Jonathan M. Niloff

A Radioimmunoassay Using a Monoclonal Antibody to Monitor the Course of Epithelial Ovarian Cancer

The murine monoclonal antibody OC 125 reacts with an antigen (CA 125) common to most nonmucinous epithelial ovarian carcinomas. An assay has been developed to detect CA 125 in serum. By this assay, only 1 per cent of 888 apparently healthy persons and 6 per cent of 143 patients with nonmalignant disease had serum CA 125 levels above 35 U per milliliter. In contrast, 83 of 101 patients (82 per cent) with surgically demonstrated ovarian carcinoma had elevated levels of antigen. In 38 patients with epithelial ovarian carcinoma monitored on 2 to 18 occasions during 2 to 60 months, antigen levels ranged from less than 1 to more than 8000 U per milliliter. Rising or falling levels of CA 125 correlated with progression or regression of disease in 42 of 45 instances (93 per cent). Determination of CA 125 levels may aid in monitoring the response to treatment in patients with epithelial ovarian cancer.

Elevated serum concentrations of CA-125 in patients with advanced endometriosis

CA-125 is a high-molecular-weight glycoprotein that is expressed on the cell surface of some derivatives of embryonic coelomic epithelium. Based on results of an immunoradiometric assay developed to detect CA-125 in peripheral blood, 82% of patients with ovarian cancer and less than 1% of apparently healthy controls have elevated peripheral blood levels of CA-125. Because endometriotic lesions are likely to be derivatives of embryonic coelomic epithelium, the authors investigated serum CA-125 levels in patients with endometriosis. Preoperative serum CA-125 concentrations were measured in 147 patients undergoing diagnostic laparoscopy or laparotomy. Serum CA-125 concentrations were elevated in patients with stage III or IV endometriosis, compared with controls with negative diagnostic laparoscopies (66.5 +/- 14.5 versus 8.20 +/- 0.59 U/ml, mean +/- standard error of the mean; P less than 0.001). Fifty-four percent of patients with stage III or IV endometriosis and 0% of the controls had CA-125 levels greater than 35 U/ml. Occasional patients with stage II endometriosis (13%), leiomyomata uteri (14%), and chronic pelvic inflammatory disease (5%) also had serum CA-125 concentrations greater than 35 U/ml. Immunocytochemical techniques demonstrated the presence of CA-125 on the cell surface of endometriotic lesions.

Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix.

An immunoradiometric assay with the use of a monoclonal antibody can detect an antigenic determinant (CA125) in peripheral blood from more than 80% of patients with epithelial ovarian cancer. In this report elevated levels of CA125 were detected in serum from patients with adenocarcinomas of the fallopian tube, endometrium, and endocervix. Among patients with endometrial cancer, CA125 levels were elevated in recurrent or disseminated disease but not with tumors confined to the uterus.

Predictive value of CA 125 antigen levels in second-look procedures for ovarian cancer

Serum CA 125 levels were evaluated in 44 patients undergoing 56 second-look or subsequent laparoscopies (43) and laparotomies (13) for ovarian cancer. In each patient studied, a previous CA 125 level had been greater than or equal to 35 U/ml. Clinical or radiologic evidence of tumor was absent in all patients at the time of surgical evaluation. CA 125 levels were less than 35 U/ml in 36 cases (64%); 14 patients were free of tumor, while 22 were found to have tumor at surgery. CA 125 levels were greater than or equal to 35 U/ml in 20 cases; 18 had tumor at surgery, one has had recurrence of tumor, and the other remains clinically free of tumor at 3 months. A CA 125 level less than 35 U/ml was not predictive of the presence of intraperitoneal tumor; however, when tumor was present in this group of patients, the largest tumor mass did not exceed 1 cm. In contrast, a CA 125 level greater than or equal to 35 U/ml was a strong predictor of the presence of intraperitoneal tumor or future recurrence. These data suggest that second-look procedures may not be required in the select group of patients with CA 125 levels greater than or equal to 35 U/ml.

Occult Ovarian Tumors in Women With BRCA1 or BRCA2 Mutations Undergoing Prophylactic Oophorectomy

PURPOSE To review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic. MATERIALS AND METHODS Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patients risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data. RESULTS From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%. Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features. The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonography examinations within 6 months before prophylactic surgery. CONCLUSION Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted.

Monitoring human ovarian carcinoma with a combination of CA 125, CA 19-9, and carcinoembryonic antigen

CA 125 and CA 19-9 are antigenic determinants associated with human epithelial ovarian carcinomas. Murine monoclonal antibodies have been raised against these determinants, and immunoradiometric assays have been developed to monitor antigen levels in the serum of cancer patients. This study was undertaken to determine whether concomitant measurement of CA 125, CA 19-9, and carcinoembryonic antigen would provide a more precise correlation with tumor progression or regression than could be obtained with any single assay. Among 105 patients with surgically demonstrable epithelial ovarian carcinoma, serum CA 125 levels were elevated (greater than 35 U/ml) in 83%, CA 19-9, levels (greater than 37 U/ml) in 17%, and carcinoembryonic antigen levels (greater than or equal to 2.5 ng/ml) in 37%. Within individual samples, no correlation was found among values for the three markers, but patients with elevated CA 19-9 levels also had increased levels of CA 125. At least one of the three markers was elevated in 90% of the subjects. When 41 patients were monitored serially over 2 to 60 months, alterations in CA 125 levels correlated with disease progression or regression in 94% of instances, whereas alterations in CA 19-9 levels correlated in 33% and alterations in carcinoembryonic antigen levels in 25% of instances. Concomitant measurement of CA 125, CA 19-9, and carcinoembryonic antigen did not prove superior to measurement of CA 125 alone in the monitoring of patients with epithelial ovarian carcinoma.

CA 125 serum levels correlated with second-look operations among ovarian cancer patients

CA 125, which is an antigenic determinant expressed by many epithelial ovarian cancers, is measured in serum using a solid phase immunoradiometric assay. Sera from 55 patients who were in clinical remission and underwent a second-look operation to assess disease status after chemotherapy were studied prospectively. All patients had the CA 125 assay performed within one week before their second-look operation. Twenty-four patients (44%) had no histologic or cytologic evidence of disease, seven patients (13%) had microscopic disease, 13 patients (24%) had disease measuring 1 mm to 1.5 cm, and ten patients (18%) had disease greater than or equal to 1.5 cm in maximum tumor dimension. None of the 24 patients with a negative second-look operation had a positive CA 125 antigen level (greater than or equal to 35 U/mL), compared with six of 20 patients (30%) with less than 1.5 cm disease, and six of ten (60%) with greater than or equal to 1.5 cm disease (P less than .0001). All 12 patients with an elevated CA 125 antigen level (greater than or equal to 35 U/mL) had disease discovered at their second-look operation. Thus, in this setting the predictive value of a positive CA 125 titer (greater than or equal to 35 U/mL) was 100%. The predictive value of a negative CA 125 antigen level (less than 35 U/mL) was 56%, ie, the test did not exclude the presence of disease in 44% of patients with a positive second look. The maximum tumor size associated with at least one prior negative antigen level was 1.9 cm.(ABSTRACT TRUNCATED AT 250 WORDS)

The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer

Abstract Serum CA 125 levels were obtained from 55 women with epithelial ovarian cancer before a second-look surgical procedure and serially thereafter. All patients were clinically and radiographically free of tumor at the time of the second-look operation and were followed to clinical recurrence. Median follow-up was 12 months. CA 125 levels obtained at the second-look operation had a sensitivity and specificity for predicting clinical recurrence of 94% and 88%, respectively. Patients with an elevated CA 125 level (≥35 U/ml) had a 60% chance of clinical recurrence within 4 months, while patients with levels

CD44 variant expression is a common feature of epithelial ovarian cancer: lack of association with standard prognostic factors.

PURPOSE CD44 is a hyaluronic acid receptor that exists as a standard 90-kd form (CD44S) as well as several CD44 variant isoforms produced through alternative splicing. Expression of CD44 variants is associated with clinically aggressive behavior in some human tumors. The purpose of the present study is to define the expression of CD44 variant isoforms in ovarian cancer and to investigate whether the expression of these molecules is associated with adverse prognosis. MATERIALS AND METHODS Six specimens of normal ovarian surface epithelium (NOSE) and 31 separate cases of newly diagnosed ovarian cancer were studied by a combination of reverse-transcription polymerase chain reaction (RT-PCR) and immunoperoxidase staining. Clinical correlation was made between CD44 variant expression and stage (I/II v III/IV), residual disease (< or = 2.0- v > 2.0-cm mass), age (< or = 65 v > 65 years), histology (papillary serous v other), grade, and survival. RESULTS RT-PCR analysis revealed that NOSE predominantly expressed transcripts for CD44S, as well as a restricted pattern of transcripts characteristic of CD44 splice variants. CD44S and CD44 variant exon nine sequences (CD44-9v) were focally expressed in one of two NOSE specimens examined by immunoperoxidase staining. In comparison, the majority (71%) of ovarian cancer specimens expressed a complex pattern of CD44 splice variants by RT-PCR analysis. Immunoperoxidase studies revealed that the majority of ovarian cancer specimens expressed both CD44S and CD44-9v, whereas expression of sequences from variant exons 3, 4, and 6 was uncommon. There was no association between CD44 variant expression (transcript or protein) and stage, residual disease, age, histology, grade, or survival. CONCLUSION Expression of CD44S and CD44-9v is a common feature of epithelial ovarian cancer cells. The lack of a significant association between CD44 variant expression and prognosis suggests that other factors may be more important in determining the clinical behavior of this disease.

Use of peripheral-blood progenitor cells abrogates the myelotoxicity of repetitive outpatient high-dose carboplatin and cyclophosphamide chemotherapy.

PURPOSE Attempts to increase dose-intensity in clinical practice have been limited by cumulative hematologic toxicity despite the use of hematopoietic growth factors. To address this problem, we designed a study to determine whether four cycles of dose-intensive chemotherapy with carboplatin could be administered in the outpatient setting using granulocyte-macrophage colony-stimulating factor (GM-CSF) and peripheral-blood progenitor cells (PBPCs) that had been harvested before initiation of treatment. PATIENTS AND METHODS An initial cycle (cycle no. 0) of cyclophosphamide 4 g/m2 followed by GM-CSF was used to mobilize PBPCs harvested by leukapheresis for 6 consecutive days. Cycles no. 1 through 4 consisted of outpatient carboplatin 600 mg/m2 and cyclophosphamide 600 mg/m2 followed by GM-CSF 5 micrograms/kg subcutaneously (SC) twice per day every 28 days. In cycle no. 1, PBPC were not reinfused to assess the effects of GM-CSF alone. In cycles no. 2 through 4, PBPCs were reinfused on day 3 in an outpatient setting. RESULTS In eight assessable patients, the addition of PBPCs in cycle no. 2 resulted in a significant reduction in the median duration of thrombocytopenia less than 20,000/microL (6.5 v 1 day; P = .016), days to platelets more than 50,000/microL (20.5 v 15 days; P = .020), number of platelet transfusions (five v 1.5; P = .016), and duration of neutropenia (absolute neutrophil count [ANC] < 1,000/microL (7 v 2.5 days; P = .008) when compared with cycle no. 1. Dose-limiting hematologic toxicity, defined as more than 7 days of platelets less than 20,000/microL or ANC less than 500/microL, was observed in four of eight patients during cycle no. 1, but not during cycles no. 2, 3, and 4 of chemotherapy supported by PBPCs (a total of 19 cycles in eight patients). Five of eight patients completed all four cycles of high-dose therapy. Three patients did not complete four cycles due to late thrombocytopenia (n = 2) or tumor progression (n = 1). CONCLUSION These results indicate a benefit of PBPCs in addition to GM-CSF in alleviating myelosuppression of dose-intensive chemotherapy. Initial collection of PBPCs may allow administration of repetitive cycles of high-dose chemotherapy with acceptable toxicity to outpatients at disease onset.