Preliminary results of chemoradiation as a primary treatment for vulvar carcinoma.

PURPOSE: To assess the role of chemoradiation as a primary treatment for vulvar carcinoma. METHODS AND MATERIALS: Between December 1989 and August 1997, there were 14 patients with the diagnosis of squamous cell carcinoma of the vulva. Two patients were excluded from this study because of advanced stage at presentation. Key information about the remaining 12 patients was extracted from their charts. All patients had biopsy prior to treatment, and were treated with chemoradiation. Radiation was administered to the vulva only. Surgical biopsies from the vulva and inguinal nodal dissection were done 4-6 weeks after radiation treatment. All patients were followed for evaluation of response and clinical detection of recurrence. The period of follow-up ranged from 8 to 125 months. Mean follow-up period was 41 months. RESULTS: All 12 patients showed complete response to the treatment. Only 1 patient (8.3%) developed local recurrence at 3 months posttreatment. Another patient (8.3%) developed nodal recurrence at 30 months posttreatment. Both patients were salvaged by surgical treatment and remained disease free. The actuarial 5-year disease-free survival was 43%. The actuarial 3-year disease-free survival was 84%. The majority of patients developed mild-to-moderate complications due to chemoradiation. These were well tolerated and responded to medical treatment. None of the patients developed late complications to chemoradiation treatment. CONCLUSIONS: Chemoradiation is an effective primary treatment for vulvar carcinoma as shown by these successfully managed cases.

Potentiation of cisplatin cytotoxicity by methylxanthines in vitro.

The ability of two supposed DNA-repair inhibitors to modulate cisplatin-induced cytotoxicity in a human ovarian cancer cell line (CAOV-3) and a human cervical cancer cell line (Me-180) was investigated using a short-term chemosensitivity assay based on bioluminescence of cellular adenosine triphosphate (ATP). Cisplatin concentrations bracketing the reported peak plasma concentration (2.5 micrograms/ml) were used and the 50% inhibitory concentrations were determined by linear regression of log-transformed survival data. At 2.5 mM, the methylxanthine caffeine enhanced cisplatin sensitivity 2.9-fold in CAOV-3 cells and 2.7-fold in Me-180 cells. At 2.5 mM, pentoxifylline, a closely related methylxanthine, increased cisplatin sensitivity 2.9-fold in CAOV-3 cells and 3.4-fold in Me-180 cells. Chemical modification of cisplatin-induced cytotoxicity by assumed inhibition of DNA-repair mechanisms may hold promise for clinical application in the treatment of gynecological cancer.

Trichloroacetic acid in the treatment of human papillomavirus infection of the cervix without associated dysplasia.

Human papillomavirus-induced cytologic changes were found in 379 (10.9%) of 3461 Papanicolaou smears done at the Gynecology Clinic at Wayne State University. Of these 379 patients, 98 (25.8%) had no cytologic evidence of dysplasia. Forty-six of the 98 patients, who had colposcopic and histologic evidence of human papillomavirus without dysplasia, agreed to participate in this study. All patients underwent a Q-Tip application of 85% trichloroacetic acid to the entire cervix, including the endocervical canal and the transformation zone, until the mucosa turned white. Coexistent vaginal and vulvar condyloma were treated simultaneously in six patients. The patients were reexamined at two-week intervals to ascertain the need for reapplication of trichloroacetic acid. No colposcopic evidence of human papillomavirus was found in 18 patients at the first visit, whereas 28 patients required reapplication of trichloroacetic acid. Three months after treatment, a follow-up Papanicolaou smear and colposcopic examination revealed no human papillomavirus infection in 31 patients. Seven patients had persistent infection and eight patients were lost to follow-up. Our preliminary data from this study suggest that 85% trichloroacetic acid is effective treatment of human papillomavirus infection of the cervix without dysplasia.

Ovarian cancer in women with prior hysterectomy: a 14-year experience at the University of Miami.

Between 1977-1990, 755 women were evaluated and treated for ovarian cancer at the University of Miami/Jackson Memorial Medical Center. Ninety-five of them (12.6%) had previously undergone hysterectomy with preservation of one or both ovaries. Sixty women (7.9%) had undergone hysterectomies after the age of 40. Review of the literature reveals a 4.5-14.1% incidence of prior hysterectomy in women developing ovarian cancer. Prophylactic oophorectomy in women undergoing hysterectomy at age 40 or older would have prevented 138 of 2632 cases (5.2%) of ovarian cancer in a combined literature series. Applied nationally, such an approach could be expected to prevent over 1000 cases of ovarian cancer annually. We recommend routine prophylactic oophorectomy in all women undergoing hysterectomy after the age of 40. This strategy would have prevented 60 cases of ovarian cancer treated at the University of Miami during the past 14 years.

A possible role for cysteine proteinase and its inhibitors in motility of malignant melanoma and other tumour cells.

The metastasis of malignant tumour cells depends on their rapid replication, and their ability to adhere to the matrix of a biological barrier such as basement membrane, to degrade the matrix, and to migrate through this more permeable barrier. Secreted enzymes, including the cysteine proteinases cathepsins B and L, are known to degrade basement membrane components. Using a barrier-free substratum we studied the possible role of cysteine proteinases in influencing the motility per se of metastatic cells. We found that stefins, the natural inhibitors of cysteine proteinases, markedly decreased the stimulated motility of both human melanoma cells and W256 carcinosarcoma cells at low concentrations (0.5 microM). A stefin also inhibited melanoma cell adherence, but to a lesser extent than motility. Additionally, synthetic inhibitors (E-64, diazomethyl ketones) of cysteine proteinases were found to depress stimulated motility of W256 cells. These results suggest that cysteine proteinases and their inhibitors may have a direct role in the development of a migratory response per se in tumour cells.

Asymptomatic endometrial carcinoma after endometrial ablation.

Endometrial ablation has been recently introduced as a surgical alternative to hysterectomy for the treatment of dysfunctional uterine bleeding. The procedure itself is reasonably safe. However, if occult endometrial cancer is present before the procedure and is not detected, it may be more difficult to diagnose later. Endometrial cancer may also arise de novo from missed endometrial tissue. Two cases of endometrial cancer following endometrial ablation have been reported, but its overall incidence is unknown. A 58-year-old woman was treated with endometrial ablation for dysfunctional uterine bleeding. Three years later she underwent hysterectomy and Marshall-Marchetti-Krantz procedure for urinary incontinence; incidental, asymptomatic endometrial adenocarcinoma was discovered. The final pathology was grade 1 adenocarcinoma, invading more than 50% of the myometrium (FIGO stage Ic). Endometrial cancer may occur following endometrial ablation and it may be asymptomatic. Careful patient selection and close follow-up are essential.

Adenocarcinoma in a mature cystic teratoma. A case report.

A mucin-producing adenocarcinoma arose in a well-differentiated, mature, cystic teratoma. The patient underwent a total abdominal hysterectomy, left salpingo-oophorectomy, omentectomy and paraaortic lymph node biopsy. The prognosis is unfavorable when the tumor extends through the cyst wall and involves intraperitoneal structures.

Intraperitoneal doxorubicin in combination with systemic cisplatinum and cyclophosphamide in the treatment of stage III ovarian cancer.

Recent concepts and technical development have led to the successful application of the principles of intraperitoneal chemotherapy in the management of advanced epithelial ovarian cancer. In a pilot study we treated five patients with Stage III ovarian cancer after maximal cytoreductive effort (residual tumor less than or equal to 2 cm) with combination chemotherapy consisting of intraperitoneal doxorubicin and intravenous cisplatinum and cyclophosphamide. Although intraperitoneal doxorubicin demonstrates a pharmacologic advantage over the intravenous administration of this drug, its use is limited by severe abdominal pain requiring narcotic analgesics. Chemical peritonitis and extensive peritoneal adhesions are frequent complications. The role of combination intraperitoneal and systemic chemotherapy in ovarian cancer warrants further study.

Laparoscopic descending colostomy in three patients with cervical carcinoma.

Three patients with cervical carcinoma underwent laparoscopic descending colostomy. The indications for colostomy included severe radiation proctitis, enterovaginal fistula secondary to progressive pelvic tumor, and large bowel obstruction from progressive pelvic tumor. Two patients were treated with laparoscopic descending end colostomy with creation of a Hartman's pouch, and the third patient underwent laparoscopic descending loop colostomy. The techniques utilized are discussed.

Cisplatin and pentoxifylline in advanced or recurrent squamous cell carcinoma of the cervix: a phase II trial of the Gynecologic Oncology Group.

OBJECTIVE: The aim of this study was to determine the antitumor activity and toxicity of cisplatin and pentoxifylline in previously treated patients with squamous cell carcinoma of the cervix. METHODS: A Gynecologic Oncology Group (GOG) Phase II trial of recurrent squamous cell cervical cancer using standard GOG response and toxicity criteria was performed. RESULTS: A total of 47 patients with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 75 mg/m(2) of cisplatin every 21 days and 1600 mg of pentoxifylline PO every 8 h for nine doses during each course. Forty patients were evaluable for response and 44 were evaluable for toxicity. Of the 40 evaluable patients, 37 had received prior radiotherapy and 35 had received prior chemotherapy. A median of three courses were given (range: 1-7). Among evaluable patients, 1 had a complete response (2.5%) and 3 had a partial response (7.5%) for an overall objective response rate of 10%. The complete responder had not previously had chemotherapy. Grade 3 or 4 toxicity was predominantly nausea and vomiting (32%) and hematologic toxicity (23%). CONCLUSIONS: The combination of cisplatin and pentoxifylline at the dose and schedule tested has limited activity in previously treated advanced or recurrent cervical cancer.

Surgical approach to diaphragmatic metastases from ovarian cancer.

Fourteen patients underwent surgical debulking of diaphragmatic metastases as part of cytoreductive surgery for advanced ovarian epithelial cancer from 1983 to 1984. The surgical technique is described. Morbidity from this approach was not excessive in this small series of patients. It is suggested that this technique can be safely used and may benefit a few patients with advanced ovarian cancer.

Treatment of small intestinal fistulas with octreotide, a somatostatin analog.

Three patients with external small bowel fistulas were successfully treated with bowel rest, total parenteral nutrition, and the somatostatin analog, octreotide. Two of the patients had received prior multimodality therapy, including radiation, for gynecologic cancer. The time intervals to fistula closure were 2 days, 10 days, and 5 weeks after initiation of octreotide therapy. The efficacy of octreotide combined with total parenteral nutrition in the treatment of external enteric fistulas supports its routine use, especially in previously irradiated patients.

Feasibility of laparoscopic management of presumed stage I endometrial carcinoma and assessment of accuracy of myoinvasion estimates by frozen section: a gynecologic oncology group study.

INTRODUCTION: To assess laparoscopic management of presumed stage I endometrial cancer, and to compare gross, frozen, and paraffin section methods measuring myoinvasion. PATIENTS AND METHODS: Eligible patients underwent laparoscopic exploration. Patients with preoperative grade 1 histology underwent laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy (LAVHBSO). Pelvic and periaortic lymph node sampling (PPANS) was performed for deep (> or =50%) myoinvasion confirmed by frozen section. Patients with preoperative grade 2 or 3 histology without evidence of extrauterine metastasis underwent PPANS + LAVHBSO. RESULTS: Of 50 eligible patients selected, LAVHBSO was successfully completed in all but five. There was one trocar bowel perforation. Myoinvasion depth was correlated between paraffin section and gross estimate, and between paraffin and frozen section estimate, in 89 and 90% of cases, respectively. Myoinvasion was underestimated by gross versus paraffin in three of five discrepancies, and by frozen versus paraffin section in one of three discrepancies. CONCLUSIONS: Laparoscopic surgical staging for early stage endometrial cancer is feasible. Gross/frozen section methods correlate with paraffin section to measure myoinvasion. Tumor grading and gross/frozen section myoinvasion estimates can guide operative management.

Pharmacokinetics of intraperitoneal doxorubicin in combination with systemic cyclophosphamide and cis-platinum in the treatment of stage III ovarian cancer.

The pharmacokinetics of intraperitoneal doxorubicin in three previously untreated patients with ovarian cancer are described. All patients were maximally cytoreduced (largest residual tumor less than or equal to 2 cm). The average total body clearance (TBC) was 16.3 ml/kg/min (range 10.6-20.4 ml/kg/min) and the mean volume of distribution (VD) was 42.4 liter/kg (range 27.6-46.9 liter/kg). Half-life of elimination (t 1/2 beta) was 2.6 hr. In spite of a therapeutic advantage of 60 when administered intraperitoneally, prohibitive local toxicity limited the use of doxorubicin via the intraperitoneal route in patients with ovarian cancer.

Mycotic aneurysms in pregnancy.

The presentation, management, and outcome of three cases of femoral artery mycotic aneurysm in pregnancy are described. All resulted from illicit intravenous drug use. While the literature dealing with drug abuse in pregnancy is large, this specific problem has received little attention. Comparison of these cases to a large reported series of nonpregnant patients with mycotic aneurysms from our institution demonstrates that pregnancy does not alter the natural course of this condition. The presence of a mycotic aneurysm in pregnancy does, however, appear to lead to significant maternal and fetal morbidity.

Incidence of preeclampsia among asthmatic patients lower with theophylline.

The incidence of preeclampsia was reduced among asthmatic patients taking theophylline (one of 85) compared to other asthmatic patients (six of 68, p less than 0.05). Other factors did not appear to account for these results. Theophylline, which is known to inhibit platelet aggregation and alter vascular tone, may reduce the incidence of preeclampsia, at least among asthmatic patients.

Pharmacokinetics of mitomycin-C in plasma and tumor tissue of cervical cancer patients and in selected tissues of female rats.

Mitomycin-C (MMC) is an alkylating agent which has shown significant activity in gynecologic cancers, both in vivo and in vitro. We determined the delivery of MMC to target tissue by comparing plasma and tumor tissue concentrations of MMC as measured by high-performance liquid chromatography (HPLC) in five patients with cervical cancer. In a companion study, we measured MMC concentrations in plasma and selected tumors of female rats given an equivalent dose. In patients, the mean terminal half-life and total body clearance rates of MMC were 40 min and 275 ml/min/m2, respectively. The mean cervical tumor to plasma concentration of MMC was 1.26 +/- 0.34 (mean +/- SE, n = 4). In female rats, the terminal half-life and total body clearance rates of MMC were 28.4 min and 270 ml/min/m2, respectively. Tissue concentrations of MMC in rats were lower than plasma concentrations measured at corresponding times. The highest concentrations were found in lung and uterus (including cervix) with lower concentrations in ovary and liver. The mean half-life for elimination of MMC from tissues of rats was 20.3 +/- 2.8 min (mean +/- SE, n = 6). Based on similar pharmacokinetic parameters in rats and patients, the rat appears to be a suitable model for the disposition of MMC in human patients. The near equivalent drug concentrations found in tumor and plasma of patients suggests that the in vitro tests conducted at concentrations based on plasma level may be relevant to cervical tumor tissue, as well.

Laparoscopically assisted vaginal hysterectomy in a university hospital: report of 82 cases and comparison with abdominal and vaginal hysterectomy.

OBJECTIVE: The objective of this study was to critically review the indications, outcomes, complications, and costs of laparoscopically assisted vaginal hysterectomy in comparison with abdominal and vaginal hysterectomy. STUDY DESIGN: The operating room log was reviewed to determine the number and route of hysterectomies performed over a 1-year period. The charts of 50 consecutive laparoscopically assisted vaginal hysterectomies and 50 vaginal hysterectomies were reviewed. Charts from 50 selected abdominal hysterectomies were also reviewed. Information on patient characteristics, indications, complications, uterine weights, hospital stay, and patient costs were obtained and analyzed. RESULTS: Of 509 hysterectomies, 82 were performed as laparoscopically assisted vaginal hysterectomies and 73 as vaginal hysterectomies. The patient characteristics and indications of the laparoscopically assisted group more closely matched those of the abdominal hysterectomy group. The complication rate in the laparoscopically assisted group was intermediate between the other two groups, but the hospital stay was significantly less. Patient cost for laparoscopically assisted vaginal hysterectomy was significantly greater than either abdominal or vaginal hysterectomy, in spite of the shortened hospital stay. CONCLUSIONS: Laparoscopically assisted vaginal hysterectomy offers a technique to convert some abdominal hysterectomies into vaginal hysterectomies. It appears particularly useful when an adnexal indication for surgery exists. Uterine leiomyoma does not appear to be an indication for laparoscopically assisted vaginal hysterectomy. The costs are significant because of increased operating time and costs of disposable equipment.

Hemodynamic and hormonal changes during pneumoperitoneum and trendelenburg positioning for operative gynecologic laparoscopy surgery.

Objective: The number and types of surgical procedures being preformed using laparoscopic technique is increasing due to technological advances. Recent studies suggest the carbon dioxide pneumoperitoneum and patient positioning causes hemodynamic alterations, respiratory acidosis, and a release of stress hormones. However, to date, no studies have investigated the physiological effect of laparoscopic procedures lasting more than 60 minutes on the stress response and the effect of Trendelenburg positioning. The purpose of this study was to identify the physiological effect of pneumoperitoneum and positioning during prolonged laparoscopy on hemodynamic (cardiac index, mean arterial pressure, heart rate, systemic vascular resistance, and stroke volume), metabolic (arterial blood gases), and hormone (arginine vasopressin, aldosterone, and plasma renin activity) parameters. We hypothesized that pneumoperitoneum and patient positioning will alter the hemodynamic, hormone, and metabolic parameters.Methods: The study was longitudinal in design and sampled a total of 31 healthy subjects having a gynecologic oncologic laparoscopic procedure at Hurley Medical Center, Flint, Michigan. The subjects were randomly assigned one of three groups receiving an initial insufflation pressure of either 10, 15, or 18 mmHg. After obtaining informed consent hemodynamic, metabolic, and hormone measurements were obtained at the following times: 1) pre-induction, 2) post-induction, 3) post-insufflation, 4) post-Trendelenburg 5 minutes and at 30, 60, 90, and 120 minutes post-insufflation. The results were analyzed using multivariate analysis of variance for repeated measures with a P <.05. A power of 0.9 was obtained to identify changes over time.Results: During the time course of the study the hemodynamic, metabolic, and hormonal parameters showed significant alterations. The most dramatic hemodynamic changes occurred post-insufflation characterized by a decrease in cardiac index and stroke volume with a concurrent increase in systemic vascular resistance. The metabolic parameters showed a significant decrease in pH and corresponding increase in PaCO(2). However, the pH and PaCO(2) remained within normal limits through the study. As part of the study's protocol the investigators increased minute volume to control for a rise in PaCO(2) during the procedure. A significant increase was noted in aldosterone and arginine vasopressin at post-insufflation and Trendelenburg positioning. Plasma renin activity showed a dramatic increase following post-insufflation. None of the subjects developed any post anesthetic complications.Conclusion: Our study demonstrated that pneumoperitoneum and Trendelenburg positioning cause statistically significant elevations in the stress hormones and concurrently cause a decrease in hemodynamic parameters. A healthy patient may tolerate these changes but a patient with cardiovascular disease or pulmonary problems may not be able to compensate as efficiently.