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Biomedical subjects

D A Fishman

Publications and source records attributed to D A Fishman.

At least 19 recordsLinked to original sources
PubMed2004

High-resolution serum proteomic features for ovarian cancer detection.

Serum proteomic pattern diagnostics is an emerging paradigm employing low-resolution mass spectrometry (MS) to generate a set of biomarker classifiers. In the present study, we utilized a well-controlled ovarian cancer serum study set to compare the sensitivity and specificity of serum proteomic diagnostic patterns acquired using a high-resolution versus a low-resolution MS platform. In blinded testing sets, the high-resolution mass spectral data contained multiple diagnostic signatures that were superior to the low-resolution spectra in terms of sensitivity and specificity (P<0.00001) throughout the range of modeling conditions. Four mass spectral feature set patterns acquired from data obtained exclusively with the high-resolution mass spectrometer were 100% specific and sensitive in their diagnosis of serum samples as being acquired from either unaffected patients or those suffering from ovarian cancer. Important to the future of proteomic pattern diagnostics is the ability to recognize inferior spectra statistically, so that those resulting from a specific process error are recognized prior to their potentially incorrect (and damaging) diagnosis. To meet this need, we have developed a series of quality-assurance and in-process control procedures to (a) globally evaluate sources of sample variability, (b) identify outlying mass spectra, and (c) develop quality-control release specifications. From these quality-assurance and control (QA/QC) specifications, we identified 32 mass spectra out of the total 248 that showed statistically significant differences from the norm. Hence, 216 of the initial 248 high-resolution mass spectra were determined to be of high quality and were remodeled by pattern-recognition analysis. Again, we obtained four mass spectral feature set patterns that also exhibited 100% sensitivity and specificity in blinded validation tests (68/68 cancer: including 18/18 stage I, and 43/43 healthy). We conclude that (a) the use of high-resolution MS yields superior classification patterns as compared with those obtained with lower resolution instrumentation; (b) although the process error that we discovered did not have a deleterious impact on the present results obtained from proteomic pattern analysis, the major source of spectral variability emanated from mass spectral acquisition, and not bias at the clinical collection site; (c) this variability can be reduced and monitored through the use of QA/QC statistical procedures; (d) multiple and distinct proteomic patterns, comprising low molecular weight biomarkers, detected by high-resolution MS achieve accuracies surpassing individual biomarkers, warranting validation in a large clinical study.

Biomarkers, Tumor↗
PubMed2001

Lysophosphatidic acid promotes matrix metalloproteinase (MMP) activation and MMP-dependent invasion in ovarian cancer cells.

Ovarian cancer is an highly metastatic disease characterized by ascites formation and diffuse i.p. adhesion, invasion, and metastasis. Levels of lysophosphatidic acid (LPA) are elevated in the plasma of patients with ovarian carcinoma, including 90% of patients with stage I disease, suggesting that LPA may promote early events in ovarian carcinoma dissemination. Expression of matrix metalloproteinases (MMPs) is also up-regulated in ovarian cancer tissues and ascites, and numerous studies have provided evidence for a direct role of MMPs in i.p. invasion and metastasis. Using three-dimensional type I collagen cultures or immobilized beta1 integrin subunit-specific antibodies, we previously demonstrated that beta1 integrin clustering promotes activation of proMMP-2 and processing of membrane type 1 MMP in ovarian cancer cells (S. M. Ellerbroek et al., Cancer Res., 59: 1635-1641, 1999). In the current study, the effect of LPA on MMP expression and invasive activity was investigated. Treatment of ovarian cancer cells with pathophysiological levels of LPA increased cellular adhesion to type I collagen and beta1 integrin expression. A significant up-regulation of MMP-dependent proMMP-2 activation was observed in LPA-treated cells, leading to enhanced pericellular MMP activity. As a result of increased MMP activity, haptotactic and chemotactic motility, in vitro wound closure, and invasion of a synthetic basement membrane were enhanced. These data indicate that LPA contributes to metastatic dissemination of ovarian cancer cells via up-regulation of MMP activity and subsequent downstream changes in MMP-dependent migratory and invasive behavior.

Cell Adhesion↗
PubMed2001

Three-dimensional power Doppler ultrasound improves the diagnostic accuracy for ovarian cancer prediction.

OBJECTIVE: The goal of this study was to determine if three-dimensional power Doppler ultrasound improves the specificity for ovarian cancer detection as compared with two-dimensional ultrasound. METHODS: Seventy-one women with a known complex pelvic mass were referred for a preoperative ultrasound evaluation with both two-dimensional and three-dimensional gray-scale ultrasonography. The 3D studies were performed with the Kretz Voluson 530D using a mechanized transvaginal probe. Surface rendering and power Doppler imaging were performed by the same gynecologic sonologist, and reassigned to one of four echo patterns: cystic, multicystic, complex, or solid. Sonographic criteria used for diagnosing ovarian cancer were based on a system that included morphological characteristics, histological prediction, and power Doppler imaging. RESULTS: Seventy-one women underwent surgical exploration: 14 (19.7%) had ovarian cancer (2 FIGO stage I, 2 stage II, 7 stage III, and 3 metastatic colon) and 2 had uterine cancer. Two-dimensional gray-scale ultrasound identified 40 masses as suspicious for cancer, including all 14 malignancies, yielding a sensitivity, specificity, and positive predictive value of 100, 54, and 35%, respectively. However, evaluation with 3D power Doppler identified only 28 cases as suspicious (including all 14 cancers), resulting in a sensitivity, specificity, and positive predictive value of 100, 75, and 50%, respectively. CONCLUSIONS: Three-dimensional power Doppler imaging better defines the morphological and vascular characteristics of ovarian lesions. All malignancies were correctly identified by both 2D and 3D imaging; however, the specificity significantly improved with the addition of 3D power Doppler. This improved diagnostic accuracy may promote improved patient care by separating complex benign masses from ovarian cancer, therefore facilitating appropriate physician referral.

Adult↗
PubMed2001

Evaluating the total costs of chemotherapy-induced toxicity: results from a pilot study with ovarian cancer patients.

PURPOSE: While chemotherapy-related toxicities affect cancer patients' activities of daily living and result in large expenditures of medical care for treatment, few studies have assessed the out-of-pocket and indirect costs incurred by patients who experience toxicity. The objective of this study was to evaluate the feasibility of obtaining detailed and comprehensive cost information from patients who experienced neutropenia, thrombocytopenia, or neurotoxicity during treatment. METHODS: Ovarian cancer patients who experienced chemotherapy-associated hematologic or neurologic toxicities were asked to record detailed information about hospitalization, laboratories, physician visits, phone calls, home visits, medication, medical devices, lost productivity, and caregivers. Resource estimates were converted into cost units, with direct medical cost estimates based on hospital cost-accounting data and indirect costs (i.e., productivity loss) on modified labor force, employment, and earnings data. RESULTS: Direct medical costs were highest for neutropenia (mean of $7,546/episode), intermediate for thrombocytopenia (mean of $3,268/episode), and lowest for neurotoxicity (mean of $688/episode). Indirect costs relating to patient and caregiver work loss and payments for caregiver support were substantial, accounting for $4,220, $3,834, and $4,282 for patients who developed neurotoxicity, neutropenia, and thrombocytopenia, respectively. The total costs of chemotherapy-related neurotoxicity, neutropenia, and thrombocytopenia were $4,908, $11,830, and $7,550. CONCLUSION: Our study has shown that, with the assistance of patients who are experiencing toxicity, estimation of the total costs of cancer-related toxicities is feasible. Indirect costs, while not included in prior estimates of the costs of toxicity studies, accounted for 34% to 86% of the total costs of cancer supportive care.

Adult↗
PubMed1999

Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator N-terminal fragment.

Ovarian carcinomas secrete single-chain urinary-type plasminogen activator (scuPA) and expression of uPA is up-regulated relative to normal ovarian epithelium, leading to an enhanced proteolytic capacity which may facilitate invasion. Furthermore, the uPA receptor (uPAR) is present on ovarian carcinoma cells and is occupied in tumour tissues. In the present study, incubation of scuPA with serum-free conditioned medium from ovarian carcinoma cells resulted in release of a 14 kDa polypeptide. N-terminal sequence analysis identified this fragment as the uPA N-terminal fragment (NTF), which contains a growth-factor and a kringle domain. NTF generation was abolished by serine-proteinase inhibitors, but not inhibitors of matrix metalloproteinases, and was not enhanced by the addition of plasminogen or plasmin. To determine whether ovarian carcinoma-cell growth is altered by uPA, the effect of exogenous scuPA or NTF on proliferation was analysed. Both NTF and scuPA induced a dose-dependent increase in proliferation, with maximal stimulation obtained at 10-20 nM. Furthermore, blocking the interaction of endogenous uPA with uPAR using anti-NTF antibodies significantly inhibited proliferation. Together these data indicate that, in addition to enhancing the invasive activity of ovarian carcinoma cells via increased pericellular proteolysis, uPA also acts as a mitogen for ovarian carcinoma cells, suggesting a biochemical mechanism whereby uPA may contribute to ovarian carcinoma progression by modulating both cell invasion and proliferation.

Cell Division↗
PubMed1999

Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin.

Culturing DOV 13 ovarian carcinoma cells on three-dimensional collagen lattice but not on thin-layer collagen induces processing of promatrix metalloproteinase (MMP)-2 to a M(r) 62,000 form, suggesting that multivalent integrin aggregation may participate in proteinase regulation. To address the role of collagen-binding integrins in this event, we treated DOV 13 cells with soluble beta1 integrin antibodies (clones P4C10 or 21C8) or beta1 integrin antibodies immobilized on latex beads to promote integrin aggregation. Divalent ligation of beta1 integrins with soluble P4C10 antibodies stimulated expression of pro-MMP-2 and its inhibitor, tissue inhibitor of metalloproteinase-2, whereas soluble 21C8 antibodies had no effect. Aggregation of beta1 integrins with immobilized 21C8 or P4C10 antibodies stimulated MMP-dependent pro-MMP-2 activation and accumulation of a M(r) 43,000 form of membrane type 1 MMP (MT1-MMP), a cell surface activator of pro-MMP-2, in cell extracts. beta1 integrin-mediated MMP-2 activation required protein synthesis and tyrosine kinase signaling and was reduced by an inhibitor of gene transcription. Treatment of control cells with concanavalin A stimulated MMP-dependent pro-MMP-2 activation and accumulation of M(r) 55,000 and 43,000 forms of MT1-MMP in cell extracts. Addition of either the MMP inhibitor GM-6001-X or exogenous tissue inhibitor of metalloproteinase-2 to concanavalin A-treated cells resulted in loss of the M(r) 43,000 form of MT1-MMP and accumulation of the M(r) 55,000 form of the enzyme in cell extracts, suggesting that the M(r) 43,000 form is a product of MMP-dependent M(r) 55,000 MT1-MMP proteolysis. Together, these data suggest that beta1 integrin stimulation of pro-MMP-2 activation involves MT1-MMP posttranslational processing and requires multivalent integrin aggregation.

Collagen↗
PubMed1998

Perceptions of cisplatin-related toxicity among ovarian cancer patients and gynecologic oncologists.

BACKGROUND: We conducted a pilot study to evaluate issues related to chemotherapy-induced toxicities by eliciting assessments of toxicity from women with advanced stage ovarian cancer and gynecologic oncologists. PATIENTS AND METHODS: Fifteen ovarian cancer patients and ten gynecologic oncologists completed the survey exercises. All patients surveyed had received at least six courses of a cisplatin-containing chemotherapy regimen. RESULTS: For both patients and physicians, there was good face validity to the utility exercise as assessments of health states with cisplatin were (1) consistently associated with less favorable assessments than the health state with no toxicity and (2) neurotoxicity was viewed less favorably than either ototoxicity or nephrotoxicity. While the 15 patients as a group viewed health states with toxicity more favorably than physicians (P < 0.05 for each toxicity), patient assessments varied, depending on individual experiences with cisplatin. Physician assessments of toxicity were most similar to those obtained from patients who had not experienced cisplatin toxicity and were less favorable than those elicited from patients who had experienced any toxicity. CONCLUSIONS: In deciding upon therapeutic strategies, women with advanced stage ovarian cancer and treating physicians markedly differ in their assessment of the impact of specific toxicities on quality of life.

Adult↗
PubMed1998

Management of twin pregnancies consisting of a complete hydatidiform mole and normal fetus.

OBJECTIVE: To report the clinical features, management, and outcome of twin pregnancies consisting of a complete hydatidiform mole and a coexisting normal fetus. METHODS: Between 1966 and 1997, seven women with complete hydatidiform mole and coexisting normal fetus were treated at the John I. Brewer Trophoblastic Disease Center of Northwestern University Medical School. Clinical features, including presenting symptoms, gestational dates, hCG levels, and complications, as well as route of delivery or evacuation, pregnancy outcome, genetic analysis, and need for chemotherapy were assessed. RESULTS: Four women required uterine evacuation before 20 weeks' gestation because of vaginal bleeding or medical complications, one woman required an emergency hysterotomy because of hemorrhage at 24 weeks, and two women delivered normal, viable infants at 26 and 34 weeks. The pathologic diagnosis of complete hydatidiform mole was confirmed in each case and the chromosome complement was 46,XX in all molar gestations. Four of seven women required chemotherapy for treatment of nonmetastatic gestational trophoblastic tumors, including both women who delivered viable infants and two of the five women whose pregnancies were evacuated before 24 weeks' gestation. All four patients were treated with five to seven cycles of a 5-day methotrexate regimen and achieved complete remission. CONCLUSION: Patients with a twin pregnancy consisting of a complete mole and a normal fetus are at increased risk for hemorrhage and medical complications, as well as the development of persistent gestational trophoblastic tumor.

Adult↗
PubMed1998

Ectopic pregnancy causing hemothorax managed by thoracoscopy and actinomycin D.

BACKGROUND: Most patients with extratubal ectopic pregnancies present with vaginal bleeding and lower abdominal pain. We report a case of an extratubal ectopic pregnancy with extra-abdominal manifestations. CASE: An ectopic pregnancy implanted on the diaphragm resulted in spontaneous hemothorax due to trophoblastic invasion into the pleura. Thoracoscopic excision followed by actinomycin D chemotherapy provided successful resolution of the ectopic pregnancy. CONCLUSION: Abdominal pregnancies may have bizarre clinical presentations.

Adult↗
PubMed1998

Metastatic dissemination of human ovarian epithelial carcinoma is promoted by alpha2beta1-integrin-mediated interaction with type I collagen.

Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the mesothelial extracellular matrix and in the peritoneal cavity of ovarian carcinoma patients, may function on multiple levels to promote metastatic dissemination of ovarian carcinoma cells.

Cell Adhesion↗
PubMed1998

The role of proteolytic enzymes in the pathology of epithelial ovarian carcinoma.

Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy among North American women. The vast majority of women are diagnosed after the cancer has metastasized into the peritoneum, resulting in a low 5-year survival. Because of difficulties associated with early detection of ovarian carcinoma and the invasive potential of these malignancies, a more detailed understanding of the mechanism(s) by which ovarian carcinomas metastasize may suggest novel therapeutic approaches which could impact favorably on long-term survival. Connective tissue degrading proteinases are necessary for tumor cell invasion and enzymes in the plasminogen activator (PA) and matrix metalloproteinase (MMP) families have been implicated in ovarian cancer metastasis. The goal of this review is to summarize current data regarding the role of these proteinases in ovarian carcinoma invasion.

Carcinoma↗
PubMed1997

Production of extracellular matrix-degrading proteinases by primary cultures of human epithelial ovarian carcinoma cells.

BACKGROUND: The authors analyzed the secretion of extracellular matrix-degrading proteinases, including urinary-type plasminogen activator (u-PA), matrix metalloproteinase-2 (MMP-2, gelatinase A), and MMP-9 (gelatinase B), by short term primary cultures of epithelial ovarian carcinoma cells derived from primary ovarian tumors, intraperitoneal metastases, or ascites. The presence of these enzymatic activities in samples of ascites was also evaluated. The effect of adhesive substratum on proteinase production was determined. METHODS: A coupled spectrophotometric assay was utilized to evaluate the initial rate of plasminogen activation by u-PA in conditioned medium; this involved monitoring the activity of generated plasmin with a colorimetric substrate. MMP activity was evaluated by gelatin zymography. RESULTS: Ascitic fluids from 18 patients contained u-PA, MMP-2, and MMP-9. However, short term primary cultures of cells derived from primary ovarian tumors (OVET), metastatic lesions (OVEM), or ascites (OVEA) produced very low levels of u-PA. Production of u-PA by OVET and OVEM cells was regulated by adhesive substratum. Conditioned media from OVET, OVEM, and OVEA cells contained high levels of both MMP-2 and MMP-9. MMP-9 levels decreased with increasing passage in culture, whereas MMP-2 activity was maintained. Production of neither MMP-2 nor MMP-9 was regulated by adhesive substratum. CONCLUSIONS: These results demonstrate that primary cultures of epithelial ovarian carcinoma cells derived from three distinct anatomic locations produce MMP-2 and MMP-9, with low level secretion of u-PA. These data suggest that MMPs, particularly MMP-2, may play a significant role in the intraperitoneal invasion of ovarian carcinoma cells.

Adult↗
PubMed1997

Ovarian carcinoma initially presenting as metastatic axillary lymphadenopathy.

BACKGROUND: Ovarian carcinoma usually presents at advanced stage due to diffuse intraabdominal disease. Presenting signs and symptoms often relate to the degree of intraabdominal spread. It is rare to have distant lymph node metastases, in conjunction with minimal intraabdominal disease, at initial presentation. CASE: A 78-year-old woman was noted to have an enlarged axillary lymph node on a routine, screening mammogram. Biopsy revealed metastatic adenocarcinoma, consistent with primary breast cancer. Physical examination, diagnostic mammogram, and magnetic resonance imaging of the breasts were normal. A pelvic computed tomography scan revealed a 7-cm complex, right adnexal mass. At exploratory laparotomy, there was minimal intraabdominal tumor burden; only a 6-cm right ovarian tumor and a single 1.0-cm nodule adherent to the bladder peritoneum were found. After optimal cytoreductive surgery, she received tamoxifen for presumed metastatic breast cancer. One year later, recurrent disease developed in the pelvis. After reexploration and excision of all gross pelvic disease, a revised diagnosis of recurrent ovarian cancer was made, and therapy was changed to carboplatin and paclitaxel chemotherapy. The patient is currently without evidence of disease. CONCLUSION: Ovarian carcinoma usually presents with signs and symptoms related to the tumor burden within the peritoneal cavity. The finding of isolated, distant metastatic lymphadenopathy with minimal intraabdominal disease is very unusual. Immunohistochemical tumor markers can help determine the origin of a metastatic adenocarcinoma when the clinical presentation is atypical.

Adenocarcinoma↗
PubMed1997

Ovarian carcinoma metastatic to the choroid of the eye.

A case of papillary serous ovarian adenocarcinoma with choroidal metastasis to the eye is reported. Central nervous system metastasis of any kind is rare from this tumor, and only three cases of choroidal metastases have been reported to date. A 67-year-old women presented 2 years after diagnosis of Stage IIIC papillary serous ovarian adenocarcinoma with complaints of a "teardrop"-shaped visual field defect in her right eye. Fundoscopic examination revealed metastasis to the superior-temporal right choroid. No coexisting sites of recurrence were discovered. This case highlights the need to thoroughly and promptly investigate the etiology of visual field complaints in patients with a history of ovarian cancer.

Aged↗
PubMed1997

Endometrial adenocarcinoma metastatic to the scalp: case report and literature review.

A rare case of scalp metastasis from endometrial adenocarcinoma, demonstrating the poor prognosis for these patients, is reported. A 56-year-old woman with FIGO Stage IC, Grade 1 endometrial adenocarcinoma presented 15 months after initial surgery and radiation therapy with a scalp metastasis. Metastatic evaluation revealed widespread extrapelvic disease. She did not respond to chemotherapy and died 3 months after recurrence. Her course typifies that of patients with other cutaneous metastases as described in the literature: disease noted elsewhere at the time of recurrence, poor response to therapy, and death within 6 months.

Adenocarcinoma↗
PubMed1997

Biochemical characterization of primary peritoneal carcinoma cell adhesion, migration, and proteinase activity.

Primary papillary serous carcinoma of the peritoneum (PPC) is clinically and histologically similar to advanced stage epithelial ovarian carcinoma. PPC classically presents with widespread intraperitoneal dissemination, superficial invasion, and minimal ovarian involvement. Surgical cytoreduction and combination chemotherapy utilized for patients with epithelial ovarian carcinoma have produced varying results for patients with PPC. These differences in response may be secondary to the stage of disease or due to biological differences in metastatic behavior between these carcinomas. In this study, short-term primary cultures of PPC and epithelial ovarian carcinoma (OVCA) were compared to enable biochemical comparison with respect to components of the metastatic cascade including adhesion, migration, and proteinase activity. These data demonstrated similar properties in adhesive profiles of PPC and OVCA, with preferential adhesion to type I collagen and vitronectin. Matrix-degrading proteinases including matrix metalloproteinases (MMP)-2, MMP-9, and urinary-type plasminogen activator were produced by both cell types. PPC migration was stimulated by multiple extracellular matrix proteins, whereas OVCA cells demonstrated maximal migration on type I collagen coated surfaces. Together our data suggest biochemical similarities between PPC and OVCA with respect to individual components of the metastatic cascade.

Cell Adhesion↗