Interleukin-11 receptor expression in primary ovarian carcinomas.

OBJECTIVES: The objectives of this study were to determine (1) the frequency of expression of the interleukin-11 receptor alpha subunit (IL-11Ralpha) and its signal transducing subunit, gp130, among primary ovarian carcinomas; (2) the frequency of expression of IL-11 in ovarian carcinomas; and (3) the potential role IL-11 might have in ovarian cancer cell biology. METHODS: An immunohistochemical assay was used to determine the expression of IL-11Ralpha and the gp130 cofactor among primary ovarian carcinomas; the expression of IL-11 in ovarian malignancies was determined using reverse transcription polymerase chain reaction (RT-PCR). The ability of IL-11 to stimulate [3H]thymidine incorporation in IL-11R-expressing ovarian carcinoma cell lines (OVCAR-3 and SKOV-3) and/or abrogate cell death mediated by apoptosis-inducing agents using an ELISA assay that quantitates DNA fragmentation was also studied. RESULTS: IL-11Ralpha was expressed in the malignant epithelial cells of 45 of 48 (93.8%) primary ovarian carcinoma samples studied. In 45 primary ovarian carcinoma samples where both components of the IL-11 receptor (IL-11Ralpha and gp130) were examined, coexpression was observed in 42 (93.3%). Expression of the IL-11 receptor components was also found in the stromal layer. Coexpression of IL-11Ralpha and gp130 was commonly observed in both benign ovarian tumors and in the epithelial layer of normal ovaries. In contrast, IL-11 mRNA was expressed in only 3 of 21 malignant samples studied (14.3%). Recombinant human IL-11 was unable either to stimulate [3H]thymidine incorporation or to block cell death effected by paclitaxel or Fas-activating antibodies in in vitro assays using OVCAR -3 or SKOV-3 cells. CONCLUSIONS: The IL-11 receptor system is commonly expressed in both malignant and nonmalignant ovarian tissues, although its function in ovarian epithelial cell biology remains unclear.

Coexpression of granulocyte colony stimulating factor and its receptor in primary ovarian carcinomas.

Immunohistochemistry was used to determine the expression of granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in primary ovarian carcinomas. The expression of G-CSFR was observed in the malignant cells of each of the 46 primary carcinomas examined; G-CSF was coexpressed in both the malignant epithelial cells and the stroma of 56.5% of the specimens. Thus the majority of ovarian carcinomas harbor both potential autocrine and paracrine G-CSF axes. In 37% of the samples, G-CSF was expressed only within stromal cells, suggesting that only a potential paracrine system is in place. In a preliminary, retrospective, evaluation, the survival of patients whose tumors expressed only the apparent paracrine loop was significantly worse than patients whose tumors expressed both potential autocrine and paracrine G-CSF-based regulatory loops (14.5 vs. 42.5 months, respectively). Studies on the potential function of G-CSF were performed using the G-CSFR-expressing OVCAR-3 ovarian carcinoma line. As a single agent, rhG-CSF failed to stimulate [3H]-thymidine incorporation in these cells, but enhanced the mitogenic action of epidermal growth factor (EGF) in a dose-dependent manner. Thus, potential autocrine and/or paracrine loops involving G-CSF and its receptor occur in over 90% of primary ovarian carcinomas, and may act to modulate the action of growth factors.

Use of a dielectric stack as a one-dimensional photonic crystal for wavelength demultiplexing by beam shifting.

We demonstrate the use of a 30-period dielectric stack structure as a highly dispersive device to spatially separate two beams with a 4-nm wavelength difference by more than their beam width. Unlike previous devices, our structure is simple to fabricate and relatively compact. We discuss possible applications of our device within wavelength-division multiplexing systems.

Intraperitoneal alpha-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study was to study the combination of intraperitoneal alpha-interferon and cisplatin administered second-line in an alternating sequence in small volume residual epithelial ovarian cancer after second-look surgery and the activity of this combination based on prior response to first-line platinum compounds. METHODS: Sixty-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal alpha-interferon alternating with cisplatin given for eight cycles unless disease progression or unacceptable toxicity occurred. The patients were considered favorable if they were platinum-sensitive and/or relapsed 6 months or longer after completing treatment. Another reassessment laparotomy was performed within 12 weeks of completion of treatment in patients who were in clinical remission. RESULTS: Fifty-four patients were clinically evaluable and 18 were surgically reassessed, 5 of whom had a negative reassessment operation (20% complete response and 8% partial response). Of the 54 patients evaluable for toxicity, the most common adverse effects of more than grade 2 were gastrointestinal in 13 (47%), neutropenia in 9 (17%), and leukopenia in 6 (12%). Grade 4 toxicity was seen in 10 instances: 4 gastrointestinal, 2 neutropenia, 2 thrombocytopenia, 1 wound infection, and 1 allergic reaction. CONCLUSIONS: alpha-Interferon and cisplatin are active agents in favorable patients with minimal residual epithelial ovarian cancer at second-look. The combination of the two drugs administered in an alternating sequence appears to be associated with more side effects than when either drug is administered alone. The combination produced response rates similar to those seen when either drug is given alone.

Brachytherapy for early endometrial carcinoma: a comparative study with long-term follow-up.

The current study was undertaken to evaluate the effect of preoperative uterine or postoperative vaginal brachytherapy compared to no adjuvant therapy on the disease-free interval, sites of recurrence, and survival in favorable stage IB endometrial carcinoma. One hundred and forty-six patients with FIGO grade 1 and 2 endometrial carcinoma and 1-33% myometrial invasion treated between 1974 and 1992 were retrospectively studied. The use of brachytherapy varied among the treating physicians during the study period. A Kaplan-Meier survival analysis was used to estimate disease-free survival and differences between treatment groups were evaluated with the Mantel-Cox statistic. Recurrent disease occurred in 7 patients (5.3%). Vaginal recurrences accounted for 6 of the 7 sites of recurrences. Recurrences occurred in 1.3% of grade 1 vs. 8.7% of grade 2 tumors (P = 0.04). Among 69 grade 2 tumors, recurrences occurred in 7.5% of those treated with brachytherapy vs. 10.3% of those not treated (P = 0.68). Brachytherapy did not affect the disease-free or overall survival. No serious complications directly related to therapy occurred. Vaginal recurrences occur even in early endometrial carcinoma. This study demonstrates no apparent benefit to brachytherapy. A larger study would be required to see a recurrence or survival difference.

A phase II trial of isotretinoin and alpha interferon in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

From January 1993 through January 1996, 37 patients with unresectable squamous carcinoma of the cervix were entered on study and scheduled to receive oral isotretinoin 1 mg/kg per day with subcutaneous alpha interferon 6,000,000 units/day. A course was defined as 4 continuous weeks of therapy. The mean number of four-course cycles delivered was 1.8. One patient was ineligible because of wrong cell type and two were never treated. Thus, 34 patients were evaluable for toxicity. Eight patients were inevaluable for response. Five did not receive a complete 4-week course and three did not have additional tumor measurements; thus 26 were evaluable for response. Prior radiotherapy had been given to 25 patients and prior chemotherapy to 23 patients. There was no grade 4 neutropenia. The incidence of Gynecologic Oncology Group (GOG) grade 3 granulocytopenia and thrombocytopenia was 8.8% and 5.8%, respectively. Six patients (17.6%) developed grade 3 or worse nausea and vomiting. Four (11.7%) patients developed grade 3 neurologic symptoms. There were no complete responses and one partial response. The overall response rate was 3.8% (95% confidence interval, 0.1-19.6%). In this pretreated population, isotretinoin and alpha interferon in the dose and schedule employed exhibit minimal activity.

Accuracy of frozen-section (intraoperative consultation) diagnosis of ovarian tumors.

OBJECTIVE: Frozen-section evaluation of ovarian tumors can be used to establish a histopathologic diagnosis and guide the surgeon to perform the appropriate surgical procedure. A retrospective study was conducted to determine the accuracy of frozen-section diagnosis of ovarian tumors. STUDY DESIGN: Frozen- and permanent-section diagnoses were divided into three categories (benign, borderline, and malignant). The sensitivity, specificity and predictive values, and 95% percent confidence intervals of each frozen-section diagnosis were determined. RESULTS: Three hundred eighty-three ovarian tumors that underwent frozen-section evaluation between June 1983 and June 1993 were studied. The final histopathologic diagnosis was 61.1% benign, 7.6% borderline, and 31.3% malignant. Frozen section was accurate in 92.7% of all cases and inaccurate in 7.3%. The sensitivity for malignant tumors was 92.5% tumors (95% confidence intervals 87.7% to 97.2%), the sensitivity for borderline tumors was 44.8% (95% confidence interval 26.4% to 63.2%). The specificity for benign tumors was 92.0% (95% confidence interval 88.6% to 95.4%) but increased to 97.9% (95% confidence interval 96.1% to 99.7%) if borderline tumors were excluded. The positive predictive value and 95% confidence intervals were 92.0% (88.6% to 95.4%) for benign tumors, 65% (43.6% to 86.5%) for borderline tumors, and 99.1% (97.3% to 100.0%) for malignant tumors. Thirteen of 16 (81%) ovarian lymphomas and tumors metastatic to the ovary were correctly identified by intraoperative frozen section. The sensitivity for borderline serous tumors was 64.3% and for borderline mucinous tumors 30.8% (p = 0.48). CONCLUSION: With the exception of borderline tumors, the sensitivity and specificity of frozen-section diagnosis of ovarian tumors are high. Borderline tumors remain difficult to accurately diagnose at frozen section because of the extensive sampling required. Frozen-section diagnoses have important implications regarding the type and extent of surgery performed at the initial operation.

Serial serum CA 125 measurements for evaluation of recurrence in patients with endometrial carcinoma.

OBJECTIVE: To evaluate the usefulness of serum assays for CA 125 to detect recurrent endometrial carcinoma. METHODS: Two hundred sixty-six patients were studied with 1101 post-treatment assays. Patients were categorized as low, medium, or high risk based on surgical-pathologic findings. CA 125 values were analyzed with respect to each patient's disease status. RESULTS: Serial CA 125 levels were elevated (greater than 35 U/mL) in 19 of 33 patients (58%) with recurrent disease. Among 236 surgically treated patients, 97 (41.1%), 42 (17.8%), and 97 (41.1%) were considered low, medium, and high risk, respectively. None of the low-risk and only two (4.7%) of the medium-risk patients developed recurrent disease. One of the latter patients was detected based on an elevated CA 125 level alone. Twenty-seven (27.8%) of the high-risk patients developed recurrent disease, 23 of whom had elevated pre-treatment CA 125. Fifteen of 16 (94%) with recurrent disease had an elevated CA 125 level. Nine of 12 patients with papillary serous carcinoma experienced recurrence; eight of these nine had elevated CA 125 levels at diagnosis and recurrence, in contrast to only one patient with a normal pre-treatment level (P = .018). False elevations were noted in 13 patients, 12 of whom had received radiation therapy. CONCLUSIONS: CA 125, if elevated at diagnosis of endometrial carcinoma, is an important marker for recurrent disease. The use of serial CA 125 assays is most beneficial in diagnosing recurrence in a high-risk population, including patients with papillary serous carcinomas. False elevations may occur following radiation therapy.

Estrogen and progesterone in breast and gynecologic cancers. Etiology, therapeutic role, and hormone replacement.

Cancers of the endometrium, ovary, and breast share common risk factors, including obesity, high fat diet, and late menopause as well as an increased risk with a family and personal history of any of these cancers. Despite an extensive literature investigating the role of estrogen and progesterone in these malignancies, the exact etiologic capacity of these hormones is not yet determined. Until current studies mature, assessment of the possible risks and known benefits is the only platform on which to base treatment decisions for the individual patient.

Experience with the intravenous totally implanted port in patients with gynecologic malignancies.

The purpose of this paper was to assess the intraoperative and long-term complications associated with intravenous totally implanted devices in women with pelvic cancers. Retrospective review of medical records was performed for 67 consecutive women with pelvic cancers who underwent port insertion. Seventy catheters were successfully placed in 67 patients. Pneumothorax occurred in three cases (4.3%), none requiring chest tube placement. Malposition of the catheter occurred in four patients (5.7%). Two infected ports (2.9%) were removed after a failed trial of antibiotics. Venous thrombosis developed in one woman, requiring removal of the system. In conclusion, semipermanent central venous catheters facilitate delivery of chemotherapy, parenteral nutrition, blood products, antibiotics, and hydration in cancer patients. This is the first report detailing the experience with a totally implanted subcutaneous port in patients with gynecologic malignancies. We demonstrate that such devices may be inserted and utilized with a low incidence of complications in this patient population.

Primary radiation therapy for endometrial carcinoma: a case controlled study.

PURPOSE: Primary radiation therapy is generally considered inferior to a surgical approach for patients with endometrial carcinoma and is reserved for patients with a high operative risk. These patients are usually elderly, have multiple medical problems and frequently die of intercurrent disease. To evaluate the efficacy of primary radiation therapy a case controlled analysis comparing corrected survival of patients treated with primary radiation to patients treated with surgical therapy with or without radiation therapy was performed. METHODS AND MATERIALS: Sixty-four patients treated with primary radiation therapy were retrospectively studied. A Kaplan-Meier product limit survival analysis was used to estimate survival among patients treated with primary radiation therapy. A case control study matched by clinical stage, tumor grade, and time of diagnosis was performed. The Mantel-Cox statistic was used to evaluated the equality of the survival curves. RESULTS: Primary radiation therapy was used to treat 9.0% of the patients with endometrial carcinoma during the study period. Cardiovascular disease, diabetes, age greater than 80 and morbid obesity were the most common indications. Ninety percent of patients had either Stage I or II disease. Forty-eight of the 64 patients (75%) completed treatment which included both teletherapy and brachytherapy. Ten patients received brachytherapy only. Twelve complications, both acute and chronic, occurred in eleven patients (17%). Intercurrent disease accounted for 13 of the 36 (36%) of the deaths. Clinical stage of disease and histologic grade of the tumor were significant predictors of survival, p = 0.0001 and p = 0.013, respectively. The case controlled study of Stage I and II patients treated by primary radiation therapy matched to surgically treated controls showed no statistical difference in survival. Dilatation and curettage after the completion of radiation therapy was predictive of local control, p = 0.003. CONCLUSION: Although surgery followed by tailored radiation therapy has become widely accepted therapy for Stage I and II endometrial carcinoma, even in patients who are a poor operative risk, the survival with primary radiation therapy is not statistically different.

Accuracy of frozen section for lymph node metastasis in patients undergoing radical hysterectomy for carcinoma of the cervix.

The efficacy of frozen section in detecting metastases in pelvic and or periaortic lymph nodes during radical hysterectomy is unknown. The finding of positive nodes may result in termination of the operative procedure. In this study, we attempted to determine the accuracy of frozen sections in this situation. Intraoperative pathology consultation records were examined for 127 patients undergoing surgical exploration for radical hysterectomy between 1977 and 1992. Microscopic slides of lymph nodes were reviewed for accuracy. Metastasis diameters were measured and blocks cut five close microtome levels deeper. In 19 cases (15%) positive nodes were documented on permanent section, with metastases ranging in size from less than 1 to 19 mm. Thirteen cases of node metastasis were diagnosed at frozen section. All were suspicious to the pathologist on palpation and gross inspection after bisection. Six cases were missed by sampling error on frozen section; in 4, metastases were smaller than 1 mm; in 1, between 2 and 3 mm; and in 1, 19 mm. The sensitivity was 68%, the false-negative rate was 32%, and the specificity was 100%. No cases were false positive at frozen section. The frequency of nodal metastasis and detection rate by frozen section did not differ significantly between carcinoma types. No micrometastases (< 2 mm) were detected by frozen section. All micrometastases were no longer present within five microtome levels. Frozen section diagnosis of pelvic node metastasis is a highly specific procedure which should alter intraoperative management of early-stage cervical cancer.

Isolated parenchymal splenic metastasis in epithelial ovarian cancer.

Metastatic parenchymal splenic disease in patients with ovarian cancer is unusual. It is most commonly seen in the presence of large-volume upper abdominal disease when parenchymal involvement occurs by surface extension. A patient with isolated parenchymal splenic metastasis and no peritoneal disease in the abdomen at primary surgery is described.

Serum squamous cell carcinoma antigen levels in invasive cervical cancer: prediction of response and recurrence.

OBJECTIVE: The rate of normalization of human chorionic gonadotropin or CA 125 in other gynecologic malignancies is highly predictive of response to therapy and recurrence. Serum squamous cell carcinoma antigen (SCC antigen) levels were studied in patients with invasive cervical carcinoma to determine if the rate of normalization was associated with outcome. STUDY DESIGN: One hundred eighty-four patients were studied. A logistic regression of elevated SCC antigen levels was performed. RESULTS: In primary squamous cell carcinoma the SCC antigen level was elevated in stages I, II, III, and IV disease and all stages combined in 24%, 57%, 67%, 71%, and 43% of cases, respectively. Only 27% of patients with nonsquamous carcinoma of the cervix had elevated SCC antigen levels. SCC antigen levels were elevated in 50% of patients with recurrent disease. In both primary and recurrent disease elevated SCC antigen levels decreased with effective therapy. Normalization of elevated SCC levels was associated with a complete response; however, logistic regression of SCC antigen values was not. CONCLUSION: When initially elevated, SCC antigen assays aided in determination of response and detection of recurrences.

Malignant pericardial effusion from squamous cell cancer of the cervix.

UNLABELLED: Although rarely diagnosed in women with gynecologic cancers, pericardial metastasis and effusion are often considered preterminal events. As newer therapies result in prolongation of survival for women with advanced cervical cancer, uncommon metastatic sites may be seen with increasing frequency, and warrant increased attention by the gynecologist with oncologic expertise. CASES: Two women with squamous cell carcinoma and symptomatic pericardial effusion, one at initial presentation and the other as recurrent disease, are presented. Following pericardiocentesis, both patients received cisplatinum-based chemotherapy. The patient with effusion at diagnosis survived four months, with recurrent effusion at death. The second patient had no return of cardiac symptoms, with twelve month survival. As demonstrated by the cumulative experience of the six reported cases of this entity, many women with pericardial involvement are candidates for aggressive radiation or chemotherapy. Duration of time from primary therapy prior to occurrence of effusion correlates with survival.

Preoperative abdominopelvic computed tomographic prediction of optimal cytoreduction in epithelial ovarian carcinoma.

PURPOSE: This study was undertaken to assess the ability of computed tomography (CT) to predict the likelihood of optimal primary tumor cytoreduction in women with epithelial ovarian carcinoma. PATIENTS AND METHODS: Fifty-one women with preoperative CT and a histologic diagnosis of epithelial ovarian carcinoma following primary tumor operation by a gynecologic oncologist were identified. Forty-two CT scans were retrospectively analyzed. CT findings of attachment of the omentum to the spleen or disease greater than 2 cm on the diaphragm, liver surface, or parenchyma, pleura, mesentery, gallbladder fossa, or suprarenal paraaortic nodes were coded to represent unresectable disease. CT results were compared with surgical outcome. RESULTS: Twenty-nine of 42 (69%) patients underwent optimal cytoreduction to less than 2 cm residual disease. Successful cytoreduction was accomplished in 23 of 24 patients who fulfilled CT criteria for cytoreduction and six of 18 with CT criteria predictive of inability to perform cytoreduction. CT was highly sensitive for detection of ascites, mesenteric, and omental disease, but was poor for detection of liver involvement, omental attachment to the spleen, gallbladder fossa disease, and peritoneal nodules smaller than 2 cm. The CT findings accurately predicted surgical outcome with a sensitivity of 92.3% and specificity of 79.3%. The positive predictive value was 67% and the negative predictive value was 96%. CONCLUSION: CT scan is an accurate method for the prediction of successful surgical cytoreduction and may have utility in the decision to offer neoadjuvant chemotherapy to certain medically disabled patients, a hypothesis currently under evaluation.

Intraabdominal hemorrhage with pulmonary large cell carcinoma metastatic to the ovary.

Secondary tumors comprise nearly 10% of ovarian malignancies; however, metastatic cancers arising from the lung are uncommon, with fewer than 15 cases reported. A patient with pulmonary large cell carcinoma and ovarian metastases resulting in recurrent refractory intraabdominal hemorrhage is presented. Metastatic involvement of the ovary from pulmonary malignancy is reviewed.

Ovarian cancer staging: does it require a gynecologic oncologist?

Forty-seven patients with presumed Stages I-II invasive ovarian epithelial carcinoma were treated with intravenous 50 mg/m2 cis-platinum, for 2-18 cycles (median, 9), 50 mg/m2 doxorubicin for 2-14 cycles (median, 9), and/or 600 mg/m2 cyclophosphamide for 2-14 cycles (median, 6) after surgical staging by a gynecologic oncologist or a nononcologic surgeon. Mean follow-up is 6.8 years. Cumulative 5-year actuarial survival is 73 +/- 6%; 75 +/- 12% for Stage I and 71 +/- 8% for Stage II disease. When screened for poor prognosticators, only the specialty of the operating surgeon was identified (P < 0.05). Five-year actuarial survival and disease-free survival, respectively, for Stages I-II patients surgically staged by a gynecologic oncologist were 83 +/- 7% and 76 +/- 8%, compared to 59 +/- 11% (P < 0.05) and 39 +/- 11% (P < 0.03) for the group operated upon by a nononcologist.

False-positive elevation of CA-125 in papillary serous carcinoma of the endometrium treated with postoperative whole abdominal radiation.

Two patients with Stage I papillary serous carcinoma of the endometrium treated with postoperative whole abdominal radiation developed elevated CA-125 levels. In neither patient was evidence of recurrent disease identified. Hepatic veno-occlusive disease, a known complication of whole abdominal radiation and certain chemotherapy regimens, was confirmed by liver biopsy in both cases. CA-125 levels may not be reflective of disease status in this setting.

Serum squamous cell carcinoma antigen levels in invasive squamous vulvar cancer.

Squamous cell carcinoma (SCC) antigen levels were studied in 34 patients with primary (N = 27) or recurrent (N = 7) SCC of the vulva. In primary disease, the SCC antigen level was greater than 2.5 ng/ml in only four patients (15%). Elevated antigen levels ranged from 2.7-18.0 ng/ml. All of these patients had advanced disease by either clinical or surgical staging systems. Four of twelve patients with inguinal metastasis had elevated SCC antigen levels. In two of these patients the inguinal nodes were abnormal to palpation. No association of the SCC level and the degree of tumor differentiation was observed. SCC antigen levels were increased slightly (2.7-4.5 ng/ml) in three of six patients with locally recurrent disease. In one patient with distant recurrence the SCC antigen was 15.3 ng/ml. In both primary and recurrent disease all elevated SCC antigen levels decreased with effective therapy. Vulvar cancer is primarily a local disease that is easily assessed by physical examination. An effective tumor marker in vulvar cancer would benefit only the rare patient with distant but not local disease.