Ureteroarterial fistulas after radical pelvic surgery: pathogenesis, diagnosis, and therapeutic modalities.

Ureteroarterial fistulas (UAF) are a rare but potentially life-threatening complication of intra-abdominal malignancy, typically occurring after vascular or pelvic surgery. Patients with a history of radical pelvic surgery, chronic indwelling ureteral stents, and prior pelvic radiation appear to be at increased risk. The predisposing risk factors suggest that gynecological oncologists are the likely specialty to face this problem and should be familiar with the clinical presentation and etiology of UAF. We present two such cases to illustrate these salient points of clinical diagnosis and management.

The HRAS1 minisatellite locus and risk of ovarian cancer.

Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.

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.

Lymphatic mapping in gynecologic malignancies.

Gynecologic malignancies account for 15% of all cancer diagnosis in women. Primary lymphatic spread is well recognized in vulvar, cervical, uterine, and ovarian carcinomas. Vulvar carcinoma spreads locally to the inguinofemoral lymph nodes in a relatively predictable fashion similar to the local spread of breast carcinoma. Lymphatic mapping using radioactive colloid should provide adequate means to sample these nodal basins while attempting to reduce postoperative morbidity. Methods of vulvar lymphoscintigraphy are described.

What is the role of interval blood testing in the management of chemotherapy for gynecologic malignancies.

PURPOSE: To determine the safety of omitting routine interval laboratory assessments, dietary restrictions, and isolation precautions between cycles of chemotherapy for gynecologic malignancies. METHODS: Data were retrospectively obtained from the records of women receiving chemotherapy for gynecologic cancer from July 1999-June 2000. Routine nadir determinations were not performed between treatment cycles; social interaction was encouraged, and pathogen-free diet recommendations were not provided. RESULTS: Eighty women received 449 cycles of chemotherapy. Four (5%) patients developed neutropenic fevers, and one of these women succumbed to sepsis. Eighteen (22.5%) women had 29 cycles delayed due to persistent myelosuppression when the ensuing chemotherapy infusion was to be administered. Hematopoietic growth factors overcame these delays during subsequent cycles in all but two patients. CONCLUSION: Omitting scheduled interval laboratory monitoring, dietary restrictions, and isolation precautions between chemotherapy cycles is convenient for patients, likely cost-effective, and does not increase morbidity in the gynecologic oncology population.

Overview of a chemoresponse assay in ovarian cancer.

The objective of this review is to summarize recent scientific and medical literature regarding chemoresponse assays or chemotherapy sensitivity and resistance assays (CSRAs), specifically as applied to epithelial ovarian cancer. A total of sixty-seven articles, identified through PubMed using the key words "in vitro chemoresponse assay," "chemo sensitivity resistance assay," "ATP," "HDRA," "EDR," "MiCK," and "ChemoFx," were reviewed. Recent publications on marker validation, including relevant clinical trial designs, were also included. Recent CSRA research and clinical studies are outlined in this review. Published findings demonstrate benefits regarding patient outcome with respect to recent CSRAs. Specifically, analytical and clinical validations, as well as clinical utility and economic benefit, of the most common clinically used CSRA in the United States support its use to aid in making effective, individualized clinical treatment selections for patients with ovarian cancer.

Gynecologic oncology: progress not withstanding.

This issue of Current Opinion in Obstetrics and Gynecology focuses on the rapidly changing field of gynecologic oncology. Initially regarded as pure radical pelvic and abdominal surgery, the subspeciality has evolved into a field of significant scientific discovery ranging from research in evolving surgical technology on a macroscopic level to DNA sequencing and gene therapy on a submicroscopic scale. The following reviews focus on some of these recent efforts to study, diagnose and treat gynecologic malignancies.

Innovations in the management of vulvar carcinoma.

Radical surgery has resulted in impressive cure rates in women with locally advanced vulvar carcinoma. Unfortunately, morbidity mostly related to inguinofemoral lymphadenectomy, is common. The present review discusses innovations in the management of vulvar disease with attempts to reduce attendant morbidity.

Reproductive technologies and risk of ovarian cancer.

Use of artificial technologies is increasing within the United States. Unfortunately, data describing the possible effects of 'superovulation' and potential risk of subsequent ovarian carcinoma are not well defined. This discussion focuses on current data regarding the potential for increased risk for ovarian carcinoma in patients who have undergone infertility evaluation and subsequent treatments.

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.

Spontaneous preoperative internal jugular and subclavian vein thrombosis associated with an early-stage synchronous ovarian/endometrial malignancy.

A case of preoperative spontaneous internal jugular/subclavian vein thrombosis documented with magnetic resonance imaging associated with a synchronous stage II ovarian/stage I endometrial malignancy is presented. This unusual deep venous thrombosis site is classically associated with trauma, infection, head and neck malignancies, or central venous catheterization and is rarely associated with distant malignancies. Neck pain and swelling in a gynecologic oncology patient should prompt consideration of this diagnosis.

Preservation of multiple oncogenic human papillomavirus types in recurrences of early-stage cervical cancers.

OBJECTIVES: Our purpose was to determine the relationship between human papillomavirus genotypes contained in primary early stage cervical cancers and those contained in the respective recurrences. STUDY DESIGN: Six early-stage cervical cancers that were considered cured by surgical extirpation subsequently recurred within 21 months of the original surgery. The primary tumors and the recurrences underwent polymerase chain reaction for human papillomavirus typing with confirmation of types performed by means of diagnostic restriction fragments. RESULTS: All primary tumors and recurrences contained human papillomavirus, with all primary tumors positive for multiple types. The concordance rate between the primary tumors and recurrences for specific types was 73% (11/15). Among the highly oncogenic types 16 and 18 there was 100% concordance between primary and recurrent tumors. CONCLUSIONS: Highly oncogenic types of human papillomavirus are preserved between primary tumors and their recurrences in cervical cancers. This further supports the role of oncogenic types in the maintenance of the malignant state and supports the clonogenic nature of cervical cancer recurrence.

A phase II Gynecologic Oncology Group trial of ifosfamide and mesna in advanced or recurrent adenocarcinoma of the endometrium.

In other Gynecologic Oncology Group (GOG) studies, ifosfamide demonstrated antineoplastic activity against ovarian epithelial tumors, squamous carcinomas of the cervix, uterine sarcomas, and trophoblastic disease. Responses were also observed in 15% of patients with endometrial adenocarcinoma previously exposed to chemotherapy. This is a phase II trial of ifosfamide in patients with chemotherapy-naive advanced or recurrent endometrial adenocarcinoma. Thirty-seven patients with advanced adenocarcinoma of the endometrium recurrent after surgery and/or radiotherapy were treated with ifosfamide 1.2 g/m2 intravenously daily for 5 days every 4 weeks and mesna 300 mg/m2 intravenously every 4 hr for 3 doses daily for 5 days with each course. Three patients were ineligible--one due to a second primary, one did not have an endometrial primary, and the other because of wrong cell type. One patient was inevaluable for response; thus, 33 were evaluable for response. All patients had undergone hysterectomy and 24 had received radiotherapy before entering the trial. Eleven had GOG performance status of 0, 18 had a status of 1, and 4 had performance status of 2. Median age was 68 years (range, 41-86 years). Grade 3 or 4 neutropenia occurred in eight patients each and grade 3 thrombocytopenia was observed in one patient. One patient had a grade 4 neurotoxicity. Complete responses were observed in two patients (6.1%) and partial responses in six (18.2%) for an overall response rate of 24.3%. Ifosfamide in this dose and schedule is an active drug in the treatment of patients with advanced or recurrent adenocarcinoma of the endometrium.

Bartholin's gland carcinoma: a 15-year experience.

OBJECTIVE: Our objective was to review our experience with carcinoma of Bartholin's gland relative to treatment and oncologic outcome. METHODS: Patient names were collected from our vulvar cancer database for the period September 1985 to September 2000. The medical records were retrospectively reviewed, and data were abstracted relative to demographics, presenting symptoms, treatment, and oncologic outcome. RESULTS: We treated 12 women with Bartholin's gland carcinoma, and 11 patients are reported. Seven women presented with a painless vulvar mass, and 8 of 11 had initially been treated for an infectious process before referral to our institution. Squamous histology was most common, and the right gland was more frequently involved. Ten patients were treated with primary surgery, followed by adjuvant radiation in 7 for inadequate resection margins or lymphatic metastases. One patient was treated with primary chemoradiation. Stage I, II, III, IVA, and IVB disease was present in 3, 1, 4, 2, and 1 patient, respectively. Recurrence was suffered by 54.5% during a mean follow-up time of 73.5 months (median, 60; range, 8-180 months). Overall survival is 58.3% to date. CONCLUSIONS: Conventional therapy for Bartholin's gland carcinoma yielded a 67% 5-year survival. Seventy-one percent of women receiving adjuvant radiotherapy recurred despite this precaution. Work is needed to identify an effective systemic therapy and to better determine which patients may benefit from pelvic radiotherapy.

Insertion of Groshong central venous catheters utilizing fluoroscopic techniques.

Groshong central line indwelling catheters are extensively used in gynecologic oncology patients for administration of chemotherapy, intravenous fluids, and pain medications. They are easy to maintain and have a good safety record. We report on the placement of these central venous catheters under direct fluoroscopic visualization as a method which is safe, inexpensive, and efficacious in high-risk patients. Fluoroscopic visualization during insertion provides several advantages: visualization of bony landmarks, placement of the guidewire into the subclavian vein and superior vena cava under direct visualization, and confirmation of appropriate distal placement of the Groshong catheter. Patient advantages include the following: (1) avoidance of unnecessary punctures to access the subclavian vein; (2) verification of guidewire placement to avoid cephalic placement; (3) passage of the guidewire only as far as the right atrium to avoid potential dysrrhythmias secondary to right ventricular irritation; and (4) a savings of approximately 60% over insertion in the general operating room. Thirty patients had placement under fluoroscopic visualization in the angiography suite of Georgetown University Hospital. The average age of the patients was 58 years (42-78). Sixteen patients had ovarian cancer, 6 had endometrial cancer, 5 had cervical cancer, and 3 had other gynecologic malignancies. Fifteen patients had catheters placed for chemotherapy, 14 for hydration, and 1 for pain control. Ten patients had had previous central venous catheters: 6 had been removed for infection, 2 for thrombus, 1 for completion of chemotherapy, and 1 for catheter kinkage. All 10 with previous catheters had successful placement of catheters in the angiography suite. Complications from insertion were minimal with one asymptomatic pneumothorax and one proximal port in an extravascular position. We present the technique of fluoroscopic insertion of Groshong catheters which is an effective method of placement in high-risk patients.

Prognostic factors and long-term survival in endometrial adenocarcinoma with cervical involvement.

The clinical, surgical, and histopathologic data from 202 patients with endometrial adenocarcinoma with cervical involvement are presented. One hundred fifty-one (75%) had histopathologically confirmed cervical involvement at the time of their definitive surgery, while in 51 (25%) no cervical involvement was conclusively identified. The 5-year actuarial survival for patients with true surgical stage II endometrial carcinoma (N = 24) was 76%. Extrauterine disease was documented in 32% (27/84) of patients in which the primary treatment modality was surgical. The 5-year actuarial survival was 65% for all patients with clinical surgical stage II disease. There appeared to be a survival advantage for patients treated by radical surgery as compared with more conventional treatments, especially in patients with numerous high-risk factors. The subgroup of patients (N = 53) having tumor grossly involving the cervix had a 5-year survival of 48%. In this subgroup of patients, radical hysterectomy offered improved 5-year survival over more traditional forms of treatment, particularly compared with simple hysterectomy or combined treatment with radiation and surgery. Multivariate analysis positively correlated myometrial invasion, grade, uterine serosal involvement, lower uterine segment involvement, adnexal metastasis, pelvic metastasis, aortic node metastasis, and peritoneal cytology, with disease-free survival. Clinical and surgical findings correlated poorly; therefore, primary surgical evaluation is recommended when possible.