Nodal metastasis in endometrial cancer.

PURPOSE: Besides hysterectomy and bilateral salpingo-oophorectomy, the goal of surgery in early endometrial cancer is to identify extrauterine disease. The purpose of this study was to evaluate disease characteristics and survival of patients found to have nodal metastasis at staging for endometrial cancer. METHODS: All patients presenting to our practice from January 1993 to July 2009 with a new diagnosis of early endometrial cancer underwent pelvic and paraaortic lymph node sampling at the time of surgery as permitted by the body mass index. Patient and disease characteristics of patients with nodal metastasis were abstracted by retrospective chart review. Factors contributing to disease-free and overall corrected survival were evaluated. RESULTS: Forty-three patients with an early endometrial cancer were found to have pelvic and/or paraaortic nodal metastasis. Thirty-three percent of patients with nodal metastasis had papillary serous or clear cell cancers. Such tumors were often superficially invasive, yet were more likely to demonstrate lymphovascular space involvement as compared to endometrioid cancers. Furthermore, in a global model of disease-free and overall corrected survival, only tumor histology (endometrioid vs non-endometrioid) was a significant prognostic factor. Excluding clear cell and papillary serous tumors, only tumor grade was a significant prognostic factor in disease-free survival and overall corrected survival in patients with endometrioid adenocarcinomas and nodal involvement. Following adjuvant treatment after surgery, the recurrences were nearly evenly divided between pelvic, paraaortic nodal and distant sites. Only four of 33 (12%) patients treated with adjuvant pelvic radiation experienced a failure in the irradiated field. Furthermore, none of the patients experiencing a paraaortic nodal recurrence received adjuvant radiation to this site. CONCLUSIONS: The data suggest a benefit to the use of adjuvant radiation for local control of disease. Furthermore, the use of paclitaxel and carboplatinum chemotherapy also appears a promising adjunct in patients with endometrioid histologies and nodal spread. Papillary serous and clear cell cancers contributed disproportionately to the incidence of nodal metastasis and an adverse prognosis following further adjuvant therapy of patients with nodal disease. Despite taxol/carboplatinum chemotherapy, over half of the patients with non-endometrioid cancers recurred, as opposed to one of 19 endometrioid cancers so treated. The ideal form of adjuvant treatment for such patients remains problematic.

Elevated plasma platelet-derived growth factor B-chain levels in cancer patients.

Platelet-derived growth factor (PDGF) is produced by a variety of normal and tumor cells in vitro. We have developed an enzyme-linked immunosorbent assay for the detection of the B-chain of PDGF. This assay can reliably detect 0.1 ng/ml of homodimeric recombinant PDGF B-chain and does not cross-react with recombinant PDGF-AA, epidermal growth factor, basic fibroblast growth factor, or transforming growth factor-beta. Citrated plasma from 72 control individuals had a PDGF B-chain (PDGF-B) level of 0.32 +/- 0.14 ng/ml (mean +/- SD) with a range of 0.10-0.69 ng/ml. The plasma platelet factor 4 (PF4) level was 97 +/- 70 ng/ml, with a range of 34-363 ng/ml. Citrated plasma was obtained from 131 cancer patients, and plasma PDGF-B was elevated in 19 (15%) of the patients. Both PDGF-B and PF4 were elevated in 14 (11%) of these patients, consistent with a platelet source of PDGF-B. In 5 patients (4%), however, PDGF-B was elevated and PF4 was not elevated compared to the control group. This last group of patients may have a tumor-derived source of PDGF-B which could be important in autocrine or paracrine growth stimulation of the tumor cells.

Elevated soluble c-erbB-2 antigen levels in the serum and effusions of a proportion of breast cancer patients.

PURPOSE: An enzyme-linked immunosorbent assay (ELISA) for the extracellular domain of the c-erbB-2 oncogene product was developed and evaluated to determine if soluble c-erbB-2 could be detected in the serum and effusions of cancer patients. PATIENTS AND METHODS: Sera from 208 previously untreated or progressing cancer patients and 69 healthy controls were assayed in a double-antibody sandwich ELISA that used two monoclonal antibodies to the native extracellular domain of the c-erbB-2 receptor. Fisher's exact test was used to analyze the statistical significance of the frequency of elevated serum c-erbB-2 levels. Immunoprecipitation and Western blotting were used to characterize further the c-erbB-2 immunoreactivity in the serum of four breast cancer patients. RESULTS: Sera from 12 of 53 patients (23%) with metastatic or locally advanced breast cancer, zero of 69 controls, one of 31 patients with ovarian cancer (3%), and two of 124 other cancer patients (2%) had soluble c-erbB-2 values greater than or equal to 5 U/mL. The number of breast cancer patients with elevated serum c-erbB-2 levels was significantly greater than that of the control group (P less than .0001), the ovarian cancer group (P less than .03), and the other cancers group (P less than .0001). Also, two of five effusions (40%) from breast cancer patients had an elevated soluble c-erbB-2 antigen level, compared with zero of 17 effusions from patients with benign diseases. Western blotting of four sera from breast cancer patients with elevated serum c-erbB-2 antigen levels produced bands of approximately 105 kD that seemed to correlate in intensity with increasing ELISA serum levels. CONCLUSION: Serum c-erbB-2 levels are elevated in approximately one fourth of patients with locally advanced or metastatic breast cancer.

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.

Analysis of prognostic factors and survival in patients with ovarian cancer treated with second-line hexamethylmelamine (altretamine).

Hexamethylmelamine (altretamine, HMM) 260 mg/m2/day p.o. for 14 days followed by a 14-day drug-free interval was administered to 52 outpatients with advanced ovarian cancer who had previously been treated with chemotherapy. Prior to HMM, 92% (48/52) of these patients had received cisplatin and cyclophosphamide with or without doxorubicin. Two more patients received other cisplatin-based regimens. At the completion of HMM therapy, 15% (8/52) displayed no evidence of disease (NED). Of these eight patients, five are still alive 32 to 82 months after altretamine therapy (median follow-up of 46 months). At 41 months, one patient died of intercurrent illness with no clinical evidence of recurrence; the other two patients died of their disease at 21 and 31 months following HMM therapy. The median survival of the total group was 11 months: nine months for patients who did not respond to altretamine and 46+ months for patients with NED after altretamine (p less than 0.05). Intermittent oral administration of single-agent altretamine was well tolerated: eight patients reported moderate gastrointestinal symptoms, and only one patient reported severe gastrointestinal symptoms. Moderate neurologic toxicity was reported by five patients. No WBC fell below 2000 mm3 and platelet counts fell below 100,000 mm3 in only three patients; no patient experienced severe hematologic toxicity. In this series of patients, the overall response (15%) was comparable to or better than those reported for more toxic chemotherapeutic regimens. On the basis of these data and those reported by other investigators, HMM warrants consideration as a reasonable option in the management of recurrent or persistent ovarian cancer.

Correction of massive vaginal prolapse in an older population: a four-year experience at a rural tertiary care center.

OBJECTIVE: To ascertain the success of complex reconstructive vaginal surgery in older women. DESIGN: Retrospective review of hospital and outpatient records. SETTING: Rural tertiary care referral center, Pennsylvania State University Hospital, Hershey, Pennsylvania. PATIENTS: Twenty-four patients referred for massive erosion of the vagina and/or complete procidentia. MEASUREMENTS: Symptoms and anatomic correction of patients' complaints. RESULTS: After surgery, 83 percent were asymptomatic without pelvic relaxation, 4 percent were asymptomatic with pelvic relaxation, 4 percent were symptomatic without pelvic relaxation, and 9 percent were symptomatic with relaxation. CONCLUSIONS: Older women can undergo major vaginal reconstructive surgery with relief of symptoms and restoration of vaginal depth and axis.

Recurrent Paget disease of the vulva in a split-thickness graft.

Recurrent Paget disease developed in a vulvar split-thickness skin graft, the second reported case of recurrence of this type and the first without an underlying dermal adnexal adenocarcinoma.

Autoantibodies associated with endometriosis: can their detection predict presence of the disease?

To evaluate the usefulness of autoantibody detection as a nonoperative method of diagnosing endometriosis, we tested 221 sera from 215 patients from the infertility, gynecology, and gynecologic oncology services by an indirect immunofluorescence assay using monolayer cultures of an endometrial carcinoma cell line. The assay showed positive cytoplasmic staining, demonstrating a sensitivity of 83% in the patients with laparoscopically confirmed endometriosis. The specificity of the assay was 65% for the infertility patients and 76% for the infertility and gynecology patients combined. Several gynecologic cancer patients showed either nuclear or nuclear and cytoplasmic staining, but few showed exclusive cytoplasmic staining. These initial results suggest that detection of antibodies might be useful for the diagnosis of endometriosis.

Primary invasive carcinoma of the vagina.

A retrospective study of 29 patients with invasive carcinoma of the vagina was completed at The Milton S. Hershey Medical Center, Pennsylvania State University, for a ten-year period from 1976-1986. The overall incidence was 1.3% of all gynecologic malignancies. Twenty-four patients (83%) had squamous cell carcinoma and five (17%) had adenocarcinoma. Squamous cell carcinoma was most commonly located in the upper anterior and lateral vaginal vaults, whereas adenocarcinoma was found more often in the lower anterior and lateral vaginal vaults. The majority of the patients (96%) were managed by a combination of whole-pelvis irradiation and brachytherapy. Twenty-four percent of the patients had a recurrence in the vagina only, indicating the need for better local control. The overall survival rate was 48%. Patients with previous hysterectomy were more likely to develop serious treatment-related complications.

Endometrial antibodies versus CA-125 for the detection of endometriosis.

Detection of endometrial antibodies using an indirect immunofluorescence method along with a well-established human endometrial carcinoma cell line was evaluated and compared with CA-125 for detecting endometriosis. Two hundred two patient sera from the infertility, gynecological, and gynecological oncology services were evaluated. The sensitivity for antibody testing was 83.1% with a specificity of 78.8%, in contrast to a sensitivity of 27.3% and a specificity of 82.6% for CA-125. These preliminary findings offer promise that antibody detection methods may be a useful adjunct in the diagnosis of endometriosis.

Hormonal treatment of endometrial cancer: past, present and future.

The concept that hormonal therapy may be useful in the treatment of endometrial cancer antedated the pharmaceutical availability of progestational compounds. By 1959, initial studies demonstrated the ability of progestins to reverse endometrial hyperplasias. Thereafter, progestins and other hormonal agents have been used in various roles as treatment for endometrial cancers. This chapter reviews the use of hormonal agents for the treatment of primary and metastatic/recurrent endometrial cancer, as well as such treatment in an adjuvant setting. Major problems in enhancing the efficacy of endocrine therapy of cancers arising from hormonally responsive tissues are also considered. The regulations of steroid-hormone receptor expression in endometrial and breast cancers continues to be an active area of research interest.

A phase II trial of amonafide in patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study.

Amonafide demonstrated a poor response rate and substantial toxicity in patients who had measurable, advanced mixed mesodermal tumors of the uterus. Amonafide-a drug that acts through intercalation of tumor DNA-was used to treat 16 patients who had measurable, advanced mixed mesodermal tumors of the uterus as part of a Gynecologic Oncology Group (GOG) Phase II study. The starting dose was 300 mg/m2 intravenously over 1 hour for 5 consecutive days every 3 weeks. Severe or life-threatening hematologic toxicity occurred in 50% of the patients. Two patients experienced vomiting requiring hospitalization. Other toxicities were not severe. One patient had a partial response and one had stable disease, each lasting 4 months. This dose schedule was associated with poor response rate and substantial toxicity.

The prognostic value of HER-2/neu oncogene in cervical cancer.

BACKGROUND: Expression of the HER-2/neu oncogene has been suggested to confer added virulence or aggressive behavior in gynecologic malignancies. The aim of this study is to determine the frequency of HER-2/neu expression in invasive cervical cancer and its impact on survival in women with cervical cancer. DESIGN: Archival tissue from 150 patients with cervical carcinoma was evaluated immunohistochemically for HER-2/neu oncoprotein expression. Survival information was retrieved retrospectively from patients' medical records. RESULTS: The HER-2/neu expression was observed in 34 out of 150 tumors (22%). The HER-2/neu positive tumors exhibited considerable heterogeneity in the distribution of immunoreactive tumor cells. Tumor grade and histology did not influence the pattern or intensity of HER-2/neu expression. There was no statistically significant difference in survival of patients with HER-2/neu positive and those with HER-2/neu negative tumors (P = 0.50). Tumor stage at diagnosis was the only covariate with prognostic significance in patient survival (P < 0.001). CONCLUSION: Expression of HER-2/neu oncogene is a rare event in cervical cancer. Immunohistochemical detection of HER-2/neu expression is neither a predictor of survival of patients with cervical cancer nor does it identify subgroups of patients at higher risk for recurrence of disease.

Ovarian cancer complicating pregnancy.

Ovarian cancer is the second most frequent gynecologic cancer complicating pregnancy. Although uncommon, this is a topic that encompasses multiple aspects of obstetrics and gynecology. The management of the adxenal mass in pregnancy, surgery for ovarian cancer, chemotherapy during gestation, and the use of tumor markers during pregnancy are discussed.

Acute lupus pneumonitis in the puerperium. A case report and literature review.

A patient presented with acute lupus pneumonitis in the puerperium. This complication of systemic lupus erythematosus has not been reported before in pregnancy. A review of the literature of pleuropulmonary complications of systemic lupus erythematosus and specifically acute lupus pneumonitis in nonpregnant patients is also presented. Clinical, diagnostic and therapeutic considerations are discussed, also.

Effect of alpha-difluoromethylornithine (DFMO) on the growth of human ovarian carcinoma.

The antiproliferative effect of alpha-difluoromethylornithine (DFMO) was investigated in a human ovarian cancer cell line (NIH:OVCAR3) both in vitro and in vivo. DFMO at 5 X 10(-5) M, 5 X 10(-4) M and 1 X 10(-3) M concentrations showed growth inhibition of NIH:OVCAR3 cells in culture. Parallel determination of CA 125 in the culture media of these cells show significant decrease in the presence of DFMO compared to controls. Oral administration of DFMO (2% aqueous solution) to nude mice bearing intraperitoneal tumors resulted in a mean survival of 45 days (38-60) versus 25 days (20-35) for control. Both in vitro and in vivo results suggest that DFMO has potential value in the treatment of ovarian carcinoma and should be considered for clinical trials in appropriate cancer patients.

Multimodality approach to a massive carcinoma of the vulva.

The presentation, combination therapy and clinical course of a patient with a massive vulvar carcinoma are described. Therapeutic aspects in the treatment of such advanced malignancies are considered. A multimodality approach to locally advanced, unresectable vulvar carcinomas may benefit this group of patients.

Primary mass closure of fascial incisions using a continuous absorbable suture.

Investigations with animal models and reported studies from the obstetric and gynecologic literature as well as the general surgical literature have suggested that a single mass closure is equal or superior to interrupted suture techniques. Over a 12-month period, 150 patients were operated on using a continuous mass technique for fascial closure with No.1 polydioxanone suture (PDS). One hundred thirty-five patients (90%) had risk factors that placed them at increased likelihood for wound complications. No fascial disruptions occurred. Wound complications were noted in 15 patients (10%). This technique merits wider use.

Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature.

From December 1982 to December 1986, 52 patients with recurrent ovarian cancer were treated with single-agent HMM. Chemotherapy was given for a period of 1 year unless progression of disease or toxicity was noted. Survival was determined from the time of diagnosis to the date of death or September 30, 1992. The regimen was well tolerated with only one case of severe gastrointestinal toxicity. Nine patients were found to be clinically free of disease following completion of HMM treatment; they had initially responded to cisplatin-based therapy (i.e., potentially cisplatin-sensitive) and subsequently recurred. Four were found to have gross disease at the time of reassessment laparotomy. Three of these 9 patients are alive 81-92 months since diagnosis, having maintained disease-free intervals of up to 6 years. The median survival for the 9 patients without evidence of disease at the end of therapy was 75 months versus 9 months for the nonresponders. No patient who had progressive disease on first-line cisplatin-based combination chemotherapy (i.e., primary cisplatin-resistant) responded to second-line single-agent oral hexamethylmelamine. With a follow-up close to 10 years, our data show that hexamethylmelamine, with reasonable toxicity, can provide an extended, disease-free interval to a selected group of patients.

Risk of venous access device wound complications in patients undergoing paclitaxel chemotherapy for gynecologic malignancies.

OBJECTIVE: To determine if wound complications after placement of a central venous catheter access device are related to the type of postsurgical cytotoxic chemotherapy administered. METHODS: All patients in a 10-year period undergoing placement of central venous access device followed by postsurgical chemotherapy for gynecologic malignancies were included in this retrospective case-control study. RESULTS: Sixty-eight patients underwent 78 placement procedures followed by chemotherapy. Six catheters (7.7%) in five patients developed wound complications. Variables evaluated included the type of gynecologic malignancy, previous use of chemotherapy, patient age and weight, preoperative white blood cell count, type of access device and insertion site, use of prophylactic antibiotics, type of chemotherapy and interval to administration, development of wound complication, and catheter removal. Univariate analysis shows an association between subsequent catheter site wound complication and paclitaxel use (P = 0.02) as well as wound complication and combined paclitaxel and cisplatin use (P = 0.005). Multivariate analysis with stepwise linear regression confirms that a paclitaxel containing regimen is associated with an increase in wound breakdown (P = 0.04). CONCLUSION: The use of a paclitaxel containing chemotherapeutic regimen administered after placement of an indwelling central venous access device in gynecologic oncology patients is associated with wound complications of the catheter site.