Upper abdominal cytoreduction and thoracoscopy for advanced epithelial ovarian cancer: unanswered questions and the impact on treatment.

Gynaecological oncologists, by conducting Phase II and III chemotherapy trials, have sought to improve survival in women with epithelial ovarian cancer. The greatest impact on survival has been the use of intraperitoneal chemotherapy in women who have had all visible disease removed. No change in drug regimen has had an impact on survival equivalent to that associated with complete cytoreduction or the use of intraperitoneal chemotherapy. Interestingly, these two treatment modalities (complete cytoreduction and intraperitoneal chemotherapy) have not been universally adopted. Most often it is the inability to achieve optimal cytoreduction in the upper abdomen that defines the limit of the cytoreductive effort, and ultimately the integration of intraperitoneal chemotherapy. The importance of identifying disease outside the abdominal cavity, along with achieving complete cytoreduction, is paramount, if the use of intraperitoneal chemotherapy is to be logically integrated in treatment algorithms for women with advanced-stage epithelial ovarian cancer. This report summarises pertinent literature on upper abdominal cytoreduction, discusses surgical techniques and introduces new data on women with epithelial ovarian cancer undergoing thoracoscopy, suggesting consideration of its incorporation into the surgical management of advanced epithelial ovarian cancer.

Feasibility of intravenous gemcitabine and an intraperitoneal platinum agent in the treatment of ovarian cancer.

The goal of this study is to determine the feasibility of intravenous gemcitabine and an intraperitoneal platinum agent in the treatment of patients with ovarian cancer. We performed a retrospective chart review of patients with primary, persistent or recurrent ovarian cancer, who received intravenous gemcitabine and an intraperitoneal platinum agent. Patients received gemcitabine (750 mg/m²) intravenous on days 1 and 8 and cisplatin (100 or 60 mg/m²) intraperitoneal on day 1 every 21 - 28 days. An alternate regimen was composed of gemcitabine (750 mg/m²) intravenous and carboplatin (AUC 5) intraperitoneal on day 1 every 21 days. Dose reductions occurred at the discretion of the prescribing physician.Intravenous gemcitabine and an intraperitoneal platinum agent were administered to 12 patients with advanced primary or recurrent ovarian cancer. Myelosuppression was the most common toxicity. Grade 3 or 4 thrombocytopenia, neutropenia and anemia occurred in 7, 8 and 2 patients respectively. Dose reductions were required in 7 of 12 patients. 10 of 12 patients received 6 cycles of the regimen. Treatment was discontinued prior to 6 cycles in 2 of 12 patients secondary to progression in one case and to grade 4 neutropenia and thrombocytopenia in another.The combination of intravenous gemcitabine and an intraperitoneal platinum agent appears to be a feasible regimen in patients with ovarian cancer. The most common toxicity was myelosuppression, which resulted in dose reductions in almost half of the patients.

Correlation of extreme drug resistant assay results and progression-free survival following intraperitoneal chemotherapy for advanced ovarian cancer.

The aim of this study was to determine if in vitro extreme drug resistance (EDR) to platinum and/or taxane chemotherapy was predictive of patient response to intraperitoneal (I.P.) chemotherapy in patients with stage III or recurrent epithelial ovarian cancer (EOC). Fifty-six patients were retrospectively identified who underwent optimal cytoreductive surgery for primary or recurrent eOC and then received at least three cycles of either intravenous (I.V.) or I.P. chemotherapy with platinum and paclitaxel-based chemotherapy. EDR to platinum and/or paclitaxel was determined using a commercially available assay (Oncotech, Inc., Tustin, CA). The primary outcome measure was progression-free survival (PFS). Twenty-nine (52%) patients received I.P. chemotherapy and 27 (48%) received I.V. chemotherapy. The patients were well matched in terms of age, stage, grade and histology. Ten (35%) patients in the I.OP. arm and ten (37%) patients in the I.V. arm showed EDR to either platinum and/or paclitaxel. Median PFS for all I.P. chemotherapy patients was 23 months, compared with 13 months for those receiving I.V. chemotherapy (p = 0.04). Patients with EDR to platinum and/or taxane who underwent I.V. chemotherapy had a median PFS of 13.5 months, whereas those who underwent I.P. treatment had a median PFS of 15 months (p = 0.69). Median overall survival had not been reached at the time of analysis.No significant difference in PFS was noted between patients who underwent I.P. and those who underwent I.V. chemotherapy when EDR was predicted to either platinum or paclitaxel or both. These data suggest that the decision to offer I.P. chemotherapy, with the attendant increase in morbidity, in the setting of EDR to platinum and/or taxane chemotherapy, may not be beneficial. Prospective studies, preferably analyzing platinum or taxane EDR individually, are required to validate these observations.

Metastatic leiomyosarcoma diagnosed after uterine artery embolization.

Uterine artery embolization (UAE) allows treatment of recalcitrant fibroids, but does not provide a surgical specimen. In the rare instance that a uterine mass represents a uterine leiomyosarcoma (LMS), UAE may delay diagnosis. We report a case of a 45-year-old woman who underwent resection of a substernal mass five years after UAE. Pathology demonstrated LMS. She received radiation therapy to the surgical site. Upon recovery, she underwent a hysterectomy and bilateral salpingo-oophorectomy. Pathology demonstrated uterine LMS. She was managed conservatively and is without evidence of disease over two years after excision of her substernal mass. Multiple case reports have described a delay in diagnosis of uterine LMS after UAE. The current case is unique in that it the diagnosis was made based on the presence of a distant metastasis, which occurred years after UAE.

Differences of chemoresistance assay between invasive micropapillary/low-grade serous ovarian carcinoma and high-grade serous ovarian carcinoma.

The objective of this study was to evaluate the pattern of chemoresistance in invasive micropapillary/low-grade serous ovarian carcinoma (invasive MPSC/LGSC) and high-grade serous ovarian carcinoma (HGSC) according to extreme drug resistance (EDR) assay testing. Surgical specimens of 44 recurrent ovarian cancer patients harvested at the time of cytoreductive surgery between August 1999 and February 2004 were identified retrospectively from the tumor registry database. Thirteen patients (29.5%) had recurrent invasive MPSC/LGSC and 31 (70.5%) patients had recurrent HGSC. Eight drugs were evaluated; EDR assay results were compared between LGSC and HGSC groups using Fisher exact tests and exact logistic regression models. Compared to HGSC, invasive MPSC/LGSC were more likely to manifest EDR to the drugs paclitaxel (69% vs 14%, P < 0.001), carboplatin (50% vs 17%, P= 0.05), cyclophosphamide (40% vs 23%, P= 0.41), gemcitabine (36% vs 19%, P= 0.40), and cisplatin (33% vs 28%, P= 0.72) and less likely to be resistant to etoposide (0% vs 44%, P= 0.007), doxorubicin (8% vs 45%, P= 0.03), and topotecan (8% vs 21%, P= 0.65). Exact logistic regression estimates revealed that invasive MPSC/LGSC patients had significantly increased probabilities of paclitaxel resistance odds ratio (OR) = 12.5 (95% CI: 2.3-100.0), P= 0.001 and carboplatin resistance OR = 4.8 (95% CI: 0.9-25.0), P= 0.07, while the HGSC cases were more likely to be resistant to etoposide OR = 12.1 (95% CI: 1.7-infinity), P=0.009 and doxorubicin OR = 8.6 (95% CI: 1.0-413.7), P= 0.05. In this retrospective analysis, patients with recurrent invasive MPSC/LGSC were more likely to manifest EDR to standard chemotherapy agents (platinum and paclitaxel). These observations may help to guide chemotherapeutic decision making in these patients if confirmed in a large-scale study.

Mucin gene expression in ovarian cancers.

Ovarian cancer is a highly lethal disease with metastases present in the majority of patients at the time of diagnosis. The molecular mechanisms underlying the metastatic process of this cancer are not well understood. One family of cell-associated and secreted glycoproteins, the mucin glycoproteins, has been implicated in events leading to metastasis of several epithelial cancers including gastrointestinal and lung cancers. The purpose of this study was to characterize mucin gene expression in ovarian cancers and relate expression to tumor histology, stage, and patient survival. RNA was isolated from 29 epithelial ovarian cancers, 1 neuroendocrine carcinoma, 3 mixed mesodermal tumors, and two transformed, yet nonmalignant, ovarian epithelial cell lines. The expression of mucin genes, MUC1, 2, 3, 4, 5AC and 5B, was determined by northern analyses. Epithelial ovarian cancers expressed several mucins including MUC1, 2, 4, and 5AC; MUC3 and 5B were rarely expressed. In contrast, the transformed nonmalignant ovarian epithelial cell lines expressed only MUC1 and 5AC. Although there was no correlation of mucin expression with tumor histology, there was a significant decrease in expression of MUC3 and MUC4 with increasing cancer stage (P < 0.05). In addition, a trend toward improved patient survival occurred with increased expression of MUC4. These observations suggest a relationship between mucin gene expression and the metastatic process in epithelial ovarian cancers. Additional investigation of MUC3 and MUC4 in ovarian cancers may lead to new approaches for early detection and therapy.

Expression of GDP-L-Fuc: Gal(beta 1-4)GlcNAc-R (Fuc to GlcNAc) alpha-1,3-fucosyltransferase and its relationship to glycoprotein structure in a human erythroleukemia cell line, HEL.

Terminal glycosylation may be a mechanism to control the function of specific biologically active glycoproteins. The biosynthesis of terminal sialyl and fucosyl residues on certain glycoproteins has been linked to the expression of the respective glycosyltransferase. In contrast, a human erythroleukemia cell line, HEL, contained a highly active GDP-L-Fuc: Gal(beta 1-4)GlcNAc-R (Fuc to GlcNAc) alpha-1,3-fucosyltransferase (alpha-1,3-fucosyltransferase) but no detectable alpha-1,3-linked fucosyl residues on the glycoproteins. The alpha-1,3-fucosyltransferase gave apparent Km values for Fuc(alpha 1-2)Gal(beta 1-4)GlcNAc beta-O-benzyl, Gal(beta 1-4)GlcNAc and GDP-fucose of 0.04, 0.68 and 0.12 mM, respectively. The lack of detectable fucosyl residues in alpha-1,3-linkage to GlcNAc on the [3H]fucose-labeled glycoproteins was shown with the use of almond alpha-1,3/4-fucosidase and internal controls to verify that the enzyme was active. Using Western-blot analysis, HEL cell glycoproteins reacted with blood group H type-2 antibody, confirming the presence of Fuc(alpha 1-2)Gal(beta 1-4)GlcNAc as reported by others and the presence of the preferred substrate for the enzyme. It is proposed that controls for terminal glycosylation in addition to glycosyltransferase expression are operative in HEL cells and that they are part of a multi-regulated process controlling terminal modifications of glycoproteins.

Database management for a gynecologic oncology service.

With the ready availability of powerful desktop computers, the ability to manage large clinical databases has become practical. A computer can enhance the capability of a gynecologic oncology service to catalog, recall, and analyze data about patients, tumors, and therapies. While commercially available database packages can be used for this purpose, we have developed a custom database for tracking the clinical activity of a busy gynecologic oncology service. The system catalogs data about patients, admissions, tumors, and therapeutic modalities and uses this information to generate several useful reports. The reports are used for daily patient care, fellow and resident case statistics, and clinical research. What is unique about the system is that it is optimized for ease of use. The development of this tumor registry, its user friendliness, and advantages over a manual recordkeeping system are described. Unlike other tumor registries, our system is utilized on a daily basis for patient care. Therefore, the data being entered have an immediate usefulness in addition to being simultaneously added to the tumor register for retrospective clinical research. One may hypothesize that it would be useful if all gynecologic oncology services used a common computerized tumor registry that could allow for the sharing of information on a national or global scale.

The second-look celiotomy in ovarian cancer.

Thirty-six patients with primary ovarian carcinoma who had 42 second-look procedures performed are reported. Twenty-three patients had no tumor found at the second-look celiotomy and were given no further treatment. Thirteen patients had tumor at the second-look procedure and were continued on therapy. Six patients have died with disease and all had a positive second-look celiotomy. Two patients have died with leukemia but with no evidence of ovarian cancer, one after a negative second-look and the other a negative third-look. No patient with a negative second-look celiotomy has died with disease. A correlation with respect to the findings at the second-look was found with respect to the stage of disease and the amount of residual tumor at the initial surgery. The use of the second-look celiotomy in patients with disease in the early stages and in patients treated with irradiation is discussed, along with the utilization of the laparoscopy.

Pregnancy outcome in 98 women exposed to diethylstilbestrol in utero, their mothers, and unexposed siblings.

The reproductive capability and labor complications of 98 women exposed to diethylstilbestrol (DES) in utero were compared with those of 3 separate control groups. The controls consisted of 167 age-matched, normal women, 20 siblings not exposed to DES who had achieved pregnancy, and their mothers. Spontaneous abortion, ectopic pregnancy, incompetent cervix, and premature labor occurred significantly more often in the DES-exposed population than in the normal controls. The controls also achieved a higher percentage of desired pregnancies overall; this was statistically significant (89.6 versus 75.0%, P less than .001). When compared with their mothers, however, the DES-exposed population achieved a greater percentage of desired, viable pregnancies (75.6 versus 67.0%, P less than .001). The unexposed siblings of the DES women achieved a higher percentage of desired, viable pregnancies than did their exposed sisters (86.9 versus 73.6%, P = .274), but less than the normal population (86.9 versus 89.6%).

Oral contraceptives and neoplasia.

PIP: Some of the available data concerning the suspected association between oral contraceptive (OC) use and the development of cancer is surveyed, and the attempt is made to evaluate possible associations between OCs and human neoplasia in light of pregnancy risk or benefit of oral contraception. The principal investigative methods in humans include various epidemiologic approaches, and the methodologies most often used are case reports (tumor registries), disease rates and trends, case-control studies, and cohort studies. These methods cannot prove a causal relationship between exposure to a possible carcinogen and the occurrence of disease. Consistent positive or negative evidence, confirmed by multiple epidemiologic approaches, can be used to guide physicians and regulatory agencies in formulating policy for the clinical use of OCs. Both the progestogen-only and the combined OCs have been shown to have a protective effect on the development of benign breast disease with this protective effect not appearing until 2 years of use. Long-term combined OC use appears to be related to the development of benign liver neoplasia, and this risk increases with the dose of the steroid and the age of the user. These lesions are quite rare but may be life threatening because of potential spontaneous rupture and hemorrhage. Long-term postmenopausal use of estrogens appears to increase significantly the risk of developing endometrial hyperplasia and adenocarcinoma of the endometrium. Estrogens appear to be related to the growth of pre-existing uterine leiomyomas. Endocervical cells under the influence of progestogens may develop adenomatous changes, and these benign changes have on occasion been misinterpreted as carcinoma.^ieng

Successful treatment of human genital herpes infections with 2-deoxy-D-glucose.

Thirty-six women with genital herpes infections (proved by virological or cytological means) were treated in a double-blind placebo-controlled study with the glucose analogue 2-deoxy-D-glucose for a three-week period. In initial mucocutaneous cases, 89% were cured, with two recurrences after 24 months; in the case of recurrent or secondary infections, 90% had a notable improvement manifested by no or less-frequent recurrences, fewer lesions, or shortened duration of symptoms. In initial infections, discomfort cleared within 12 to 72 hours of therapy; 90% of the patients were asymptomatic within four days. In both cases, virus shedding was notably reduced by 2-deoxy-D-glucose. Concomitant controls treated with placebos failed to respond within this time frame. The use of 2-deoxy-D-glucose provides a simple and unique approach to the treatment of genital herpesvirus infections.

Intralymphatic BCG in the treatment of gynecologic malignancies: a phase I study.

Thirteen patients with a variety of advanced gynecologic malignancies were administered BCG via the dorsal lymphatics of the lower extremity in addition to standard accepted forms of therapy. Prolonged febrile courses, lymphangitis and suppurative adenitis were observed along the lymphatic pathway of the injected lower limbs. There was no correlation between reaction to a standard anergy panel and survival. There was also no correlation between reaction to a standard anergy panel and the inflammatory response to intralymphatic BCG (ILP-BCG). There was, however, a positive correlation between the inflammatory response to ILP-BCG and survival. Intralymphatic administration of immunostimulants may conceivably be of value as ancillary therapy for use in gynecologic malignancy. However, complications of this approach to immunotherapy are significant and the method should not be used until complications are decreased.

The 'problem' radical hysterectomy.

This is a study of 243 radical hysterectomy and pelvic lymphadenectomy procedures performed for gynecologic malignancy. The term 'problem' radical hysterectomy was applied to those patients with one of the following conditions: (1) recent cervical conization (within 21 days). (2) previous total or supravaginal hysterectomy, (3) pregnancy, or (4) previous pelvic radiation. There were 88 patients in theses categories. One hundred and fifty-five patients had none of these predisposing problems which might influence operative or postoperative complications. There were two deaths (0.82 per cent). There was no statistically significant difference in operative injuries to the bladder, ureters, or rectum or in the mean operative time and mean blood loss across the categories. However, there was a statistically significant difference across the categories in postoperative complicatons, both major and minor. The greatest incidence of such complications occurred in patients who had previous radiation therapy and the second greatest incidence was in patients who had recent cervical conization. Pregnant patients had the least number of complications.

Androgenic function of a granulosa cell tumor.

Virilizing granulosa cell tumors are uncommon and have not been well studied hormonally. A hirsute woman with a cystic granulosa cell tumor of the ovary is presented. Plasma hormone levles obtained before and after surgery indicate testosterone production by the tumor with LH and FSH suppression. Plasma testosterone (T) and T-index returned to normal after tumor removal, and ovulation resumed.