Aromatization of testosterone by epithelial tumor cells cultured from patients with ovarian carcinoma.

Ovarian epithelial carcinoma originates from the surface mesothelium. It is controversial whether these tumors possess steroidogenic enzymes, similar to malignancies of other ovarian cell types. This study reports aromatase enzymatic activity for three epithelial cell lines, OV1225, OV166, and 2774, established from patients with ovarian adenocarcinoma. Aneuploidy of the cells was demonstrated by flow cytometric DNA analyses which showed OV1225 tetraploid, OV166 near diploid, and 2774 triploid. Estrogen synthesis was confirmed by measurement of estradiol (6 to 11 pg/10(7) cells/24 h) by radioimmunoassay in extracts of conditioned medium. To directly assay aromatase enzymatic activity, intact cells were incubated with tritiated testosterone. Medium was extracted with organic solvent after addition of trace 14C-labeled 17 beta-estradiol and 14C-labeled estrone. Androgen was separated from estrogen by celite column chromatography. Estrogen was further purified by silica gel thin-layer chromatography and derivatization of separate products to acetates. Purity of compounds was confirmed by consistency of the 3H:14C ratio of acetylated product versus that of product recrystallized with authentic standard. Conversion of testosterone to estradiol proceeded with apparent Michaelis-Menten kinetics. The apparent Km was 4 microM, 15 microM, and 59 microM, and the Vmax was 20 pmol/h/mg of cell protein, 52 pmol/h/mg of cell protein, and 152 pmol/h/mg of cell protein for 2774, OV166, and OV1225, respectively. We conclude that at least a portion of ovarian adenocarcinoma possesses sufficient aromatase activity to convert ovarian stromal androgen to estrogen.

Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group.

PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1, 000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.

Randomized placebo-controlled multicenter evaluation of diethyldithiocarbamate for chemoprotection against cisplatin-induced toxicities.

PURPOSE: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxicities in animal models without inhibiting antitumor effects. DDTC chemoprotection was tested in a randomized, multicenter, double-blind comparison versus placebo (PB) in patients with lung or ovarian cancer. Primary end points were nephrotoxicity, ototoxicity, neuropathy, and completion of therapy. PATIENTS AND METHODS: Between April 1990 and February 1992, 221 patients were registered with small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m2) and cyclophosphamide (in ovarian cancer) or etoposide (in lung cancer) were administered with either DDTC (1.6 g/m2 over 4 hours) or PB intravenously, every 4 weeks for a planned six cycles. RESULTS: At an interim safety analysis, data were available for 195 patients from the combined lung and ovarian cancer populations (PB, 99 patients; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxicities occurred in 9% of PB-treated patients and 23% of DDTC-treated patients (P = .008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m2/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m2 on the PB arm, compared with 247 mg/m2 on the DDTC arm (P = .0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P < .001). Although, clinical hearing loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicities related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either tumor type. CONCLUSION: This study did not demonstrate a significant chemoprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumulative doses of cisplatin, but were more likely to be withdrawn from treatment early due to chemotherapy-related toxicities.

Lupron retards proliferation of ovarian epithelial tumor cells cultured in serum-free medium.

Some patients with recurrent ovarian epithelial cancer respond favorably to treatment with GnRH agonists. This effect was proposed to be mediated by suppression of pituitary gonadotropin release. The present in vitro study investigated effects of human gonadotropin (Pergonal LH/FSH, 1:1) and Lupron, a GnRH agonist, on proliferation of an ovarian cancer cell line, 2774, which is estrogen receptor negative and grows well in serum-free, defined medium. Pergonal, 10 IU/mL or 30 IU/mL, did not enhance cell proliferation, which argues against stabilization of ovarian tumors in vivo due to decreased serum gonadotropin. Lupron, 1.4 micrograms/mL and 140 micrograms/mL, retarded cell division by day 6-8 of culture, in a dose-dependent manner. Flow cytometric cell cycle phase DNA analysis demonstrated Lupron caused a reversible 5-6% increase in the portion of cells in rest phase, G0/G1, compared to controls during log growth, and a corresponding decrease in the portion of cells in DNA synthesis, S phase. However, long-term culture, 3 weeks, with Lupron failed to arrest cells in G0/G1, and experimental cultures plateaued at cell number similar to control cultures. We conclude Lupron's effect on ovarian cancer cell proliferation is independent of gonadotropin and steroid, involves a cell cycle regulatory event, and duration of benefit observed in vivo for some patients may be related to total tumor volume at the time of treatment.

Palliative radiotherapy for ovarian cancer.

Large single-fraction irradiation is effective palliation for advanced ovarian cancer. It has an acceptable complication rate and requires only a limited number of visits (i.e., one treatment per 4-week course) to administer. Forty-two patients received single or multiple fractions of (three maximum) 10 Gray (Gy) to the pelvis. Most patients had advanced disease, 71.4% had Stage III or IV and 90.5% Grade 2 or 3 at the time of diagnosis. Forty patients had received preirradiation chemotherapy. Tumor size before and after radiotherapy was evaluable in 34 patients and decreased in 25. Bleeding decreased or stopped in 15 of 21 patients, and pain lessened or ceased in 11 of 20 patients. Thirteen patients had surgical procedures performed after irradiation therapy. Ten had gastrointestinal procedures, and in six radiation injury was believed to be the main contributor to complication. Hemorrhagic cystitis or proctitis occurred 6 to 18 months after irradiation in four patients. Three of these four patients received three 10 Gy fractions. The safest and most efficient dose may be one or two fractions, since three 10 Gy fractions may not increase palliation.

Evaluation of two commercially available nucleic acid hybridization assays for the detection and typing of human papillomavirus in clinical specimens.

Southern blot (Oncor, Gaithersburg, MD) and dot blot (Life Technologies, Gaithersburg, MD) nucleic acid hybridization assays were compared for their ability to detect and type human papillomavirus (HPV) DNA in 50 cervical swab specimens and 11 biopsy specimens. Overall agreement between the two methods was 78.7%. With the use of Southern blot analysis, HPV 6, 11, 16, or 18 was detected in 22 specimens, however, 4 were untypable because of abnormal or smeared band patterns. Dot blot analysis detected HPV 6/11, 16/18, or 31/33/35 in those same 22 specimens and in 9 additional specimens. Eight of the 13 specimens in which HPV was not detected or untypable by Southern blot contained type 31/33/35 by dot blot. Based on convenience of specimen collection and transport, ease of performance and the ability to detect HPV types 31, 33, and 35, the authors are currently using the dot blot assay for the detection and typing of HPV in clinical specimens.

Use of the intestinal isolation bag in gynecologic surgery.

Exposure of the operative site during laparotomy is, at times, suboptimal. The major viscera requiring retraction out of the operative field are the small intestines. Usually, multiple cloth laparotomy packs are used to compress and displace the intestines. We describe the use of an intestinal isolation bag to house the small intestines and keep them out of the operative field. Using this technique, laparotomy packs are not required. Because the bag itself takes up very little space, the size of the operating field is not compromised. In addition, the bag does not abrade or desiccate the bowel, potentially reducing serosal injury and adhesion formation.

Percutaneous endoscopic drainage gastrostomy in the treatment of gastrointestinal obstruction from intraperitoneal malignancy.

We evaluated the effectiveness of a percutaneous technique for placement of a drainage gastrostomy. Progressive dilatation of the abdominal and gastric walls was used to place a Malecot catheter (28 French). Endoscopic guidance assured proper placement and assisted in the dilatation. Fourteen drainage gastrostomy tubes were placed in 12 patients. The tube could not be placed in on additional patient with tumor infiltration into the anterior gastric wall. No surgical complications occurred, but there was one postoperative complication, peritonitis treated with antibiotics without catheter removal. All catheters provided unobstructed drainage and decompression of gastrointestinal obstruction. Percutaneous endoscopic drainage gastrostomy seems to be an effective means of palliating small-bowel obstruction and its complication rate appears low. This method may be suitable to replace open laparotomy techniques for gasrostomy placement.

Erythrocytosis associated with a placental-site trophoblastic tumor.

We present a case of placental-site trophoblastic tumor associated with erythrocytosis. This 42-year-old woman had persistent amenorrhea and low elevations of her hCG titer after term delivery of a healthy female infant. The woman was noted to have polycythemia of uncertain etiology and was treated with serial phlebotomy. Placental-site trophoblastic tumor was diagnosed and hysterectomy was performed, with subsequent resolution of the polycythemia. Although erythrocytosis has been reported with other gynecologic tumors, this is the first reported association with a placental-site trophoblastic tumor. A role has been suggested for placental lactogen in erythropoiesis during pregnancy based on previous animal studies. Diffuse positive staining for hPL is characteristic of placental-site trophoblastic tumors. We postulate that hPL may have played an ancillary role to erythropoietin in the erythrocytosis demonstrated in this case. Spider angiomata and splenomegaly are interesting clinical features previously described in association with placental-site trophoblastic tumors, and were demonstrated in this patient.

Cytoreduction of ovarian cancer with the Cavitron ultrasonic surgical aspirator.

The Cavitron ultrasonic surgical aspirator was used for cytoreduction in ten patients with intra-abdominal malignancy (nine ovarian and one fallopian tube). The mean age was 65 years, and eight patients had stage IIIC disease. Standard surgical techniques were used to resect the adnexa, uterus, and omentum. The Cavitron was used to remove disease from the diaphragm, spleen, stomach, and small bowel without resection or injury. These nongenital viscera would have required resection using surgical techniques for cytoreduction. The mean Cavitron surgical time was 49 minutes. Cytoreduction by the Cavitron facilitates tumor removal and reduces the requirement for nongenital visceral resection.

Endometrial adenocarcinoma without prior hormone replacement in a diabetic patient with gonadal dysgenesis.

Patients with dysgenetic gonads and Turner syndrome are unlikely to develop endometrial carcinoma unless they have received unopposed estrogen replacement therapy. This case describes a 54-year-old woman with Turner syndrome and primary amenorrhea who developed adenocarcinoma of the endometrium without having received hormone replacement. Vaginal bleeding, a pelvic mass, and sepsis were the presenting symptoms. The patient also had diabetes mellitus and hypothyroidism. Polyglandular endocrine patterns are known to occur with a high frequency in these patients. The woman's chromosome studies revealed a modified 46,X,i(Xq) (isochromosome X). This is the first report of an isochromosome X patient to develop endometrial cancer without receiving estrogen replacement. The etiology of this rare case may be an increased propensity for patients with X-chromosome deletions to develop neoplasms in general, or extragonadal estrogen production.

Quantitative evaluation of the skin and accessory appendages in vulvar carcinoma in situ.

Fifty cases of vulvar carcinoma in situ comprising over 1000 histologic sections were studied. Each case was evaluated to determine the thickness of the neoplastic epidermis and the depth of involved skin appendages. Two precise techniques were used to perform the microscopic measurements. The areas most frequently afflicted with neoplasia were: one or both labia (45%), interlabial folds (27%), perineum-fourchette (15%), and perianal skin (10%). Multicentric disease was observed in 68% of the cases. The epidermal thickness ranged between 0.35-1.66 mm. The mean depth (+/- SD) of the epidermis was 0.93 +/- 0.37 mm. Eighteen of the 50 patients demonstrated involvement of the skin appendages to a mean depth of 1.53 +/- 0.77 mm, suggesting that laser vaporization to a depth of 2.5 mm will, with the anticipated additional thermal necrosis, eliminate appendages involved with carcinoma in situ in 95% of instances. The most common sites of skin appendage involvement were the labia majora or minora and the interlabial folds.

Brachial plexus neuropathies after advanced laparoscopic surgery.

A retrospective review of 3,200 advanced laparoscopic procedures demonstrated five brachial plexus injuries during a 5-month period in 1986 (0.16% incidence rate). Brachial plexus injury can occur during laparoscopic surgery using steep Trendelenburg's position with shoulder braces and the patient's arm extended at 90 degrees. Position modification can reduce the risk for upper extremity neuropathies.

A phase II trial of gallium nitrate (NSC #15200) in previously treated ovarian carcinoma. A Gynecologic Oncology Group Study.

Twenty-six evaluable patients with advanced or recurrent epithelial ovarian cancer were treated with 750 mg/m2 of gallium nitrate every three weeks. All patients had prior cisplatin chemotherapy. One patient had a complete response (3.8%), two patients had partial responses (7.7%), and six patients had stable disease (23.1%). The 95% upper confidence bound for response is 27.2%. The major toxicity was nausea and vomiting which was modest, and anemia, which was moderate to severe. Myelosuppression was minimal. Gallium nitrate has modest activity in previously treated patients with epithelial ovarian cancer.

Echinomycin (NSC 526417) in advanced ovarian cancer. A phase II trial of the Gynecologic Oncology Group.

Twenty-two patients with recurrent carcinoma of the ovary progressive after initial chemotherapy (21 with cisplatin-based treatment) were entered on a phase II trial utilizing Echinomycin at a dosage of 1,500 micrograms/m2 every 4 weeks. There were two complete responders and no partial responders (9% response, 95% confidence intervals for complete and partial responses of 1-29%). Major toxicity was modest and consisted mainly of nausea and vomiting. Echinomycin displays minimal activity as salvage therapy in women with advanced ovarian cancer at this dose and schedule.

A phase II trial of vincristine in advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study.

Thirty-three evaluable patients who had not received prior chemotherapy were entered on a study of vincristine therapy for advanced or recurrent endometrial carcinoma. Vincristine 1.4 mg/m2 was given weekly as an i.v. bolus for 4 weeks and then every other week. There was one complete response (CR) lasting 5 months. Five patients had partial responses (PR) lasting 3-18 months. The CR+PR rate was 18% (95% confidence interval for CR+PR was 7-36%). Thirteen patients (38%) had stable disease from 2-28 months, and 14 had progressive disease. The major toxicity was neurological, with 11 patients having grade 2 or 3 peripheral neuropathy. Vincristine at this dose and schedule has modest activity, but troublesome toxicity in advanced or recurrent endometrial carcinoma.

A phase II trial of merbarone (NSC 336628) in the treatment of recurrent epithelial ovarian carcinoma. A Gynecologic Oncology Group Study.

BACKGROUND: Patients with recurrent epithelial ovarian carcinoma who progress through a cisplatin-based regimen or recur less than 6 months after discontinuing cisplatin, have limited therapeutic options. The Gynecologic Oncology Group conducted a Phase II trial of merbarone in this patient population. METHODS: Twenty-seven patients with recurrent epithelial ovarian carcinoma who had previously received one prior cisplatin-based regimen were scheduled to receive 1000 mg/m2 of merbarone by continuous intravenous infusion through a central line each day for five days every four weeks. RESULTS: Of the 27 patients entered, one was ineligible because of wrong primary, and two never received the drug, leaving 24 patients evaluable for toxicity. Twenty of 24 were evaluable for response. The regimen was well tolerated with only one episode each of GOG grade 3 leukopenia (4%) or grade 4 granulocytopenia (4%). There was one episode (4%) of GOG grade 3 gastrointestinal toxicity. Prior to increasing the infusate concentration to 4 mg/ml, there was one episode (4%) of altered mental status which, in retrospect, may have been secondary to iatrogenic hyponatremia. There were two partial responses (10%) (95% confidence interval 1.2-31.7%). CONCLUSIONS: Merbarone exhibited minimal activity at this schedule in this pretreated group of patients with epithelial ovarian carcinoma.

Aging and development of ovarian epithelial carcinoma: the relevance of changes in ovarian stromal androgen production.

There are three types of ovarian neoplasms: (1) Those which arise from the surface epithelium covering the ovary. (2) Those which are derived from the cortical mesenchymal stroma. (3) Those which develop from germ cells. Our laboratory has concentrated its effort on solid tumors in women of the first type, epithelial, which has the highest incidence and is the most lethal. Development of these tumors is correlated with aging in the ovary. They form primarily during the perimenopause. Among women, 64% of the total ovarian cancer cases are diagnosed between ages 41 and 60 years. Our approach has been to establish stable tumor cell lines from patient specimens for use as in vitro models. We have investigated the response of these cells to steroid hormones because we hypothesized that these tumors retain some metabolic characteristics which are specific to the ovary. Our data demonstrate that testosterone and androstenedione, but not cortisol, inhibited proliferation of ovarian tumor cells in vitro by a mechanism which was independent of steroid receptors. These androgens are routinely synthesized and secreted by human ovary, and in the menopausal ovary the primary source of androgen is the stromal cell compartment. Because a relatively high local concentration of ovarian androgen exists in vivo, it is possible that androgen may suppress ovarian epithelial carcinoma in women as well. If it does, then development of this carcinoma may be facilitated when the postmenopausal ovary fails to produce adequate androgen during postreproductive years.

Ultrasonic surgical aspirator in cytoreduction of splenic metastases to avoid splenectomy.

The Cavitron Ultrasonic Surgical Aspirator (Cavitron) was used to reduce the volume of splenic metastases in seven patients. Six patients had epithelial carcinoma of the ovary, and one had peritoneal mesothelioma. All patients had stage IIIC disease. Initially, six patients had malignant disease > 15 mm in diameter (of any single nodule), and one had disease 6-15 mm in diameter. In order to avoid resection of the spleen, cytoreduction could not be performed by standard means. After using the Cavitron, three patients had no gross residual disease, and four patients had disease 1-5 mm in diameter. No complication resulted from cytoreduction of splenic disease using the Cavitron, and splenectomy was not performed in any case. The Cavitron is invaluable in obtaining minimal residual disease of splenic metastases without performing splenectomy.

Emergence of imipenem-resistant Pseudomonas aeruginosa during treatment of intra-abdominal infection in a patient with ovarian carcinoma.

A 59-year-old woman was admitted to the hospital with ovarian carcinoma. After cytoreductive surgery, the patient developed intra-abdominal sepsis. After 17 days of intravenous imipenem, the patient's sputum culture grew imipenem-resistant Pseudomonas aeruginosa. On the 21st day of treatment with imipenem, her peritoneal culture also grew imipenem-resistant Pseudomonas aeruginosa.