Chorionic tumors.
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Combined Modality Therapy↗
Biomedical subjects
R S Berkowitz
Publications and source records attributed to R S Berkowitz.
Frequent microsatellite instability in epithelial borderline ovarian tumors.
To further define the genetic events that could lead to the development of borderline ovarian tumors (BOTs), we analyzed 13 microsatellite markers on chromosomes 3p and q in 18 BOTs and compared the results to 31 serous invasive epithelia] ovarian cancers (IEOCs). Five of the 18 BOTs showed microsatellite instability (MSI) at one or more loci, compared to only 2 of the 31 IEOCs studied (P < 0.04). In two of these five BOTs, MSI was found in multiple loci. All BOTs with MSI were serous, while none of the mucinous type showed any alteration. Loss of heterozygosity was found in only 1 of the 18 BOTs, but in 12 of the 31 IEOCs (P < 0.01). This first report of a relatively high percentage of MSI in BOTs opens a wide spectrum of new hypotheses for borderline ovarian tumorigenesis as well as several new research avenues.
Base Sequence↗
Loss of heterozygosity of chromosome 17 in human borderline and invasive epithelial ovarian tumors.
Polymerase chain reaction (PCR) analysis of microsatellite polymorphisms corresponding to four loci which map to chromosome 17p and 11 loci which map to chromosome 17q was performed to screen for loss of heterozygosity (LOH) in paired normal and tumor tissues from 27 cases of borderline epithelial ovarian tumors (BEOT) and 32 cases of invasive epithelial ovarian cancers (IOC). LOH was observed in six of 27 (22%) of the borderline tumors and in 29 of 32 (90%) of the invasive ovarian cancers (P<0.001). At all 15 loci studied, a lower percentage of allelic loss was detected in borderline tumors (0-14%) vs invasive cancer (8-93%). At eight loci this difference was statistically significant. For IOC, one common loss region was identified on chromosome 17p and four distinct common loss regions were on chromosome 17q, which supports the notion that multiple tumor suppressors may reside on chromosome 17 in IOC. These data suggest that LOH on chromosome 17 is an infrequent event in BEOT compared with IOC and therefore may not be important in the distinct pathogenesis of BEOT.
Alleles↗
SPARC, an extracellular matrix protein with tumor-suppressing activity in human ovarian epithelial cells.
SPARC, also termed osteonectin, BM-40 and 43K protein, is an acidic, cysteine-rich component of the extracellular matrix that has been shown to be directly regulated by progesterone and dexamethasone and indirectly by cytokines. By RNA fingerprinting technique, we cloned a SPARC homolog from the normal human ovarian surface epithelial (HOSE) cells and demonstrated that it is expressed at high levels in the normal HOSE cells but at much lower levels in ovarian carcinoma cells in vitro and in vivo. Subsequently, we transfected the full length SPARC cDNA into an ovarian carcinoma cell line SKOV3 and showed that it reduced the growth rate of the cancer cell line in culture and reduced the cell's ability to induce tumours in nude mice. These results suggest that SPARC may play an important role in growth and and differentiation of the HOSE cells and support the hypothesis that SPARC functions as a tumor suppressor.
Animals↗
A 400 kb novel deletion unit centromeric to the BRCA1 gene in sporadic epithelial ovarian cancer.
Allelic deletions on chromosome 17q21 in sporadic ovarian cancer are common, suggesting that inactivation of a tumor suppressor gene(s) in that region may be important for the etiology of these tumors. The recently identified BRCA1 gene on 17q21, involved in the development of familial breast/ovarian cancer, could be a candidate. However, inactivating mutations on BRCA1 in sporadic ovarian cancer has been rarely described. Furthermore, the potential relationship of BRCA1 gene to ovarian tumors of borderline malignancy remains also unclear. We constructed a highly detailed deletion map of chromosome 17q21 based on PCR amplification of eight polymorphic tandem repeat markers in a 650 kb area including three BRCA1 intragenic markers. DNA from 52 sporadic ovarian cancers and 26 borderline tumors, together with their corresponding normal control tissues were used. Only one borderline tumor showed loss of heterozygosity at one marker, whereas 65% of invasive ovarian cancers displayed allelic loss in at least one of the markers studied. A common deletion unit, located approximately 60kb centromeric to BRCA1, was revealed. These results suggest that inactivation of the BRCA1 gene may not be responsible for the development of borderline ovarian tumors and that another tumor suppressor gene, located centromeric to the BRCA1 gene, may play a role in sporadic ovarian cancer development.
Alleles↗
Prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions.
The authors studied the prevalence and significance of implantation site trophoblastic atypia in hydatidiform moles and spontaneous abortions. Three pathologists independently categorized 99 early abortion specimens regarding diagnosis (spontaneous abortion, partial hydatidiform mole, complete hydatidiform mole); qualitative atypia of implantation site trophoblast (absent, mild, moderate-severe); and quantitative atypia of implantation site trophoblast (absent, focal, diffuse). Interobserver agreement was good to excellent regarding diagnosis (kappa 0.66-0.79) and poor to fair regarding qualitative atypia of implantation site trophoblast (kappa 0.20-0.43). By consensus diagnosis, implantation site trophoblastic atypia was mild and focal in 5% of 22 spontaneous abortions; predominantly focal in 40% of 30 partial moles (33% mild atypia; 7% moderate-severe atypia); and, predominantly diffuse in 87% of 47 complete moles (21% mild atypia; 66% moderate-severe atypia). Among hydatidiform moles, the subsequent development of persistent gestational trophoblastic tumor did not relate to the degree of implantation site trophoblastic atypia. The authors conclude that trophoblast of the implantation site exhibits focal, mild atypia in some partial hydatidiform moles,and diffuse marked atypia in most complete hydatidiform moles. Thus, implantation site trophoblastic atypia may be a useful pathologic guideline regarding the diagnosis and classification of hydatidiform moles.
Abortion, Spontaneous↗
Gestational trophoblastic disease.
BACKGROUND: Gestational trophoblastic disease consists of a group of interrelated diseases, including molar pregnancy, placental site trophoblastic tumor, and choriocarcinoma. METHODS: Advances in the diagnosis and management of gestational trophoblastic diseases over the past 5 years were reviewed. RESULTS: Molar pregnancy is now categorized as complete or partial on the basis of gross and microscopic histopathologic and karyotypic findings. Early detection of persistent gestational trophoblastic tumor (GTT) depends on careful postmolar gonadotropin follow-up and consideration of the diagnosis for any woman of reproductive age with unexplained gynecologic and/or systemic symptoms. Triple therapy with methotrexate, actinomycin D, and cyclophosphamide was once the preferred treatment for patients with high risk metastatic GTT but induced remission in only about 50%. Treatment with etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine is now the preferred regimen for treatment of high risk metastatic GTT and has been shown to induce remission in about 70% of patients. CONCLUSIONS: Important advances have been made in the diagnosis and treatment of patients with gestational trophoblastic disease, and patients can be reassured that they can anticipate normal reproductive functioning.
Antineoplastic Combined Chemotherapy Protocols↗
Detailed deletion mapping of chromosome 9p and p16 gene alterations in human borderline and invasive epithelial ovarian tumors.
We used PCR amplification of tandem repeats to study the pattern of allelic loss in borderline and invasive ovarian epithelial tumors using 12 primer pairs to generate a detailed deletion map of chromosome 9p. In the invasive ovarian carcinomas, there were three regions displaying high frequency of loss of heterozygosity (LOH) ranging from 31-38%. In contrast, LOH was a rare event among the borderline ovarian tumors, with one region revealing a rate of 20% and the remaining regions only 0-8% LOH. Therefore, allelic loss does not seem to be important for the development of borderline ovarian tumors. We also examined p16 gene expression and mutations in ovarian cancer cell lines and invasive and borderline ovarian tumor tissues. Southern blot analysis revealed no losses of the p16 gene in either the invasive or borderline ovarian tumors. However, the ovarian carcinoma cell lines showed a 50% homozygous deletion rate. SSCP analysis detected a mobility shift in only one (borderline) tumor. Since the primary invasive ovarian tumors did not show any deletions or mutations, it appears that p16 does not play a role in the pathogenesis of these tumors.
Carrier Proteins↗
Detailed deletion mapping of chromosome 6q in borderline epithelial ovarian tumors.
We have used PCR amplification of tandem repeats and Southern blot analysis to study the pattern of allelic loss at chromosome 6q in borderline ovarian tumors and compared that with invasive ovarian carcinomas. DNA from 46 borderline ovarian tissues, 20 invasive ovarian tumor tissues, together with corresponding uninvolved (control) tissues was used. The invasive tumors demonstrated the highest percentage of loss of heterozygosity (13 of 45 informative cases, 29%) at the 6q25-27 locus site. In contrast, the borderline ovarian tumors showed only an 11% frequency of loss of heterozygosity (3 of 26). Our results display a sharp contrast in the pattern of loss of heterozygosity between invasive and borderline ovarian tumors and suggest that allelic loss at chromosome 6q may not be involved in the development of borderline ovarian tumors.
Alleles↗
Evidence for a multifocal origin of papillary serous carcinoma of the peritoneum.
Histopathological evidence suggests that papillary serous carcinoma of the peritoneum (PSCP) may be multifocal in origin. Utilizing a PCR based method to detect tandem repeat polymorphisms in formalin fixed tissue, loss of heterozygosity at eight loci on chromosomes 1, 3, 4, and 17 was studied in six cases of PSCP. Loss of heterozygosity was assessed at between 5 and 11 tumor sites/patient. Allelic losses at 4 loci (1q32-qter, 3p14.3-21.1, 17q12, 17q21.3-23) were noted. Three cases demonstrated a different pattern of allelic loss at various anatomic sites within the same patient. In an additional case, a mutation of the p53 gene, detected by quantitative PCR followed by single-strand conformation polymorphism analysis, was detected in only 2 of 5 tumor sites. The pattern of allelic loss and the mutational pattern of the p53 gene varied at tumor sites within the same patient in 4 of 6 cases of PSCP. These findings are consistent with histopathological evidence that PSCP is multifocal in origin.
Base Sequence↗
Characterization of human ovarian surface epithelial cells immortalized by human papilloma viral oncogenes (HPV-E6E7 ORFs).
Primary human ovarian surface epithelial (HOSE) cells were immortalized by a retroviral vector (LXSN-16E6E7) expressing HPV-E6E7 open reading frames (ORF). Immortalizations of primary ovarian epithelial cells were achieved in three of three attempts. Detailed analysis was carried out in one line, HOSE 6-3, selected on the basis of its epithelial morphology. The immortalized line (HOSE 6-3) was nontumorigenic in nude mice when examined at subculture number 20. Cytogenetic analysis confirmed its human origin and detailed karyotypic analysis revealed a mixed karyotype made up of about 60% of diploid and 40% of near-tetraploid cells. Clonal chromosomal aberration was observed in a subpopulation of cells involving a ring chromosome number 9. Immunofluorescence and two-dimensional gel electrophoresis revealed the presence of vimentin and several species of cytokeratin (K7, K8, K18, K19). The profile of the cytoskeletal filaments of HOSE 6-3 cells is largely identical with that of normal ovarian epithelial cells before immortalization. The immortalized ovarian epithelial cells have a lower sensitivity to TGF-beta 1 inhibition compared to normal ovarian epithelial cells. The immortalized line, HOSE 6-3, has altered growth properties including a higher proliferation rate, plating efficiency, and saturation density. The establishment of a continuous line of human ovarian epithelial cells may provide an in vitro model for study of carcinogenesis in human ovarian cancers.
Cell Division↗
Predicting endometrial cancer among older women who present with abnormal vaginal bleeding.
We studied 203 women ages 49 or over who presented with abnormal vaginal bleeding and who underwent either endometrial biopsy or dilation and curettage at the Brigham and Women's Hospital. Using information from the clinical history, we predicted their risk for endometrial cancer (36 patients) or complex endometrial hyperplasia (16 patients). Factors independently associated with endometrial cancer/complex hyperplasia included age 70 or older (OR = 9.1, P = 0.0001), diabetes (OR = 3.7, P = 0.02), and nulliparity (OR = 2.7, P = 0.02). After adjusting for age, menopause was borderline significant (OR = 2.6, P = 0.07). Our data estimated a risk of endometrial cancer/complex hyperplasia of 87% for a woman possessing all of these factors, and a risk of less than 3% if she had none of them. Our model provides an inexpensive, simple means for assessing the risk of endometrial cancer and complex hyperplasia in the post- or perimenopausal woman with abnormal bleeding.
Age Factors↗
Overexpression of the protein tyrosine phosphatase, nonreceptor type 6 (PTPN6), in human epithelial ovarian cancer.
Our current understanding of human ovarian tumorigenesis is limited by the lack of a discrete precursor lesion as well as a limited knowledge of the steps in tumor progression. Since the alterations in the regulation of the tyrosyl residues on various cellular proteins appear to be an important pathway in neoplastic transformation, it is possible that changes in the expression of the proteins that control tyrosine phosphorylation (i.e., tyrosine kinases and phosphatases) may play a role in ovarian cancer development. Protein tyrosine phosphatase, nonreceptor type 6 (PTPN6), contains two src homology 2 domains and is expressed primarily in hematopoietic and epithelial cells. Using Northern blot and immunoblotting analysis, we showed that both the PTPN6 transcripts and proteins were overexpressed two- to four-fold in 7 of the 8 ovarian epithelial carcinoma cell lines studied. In addition, we showed that there was also a two- to threefold increase in expression of the PTPN6 transcript in 10 of 11 (91%) invasive ovarian epithelial cancer tissues examined. These observations suggest that the PTPN6 gene is potentially of etiologic relevance to a majority of ovarian cancers.
Epithelium↗
Case-control study of risk factors for partial molar pregnancy.
OBJECTIVE: The purpose of our study was to identify risk factors for partial molar pregnancy from a woman's general, reproductive, and dietary history. STUDY DESIGN: Sixty-five women with pathologically confirmed partial molar pregnancy were interviewed, and their experiences were compared with those of 130 age-matched control women who had successfully completed a pregnancy with delivery of a live infant at the same hospital during the same calendar period. RESULTS: Multivariate analysis revealed that exposures which independently and significantly predicted increased risk for partial molar pregnancy included irregular cycles, pregnancy histories including only male infants among prior live births, and oral contraceptive use for > 4 years. Dietary factors previously postulated for complete molar pregnancy including protein, fat, vitamin A, or carotene were found not to be related to risk for partial molar pregnancy. CONCLUSION: Epidemiologic patterns for complete and partial molar pregnancies appear to differ somewhat; risk for partial mole is associated with reproductive history but not dietary factors.
Adult↗
Clinicopathologic variables, operative characteristics, and DNA ploidy in predicting outcome in ovarian epithelial carcinoma.
OBJECTIVE: To test the hypothesis that DNA content can predict operative morbidity and survival in patients with ovarian carcinoma. METHODS: Subjects included patients diagnosed with invasive epithelial ovarian carcinoma at Brigham and Women's Hospital between July 1987 and November 1989. Fifty-nine patients were included in this analysis. In all cases, flow cytometry was performed on fresh tissue to evaluate DNA content. The medical records were reviewed in all patients for estimated blood loss, hospitalization days, intensive care unit days, operating room time, presence and size of residual disease, grade and type of tumor, stage, size of primary tumor, lymph node status, disease status, date of last examination, and number of months of follow-up. RESULTS: Predictors for death included increasing age (P = .01), advanced stage (P = .007), the presence of malignant ascites (P = .03), residual tumor at completion of operation (P < .001), increased estimated blood loss (P < .001), increased hospitalization days (P < .001), and increased operating room hours (P < .001). When we controlled for age and stage, only estimated blood loss and residual tumor predicted poor outcome. Deoxyribonucleic acid ploidy, whether stratified as diploid or aneuploid or with DNA index cutoffs, did not predict tumor recurrence or survival rates. CONCLUSION: Deoxyribonucleic acid ploidy has not yet been proven to be of independent prognostic importance for identifying groups of patients at high risk of dying from invasive epithelial ovarian carcinoma.
Adult↗
The changing clinical presentation of complete molar pregnancy.
OBJECTIVE: To determine if the clinical presentation of complete hydatidiform mole has changed in recent years compared with historic controls (1965-1975). METHODS: Chart review of all 74 patients referred to the New England Trophoblastic Disease Center for the primary management of complete hydatidiform mole during 1988-1993 was performed and comparison made to historic controls (1965-1975). RESULTS: Vaginal bleeding remained the most common presenting symptom, occurring in 62 of 74 (84%) current patients, compared with 297 of 306 (97%) controls (P = .001). However, anemia was present in only four of 74 (5%) current patients, compared with 165 of 306 (54%) controls (P = .001). Excessive uterine size, preeclampsia, and hyperemesis occurred in only 21 of 74 (28%), one of 74 (1.3%), and six of 74 (8%) current patients, respectively, compared with 156 of 306 (51%), 83 of 306 (27%), and 80 of 306 (26%), respectively, of historic controls (P = .001). No cases of clinical hyperthyroidism or respiratory distress were found in recent years. Ultrasound diagnosed complete hydatidiform mole before the onset of clinical symptoms in seven of 69 (10%) current patients. Among patients not receiving chemoprophylaxis, persistent gestational trophoblastic tumor developed in 23% of current patients and 18.6% of historic controls. CONCLUSION: Fewer current patients with complete hydatidiform mole present with the traditional symptoms of complete hydatidiform mole (excessive uterine size, anemia, preeclampsia, hyperthyroidism, or hyperemesis) when compared with historic controls. However, there has been no statistically significant change in the development of persistent gestational trophoblastic tumor in current patients compared with historic controls.
Adolescent↗
Prophylactic chemotherapy of complete molar pregnancy.
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Antineoplastic Agents↗
Low-risk metastatic gestational trophoblastic tumors.
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Antineoplastic Agents↗