p53 gene mutation in human borderline epithelial ovarian tumors.
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Carcinoma↗
Biomedical subjects
R S Berkowitz
Publications and source records attributed to R S Berkowitz.
Molecular cloning of differentially expressed genes in human epithelial ovarian cancer.
A DNA-fingerprinting approach has been adapted to detect differentially expressed genes in human ovarian carcinoma. This method is based on the use of arbitrary primers to generate fingerprints from total RNA isolated from normal ovarian epithelial cells and ovarian carcinoma cells by polymerase chain reaction (PCR). Using this method, we cloned two cDNA fragments (DOC-1 and DOC-2) which were present in normal ovarian surface epithelial cells but consistently absent in all of the ovarian cancer cell lines from the differential display. In addition, we also identified a cDNA fragment (LF4.0) which is overexpressed in most of the tumor cell lines and tumor tissues in comparison to the normal ovarian surface epithelial cells. The differential expression of the genes in the tumor cell lines as well as in the tumor tissues was also confirmed by Northern analysis. The clone DOC-2, which is a 800-bp cDNA fragment, has one open reading frame suggesting that the gene may be translated. Assuming that this frame is the sense strand, we generated both sense and antisense riboprobe for in situ mRNA hybridization. Only the antisense DOC-2 riboprobe revealed a hybridization signal which was restricted to the human surface ovarian epithelium. The potential functional roles of these genes is now under investigation.
Base Sequence↗
Two-year follow-up of 263 patients with post/perimenopausal vaginal bleeding and negative initial biopsy.
Patients with post- or perimenopausal bleeding (PMB) whose initial endometrial biopsy or dilation and curettage (D&C) reveals benign or insufficient tissue may eventually be diagnosed with endometrial cancer or complex endometrial hyperplasia. We studied 286 consecutive patients with PMB who had either an endometrial biopsy or D&C at Brigham and Women's Hospital during November 1990 to April 1991 and reviewed their subsequent specimens after a minimum of 23 months of follow-up. Of the initial 286 patients with PMB, 6 (2%) had endometrial cancer on their index biopsy, 17 (6%) had complex hyperplasia, and 201 (70%) had other benign findings. Sixty-two (22%) had "tissue insufficient for diagnosis." Excluding the 23 with cancer/complex hyperplasia, there were 263 patients in the cohort, 86 of whom (33%) had further endometrial sampling during the follow-up period. Of these, four (2%) were subsequently found to have a uterine malignancy (2 of the benigns, 2 of the insufficients) and five (2%) were subsequently found to have complex hyperplasia. Of the four patients subsequently found to have cancer, two had stage I adenocarcinoma, one had stage IV adenocarcinoma, and one had stage I high-grade stromal sarcoma.
Aged↗
Cytokine regulation of trophoblast steroidogenesis.
Activated monocytes and lymphocytes secrete cytokines that act as autocrine and paracrine mediators to promote and regulate local immune processes. These cell types are abundant at the maternal-fetal interface, and cytokines may play a role in pregnancy maintenance or failure. The purpose of this study was to determine the effects of selected monocyte- and lymphocyte-derived cytokines on trophoblast progesterone and estradiol production. JEG-3 choriocarcinoma cells were cultured in supplemented medium alone or in various concentrations of selected recombinant monocyte or lymphocyte cytokines. The cytokines were evaluated both individually and in combination. After 48 h of incubation, the culture supernatant was aspirated and stored at -20 C. Samples were then analyzed for steroid concentration by specific RIAs. Specific interleukin-1 (IL-1)-and tumor necrosis factor (TNF)-neutralizing antibodies were evaluated for their ability to abrogate the cytokine's observed stimulatory effect. To evaluate the physiological relevance of the progesterone-stimulating effect observed with monocyte-derived cytokines, JEG-3 cells were incubated with activated monocyte supernatant or directly cocultured with activated monocytes, and supernatants from these cultures were analyzed for progesterone levels. The monocyte cytokines [IL-1 alpha (5 U/mL), IL-1 beta (5 U/mL), and TNF alpha (1000 U/mL) significantly stimulated trophoblast progesterone production (nanograms per mL): JEG-3 control, 4.1 +/- 0.5; IL-1 alpha, 7.8 +/- 0.9; IL-1 beta, 8.8 +/- 0.5; and TNF alpha 7.2 +/- 0.8 (P < 0.05). Neither the monocyte nor the lymphocyte cytokines altered trophoblast estradiol production. Activated monocyte supernatant and direct JEG-3-monocyte cocultures also significantly stimulated trophoblast progesterone production in vitro. The stimulatory effect of the monocyte-derived cytokines was specific, as demonstrated by neutralization assay. The increased trophoblast progesterone production was not due to enhanced cellular proliferation, but to enhance cellular steroidogenesis, as measured by quantitative DNA analysis. The lymphocyte cytokines (IL-2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor had no effect on trophoblast progesterone production. We conclude that monocyte IL-1 alpha, IL-1 beta, and TNF alpha may regulate trophoblast progesterone production through paracrine effects. Monocyte-trophoblast interactions may be significant in normal pregnancy as well as pregnancy disorders.
Cell Division↗
Brain metastases of gestational trophoblastic tumor.
Brain involvement by gestational trophoblastic tumor (GTT) was diagnosed by computed tomography in 23 (17%) of 131 patients with metastatic GTT at King Faisal Specialist Hospital and Research Centre between January 1980 and December 1990. All 23 patients had concurrent lung involvement, and 20 presented with neurologic symptoms. There were three treatment groups: Group A--methotrexate, actinomycin-D, chlorambucil and brain irradiation; group B--cisplatin, VP-16, actinomycin-D and intrathecal methotrexate; and group C--palliative therapy and other chemotherapy. While no patients in groups A or C survived, 4 (57%) of 7 patients in group B achieved complete, sustained remission. Serum:cerebrospinal fluid beta-human chorionic gonadotropin ratios were measured in 9 patients and were < 60 in only 4 patients. The clinical features of patients with brain metastases are reviewed in detail.
Adult↗
Pseudomyxoma peritonei: a review of 23 cases.
OBJECTIVE: To review the experience at the Massachusetts General and Brigham and Women's Hospitals with 23 women treated for pseudomyxoma peritonei between 1961 and 1991. METHODS: Patients were identified retrospectively from the tumor registry at the Massachusetts General and Brigham and Women's Hospitals, and all charts were reviewed. The median follow-up interval was 2.5 years (range 3 months to 31 years). RESULTS: The mean age at diagnosis was 58 years (range 26-76). Pseudomyxoma peritonei was found in association with ten (44%) ovarian tumors of borderline malignancy, nine (39%) ovarian cystadenocarcinomas, and four (17%) appendiceal cystadenocarcinomas. Three patients had synchronous tumors in the ovary and appendix. All patients underwent surgical staging and cytoreduction. Eleven patients received postoperative therapy and, of these, nine developed a recurrence; 12 patients received no further therapy and, of these, three developed a recurrence. However, these groups were not pathologically comparable. With respect to survival, of the ten patients with borderline malignancies, seven had no evidence of disease, one was alive with disease, and two died of disease. For the nine patients with ovarian cystadenocarcinomas, three had no evidence of disease, one was alive with disease, and five died of disease (median time to death 18 months). For the four patients with appendiceal carcinomas, two had no disease, one was alive with disease, and one died with disease. Among all 23 patients, 12 (52%) developed a recurrence, with a range of time to first recurrence of 3 months to 19 years. Eight women required at least one additional laparotomy because of accumulation of gelatinous material. CONCLUSIONS: Although pseudomyxoma peritonei is associated with borderline and well-differentiated tumors, recurrence is common and the prognosis after recurrence is guarded. Involvement of the appendix is common; therefore, appendectomy is indicated when pseudomyxoma is encountered. To date, surgery has been the only effective therapy for this disease, and adjuvant therapy has not been shown conclusively to be of benefit.
Adult↗
Current management of complete and partial molar pregnancy.
Molar pregnancy is composed of two separate entities, partial (PHM) and complete (CHM), which are distinct in terms of epidemiology, genetics, histopathology, clinical presentation and risk of persistent gestational trophoblastic tumor (GTT). The most common presenting symptom in patients with CHM is vaginal bleeding. Approximately half the patients with CHM show signs of exuberant trophoblastic growth, with uterine enlargement and high levels of human chorionic gonadotropin (hCG). In contrast, patients with PHM usually present as though they have an incomplete or missed abortion, with bleeding, small uteri and low hCG levels. Cytogenetically, all chromosomal material in CHM is derived from the male. Hence, no fetal parts are identified. In PHM, dispermy results in a triploid conceptus, in which an abnormal fetus is present and ultimately dies. The diagnosis of CHM is usually confirmed by sonography when a vesicular pattern is noted. The ultrasound pattern in PHM is less consistent and depends on careful measurement of the gestational sac. Patients with CHM with marked trophoblastic hyperplasia, elevated hCG levels and enlarged uteri can develop significant medical complications, which should be recognized early and treated aggressively. These include acute respiratory distress syndrome, hyperthyroidism, preeclampsia and theca lutein cysts. All molar pregnancies should be evacuated promptly following a definitive diagnosis. If the patient no longer wishes to preserve her fertility, a hysterectomy will reduce the risk of developing nonmetastatic GTT. Following evacuation, careful hCG monitoring is mandatory since it is the most reliable and sensitive method for the early detection of GTT.(ABSTRACT TRUNCATED AT 250 WORDS)
Abortion, Incomplete↗
Clinical features of multiple conception with partial or complete molar pregnancy and coexisting fetuses.
The estimated incidence of twin pregnancy consisting of hydatidiform mole and a coexisting fetus is 1 per 22,000-100,000 pregnancies. Since 1965, nine patients with this entity have been treated at the New England Trophoblastic Disease Center (NETDC), Boston. One patient had a partial hydatidiform mole coexisting with a normal placenta and fetus. The other eight patients had twin pregnancies with a complete hydatidiform mole (CHM) and coexisting fetus. We compared the clinical outcomes in these 8 patients and 14 additional published case reports of multiple gestations composed of CHM and coexisting fetuses with a group of 71 patients with singleton CHM treated at NETDC. Twelve of the 22 patients (55%) with CHM and coexisting fetuses developed persistent gestational trophoblastic tumor, requiring chemotherapy. Five of these patients developed metastases requiring multiple cycles of chemotherapy to achieve remission. The presenting symptoms of multiple conception with CHM and coexisting fetuses were similar to those in patients with a singleton conception and complete mole. However, as compared to singleton CHM, patients having a multiple conception with CHM and coexisting fetuses were diagnosed at a later gestational age, had higher preevacuation beta-human chorionic gonadotropin levels and had a greater propensity to develop persistent tumor. These data indicate that patients with multiple conceptions consisting of CHM and coexisting fetuses are at high risk of developing persistent gestational trophoblastic tumor.
Adult↗
Psychological, social and sexual effects of gestational trophoblastic disease on patients and their partners.
The psychological, social and sexual effects of gestational trophoblastic disease in both patients and their partners are reviewed. The results suggest that despite the favorable prognosis of this disease, mood disturbances, sexual disturbances and fertility concerns can persist in both patients and their partners. Recommendations are made concerning providing supportive care to meet the needs of patients and their partners.
Affect↗
Pulmonary metastases of gestational trophoblastic tumor. Risk factors for early respiratory failure.
Between January 1980 and December 1990, 75 (57.3%) of 131 patients with metastatic gestational trophoblastic tumor had pulmonary metastases detected on plain chest roentgenography at the King Faisal Specialist Hospital and Research Centre. Pulmonary involvement was commonly extensive, with 32 (42.7%) patients having > 10 pulmonary metastases and 45 (60%) patients having a pulmonary lesion > 5 cm in diameter. Greater than 50% lung opacification, mediastinal involvement and pleural effusion were present in 25 (33.3%), 25 (33.3%) and 36 (48%) patients, respectively. Eight (10.7%) patients developed early respiratory failure requiring mechanical ventilation within one month of presentation. The development of early respiratory failure was significantly associated with the presence of dyspnea, anemia, clinical pulmonary hypertension, cyanosis, > 50% lung opacification, mediastinal involvement and bilateral pleural effusion. Because all patients requiring mechanical ventilation died, the use of extracorporeal perfusion should be considered in patients with early respiratory failure.
Adult↗
Effects of cytokines on epidermal growth factor receptor expression by malignant trophoblast cells in vitro.
Trophoblastic cells abundantly express epidermal growth factor (EGF) receptors, which, when activated by EGF or transforming growth factor-alpha, can influence cellular growth and metabolism. Various lymphocyte and macrophage cytokines have been found to influence the proliferation of human choriocarcinoma (CCA) cells in vitro. In the current study we investigated the possibility that certain cytokine effects are mediated by changes in EGF receptor expression. JEG-3 human CCA cells were incubated with varying concentrations of interleukin 1-alpha (IL-1 alpha), interleukin 1-beta (IL-1 beta), interleukin 2, gamma-interferon, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha (TNF), and the expression of EGF receptor was measured by radioimmunoassay using a murine monoclonal antibody with specificity for the EGF receptor. Proliferative or growth suppressive effects of the cytokines were assessed by quantitative analysis of the DNA in the cell culture wells. Macrophage-derived cytokines IL-1 alpha, IL-1 beta and TNF significantly suppressed cell growth; this was associated with a significant increase in EGF receptor expression. The other cytokines had no significant effect on either EGF receptor expression or cell growth. We also studied the expression of EGF mRNA in JEG-3, Jar and BeWo CCA cell lines. By reverse transcription followed by polymerase chain reaction, low levels of EGF mRNA were detected in all three cell lines. Therefore, EGF may be synthesized by JEG-3, Jar and BeWo CCA cell lines to participate in an autocrine growth pathway. Our findings support the concept that cytokines may act as paracrine mediators of autocrine processes involved in CCA cell growth regulation by modulating growth factor receptor expression.
Blotting, Northern↗
Subsequent pregnancy experience in patients with gestational trophoblastic disease. New England Trophoblastic Disease Center, 1965-1992.
We reviewed the subsequent pregnancy outcome in patients with partial mole, complete mole and persistent gestational trophoblastic tumor treated at the New England Trophoblastic Disease Center from June 1, 1965, to December 31, 1992. Such patients can be assured that they can anticipate a normal future reproductive outcome. However, when a patient has had a molar pregnancy, she is at increased risk (1%) of developing molar disease in a subsequent conception.
Female↗
Natural history of twin pregnancy with complete hydatidiform mole and coexisting fetus.
OBJECTIVE: To investigate the clinical features and natural history of twin conceptions consisting of complete hydatidiform mole and a coexisting fetus. METHODS: Since 1973, eight well-documented cases of twin pregnancy with complete hydatidiform mole and coexisting fetus have been treated at the New England Trophoblastic Disease Center (NETDC). The clinical features of these eight patients were compared to 71 patients with singleton complete hydatidiform mole treated at the NETDC and with the published experience of other investigators. Flow cytometric analysis of DNA content was performed in addition to histologic inspection to assist in confirming the diagnosis of twin pregnancy with complete hydatidiform mole and coexisting fetus. RESULTS: Five of the eight patients in this series developed persistent gestational trophoblastic tumor requiring chemotherapy. Three of these five patients developed metastases requiring multi-agent chemotherapy to achieve remission. The presenting symptoms of twin pregnancy with complete hydatidiform mole and coexisting fetus were similar to those in patients with a singleton complete mole. However, compared to singleton complete molar gestation, a twin pregnancy with complete mole and coexisting fetus was diagnosed at a later gestational age, had higher preevacuation beta-hCG levels, and had a greater propensity to develop persistent gestational trophoblastic tumor. CONCLUSION: Our findings indicate that patients with complete hydatidiform mole and coexisting fetus are at high risk for developing persistent gestational trophoblastic tumor.
Adult↗
Mutation of K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy.
The mutation of K-ras protooncogene was examined in 44 cases of borderline ovarian epithelial tumors and 18 cases of invasive ovarian carcinomas. In borderline tumors, K-ras mutations are a common feature, having been found in 21 of 44 cases (48%). Twenty of the 21 mutations were identified at codon 12, and one was identified at codon 13. A detailed analysis of the mutation pattern of K-ras revealed a close association with the histological cell types of the tumor. Mutation of K-ras was detected at a higher frequency in mucinous borderline tumor (identified in 12 of 19 cases) compared to serous borderline tumor (identified in 9 of 25 cases). K-ras mutation was also detected in invasive mucinous and serous ovarian carcinomas, hence supporting the notion that borderline ovarian tumors may represent a pathological continuum between benign and frankly invasive diseases.
Adenocarcinoma, Mucinous↗
Molecular genetic evidence of a unifocal origin for human serous ovarian carcinomas.
The hypothesis that ovarian cancer is multifocal in origin was examined using molecular genetic techniques. Patterns of allelic deletion on chromosome 17 were studied in 16 informative cases of Stage III serous epithelial ovarian carcinoma. DNA was extracted from specimens collected from the omentum and both ovaries, and the specific alleles and chromosomal loci involved in the deletion were identified and compared. In all cases, the patterns of allelic deletion were identical for the tumors that had been collected from different sites in the same patients. In addition, 4 of the 16 cases were heterozygous for the hypoxanthine phosphoribosyl transferase (HPRT) gene on the X-chromosome and were examined for methylation status. In all 4, the same parental allele of the HPRT gene was methylated in tumor cells collected from both ovarian and omental sites, suggesting that the patterns of inactivation of the X-chromosome are identical. This pattern of allelic deletion and HPRT-gene methylation in tumor samples collected from different sites implies that ovarian carcinomas have a unifocal origin.
Alleles↗
CA125 measurement in epithelial ovarian cancer: a 10-year anniversary of clinical investigation.
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Antigens, Tumor-Associated, Carbohydrate↗
Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center.
Women with a family history of ovarian cancer represent a high-risk group for the development of epithelial ovarian cancer. From July 1990 through December 1992, 386 women with a first-degree or multiple second-degree relatives with confirmed ovarian cancer were enrolled in a study to assess the utility of screening with transvaginal sonography, color flow doppler, and CA125. The mean age of the group was 41; 85% were premenopausal and 89/384 (23%) had 2 or more relatives with ovarian cancer. An initial ultrasound examination was abnormal in 89/384 (23%), 89% of whom were premenopausal. A persistent ovarian mass was detected in 15 patients and all were surgically proven to be benign. Mean CA125 levels were significantly higher and more variable in pre- vs postmenopausal women. CA125 was > or = 35 U/ml in 42/386 (11%) (36-232 U/ml). All but one of these women were premenopausal and 50% subsequently normalized. Two patients who were surgically explored for a rising CA125 had normal ovaries. An additional 19 patients have undergone prophylactic oophorectomy with no consistent histopathologic abnormality identified. These data demonstrate the difficulty inherent in screening a predominantly premenopausal population and do not clearly establish the efficacy of these modalities in the early detection of ovarian cancer.
Adult↗
The effects of cytokines on human chorionic gonadotropin (hCG) production by a trophoblast cell line.
The present study was conducted to investigate the effects of cytokines on human chorionic gonadotropin (hCG) and its alpha- and beta-subunit release as well as protein synthesis in a trophoblast cell line. The human choriocarcinoma cell line, Jar, was used as a trophoblast model. Jar cells were incubated for 24 h with varying concentrations (5 x 10(-4)-40 micrograms/ml) of the following cytokines: Il-1, Il-2, Il-3, Il-4, Il-5, Il-6, IFN-gamma, tumor necrosis factor (TNF)-alpha, M-CSF and GM-CSF. Supernatants were assayed for hCG and its alpha- and beta-subunits by immunoradiometric methods. Cytotoxic effects were assessed by trypan blue staining. Protein synthesis was measured by [3H]leucine incorporation. The cytokines Il-1 and TNF-alpha significantly stimulated hCG release. The other cytokines had no significant effect on hCG production. Protein synthesis by the Jar cells was not significantly affected by either Il-1 or TNF-alpha. However, IFN-gamma (40 micrograms/ml) significantly suppressed protein synthesis by the Jar cells. Trophoblast viability in the presence of TNF-alpha (10 micrograms/ml) and IFN-gamma (40 micrograms/ml) was only 40% and 50%, respectively. These results suggest that cytokines may be important regulators of trophoblast function. Il-I appears to have a stimulatory effect on trophoblast hCG release, while TNF-alpha and IFN-gamma appear to have cytotoxic effects on trophoblast cells.
Biomarkers↗