The role of peptide growth factors in epithelial ovarian cancer.

We studied the effect of epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, and transforming growth factor-beta on proliferation of four epithelial ovarian cancer cell lines (OVCA 420, OVCA 429, OVCA 432, and OVCA 433). Epidermal growth factor stimulated growth of OVCA 429 cells (P = .0001) and OVCA 433 cells (P = .0002). Platelet-derived growth factor did not stimulate growth of any of the cell lines. Fibroblast growth factor stimulated growth of OVCA 420 cells (P = .003). Transforming growth factor-beta inhibited growth of OVCA 420 cells (P = .0001), OVCA 432 cells (P = .003), and OVCA 433 cells (P = .004). To detect production of known growth factors by the cancer cell lines, we tested the effect of cancer cell-conditioned media on proliferation of cell lines known to respond to growth factors. Only media exposed to OVCA 433 cells were found to contain activity that mimicked one of the known growth factors (transforming growth factor-beta). These results suggest that individual ovarian cancers vary widely in their response to and production of known peptide growth factors. Finally, we found that OVCA 429-conditioned medium significantly inhibited proliferation of mitogen-stimulated lymphocytes (P less than .0001). The characteristics of this immunosuppressive factor were distinct from those of transforming growth factor-beta. Production of this factor by an immortalized cell line provides a unique opportunity to identify an immunosuppressive substance associated with ovarian cancer.

Preoperative coagulation testing on a gynecologic oncology service.

OBJECTIVE: To determine the prevalence and clinical significance of abnormalities of preoperative coagulation tests in gynecologic oncology patients. METHODS: Three hundred fifty-one patients presenting for inpatient surgical procedures on the gynecologic oncology service at Duke University Medical Center from January 1, 1990 to December 31, 1990, underwent preoperative coagulation testing. Twenty-nine patients had only prothrombin time (PT) and partial thromboplastin time (PTT) measured; the remaining 322 had preoperative measurement of PT, PTT, fibrinogen, and fragment D-dimer. Outcomes assessed were perioperative hemorrhage resulting in death or reoperation, postoperative hematomas, and need for intraoperative and postoperative transfusion. RESULTS: Twelve of 351 patients (3.4%) had abnormally elevated PT or PTT; six of these were attributable to risk factors unrelated to malignancy. One hundred fifty-six of 322 subjects (48.4%) had abnormal levels of fibrinogen, mostly elevations above 360 mg/dL, and 88 of 322 subjects (27.3%) had positive tests for D-dimer. Fifty-seven (17.7%) had both elevated fibrinogen and positive D-dimer. One hundred eighty-eight of 322 subjects had at least one abnormal test result. There were no perioperative deaths or reexplorations because of hemorrhage. There was one postoperative hematoma. The combination of an elevated fibrinogen and a positive D-dimer test was a significant predictor of perioperative transfusion in a logistic regression model incorporating stage, preoperative hematocrit, and age (odds ratio 1.96, 95% confidence interval 1.03-3.76). However, the attributable risk associated with this abnormality was only 7.7% in patients at highest risk of transfusion. CONCLUSION: Although abnormalities in coagulation are common in patients undergoing surgery for gynecologic malignancy, preoperative testing for occult coagulopathy provides little clinically useful information.

Urethral obstruction after anterior colporrhaphy: correction by simple vaginoplasty.

OBJECTIVES: Bladder outlet obstruction is a well-known complication of anti-stress incontinence procedures including retropubic suspensions, needle suspensions, and slings. Relief of obstruction after these procedures usually requires freeing the urethra from its superior attachments. Because the anterior colporrhaphy does not involve suspension above the urethra, obstruction can be relieved by a simple plastic procedure involving the anterior vaginal wall. METHODS: We describe 2 cases in which a simple plastic procedure was used to correct urodynamically confirmed obstruction after anterior colporrhaphy. RESULTS: One patient became completely asymptomatic. The other had subjective and urodynamic resolution of her obstructive symptoms, but persistent detrusor instability. CONCLUSIONS: A simple plastic procedure can be used to correct urethral obstruction after anterior colporrhaphy.

Spontaneous conception in the presence of stage IIIC endometrioid ovarian cancer.

OBJECTIVE: To describe a rare case of spontaneous conception in a patient with a preexisting metastatic ovarian cancer. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 39-year-old Asian woman who conceived while undergoing an evaluation for primary infertility and newly detected bilateral adnexal masses. INTERVENTION(S): Staging laparotomy and total abdominal hysterectomy and bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Anatomic pathology diagnosis. RESULT(S): Blighted ovum and stage IIIC endometrioid adenocarcinoma of ovary. CONCLUSION(S): Metastatic ovarian cancer does not prevent either spontaneous ovulation or spontaneous conception.

Managing pain and psychological issues in palliative care.

The management of psychological issues and pain in dying patients have steadily improved. With currently available drugs and techniques, it should be possible for nearly all women with terminal gynaecological cancer to be pain-free. The World Health Organization (WHO) Analgesic Ladder can be effectively utilized for pharmacological treatment of cancer pain. Most side-effects of opioid therapy can be well controlled. Patients whose pain cannot be adequately relieved by systemic opioid therapy may benefit from invasive anaesthetic or neurosurgical techniques. Terminal sedation should be used only after all other therapy has failed. This chapter describes the assessment and management of opioid analgesics and the treatment of their side-effects. Adjuvant analgesic drugs and therapies are also presented.

The effect of interinstitution anatomic pathology consultation on patient care.

OBJECTIVE: To determine the effect of routine interinstitution anatomic pathology consultation on patient evaluation and treatment. DESIGN: All interinstitution anatomic pathology consultation diagnoses made during a 1-year period were compared with the original pathologic diagnoses. Patients with discrepant diagnoses were evaluated after an interval of 1 year to determine the correct clinical diagnosis. The relevance of the pathologic consultation to furthering medical evaluation and treatment was determined from a review of the medical record and when necessary from consultation with the patient's physician. SETTING: Patients referred to a university hospital. MAIN OUTCOME MEASURES: We determined the number of patients with discrepant pathologic diagnoses and whether these diagnoses changed the planned surgical procedure, chemotherapy, radiation therapy, or medical evaluation. RESULTS: Seventy-one (9.1%) discrepant diagnoses were identified among the 777 patients. Of these 71 patients, 45 (63%) demonstrated a change in therapy or clinical evaluation as a result of the interinstitution anatomic pathology consultation. In five of these patients the consultation diagnosis was in error. There was a significantly greater percentage of discordant diagnoses among the cytology and fine-needle aspiration biopsies (21%) as compared with the surgical pathology specimens (7.8%; P < .001). CONCLUSIONS: Routine interinstitution anatomic pathology consultation resulted in a change in patient evaluation or treatment in 45 (5.8%) of the 777 cases reviewed. Our interinstitution anatomic pathology consultation policy appears to provide useful diagnostic information, which should contribute to improved patient care. However, when a discrepancy is identified, additional consultation or evaluation should be considered.

Transitional cell bladder carcinoma with presentation mimicking ovarian carcinoma.

In the case described here, the patient's initial presentation suggested ovarian carcinoma. She had recurrent ascites, a pelvic mass, elevated CA-125, and extensive peritoneal carcinomatosis with transitional cell histology. The presence of hematuria prompted a cystoscopy, which revealed the true site of origin to be the urinary bladder rather than ovaries. This presentation is extremely rare for bladder cancer. Since transitional cell tumors from the bladder have a much worse prognosis than those of ovarian origin, it is important to identify the primary site correctly. Therefore, cystoscopy is essential for patients with hematuria, and should be considered in cases of apparent primary peritoneal carcinoma with transitional cell histology.

Gynecologic tumor markers.

The advent of monoclonal technology has increased the potential utility of antibody-dependent tumor marker assays in gynecologic oncology. The availability of unlimited quantities of several pure monoclonal antibodies directed against novel epitopes on tumor-associated antigens has permitted development of highly sensitive assays for serum markers. Traditional assays for human chorionic gonadotropin (hCG), NB/70K and TA-4 have been improved. CA 125 has provided a useful first-generation marker for monitoring ovarian cancer and triaging patients with pelvic masses, despite limitations in sensitivity and specificity. In the next decade, the challenge is to identify new markers that will complement CA 125 in monitoring ovarian cancer and facilitate screening for occult early-stage disease. Strategies involving multiple markers and modalities may be required. Some markers may emerge through a more fundamental knowledge of the biology of gynecologic neoplasms, including the expression of growth factors and their receptors. Finally, the application of monoclonal antibodies to immunohistochemistry and radionuclide imaging also may provide new areas of diagnostic application for monoclonal antibodies in gynecologic oncology.

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.

Preoperative assessment of fragment D-dimer as a predictor of postoperative venous thrombosis.

We used a latex agglutination assay to measure preoperative plasma fragment D-dimer levels in patients admitted to a gynecologic oncology service. Eight percent of 71 patients with gynecologic cancer had elevated fragment D-dimer levels; none of these patients developed postoperative deep venous thrombosis. Preoperative elevation of the fragment D-dimer level was not predictive of postoperative deep venous thrombosis.

Tissue distribution of TAG-72 in malignant mixed müllerian tumors of the uterus.

Malignant mixed müllerian tumors are the most frequent sarcomas arising from the uterus. Since these tumors are traditionally associated with a poor prognosis, tumor-associated antigens may be useful in the evaluation and follow-up of affected patients. The purpose of this study was to determine the frequency and tissue distribution of TAG-72, an antigen frequently expressed in endometrial carcinomas, and to compare it to CA 125 and CA 19-9 expression in malignant mixed müllerian tumors of the uterus. Consecutive, paraffin-embedded sections from 35 tumors were immunohistochemically evaluated using primary antibodies directed against the tumor-associated antigens. These antigens were demonstrated in the neoplastic glandular epithelium and not in the sarcomatous portion of the tumor. The degree of antigen expression was unrelated to the nature of the sarcomatous element present (homologous vs heterologous). Positive staining (> or = 5% of the glandular epithelium) for TAG-72 was present in 66% of the tumors; another 6% of the tumors contained focal staining (< 5% of the glandular epithelium) for TAG-72. Although cytoplasmic and intraluminal staining were present, cell surface staining was the most prominent feature of TAG-72 expression. Tumors were more likely to be positive for TAG-72 than either CA 125 (P = 0.046) or CA 19.9 (P = 0.004). The extent of TAG-72 expression was unrelated to the extent of disease (intrauterine vs extrauterine) and overall patient survival. However, antigen expression was correlated with the differentiation of the glandular component present.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue CA 125 and CA 19-9 in malignant, mixed mesodermal tumors of the uterus.

Mixed mesodermal tumors of the uterus are biphasic neoplasms composed of both a malignant epithelium and a sarcomatous stromal component. Elevated levels of tumor-associated antigens, such as CA 125, have been reported in some patients with these tumors. The purpose of this study was to determine the frequency and tissue distribution of CA 125 and CA 19-9 in malignant mixed mesodermal tumors of the uterus treated with primary surgery. Consecutive, paraffin-embedded sections from 35 tumors were immunohistochemically evaluated using primary antibodies directed against CA 125 and CA 19-9. CA 125 and CA 19-9 were demonstrated in the neoplastic glandular epithelium and not in the sarcomatous portion of the tumor. The localization of CA 125 and CA 19-9 suggested that both antigens were epithelial secretory products. Positive staining (> or = 5% of the glandular epithelium) for CA 125 was present in 46% of the tumors; another 14% of the tumors contained focal staining (< 5% of the glandular epithelium) for CA 125. Positive staining for CA 19-9 was demonstrated in 34% of tumors; another 17% contained focal staining for CA 19-9. The markers were concordant in 77% of the tumors examined. Antigen expression was unrelated to the nature of the sarcomatous element (homologous vs heterologous), the extent of disease, and patient survival. However, the epithelial component of these sarcomas frequently expressed these antigens and the degree of expression was related to the cell type and the histologic grade of the glandular element.

Endometrial squamous cell carcinoma following whole pelvic radiation therapy: response to carboplatin.

A case of Stage IV endometrial squamous cell carcinoma occurring 8 years after a low anterior resection and whole pelvic radiation therapy for a Dukes D colon carcinoma is presented. Koilocytosis was present in the tumor. There was no evidence of human papillomavirus antigen or DNA in the tumor. The patient was treated with surgery followed by six cycles of carboplatin chemotherapy. At the completion of chemotherapy there was no clinical or radiological evidence of disease. The tumor recurred 9 months postchemotherapy and the patient died of disease 17 months postdiagnosis.

Preoperative evaluation of serum CA 125, TAG 72, and CA 15-3 in patients with endometrial carcinoma.

We evaluated 109 women with endometrial carcinoma to determine the accuracy of preoperative tumor-associated antigen levels (CA 125, CA 72, CA 15-3) for prediction of extrauterine disease and whether TAG 72, CA 15-3, or both would improve the predictive value of CA 125 alone. Eleven (12%) of 80 patients with disease confined to the uterus or positive cytologic findings had CA 125 values greater than 35 U/ml versus 12 (65%) of 20 patients with extrauterine metastasis. Therefore CA 125 values had sensitivity of 65% and specificity of 88%. The TAG 72 level was elevated (greater than 6 U/ml) in 4% of patients with localized disease and 30% with metastasis. CA 15-3 was elevated (greater than 30 U/ml) in 17% and 65% in these categories, respectively. TAG 72 or CA 15-3 levels did not improve the combination of sensitivity and specificity of CA 125 alone. In addition, only one of 10 patients with microscopic metastasis (three cases) or positive peritoneal cytology (seven) had elevation of any of these tumor-associated antigen levels. Failure to detect occult metastasis and a high false-positive rate limit the role of these tumor-associated antigen assays in the preoperative evaluation of patients with endometrial carcinoma.

Gestational trophoblastic disease presenting as a large metastasis to the finger.

Cutaneous metastases of gestational trophoblastic disease are extremely uncommon. A patient with metastatic, poor prognosis disease and a large metastatic lesion on her left fifth digit is presented. The clinical course and complete response to EMACO chemotherapy are outlined. The presence of metastatic disease in a reproductive-age woman requires consideration of gestational trophoblastic disease in the differential diagnosis.

Increased LFA-1 expression in intestines of rats with GVHD after small bowel transplantation.

Experimental graft-versus-host disease (GVHD) causes immune-mediated intestinal injury. The adhesion molecule lymphocyte function associated antigen-1 (LFA-1) is involved in leukocyte homing to areas of inflammatory injury. Our hypothesis was that LFA-1 is increased in the GVHD injured small bowel and colon. We found that animals with GVHD caused by auxiliary small bowel transplantation displayed significantly increased expression of intestinal LFA-1alpha at times of clinical illness when compared to controls. The staining pattern progressed from a few discretely stained cells in the lamina propria on day 5 to diffuse confluent staining of lamina propria on day 13 and was statistically significantly increased from controls at days 10 and 13. CyA-treated animals had intermediate staining between control and day 13 GVHD animals. There was no difference between sham-operated control animals and SBTx animals with GVHD in the amount of staining for LFA-1 in extraintestinal organs normally affected by GVHD. We conclude that: (1) LFA-1 expression in the small bowel and colon progressively increased during GVHD after SBTx; and (2) CyA treatment is associated with decreased LFA-1 expression in the small bowel and colon of GVHD animals after SBTx. LFA-1 may play an important role in immune-mediated injury of the intestine.

Constitutive production of macrophage colony-stimulating factor and interleukin-6 by human ovarian surface epithelial cells.

Normal and neoplastic epithelial cells produce growth factors that can affect cells from different lineages. Epithelial ovarian cancers produce M-CSF and IL-6. In the present study, production of these cytokines has been measured in the apparently normal epithelial cells from which epithelial ovarian neoplasms are thought to arise. Epithelial cells from the surface of premenopausal human ovaries were established in short-term cultures. The cells bound anti-cytokeratin antibodies and exhibited characteristic epithelial morphology by light and transmission electron microscopy. M-CSF and IL-6 were detected in supernatants from cultures of these cells, using assays specific for each factor. Cytokine levels were comparable to those in supernatants from ovarian and breast cancer cell lines. M-CSF expression could also be demonstrated by immunohistochemical analysis with specific rabbit heteroantiserum. Thus, M-CSF and IL-6 are produced constitutively by normal as well as by neoplastic ovarian epithelium.

Epidermal growth factor receptor expression in normal and malignant endometrium.

Epidermal growth factor receptor expression in fresh-frozen uterine tissues was studied with the use of monoclonal antibody 528, which recognizes an epitope on the external domain of the epidermal growth factor receptor. Immunohistochemically detectable epidermal growth factor receptor was seen in all uterine cell types in 19 of 20 normal uteri. Staining of endometrial glands and endometrial stromal cells was consistently greater than that of myometrium, and no variation in intensity or distribution of staining was seen during the menstrual cycle. Immunohistochemically detectable epidermal growth factor receptor was found less frequently in endometrial adenocarcinomas than in normal endometrium (p less than 0.01). Thirteen of 40 endometrial adenocarcinomas (32.5%) did not express detectable receptor. Epidermal growth factor receptor expression did not correlate with histologic grade, depth of myometrial invasion, estrogen-progesterone receptor status, the presence of extrauterine metastases, or the development of recurrent disease.

Heterogeneity of antigen expression in advanced epithelial ovarian cancer.

Immunohistochemical techniques were used to evaluate the expression of six antigens (CA 125, TAG 72, CA 19-9, OVTL3, DF3, and transferrin receptor) in frozen sections from the primary tumor and metastases of 20 patients with epithelial ovarian cancer. Heterogeneous expression of most antigens was observed within a given tumor nodule, but in each patient the proportion of cells expressing an antigen was similar in the primary tumor and metastases. To explore the stability of the antigenic phenotype of individual cells, we studied CA 125 expression in an ovarian cancer cell line. Cells were separated into CA 125-positive and -negative groups using fluorescence-activated cell sorting. After the two groups of cells were recultured separately, only 38% of cells originally sorted as CA 125 positive still expressed CA 125, whereas 27% of cells sorted as CA 125 negative expressed CA 125. That cells may gain or lose CA 125 expression in culture suggests that expression of CA 125 by ovarian cancer cells is not a stable trait.

The impact of 2D versus 3D quantitation of tumor bulk determination on current methods of assessing response to treatment.

PURPOSE: Measurements from sequential axial "2D" data in cancer patients are commonly used to assess treatment response or disease progression. This study compares the volume of tumor bulk calculated with 3D reconstructions with that calculated by conventional methods to determine if it might change patient classification. METHOD: All medical, gynecologic, and pediatric oncology patients under treatment who were evaluated with serial CT scans between January 1, 1992, and July 31, 1994, for whom the digital data were available were included in this study. For each tumor site, the maximum diameter and its perpendicular were measured and multiplied together to yield an area. The sum of areas of the measured lesions was used as an approximation of overall 2D tumor volume. In addition, the 2D area of each site was multiplied by its height, yielding a 2D volume. Last, the digital data were loaded into a 3D computer system and total 3D tumor volumes determined. All medical and gynecologic oncology patients were treated based upon the 2D area of tumor. The pediatric oncology patients were treated based upon the 2D volume of tumor measured as per standard practice. The members of each treating oncologic service assessed their patients as to how the other two methods would have changed their classification of the patients' response category. RESULTS: Four hundred thirty-three CT scans were performed in 139 patients, which included 204 baseline and 294 follow-up CT examinations. Seventy patients had new tumor foci and would have been classified as failure by all three methods of tumor bulk measurement. The 3D volume versus the 2D area method of tumor bulk assessment would have changed response categories in 52 of the 294 follow-up CT examinations (p < 0.0001). Thirty-five patients were recategorized from either "no response" to "failure" (21 patients) or "no response" to "response" (14 patients) categories. If only those follow-up studies without new metastatic foci are considered, the 3D volume versus the 2D area methods of tumor assessment would have changed the treatment response category in 23.2%. The use of the 2D volume method of calculating tumor volume of bulk tended to overestimate the overall tumor size by an average of 244 cm3 (p = 0.001). CONCLUSION: The 3D method of tumor volume measurement differs significantly from conventional 2D methods of tumor volume determination. Large prospective studies analyzing the usefulness of 3D tumor volume measurements and assessing possible changes in patient response categories would be required for full utilization of this more accurate method of following disease bulk.