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Biomedical subjects

S C Rubin

Publications and source records attributed to S C Rubin.

At least 37 records · Page 2Linked to original sources
PubMed1998

Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations.

BACKGROUND: Papillary serous carcinoma of the peritoneum (PSCP) diffusely involves peritoneal surfaces, while it spares or only superficially involves the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. The molecular pathogenesis of PSCP remains unresolved, although preliminary data suggest a multifocal origin in some cases. Patients with germline BRCA1 mutations may develop PSCP in addition to breast and ovarian carcinomas. The purpose of this study was to utilize the androgen receptor (AR) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. METHODS: Specimens of normal and tumor tissues from 22 women with PSCP were obtained, and DNA was extracted. The AR gene locus was evaluated for patterns of loss of heterozygosity (LOH) and X-chromosome inactivation. The methylation-sensitive Hpa II restriction enzyme was used to differentiate the active and inactive X chromosomes. Germline BRCA1 mutation status of the patients was determined previously. RESULTS: Genetic analysis of tumor specimens indicated that five (23%) of 22 case subjects had patterns of selective LOH at the AR locus, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease (two-sided Fisher's exact test, P = .01). CONCLUSIONS: Our results show that PSCP has a multifocal origin in at least some cases. Furthermore, patients with germline BRCA1 mutations are more likely to develop multifocal PSCP than are patients without BRCA1 mutations.

Adult↗
PubMed1998

Identification of oncofetal fibronectin in patients with advanced epithelial ovarian cancer: detection in ascitic fluid and localization to primary sites and metastatic implants.

BACKGROUND: The mechanisms by which metastatic ovarian cancer adheres to peritoneal surfaces are not well understood. A role for tumor-derived extracellular matrix adhesive molecules such as fibronectin (FN) has been proposed. Because oncofetal fibronectin (onfFN) isoforms function in the adhesion of trophoblasts and have been identified in association with several malignancies, we sought to study onfFN in patients with advanced epithelial ovarian cancer. METHODS: Total FN was identified with the nonspecific anti-FN monoclonal antibody CAF. OnfFN was identified using the specific monoclonal antibodies FDC-6 and X18A4. These antibodies were applied to: 1) ascitic fluid from advanced epithelial ovarian cancer patients and peritoneal fluid from patients without pathologic conditions and 2) tissue sections of primary lesions and metastatic ovarian cancer implants. Comparative histologic specimens included normal ovarian tissue and small bowel implants of endometriosis. RESULTS: When measured by sandwich enzyme-linked immunoadsorbent assay, all peritoneal fluids (32 malignant and 32 benign) contained marked quantities of total (CAF reactive) FN, although malignant ascites had higher concentrations than benign samples (173.2 +/- 36.8 microg/mL vs. 76.4 +/- 31.8 microg/mL; P = 0.001). Malignant ascites also had significantly higher levels of onfFN than benign peritoneal fluid (FDC-6: 3.4 +/- 0.6 vs. 0.9 +/- 0.2 microg/mL; and X18A4: 5.1 +/- 1.3 vs. 1.1 +/- 0.4 microg/mL; P = 0.0001). Immunohistochemical staining of malignant lesions revealed prominent localization of both CAF reactive FN and onfFN to the stroma surrounding epithelial tumor nests. More delicate fibrillar staining within tumor nests also was evident. In contrast, implants of endometriosis revealed strong stromal staining for CAF reactive FN but not for onfFN. CONCLUSIONS: These results demonstrate the presence of onfFN in advanced ovarian malignancies. We speculate that onfFN may participate in tumor-associated peritoneal adhesive interactions.

Adenocarcinoma, Clear Cell↗
PubMed1998

Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q.

Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.

Alleles↗
PubMed1998

Endometrial adenocarcinoma with trophoblastic differentiation.

OBJECTIVE: To report a case of stage IIIc poorly differentiated endometrial adenocarcinoma with trophoblastic differentiation and to review previously reported cases. METHODS: The clinical course and histopathology of the case were reviewed, and a literature search for other reported cases was performed. RESULTS: The tumor contained syncytiotrophoblast-like giant cells that stained positively for the beta subunit of human chorionic gonadotropin (beta-hCG), and the patient's serum beta-hCG level was elevated (95 mIU/ml), but became undetectable after treatment. Beta-hCG was used as a tumor marker during further therapy. At 16 months' survival, she remains without evidence of disease and with a beta-hCG (level < 5 mIU/ml). Nine other cases of trophoblastic differentiation in gynecologic nontrophoblastic tumors have been reported, five in endometrial carcinomas which we review. CONCLUSIONS: Trophoblastic differentiation in gynecologic nontrophoblastic tumors is rare. Beta-hCG may be useful as a tumor marker in these cases. The clinical behavior of these tumors has been aggressive, with advanced stages at diagnosis, early widespread metastases or recurrences and poor patient outcomes. The patient presented in this report, however, remains without evidence of disease 16 months following diagnosis and may be the longest survivor with this tumor reported to date.

Adenocarcinoma↗
PubMed1998

Clinical characteristics of clear cell carcinoma of the ovary.

OBJECTIVE: The aim of this study is to evaluate the clinical characteristics of clear cell carcinoma of the ovary. METHODS: Between 1986 and 1996, 45 patients with clear cell carcinoma of the ovary were identified by scanning the medical records department and the tumor registry at our institution. RESULTS: Median age was 55 years (range 31-80 years). Tumors were 60% (27/45) stage I, 11% (5/45) stage II, 20% (9/45) stage III, and 9% (4/45) stage IV. All patients presented with a pelvic mass ranging in size from 2 x 3 to 20 x 30 cm and all except 1 had optimal cytoreduction. All patients received postoperative platinum-based chemotherapy, 47% (21/45) in combination with paclitaxel. One stage Ia patient refused therapy. Of the 6 stage III/IV patients with measurable residual tumor, 67% (4/6) partially responded to first line chemotherapy by CT scan or second look laparotomy. Recurrences occurred in 37% (10/27) stage I patients, including 18% (2/11) stage Ia, 33% (1/3) stage Ib, and 54% (7/13) stage Ic. Time to recurrence was 16 and 38 months for the two stage Ia patients and 35 months (median, range 18-56 months) for the stage Ic patients. Survival after recurrence was significantly related to disease-free interval after primary chemotherapy. With a median follow-up of 40 months (range 4-145 months), 93% (25/27) of stage I patients are alive, 20% (5/25) with disease, while 46% (6/13) of stage III/IV patients are alive. Median survival for the stage III/IV patients was 22 months (range 4-70 months). CONCLUSIONS: Clear cell tumors of ovary frequently present at early stages. However, these tumors have a propensity for recurrence even after primary chemotherapy in early stage tumors.

Adenocarcinoma, Clear Cell↗
PubMed1998

Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient.

A patient with breast carcinoma diagnosed at the age of 30 years and ovarian carcinoma diagnosed at the age of 41 years was found to have germline mutations in both the BRCA1 and the BRCA2 genes. The patient was of Ashkenazi Jewish descent and the BRCA2 mutation was 6174delT, known to be very common in this population. The BRCA1 mutation, however, was 3888delGA, a mutation not previously reported in this ethnic group. The patient's breast cancer exhibited loss of heterozygosity (LOH) at the BRCA1 locus but not at BRCA2, and her ovarian cancer sustained LOH at BRCA1 and BRCA2. The BRCA1 mutation originated from patient's father, who had no personal or family history of cancer. The patient's mother, who was found to carry the BRCA2 mutation, was affected by late-onset breast cancer and her tumor exhibited LOH at BRCA2. These findings indicate that compound heterozygotes for germline mutations of BRCA1 and BRCA2 exist and may be expected to develop normally and that either gene may contribute to breast or ovarian cancer development in such individuals. The implications of this case in regard to genetic testing and counseling are also substantial.

Adult↗
PubMed1998

BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing.

OBJECTIVE: Our purpose was to determine the prevalence of BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in a large, unselected population of ovarian cancer patients and to evaluate the relationship between mutation status and a routinely obtained family history of cancer. STUDY DESIGN: One hundred sixteen consecutive ovarian cancer patients seen for routine clinical care were examined for BRCA1, BRCA2, hMSH2, and hMLH1 gene mutations with use of the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct gene sequencing. Fisher's exact test was used to evaluate possible associations between BRCA1 and BRCA2 mutation status and specific familial characteristics. RESULTS: Among 116 unselected ovarian cancer patients we identified a total of 13 germline mutations in 12 patients: 10 in BRCA1, one each in hMSH2 and hMLH1, and a single BRCA2 mutation, which occurred in a patient also carrying a BRCA1 mutation. More than half the patients with BRCA1 mutations had family histories that would generally be considered unremarkable. Of 22 family history variables analyzed, only two (maternal family history of breast or ovarian cancer, p=0.037, and maternal family history of any cancer, p=0.020) conferred a significantly increased risk of carrying a BRCA1 mutation compared with ovarian cancer patients without such a history. However, the majority of ovarian cancer patients with these family histories and other suggestive histories tested negative for mutations. CONCLUSIONS: Approximately 10% of ovarian cancers occur in association with genetic mutations known to predispose to the disease. A routinely obtained family history is an unreliable way to identify patients who might harbor mutations. The majority of ovarian cancer patients with suggestive family histories test negative for known gene mutations, perhaps suggesting the existence of additional undiscovered genes predisposing to ovarian cancer.

Adult↗
PubMed1998

Chemotherapy resistance in ovarian cancer: new molecular perspectives.

OBJECTIVE: To provide the obstetrician-gynecologist with the recent advances in mechanisms of chemotherapy resistance in ovarian cancer. DATA SOURCES: A computerized search of articles published through September 1997 was performed on the MEDLINE Ovid and Cancerlit databases. Additional references were identified from the reference section of all selected papers. METHODS OF STUDY SELECTION: All identified references were evaluated as to their relevant contribution to our understanding of the basic mechanisms underlying the response to chemotherapy, the development of chemotherapy resistance in ovarian cancer, and possible strategies for therapy. TABULATION, INTEGRATION, AND RESULTS: One hundred sixteen references were reviewed. A brief summary of the classic concepts on resistance to cisplatin and paclitaxel is provided, followed by a description of the basic mechanisms governing apoptosis and cell cycle arrest as well as their involvement in cell response to chemotherapy and the development of chemoresistance. Finally, a brief summary of the molecular alterations described in ovarian cancer, together with hypothetic strategies for gene-targeted therapy, are reported. CONCLUSION: Cisplatin or paclitaxel chemotherapy induces arrest of the cell cycle or apoptosis in ovarian cancer cells. Tumor suppressor genes such as p53 play a paramount role in mediating this response and p21wAF1/CIP1 is a major mediator of p53-induced arrest of the cell cycle. Molecular alterations involving these tumor suppressor genes are related to the development of resistance to chemotherapy and represent possible targets for gene therapy in ovarian cancer.

Antineoplastic Agents↗
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

Modern treatment options in epithelial ovarian carcinoma.

Treatment options for epithelial ovarian cancers are under constant evolution. Recent advances have occurred in both first-line and second-line chemotherapeutic regimens. A newly published approach to first-line therapy incorporating intraperitoneal chemotherapy has demonstrated a benefit in selected patients. There are several new drugs showing activity in platinum-resistant epithelial ovarian cancer.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group Study.

PURPOSE: To determine the response rate of intraperitoneal (i.p.) paclitaxel in patients with small-volume residual carcinomas of the ovary, fallopian tube, or peritoneum. PATIENTS AND METHODS: Eligibility criteria included patients with one of the cancers noted above, with the largest residual disease 0.5 cm or less in maximum diameter at the end of second-look surgery, and prior treatment with systemic paclitaxel was permitted. The treatment plan was paclitaxel 60 mg/m2 i.p. weekly for 16 weeks, followed by surgical evaluation in patients without evidence of disease progression. RESULTS: Of 80 patients entered onto the study, 76 were eligible, of whom 86% were considered to be potentially cisplatin-sensitive. Although five patients (7%) did not complete the first course of therapy because of catheter leakage or blockade, 53 patients (70%) received all 16 planned courses. Only 14 patients (18%) received fewer than 11 courses. Treatment was well tolerated, which included only moderate abdominal pain (grade 2, 12 patients; grade 3, one patient) and minimal neutropenia (grade 2, three patients; grade 3, one patient). Of 28 assessable patients with microscopic disease at the start of i.p. therapy, 17 patients (61%) achieved a surgically defined complete response (CR). Only one of 31 patients (3%) with any macroscopic disease achieved a CR. Of the eligible patients, 18 of 76 (24%) achieved a CR. CONCLUSION: Salvage i.p. paclitaxel is tolerable and active in patients with microscopic residual disease. The impact of this treatment strategy on survival remains to be assessed in a phase III trial.

Aged↗
PubMed1997

Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma.

Previous allelotyping studies of epithelial ovarian carcinoma suggest that loss of heterozygosity on chromosome 14q may be a common genetic alteration in this tumor type. The purpose of this study was to determine a precise frequency of chromosome 14q allelic loss in ovarian carcinomas and to define a minimal region(s) of deletion. Seventy-six ovarian carcinomas representative of the complete spectrum of grade, stage, and histological subtype were selected for PCR-based deletion mapping analysis using 15 highly polymorphic microsatellite markers spanning the length of this chromosome arm. Loss of heterozygosity was observed in 49% of the tumors studied, placing 14q among the most frequently affected chromosomal regions in ovarian cancer. Deletions were observed in all tumor grades and stages and in all histological subtypes except tumors of low malignant potential. Deletion of the entire chromosome arm was rare; the majority of tumors displayed partial losses, providing an informative basis for detailed deletion mapping. Two distinct minimal regions of deletion were delineated. One region was defined by markers D14S80 and D14S75 at 14q12-13, and the other region was defined by markers D14S65 and D14S267 at 14q32. These data implicate the involvement of two tumor suppressor genes on chromosome 14q in a substantial fraction of ovarian carcinomas.

Chromosome Deletion↗
PubMed1997

Effect of surgical debulking on survival in stage IV ovarian cancer.

In order to determine whether optimal surgical debulking in Stage IV epithelial ovarian cancer impacts survival, a retrospective review of patients treated at the University of Pennsylvania Cancer Center (UPCC) from 1984 to 1995 diagnosed with Stage IV epithelial ovarian cancer was performed. Data were collected regarding grade, histology, reason for allocation to Stage IV, extent of surgery performed and residual disease at initial staging procedure, major perioperative complications, first-line chemotherapy regimen, length of inpatient hospital stay, outcome at second-look laparotomy, follow-up, and survival. For the purposes of this study, optimal cytoreduction was defined as a residual disease of 2 cm or less. Forty-seven patients with Stage IV epithelial ovarian cancer identified in the Society of Gynecologic Oncologists (SGO) Database at UPCC are included. Fourteen of 47 (30%) were optimally cytoreduced at the time of their staging procedure. Twenty-six of 47 (55%) were deemed Stage IV by virtue of positive pleural effusion cytology only. Twenty-one of 47 (45%) had intraparenchymal liver involvement or metastatic disease outside of the abdomen. The median survival of the suboptimally debulked group was 17 months, while median survival in the optimal group was 37 months (P = 0.0295). These data suggest that Stage IV epithelial ovarian cancer patients with less than 2 cm residual disease have a survival advantage over patients with greater than 2 cm residual.

Female↗
PubMed1997

Hereditary ovarian cancer: molecular genetics and clinical implications.

Epidemiologic data support the existence of two discrete manifestations of hereditary ovarian carcinoma: the breast and ovarian cancer syndrome and the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Genetic linkage analyses reveal that the majority of breast and ovarian cancer families are linked to the BRCA1 gene, while some cases of hereditary ovarian cancer are also apparent in breast cancer families linked to the BRCA2 gene. The majority of HNPCC families are linked to one of four genes encoding a family of DNA mismatch repair proteins. Molecular analyses demonstrate that genetic screening for germline transmission of a defective allele of one or another of these genes is now possible for high-risk individuals. The ethical, legal, and social implications of this type of analysis are multiple and complex, and genetic counseling requires a thorough understanding of these issues and a cautious approach to most effectively meet the special needs of this patient population. Increased medical surveillance and prophylactic oophorectomy are among the management options that may be appropriate for some genetically predisposed, asymptomatic women. Further research is needed regarding the most effective use of this genetic information in formulating counseling and clinical management strategies.

BRCA2 Protein↗
PubMed1997

Cycles of dose-intensive chemotherapy with peripheral stem cell support in persistent or recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. METHODS: Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m2) and cyclophosphamide (1.5 g/m2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. RESULTS: Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0-35%). CONCLUSION: Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.

Adult↗
PubMed1996

Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.

BACKGROUND: We tested the hypothesis that ovarian cancers associated with germ-line mutations of BRCA1 have distinct clinical and pathological features as compared with sporadic ovarian cancers. METHODS: We reviewed clinical and pathological data on patients with primary epithelial ovarian cancer found to have germ-line mutations of BRCA1. Survival among patients with advanced-stage cancer and such mutations was compared with that in control patients matched stage, grade, and histologic subtype of the tumors. A combination of single-strand conformation and sequencing analyses was used to examine the 22 coding exons and intronic splice-donor and splice-acceptor regions of BRCA1 for mutations in pathological specimens. Alternatively, some patients were known to be obligate carriers of the mutant BRCA1 gene because of their parental relationships with documented mutant-gene carriers. RESULTS: We identified 53 patients with germ-line mutations of BRCA1. The average age at diagnosis was 48 years (range, 28 to 78). Histologic examination in 43 of the 53 patients showed serous adenocarcinoma. Thirty-seven tumors were of grade 3, 11 were of grade 2, 2 were of grade 1, and 3 were of low malignant potential. In 38 patients, the tumors were of stage III; 9 patients (including those with tumors of low malignant potential) had stage I disease, 5 had stage IV, and 1 had stage II. As of June 1996, with a median follow-up among survivors of 71 months from diagnosis, 20 patients had died of ovarian cancer, 27 had no evidence of the disease, 4 were alive with the disease, and 2 had died of other diseases. Actuarial median survival for the 43 patients with and advanced-stage disease was 77 months, as compared with 29 months for the matched controls (P<0.001). CONCLUSIONS: As compared with sporadic ovarian cancers, cancers associated with BRCA1 mutation appear to have a significantly more favorable clinical course.

Actuarial Analysis↗