Advanced ovarian carcinoma presenting with a cerebrovascular accident.

Ovarian carcinoma usually presents in an indolent manner, most often nonspecifically with complaints of abdominal pain or swelling, bloating, constipation, anorexia, early satiety, and evidence of ascites. We present a case of ovarian cancer with a cerebrovascular accident (CVA) as the presenting symptom, with minimal classic presenting signs and symptoms. The patient is a 43-year-old female with no cardiovascular risk factors who presented with a left parietal lobe infarct and advanced ovarian carcinoma. The patient underwent an extensive workup for the etiology of her CVA and possible hypercoagulation syndrome and eventually had surgical treatment. Ovarian carcinoma with a thromboembolic event as the initial presenting symptom is extremely rare. Although this patient did not appear to have hypercoagulability, consideration of this diagnosis should be given to patients presenting in this manner.

Placenta previa percreta with bladder invasion.

BACKGROUND: Although the clinical presentation and imaging techniques can raise suspicion for placenta previa percreta, this potentially catastrophic condition may remain undiagnosed or its extent underappreciated until delivery. The decision to proceed with definitive surgery in cases of placenta previa percreta should be carefully considered. CASE: A case of placenta previa percreta with bladder invasion was diagnosed prenatally. This case illustrates the magnitude of complications that can arise despite aggressive multidisciplinary perioperative management. CONCLUSION: When possible, hysterectomy performed for placenta previa percreta is best avoided under anything other than ideal conditions. A multidisciplinary approach for preoperative, intraoperative, and postoperative management of placenta previa percreta optimizes maternal outcome.

Combined antiproliferative activity of 5-fluorouracil and mitomycin-C against primary human ovarian tumors and cell lines in a clonogenic assay.

Ovarian tumors from 389 patients were successfully grown in a human tumor clonogenic assay (HTCA). Specimens from patients with or without prior chemotherapy showed similar chemosensitivity patterns. Excluding drugs commonly used for first-line chemotherapy, 5-fluorouracil (5-FU) and mitomycin-C (MMC) are among the active second-line agents, based upon HCTA data. Using this in vitro information from primary tumor specimens, two human ovarian cancer cell lines were used to study in detail the interactions of combined 5-FU and MMC. Drug scheduling which maximized combined antitumor activity was studied. Combined 5-FU and MMC revealed positive drug interactions most consistently when both drugs were used simultaneously with long-term exposure. Pulse treatment with MMC (1 hr) followed by continuous 5-FU exposure resulted in slightly less additive interaction than simultaneous long-term exposure. Pretreatment with 5-FU followed by a continuous exposure to MMC was as effective as the simultaneous method, as long as MMC was added within an 8-hr interval. Drug schedule dependency was examined, revealing that MMC, as a single agent, is both dose and schedule dependent. The results of these in vitro studies suggest that: (1) exposure to prior chemotherapy does not induce demonstrable pleiotropic drug resistance in these ovarian cancers tested; and (2) combined 5-FU and MMC show positive interactions against ovarian cancer cell lines, with optimal scheduling seeming to be long-term simultaneous exposure to both MMC and 5-FU.

An in vitro thymidine incorporation assay for human cancers: technical details revisited.

Among the choices of laboratory methods for in vitro testing of human tumor chemosensitivity, a thymidine incorporation assay (TIA) has been described. Advantages of a TIA over a colony-forming assay include greater probability of tumor growth, requirement for fewer tumor cells, less dependence on an absolute single-cell suspension, shorter time to completion, and the ability to measure up to three logs cell-kill. Specific technical details which are reported in the literature for performing a TIA are incomplete and/or conflicting between one laboratory and another. This paper reports details of methods designed to remove unbound 3[H]-thymidine from the agarose, standardize background counts, and determine optimal cell-plating densities, labeling time, optimal concentration of 3[H]-thymidine, and the best day after seeding cultures to add the 3[H]-thymidine. Care has been taken to compare the end point of drug sensitivity determinations following these methodologic changes, both among serial TIAs as well as with colony-forming assays.

Four ovarian cancers diagnosed during laparoscopic management of 1011 women with adnexal masses.

OBJECTIVES: This study was conducted to assess the value of laparoscopic management of adnexal masses. Two concerns we wish to address are the failure to diagnose early ovarian cancer at laparoscopy and worsening the prognosis of stage I cancer by spilling fluid during surgery. STUDY DESIGN: The setting is a predominantly referral-based, private subspecialty practice. All operations were preformed in the outpatient surgical suite of a large suburban hospital. After extensive patient screenings, which included history and physical examination, preoperative serum CA 125 levels (since 1988), and pelvic ultrasonography, 1209 adnexal masses were managed laparoscopically. RESULTS: Of 1011 patients with surgical management, ovarian cancer was discovered intraoperatively in four. CONCLUSIONS: Our findings indicate that with consistent use of frozen sections of all cyst walls and suspicious tissue, laparoscopic management did not alter the prognosis. Neither CA 125 level, pelvic ultrasonography, nor peritoneal cytologic testing had sufficient diagnostic specificity to predict malignancy. Experienced surgeons using intraoperative histologic sampling may safely evaluate adnexal mass laparoscopically.

Laparoscopic radical hysterectomy with paraaortic and pelvic node dissection.

We report the first case of a laparoscopic radical hysterectomy and paraaortic and pelvic lymphadenectomy to treat a stage IA2 carcinoma of the cervix. To our knowledge, a laparoscopic radical hysterectomy with laparoscopic paraaortic lymphadenectomy has not been previously described.

What do CA 125 and other antigens tell us about ovarian cancer biology?

CA 125 is an antigenic determinant on a high molecular weight glycoprotein. A monoclonal antibody has been produced which recognizes this, and allows us to measure the expression of CA 125 in serum. Tissue distribution of the CA 125 determinant is most commonly seen in serous tumors of the ovary, with highest levels in borderline and frankly malignant serous cystadenocarcinomas. Occasionally cancers of the breast, gastrointestinal tract, and kidney will show elevated levels of CA 125. Normal tissues which show varying levels of CA 125 include decidual tissue and structures derived from celomic epithelium. CA 125 is clearly tumor associated, but not tumor specific. Quantitative correlation of CA 125 levels with tumor volume has not been demonstrated. This observation limits the clinical usefulness of CA 125 as a screening tool, particularly in premenopausal patients who do not have a diagnosis of ovarian cancer. An undetectable level of CA 125 antigen does not rule out the presence of an early ovarian cancer. When CA 125 is used to monitor disease state in patients with known ovarian cancers (whose tumors do express CA 125), changes in levels of CA 125 do correlate with gross changes in tumor volume. Good prognostic significance is attributed to a rapid decline in CA 125 levels following induction chemotherapy in patients with advanced ovarian cancer. However, an undetectable serum level of CA 125 does not predict clinical cure for a patient with ovarian cancer. Further clinical studies continue in the use of CA 125 as a screening tool and as a means to monitor treatment responses of known ovarian cancer.

Combined interferon alfa and doxorubicin in the treatment of advanced cervical cancer.

Interferon alfa and doxorubicin have been shown to have synergistic effects when tested in vitro with cells derived from cervical cancers. A clinical trial was designed, testing interferon alfa plus doxorubicin in patients with advanced or recurrent cervical cancers. Twenty-one patients were given interferon alfa, 10 million units per square meter intramuscularly and 10 million units per square meter intravenously over a 30-minute infusion period. One hour later 20 mg/m2 doxorubicin was given intravenously slowly over a 2-hour period. Treatments were repeated once weekly for 3 weeks. Initial response evaluation was done at week 5, and treatment was continued on an every-other-week schedule for patients showing favorable responses or stable disease. Bone marrow, hepatic, and renal toxicities were minimal. Fever and malaise were the major sources of toxicity. Of the 17 evaluable patients, six had clinical partial responses. Two of the responders have enjoyed more than 5 years' survival. This regimen is well tolerated and does have efficacy in some patients with advanced cervical cancers.

The effects of estrogen, progesterone, and tamoxifen alone and in combination with cytotoxic agents against human ovarian carcinoma in vitro.

The effects of estradiol (E), medroxyprogesterone acetate (MPA), and tamoxifen (TAM) on the growth of a human ovarian carcinoma cell line, BG-1, were evaluated using a tumor clonogenic assay (HTCA). BG-1 contains significant quantities of estrogen and progesterone receptors. Growth inhibition by TAM and growth stimulation by MPA were demonstrated using continuous drug exposure. Estradiol resulted in a marginal increase in colony formation. With each of these three drugs, the greatest response occurred in the larger colonies (generally greater than or equal to 60 microns). Combinations of each of these three steroidal agents with three different cytotoxic drugs were studied in the HTCA. Synergistic activities were produced with TAM combined with either cisplatin or doxorubicin. Additive effects were seen with TAM and cyclophosphamide. Although predominantly additive or synergistic, the effects were variable with MPA and all three cytotoxic agents. Combinations of estradiol with cytotoxic agents were no more active than the cytotoxics alone. These findings indicate a biological rationale for hormonal manipulation as therapy in ovarian cancer.

Intralesional interferon alfa-2b for the treatment of genital warts.

A randomized, double-blind, placebo-controlled study has been conducted, and intralesional interferon alfa-2b was tested in the treatment of genital warts. This study design was to give 1 million units interferon alfa-2b intralesionally into the base of each of five external genital warts per patient, on a Monday-Wednesday-Friday treatment schedule for 3 weeks (total of nine injections). Forty-two patients were entered (20 randomized to receive interferon and 22 placebo injections). There were 43.8% of patients on the interferon treatment arm of the double-blind portion of the study who had complete disappearance of all warts, with an additional 25% of patients showing greater than 50% shrinkage of visible warts. On the placebo arm 14.3% showed a complete response, with an additional 14.3% showing greater than 50% shrinkage. This difference between interferon and placebo treatment was statistically significant (p less than 0.03). We conclude that intralesional interferon alfa-2b has significant activity in the treatment of genital warts.

Cytotoxic interactions of heat and an ether lipid analogue in human ovarian carcinoma cells.

Ether lipid (EL) analogues of platelet activating factor are known to have a cell membrane-mediated antitumor activity. Although previous studies demonstrated additive interactions with EL and conventional DNA-interacting chemotherapeutic agents, little is known about the interaction of EL with heat. In this study, the cytotoxic interaction of one EL analogue, ET-18-OMe, with heat was measured at two different temperatures, 42 and 44 degrees C, using BG-1 human ovarian carcinoma cells. When the number of colonies, greater than or equal to 40 microns in diameter, was counted as a function of incubation time, the rate of colony formation was suppressed by treatment with ET-18-OMe alone at doses greater than or equal to 2.0 microM or with heat alone. The combination of ET-18-OMe with heat inhibited the colony formation of the slowest growing fraction of the heated cells. The dose-response curve for BG-1 cells after continuous exposure to ET-18-OMe alone was exponential with a small shoulder (Dq = 0.25 microM). The T0 value (the time to reduce survival on the exponential portion of the curve by a factor of 1/e) of the 44 degrees C dose-response curve (30 min) was reduced to half (15 min) by the addition of 0.25 to 1.0 microM ET-18-OMe, but increased again to 24 min when heat was combined with ET-18-OMe concentrations greater than or equal to 2.0 microM. The thermotolerant tail seen in the dose-response curve after continuous heating at 42 degrees C was removed by adding as little as 0.25 microM ET-18-OMe. Isobologram analysis for the combined treatments with 44 degrees C heat and ET-18-OMe at surviving fractions of 0.5, 0.3, 0.1, and 0.01 showed that the treatments were supraadditive at low concentrations (less than 0.5 microM) of ET-18-OMe and additive at moderate concentrations (0.5 to 1.0 microM) of ET-18-OMe. Similarly, the interaction of ET-18-OMe with 42 degrees C heat at surviving fractions of 0.3 and 0.1 was supraadditive at low concentrations (less than 0.5 microM) of the ET-18-OMe and additive with moderate concentrations (0.5 to 1.5 microM) of ET-18-OMe. Because the greatest interaction of ET-18-OMe and heat occurred at clinically achievable doses of both agents, this combination of agents should be considered for use in clinical trials.

Effect of acoustic shock waves on clonogenic growth and drug sensitivity of human tumor cells in vitro.

Focused acoustic shock waves were studied for their effects on human tumor cell viability, clonogenicity, and sensitivity to chemotherapeutic agents. The elastic shock waves used in this investigation were generated with the Dornier HM3-Lithotripter by underwater spark discharge with fixed electrical parameters employing a voltage of 18 kV and a capacitance of 80 nanoFarads. These waves are characterized by a fast varying compression phase, strong asymmetrical pressure and tension phases, and a maximum amplitude of roughly 10(8) Pascal (kg.m-1 s-2). Doses as high as 2000 focused shocks showed little effect on the viability of two different cell lines. There was, however, a dose dependent inhibition of tumor cell proliferation as determined by the growth of clones in soft agarose. Each of the two cell lines showed a unique degree of colony inhibition by shock waves. It was demonstrated that shock wave effects resulted from elastic shock wave interaction with the cells and were not caused by the emission of ultraviolet light coincident with shock wave generation. Shocks were applied at a rate of 100 minute-1 in a 200 l. water bath, thereby removing the possibility for temperature changes during treatments. After treatment with shock waves it was found that tumor cells became more sensitive to growth inhibition by chemotherapeutic agents. Cisplatin, doxorubicin, and 4-hydroperoxycyclophosphamide were each more effective in blocking cell growth after the target cells had been treated with acoustic shocks. Enhanced efficacies ranged from three to 10-fold potentiation of colony inhibition. These results indicate that weak shock waves, which can be focused to a defined target region, may have utility as a cancer treatment modality either alone or in combination with cytotoxic agents.

Concurrent chemotherapy and single high-dose plus whole abdominopelvic radiation for persistent ovarian carcinoma.

Twenty-two patients were treated with concurrent single high-dose and standard fractionated abdominopelvic radiation and chemotherapy (cisplatin or hexamethylmelamine). Those who had prior cisplatin received hexamethylmelamine and radiation (16 patients) while those without prior cisplatin received cisplatin and radiation (6 patients). The primary aim of the study was to assess the tolerance and effectiveness of concurrent radiation and chemotherapy in patients who had failed prior chemotherapy. All patients experienced mild to moderate nausea, vomiting, and diarrhea. Hematologic adverse effects were minimal. Three patients requiring laparotomy for radiation induced small bowel obstruction had confirmed complete responses but 2 died acutely of treatment-related complications without evidence of tumor. In the 15 patients with suboptimal disease (greater than 1 cm residual disease) prior to the study, only 1 had a complete response while 2 of 7 optimal patients (less than or equal to 1 cm residual disease) had a complete response. All 3 complete responders received cisplatin and 2 had 1 cm or less of residual disease prior to the study. In the hexamethylmelamine group 3 of 16 patients had a partial response. Concurrent single high-dose whole abdominopelvic radiation and cisplatin may be effective in patients with minimal disease (less than or equal to 1 cm); however, radiation-associated bowel complications were severe.

CA-125 values predictive of clinical response during second-line chemotherapy for epithelial ovarian cancer.

Between November 1984 and January 1987, 19 patients with epithelial ovarian cancer were monitored with CA-125 values during second-line therapy. There was a statistically significant association between clinical response to therapy and CA-125 trend when trend was defined as a greater than or equal to 26% change in CA-125 from baseline value to last value prior to demonstration of clinical response (p = 0.0002). In 8 of 11 patients (73%), increasing CA-125 values were predictive of clinical progression during second-line therapy. In six of seven patients (86%), decreasing values predicted clinical regression. Three patients began second-line therapy with baseline values less than 35 U/ml. Two of these progressed during second-line therapy while the third progressed in follow-up. Two of four complete clinical responders completed second-line therapy with values less than 35 U/ml. Both progressed in follow-up with increasing CA-125 values. In this analysis, a 26% change in CA-125 values was a useful predictor of clinical response in patients receiving second-line therapy for epithelial ovarian cancer. Patients undergoing second-line chemotherapy with values less than 35 U/ml may still benefit from CA-125 monitoring.

Characterization of a human ovarian carcinoma cell line with estrogen and progesterone receptors.

The potential significant therapeutic and prognostic roles for the sex steroid receptors in ovarian cancer are recognized. The authors present in detail the biochemical, morphologic, cytogenetic, and growth characteristics of an ovarian carcinoma cell line, BG-1, which has functional estrogen and progesterone receptors (23 and 300 fmol/mg protein, respectively) in clinically significant levels. In particular, BG-1 has a DNA index of 1.14, a stable karyotype with specific translocations, and produces and secretes CA 125 into the media.

Tenckhoff catheter cytology in patients with ovarian cancer.

In order to expose malignant cells to high concentrations of cytotoxic chemotherapeutic agents, drugs can be instilled directly into the peritoneal cavity of patients with ovarian carcinomas through a Tenckhoff catheter. The peritoneal dialysate removed during such therapy can be examined cytologically for the presence of carcinoma cells. The cytologic specimens from Tenckhoff catheters from 40 consecutive patients with primary ovarian (39) and tubal (1) cancer who received intraperitoneal chemotherapy have been reviewed retrospectively. A total of 237 specimens yielded 78 (33%) positive, 138 (58%) negative, and 21 (9%) inconclusive or suspicious fluids. The major diagnostic problem was the marked mesothelial atypia, which may be related to the high concentrations of cytotoxic agents intimately in contact with the peritoneum. Of the 15 patients who had tissue examined after placement of the catheter (mean interval, 5 months), results agreed with those of the catheter cytologic specimens in ten patients. The catheter cytologic specimen was never positive when histology was negative. Of the 36 patients with evaluable follow-up (mean, 19 months), agreement between the clinical course and the catheter cytologic results was found in 27 patients (75%). Again, interpretation of the catheter specimens was never positive in the face of a benign clinical course. Thus, evaluation of catheter specimens by cytologic examination has a diagnostic sensitivity and specificity of 59% and 100%, respectively. Tenckhoff catheter cytology has proven to be a rather valuable tool to monitor persistent or recurrent intraperitoneal ovarian carcinoma.

A phase II study of the efficacy of recombinant interferon gamma in relapsing ovarian adenocarcinoma.

Fourteen patients with relapsing ovarian cancer were treated with a regimen of intravenous interferon gamma (IFN gamma). During an initial induction phase, patients received 2 mg/m2 IFN gamma intravenously over 2 h daily for 5 days, repeated every 2 weeks for six courses. Patients who responded were continued on a maintenance phase, receiving 3 mg/m2 intravenously over 2 h, twice weekly every 2 weeks for 2 to 6 months. All patients had received prior cisplatin containing chemotherapy regimens. Of the 14 patients entered, 7 completed the six courses of the induction treatment. Four patients were clinical responders and continued on maintenance therapy. The most commonly reported toxicities included malaise, fever, and deteriorating performance status. There appears to be some clinically apparent antitumor activity demonstrated by this dosing schedule of interferon gamma in ovarian cancers.