patients with early-stage cervical carcinoma were identified. DNA was extracted from archival tumor samples. ras genes were PCR amplified using flanking primers and hybridized with a series of labeled allele-specific oligonucleotides corresponding to wild-type forms of K12,61, N12,13,61, and H12,61, as well as to all combinations of substitution mutations (7 wild-type, 45 mutants). RESULTS: ras mutations were identified in 24.2% of specimens. The detected mutations in H, K, and N-ras all occurred at codon 61. This was not the result of PCR or hybridization artifact in that mutations were detected in position 12 and 13 in appropriate control samples. CONCLUSIONS: Mutant ras has been shown to convert HPV immortalized keratinocytes to the tumorigenic state. Our results indicate that a significant percentage (24.2%) of these early-stage cervical cancers contain activated ras. Additional studies will be needed to evaluate whether codon 61 represents a characteristic "hot-spot" of ras mutation in a subset of cervical carcinoma.

Vulvar reconstruction using a mons pubis pedicle flap.

The treatment of early vulvar carcinoma has moved toward less radical surgery with reconstruction. This report describes our preliminary experience with a mons pubis flap that is simple and appears safe, reliable, and gives excellent cosmetic and functional results following radical hemivulvectomy. Four patients have undergone this procedure with excellent results. The flap brings pliable, hair-bearing skin which authentically mimics the normal side, thus providing good sexual function. The mons pubis pedicle flap should be considered in patients undergoing radical hemivulvectomy where an excellent cosmetic result is desirable.

Postoperative adjuvant external-beam radiotherapy in surgical stage I endometrial carcinoma.

A combined surgical and radiotherapeutic approach is widely in Stage I endometrial adenocarcinoma. The technique and timing of the radiotherapy varies from center to center. Postoperative external-beam (EB) radiotherapy has the advantage of patient selection based upon surgical findings, comprehensive treatment of the pelvic nodal and vaginal cuff areas, and elimination of the need for an intracavitary procedure. Although frequently utilized, this technique is surprisingly poorly described in the medical literature. From 1979 to 1986, 46 surgical Stage I patients received adjuvant postoperative EB therapy at Georgetown University Hospital (GUH) (Washington, DC). Indications for treatment were Grade greater than or equal to 2 and/or depth of myometrial invasion of greater than 33%. The 5-year actuarial survival was 90% with a disease-free survival of 82%. The failure rate within the irradiated field was 6.5% with a distant failure rate of 8.7%. The rate of significant long-term complications was acceptable at 6.5%. The authors conclude that postoperative EB radiotherapy is an effective adjuvant therapy with results comparable to other available radiotherapeutic techniques.

Villoglandular adenocarcinoma of the cervix: a report of three cases and review of the literature.

Villoglandular adenocarcinoma of the cervix is a distinct histologic type of cervical cancer. Fewer than 60 cases have been reported in the literature. Previous reports suggest that, due to the highly favorable prognosis of this rare histologic type of cervical cancer, conservative surgical therapy with cervical conization or extrafascial hysterectomy alone may be undertaken. In this series, three cases of villoglandular adenocarcinoma of the cervix are described. Preoperatively in each case, the cancer was confined to the cervix and histologic well-differentiated villoglandular adenocarcinoma of the cervix was confirmed. Extended hysterectomy was performed in all cases. In one case, residual invasive endocervical adenocarcinoma was noted. Careful review of the histologic characteristics of these tumors is needed when deciding if these patients can be managed with conservative therapy.

Recurrent granulosa cell tumor of the ovary 37 years after initial diagnosis: a case report and review of the literature.

Granulosa cell tumors of the ovary (GCTs) are uncommon neoplasms that are characterized by late recurrence and high survival rates. A case of recurrent GCT presenting 37 years after initial diagnosis is reported with a review of the literature. This case illustrates an example of a very late recurrence and emphasizes the importance of the extended follow-up required for these patients.

Generation of tumor-specific cytolytic T lymphocytes from peripheral blood of cervical cancer patients by in vitro stimulation with a synthetic human papillomavirus type 16 E7 epitope.

OBJECTIVE: Approximately 90% of squamous carcinomas of the cervix harbor the human papillomavirus and type 16 has been detected in nearly 50% of cases. Recent studies in mice have shown that the human papillomavirus type 16 E7 oncoprotein contains peptide epitopes that are processed and presented in association with a major histocompatibility antigen for recognition by cytolytic T lymphocytes. We investigated whether an epitope from human papillomavirus type 16 E7 could be used to generate specific human cytolytic T lymphocytes in patients with cervical carcinoma. STUDY DESIGN: After radiation therapy, three patients with antigen HLA-A2 and with locally advanced cervical cancer underwent leukapheresis. Epitope-specific cytolytic T lymphocytes were generated from the peripheral blood mononuclear cells by in vitro stimulation with autologous peripheral blood mononuclear cells pulsed with a human papillomavirus type 16 E7, HLA-A2-restricted, synthetic peptide, E7(11-20) (YMLDLQPETT). RESULTS: In two patients cytolytic T lymphocytes were capable of E7(11-20)-specific, HLA-A2-restricted cytolysis of the peptide-pulsed, HLA-matched, T2 target cell line. Cytolytic T lymphocytes from one of these patients also demonstrated specific cytolysis against the HLA-A2+, HPV-16+ CaSki cervical cancer cell line but did not lyse either HLA-A2+, HPV-16- MS-751 cells or HLA-A2-, HPV-16- HT-3 cells. CONCLUSIONS: These experiments demonstrate that novel cytolytic T lymphocytes that recognize a human papillomavirus type 16 E7 epitope can be generated by using the peripheral blood mononuclear cells from irradiated patients with cervical cancer. In addition, because CaSki cells were specifically lysed by the cytolytic T lymphocytes, these data indicate that the peptide E7(11-20) is endogenously processed and presented on the cell surface of the CaSki cells. The demonstration of epitope-specific lysis of cytolytic T lymphocytes of HPV-16+ cervical cancer cells supports further efforts to develop human papillomavirus peptide-based vaccines or antigen-specific adoptive immunotherapy for the prevention and treatment of cervical carcinoma.