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R S Berkowitz

Publications and source records attributed to R S Berkowitz.

At least 55 records · Page 3Linked to original sources
PubMed1998

Evidence for the multifocal origin of bilateral and advanced human serous borderline ovarian tumors.

Borderline ovarian tumors (BOTs), or ovarian tumors of low malignant potential, represent a distinct category of epithelial ovarian neoplasms that have a clinically more favorable outcome than invasive epithelial ovarian cancer. Histologically, BOTs and invasive ovarian carcinomas both show cellular proliferation and pleomorphism, but unlike invasive ovarian carcinomas, BOTs lack stromal invasion. Although serous BOTs are frequently confined to a single ovary at the time of diagnosis, bilateral or extra-ovarian spread occurs in 30-40% of cases. The purpose of this study is to determine whether bilateral or extraovarian serous borderline lesions are metastatic sites from the original tumor, or represent separate primary tumors. DNA specimens from multiple tumor sites and normal tissue controls were obtained in eight women with bilateral or extra-ovarian serous borderline tumors. The pattern of loss of heterozygosity at the androgen receptor locus on the X chromosome was evaluated in the multiple tumor sites. In addition, the pattern of X-chromosome inactivation was determined using HpaII restriction endonuclease digestion, followed by PCR amplification of the androgen receptor locus. Multifocality was determined when alternate patterns of X-chromosome inactivation occurred. In two of the eight patients, the left and right ovarian tumor sites had different androgen receptor alleles inactivated, indicating that the bilateral tumors derived independently. In a third patient, the X inactivation pattern in the left ovarian tumor differed from the two peritoneal implants, suggesting that the implants were separate primary tumors, and not metastatic, from the left ovarian tumor. The remaining five patients had the same pattern of loss of heterozygosity and X inactivation in the tumor sites studied. These results suggest that bilateral and advanced stage serous BOTs may be multifocal in origin. This result is in contrast to invasive epithelial ovarian cancer, which has been shown to be unifocal in origin.

Adult↗
PubMed1998

DOC-2, a candidate tumor suppressor gene in human epithelial ovarian cancer.

Using RNA fingerprinting (RAP) strategy and Northern blot analysis, we identified a differentially expressed sequence DOC-2 which is detectable in all normal human ovarian surface epithelial (HOSE) cell cultures but not in ovarian cancer cell lines and tissues. Subsequent cloning of DOC-2 from a cDNA library generated from the HOSE cells was carried out using the 3' and 5' RACE approach. A 3268 base pair full length cDNA of DOC-2 was isolated and sequenced. The predicted protein has a length of 770 amino acids. Homology search of all NCBI sequences indicated that the amino acid sequence of DOC-2 shares 93% homology with the mouse p96/mDab2 phosphoprotein and has a phosphotyrosine interacting domain (PID) and multiple SH3 binding motifs. Chromosomal localization by FISH showed that the DOC-2 gene is located on 5p13. Western blot analysis showed that the 105 kDa DOC-2 protein was down-regulated in all the carcinoma cell lines. In-situ immunohistochemistry performed on normal ovaries, and benign, borderline and invasive ovarian tumor tissues showed down regulation of DOC-2 protein particularly in serous ovarian tumor tissues. When DOC-2 was transfected into the ovarian carcinoma cell line SKOV3, the stable transfectants showed significantly reduced growth rate and ability to form tumors in nude mice. These data suggest that down-regulation of DOC-2 may play an important role in ovarian carcinogenesis.

Adaptor Proteins, Signal Transducing↗
PubMed1998

A novel 4 cM minimal deletion unit on chromosome 6q25.1-q25.2 associated with high grade invasive epithelial ovarian carcinomas.

Detailed deletion mapping of chromosome 6q has shown that the highest percentage of loss of heterozygosity (LOH) is located at 6q25-q27 and suggested that an ovarian cancer associated tumor suppressor gene may reside in this region. To further define the smallest region of common loss, we used 12 tandem repeat markers spanning a region no more than 18 cM, located between 6q25.1 and 6q26, to examine allelic loss in 54 fresh and paraffin embedded invasive ovarian epithelial tumor tissues. Loss of heterozygosity was observed more frequently at the loci defined by marker D6S473 (14 of 32 informative cases, 44%) and marker D6S448 (17 of 40 informative cases, 43%). Detailed mapping of chromosome 6q25-q26 in these tumor samples identified a 4 cM minimal region of LOH between markers D6S473 and D6S448 (6q25.1-q25.2). Loss of heterozygosity at D6S473 correlated significantly both with serous versus non-serous ovarian tumors (P=0.040) and with high grade versus low grade specimens (P=0.023). The results suggest that a 4 cM deletion unit located at 6q25.1-q25.2 may contain the putative tumor suppressor gene which may play a role in the development and progression of human invasive epithelial ovarian carcinomas (IEOC).

Adenocarcinoma, Mucinous↗
PubMed1998

A one centimorgan deletion unit on chromosome Xq12 is commonly lost in borderline and invasive epithelial ovarian tumors.

We have used polymerase chain reaction (PCR) amplification of tandem repeats to study the pattern of allelic loss on chromosome X11.2-q12 in borderline and invasive epithelial ovarian tumors. Using eight microsatellite markers spanning Xq11.2-q12, 41 borderline and 65 invasive ovarian tumors, together with their corresponding normal tissues, were analysed. The highest percentage of loss of heterozygosity (LOH) was observed at the DXS1194 locus in borderline tumors (four of 16 informative cases, 25%) and at the androgen receptor (AR) locus in invasive epithelial ovarian tumors (18 of 47 informative cases, 38%). X chromosome activation studies performed in cases with LOH at the AR locus showed that the allelic loss at the AR locus is not confined to the inactive allele. A one centimorgan region including the AR locus and flanked by the primers DXS1161 and PGK1P1 was identified as the smallest common loss region in both borderline and invasive epithelial ovarian tumors.

Alleles↗
PubMed1998

BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum.

OBJECTIVE: To compare BRCA1 mutations in papillary serous carcinoma of the peritoneum and papillary serous ovarian carcinoma. METHODS: Germline DNA from 17 consecutive patients with peritoneal carcinoma was screened for mutations in the BRCA1 gene using single-strand conformation polymorphism analysis. Shifted DNA bands were sequenced. Patients with germline BRCA1 mutations were screened for allelic loss in tumor DNA at the BRCA1 locus. RESULTS: Two of the 17 patients (11%, 95% confidence interval 0.07, 0.37) exhibited the 185 delAG germline BRCA1 mutation described in the Ashkenazi Jewish population. The family history of one patient was notable for a mother and five aunts with breast or ovarian cancer. The other patient had a personal history of breast cancer. Both patients exhibited allelic loss of the normal BRCA1 allele in their tumor. A third patient was found to have a previously undescribed exon 11 single base pair substitution at nucleotide 1239 (CAG to CAC) resulting in a missense mutation (Gln to His). The patient had no family or personal history of breast or ovarian cancer, and her tumor did not exhibit loss of heterozygosity. CONCLUSION: Germline BRCA1 mutations occur in papillary serous carcinoma of the peritoneum with a frequency comparable to the BRCA1 mutation rate in ovarian cancer. Although the penetrance is unknown, peritoneal carcinoma should be considered a malignancy expressed in the familial breast ovarian cancer syndrome.

Cystadenocarcinoma, Papillary↗
PubMed1998

Recent advances in gestational trophoblastic disease.

Important advances continue to occur in both our understanding and management of gestational trophoblastic disease. Complete molar pregnancy is being diagnosed earlier in pregnancy which affects its clinical and pathological presentation. The use of chemotherapy in persistent gestational trophoblastic tumors continues to be refined and our understanding of the immunobiology of these tumors has substantially advanced.

Antigens, Neoplasm↗
PubMed1998

Complete molar pregnancy. Clinical trends at King Fahad Hospital, Riyadh, Kingdom of Saudi Arabia.

OBJECTIVE: To describe the clinical trends of complete hydatidiform mole at the King Fahad Hospital (KFH), Riyadh, Saudi Arabia. METHODS: Medical record review of 71 patients admitted to KFH for the primary management of complete hydatidiform mole (CHM) during the period 1984-1995 was performed, and clinical trends were identified. RESULTS: During the study period, 48,000 live births occurred, and a total of 71 patients were admitted for management of CHM; the incidence of CHM was 1:676 live births. The mean gestational age at molar evacuation was 13.3 weeks, and 54.4% of patients were diagnosed in the first trimester. At the time of presentation, excessive uterine size, anemia, hyperemesis and preeclampsia were present in 20 (28%), 11 (15.5%), 9 (12.6%) and 1 (1.4%) patient, respectively. Persistent gestational trophoblastic tumor developed in 32 (45.1%) patients. CONCLUSION: A higher proportion of our CHM patients developed persistent gestational trophoblastic tumors when compared with those in North American studies. CHM was diagnosed earlier in pregnancy in Saudi Arabia at our hospital during the past decade, and the patients frequently did not present with the classic signs and symptoms of complete mole.

Adolescent↗
PubMed1998

Reproductive outcome after methotrexate treatment of tubal pregnancies.

OBJECTIVE: To evaluate subsequent pregnancy outcomes in women who have been treated with methotrexate for tubal pregnancies. METHODS: Descriptive study of subsequent pregnancy outcomes in 170 women who were treated with methotrexate for tubal pregnancy at Brigham and Women's Hospital during 1989-1994. Patients who agreed to participate were administered a telephone interview. Fertility rates and outcomes were calculated for patients who tried to conceive after receiving methotrexate. RESULTS: One hundred four of the 170 women with tubal pregnancies identified during the study period returned their consent forms. The other 66 patients were either unable to be reached by phone, and/or their consent form was returned without a forwarding address. Ninety-four patients (90%) agreed to participate in the study. Eighty-two (87%) women tried to conceive after receiving methotrexate for their tubal pregnancies, and 57 (70%) were successful. Forty-six (81%) of the 57 women experienced intrauterine pregnancies, and 11 (19%) had recurrent tubal pregnancies. When the first subsequent postmethotrexate outcome was examined, there were 26 (46%) term births, 5 (9%) preterm births, 11 (19%) recurrent ectopics and 15 (26%) spontaneous abortions. Over the six-year study period, 42 (74%) women had at least one live birth. There were no congenital anomalies or stillbirths in the subsequent pregnancies. CONCLUSION: Pregnancy outcomes after methotrexate treatment for tubal pregnancy are comparable to reported experience with surgical therapy. Patients who are treated with methotrexate for tubal pregnancies can be assured that their methotrexate exposure should have no untoward effects on subsequent pregnancies.

Female↗
PubMed1998

Revised FIGO staging system for gestational trophoblastic tumors. Recommendations regarding therapy.

OBJECTIVE: To evaluate the revised International Federation of Gynecology and Obstetrics (FIGO) staging system for gestational trophoblastic tumors (GTT) and to recommend therapy. STUDY DESIGN: Review of the literature regarding the development of the FIGO staging system, the World Health Organization (WHO) prognostic scoring system and Hammond's clinical classification for GTT plus analysis of response to single-agent chemotherapy in 546 patients treated at the New England Trophoblastic Disease Center. RESULTS: The revised FIGO staging system appears to successfully combine anatomic staging and a prognostic clinical classification. The revised FIGO staging system reliably predicts treatment outcome and therefore can be used to help select optimal treatment protocols. CONCLUSION: The revised FIGO staging system is capable of predicting patients who respond poorly to single-agent chemotherapy, appears to reliably predict outcome and therefore can be used to help select appropriate treatment protocols.

Antimetabolites, Antineoplastic↗
PubMed1998

Natural history of postterm choriocarcinoma.

OBJECTIVE: To review the 32-year experience of the New England Trophoblastic Disease Center (NETDC) with choriocarcinoma occurring after a term gestation and to evaluate potential prognostic factors using the World Health Organization (WHO) prognostic score. STUDY DESIGN: The charts of 44 women who were treated for postterm choriocarcinoma at the NETDC from August 1964 to January 1996 were retrospectively reviewed. Demographic data and details of the clinical course were determined. Potential risk factors, including disease duration, pretreatment human chorionic gonadotropin (hCG) level, sites of metastases and stage, as well as data regarding the infants and previous and subsequent pregnancies, were evaluated. RESULTS: Five (11%) of the infants suffered significant complications secondary to maternal choriocarcinoma. The time interval from delivery to diagnosis, pretreatment hCG level and sites of metastatic disease were all significant risk factors in predicting outcome. All 31 patients with a WHO score < or = 8 survived, and 6/13 (46%) patients with a WHO score > 8 died. CONCLUSION: Disease duration greater than four months from delivery, pretreatment hCG level > 100,000 mIU/mL, presence of liver or brain metastases, and a WHO score > 8 were all important predictors of outcome in patients with postterm choriocarcinoma.

Adolescent↗
PubMed1998

Gestational trophoblastic disease. Subsequent pregnancy outcome, including repeat molar pregnancy.

OBJECTIVE: To determine subsequent reproductive outcomes in patients treated for partial molar pregnancy, complete molar pregnancy and persistent gestational trophoblastic tumors at the New England Trophoblastic Disease Center (NETDC) between June 1, 1965, and December 31, 1996. STUDY DESIGN: Questionnaires were mailed to all patients followed at the NETDC to assess subsequent pregnancy experience. All patients and their referring physicians were also requested to inform the NETDC about later pregnancies. RESULTS: Following partial mole, complete mole and persistent gestational trophoblastic tumor, our patients had 195, 1,234 and 504 later pregnancies, respectively. These patients had a later pregnancy experience comparable to that of the general population. However, after having one molar pregnancy, the risk of molar pregnancy in a later conception was about 1%. Twenty-nine of our patients had at least two episodes of molar pregnancy; following two episodes of molar pregnancy, 6 (23.1%) of 26 later conceptions resulted in another molar gestation. CONCLUSION: Patients with partial mole, complete mole and persistent gestational trophoblastic tumor can be reassured that in general they can anticipate a normal future reproductive outcome.

Female↗
PubMed1998

c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma.

OBJECTIVE: To determine the expression of bcl-2, c-myc, c-fms and c-erbB-2 oncoproteins in normal placentas, partial and complete hydatidiform moles, and choriocarcinomas and to examine the possible presence of mutations in the K-ras gene in complete moles and choriocarcinomas. STUDY DESIGN: The expression of the above oncoproteins was determined immunohistochemically by specific antibodies for these proteins on formalin-fixed paraffin sections of 18 normal placentas, 17 partial moles, 25 complete moles and 11 choriocarcinomas. This was followed by polymerase chain reaction analysis (exons 12 and 13) of K-ras gene for possible mutations in complete moles and choriocarcinomas. RESULTS: Expression of c-fms oncoprotein appeared confined to the cytoplasm of syncytiotrophoblastic cells. The c-fms protein staining intensity of the syncytiotrophoblastic layer showed no significant difference among the four gestational tissues. c-erbB-2 antibody expression was confined to the cellular membrane of the extravillous trophoblast. When compared with normal placenta or partial mole, the expression of c-erbB-2 protein was significantly stronger in complete mole (P < .0001 and P < .0001, respectively) and choriocarcinoma (P < .0001 and P < .0001, respectively). Expression of bcl-2 protein was significantly stronger in the syncytiotrophoblast in complete mole and choriocarcinoma as compared to both normal placenta and partial mole (P < .0001 and P < .0001, respectively). Staining of c-myc of the syncytiotrophoblastic layer was significantly stronger in placenta, complete mole and choriocarcinoma than in partial mole (P < .0001, P < .0001 and P < .0001, respectively). Mutation in K-ras gene was not found in any of the 22 complete moles or 11 choriocarcinomas examined. CONCLUSION: Our data suggest that c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma. However, while both complete mole and choriocarcinoma were characterized by overexpression of c-myc, c-erbB-2 and bcl-2, partial mole generally did not strongly express these three oncoproteins.

Cell Membrane↗
PubMed1998

p53, p21, Rb and mdm2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma.

OBJECTIVE: To determine the expression of p53, p21, Rb and mdm2 proteins in normal placentas, partial and complete hydatidiform moles, and choriocarcinomas and to examine possible p53 mutations in specimens from p53-positive cases. STUDY DESIGN: Expression of the above oncoproteins was determined immunohistochemically by specific antibodies for these proteins on formalin-fixed paraffin sections of 18 normal placentas, 17 partial moles, 25 complete moles and 11 choriocarcinomas. This was followed by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis (exons 5, 6, 7, 8, 9, 10, 11) for possible p53 mutation in specimens from p53-positive cases of complete mole and choriocarcinoma. RESULTS: p53 Oncoprotein immunoreactivity was significantly stronger in complete mole and choriocarcinoma than in normal placenta (P < .0001, P < .0001) and in partial mole (P < .0001, P < .0001). Positive staining for p21 oncoprotein was also significantly stronger in complete mole (P < .0001, P < .0001) and in choriocarcinoma (P < .0001, P < .0001) than in placenta and partial mole. We found significantly stronger staining for Rb protein in complete mole (P < .03) and choriocarcinoma (P < .03) than in partial mole. Partial mole and complete mole expressed significantly stronger staining of mdm2 than placenta (P < .007, P < .07, respectively). We found only one nonsense mutation in p53 with PCR analysis; that strongly suggests that in complete mole and choriocarcinoma the overexpressed p53 protein was wild type. CONCLUSION: Altered expression of p53, p21, Rb and mdm2 may be important in the pathogenesis of both complete mole and choriocarcinoma. However, unlike complete molar pregnancy, partial mole is not characterized by overexpression of p53. Overexpression of p53 and mdm2 proteins in complete mole and choriocarcinoma may be associated with more aggressive behavior in gestational trophoblastic disease.

Choriocarcinoma↗
PubMed1997

Identification of a 1300 kilobase deletion unit on chromosome 7q31.3 in invasive epithelial ovarian carcinomas.

We have used polymerase chain reaction (PCR) amplification of tandem repeats to study the pattern of allelic loss on chromosome 7q31 in invasive epithelial ovarian carcinomas and borderline ovarian tumors. Using 13 primer sets spanning loci from 7q31 to 7q32, 16 borderline and 54 invasive ovarian tumor tissue, together with their corresponding normal tissue, were analysed. Invasive epithelial ovarian tumors demonstrated loss of heterozygosity (LOH) at one or more loci on 7q in 32 of 54 cases (59%). The invasive epithelial ovarian tumors demonstrated the highest percentage of LOH at the loci D7S643 (20 of 40 informative cases, 50%) and GATA44F09 (18 of 42 informative cases, 43%). In contrary, only one borderline ovarian tumor showed LOH at one locus (GATA44F09, one of 14 informative cases, 7%). Our results display a sharp contrast in the pattern of LOH between invasive and borderline ovarian tumors suggesting that allelic loss at chromosome 7q31.3 may be involved in the development and progression of invasive epithelial ovarian tumors but not borderline ovarian tumors. Further analysis of the deletion map for the invasive epithelial ovarian tumors showed two regions likely to harbor ovarian tumor suppressor genes including a novel 1300 kilobase common loss region flanked by GATA44F09 and D7S643.

Alleles↗
PubMed1997

A novel 4-cM minimally deleted region on chromosome 11p15.1 associated with high grade nonmucinous epithelial ovarian carcinomas.

Prior cytogenetic and restriction fragment length polymorphism studies have demonstrated that allelic deletion of chromosome 11p is common in human invasive epithelial ovarian tumors. To construct a highly detailed deletion map of chromosome 11p, we used 13 polymorphic microsatellite CA repeat primers to identify regions harboring potential tumor suppressor genes. Twenty-three of 48 samples (48%) of invasive epithelial ovarian cancer showed LOH involving at least one locus, consistent with prior studies. None of the five mucinous tumors showed allelic deletion at any of the 13 primers, suggesting that loss of heterozygosity at chromosome 11p may not be involved in the pathogenesis of mucinous ovarian cancer. Two separate minimally deleted regions were identified in nonmucinous ovarian cancer. The first is an 11-cM region on chromosome 11pl5.5-15.3 that extends from D11S2071 to D11S988 and includes the HRAS locus. The second is a novel 4-cM region on 11p15.1, defined by marker D11S1310. Deletion of both regions at 11p15.5-15.3 and 11p15.1 is strongly associated with high grade nonmucinous epithelial ovarian cancer.

Chromosome Deletion↗
PubMed1997

The management of gestational trophoblastic tumors with etoposide, methotrexate, and actinomycin D.

OBJECTIVE: To evaluate the efficacy and safety of etoposide, methotrexate, and actinomycin D (EMA) as primary and secondary therapy for gestational trophoblastic tumor (GTT). METHODS: In a retrospective study, the medical records of all patients with middle-risk metastatic GTT or nonmetastatic choriocarcinoma receiving primary EMA and patients with GTT resistant to single-agent regimens treated with secondary EMA were reviewed. Hematologic toxicity was graded using WHO criteria. RESULTS: Seven patients received primary EMA with 5 (67%) achieving remission. Twenty-two patients with resistance to single-agent regimens received secondary EMA with 21 (95%) achieving remission. The most acute hematologic toxicity was grade 1 or 2. Only 2 of 90 EMA cycles were associated with grade 4 toxicity requiring hospital admission. CONCLUSION: Although EMA effectively induces remission with minimal acute hematologic toxicity in the primary and secondary therapy of GTT, recently published data regarding secondary tumors associated with etoposide exposure should restrict its use to patients who absolutely require etoposide to achieve remission.

Adult↗
PubMed1997

Enhancement of 131I-mediated cytotoxicity by caffeine.

In cell culture, caffeine has been shown to enhance the lethality of DNA-damaging agents including ultraviolet rays, X-irradiation, and alkylating agents. We have previously reported a Phase I clinical trial demonstrating the feasibility of intraperitoneal radioimmunotherapy in patients with refractory ovarian cancer using 131I-labeled monoclonal antibody OC125. We are now exploring the possibility of using caffeine to enhance the toxicity of 131I-irradiation in target cells. As an in vitro model we tested this hypothesis using Chinese hamster ovary (CHO) cells exposed to 131I-labeled human serum albumin at various doses (4 to 70 microCi/ml) for 24 hr followed by 24 hr of incubation with caffeine. Cytotoxicity was measured by clonogenic survival and a nuclear fragmentation assay. The results show that caffeine, at a concentration of 7.7 mM, significantly enhances the cytotoxicity of 131I-irradiation.

Animals↗