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Biomedical subjects

J S Berek

Publications and source records attributed to J S Berek.

At least 19 recordsLinked to original sources
PubMed1992

Stimulation of ovarian tumor cell proliferation with monocyte products including interleukin-1, interleukin-6, and tumor necrosis factor-alpha.

OBJECTIVE: We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells. STUDY DESIGN: Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test. RESULTS: Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies. CONCLUSIONS: Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.

Cell Division↗
PubMed1992

Characteristics of patients with small-volume residual ovarian cancer unresponsive to cisplatin-based ip chemotherapy: lessons learned from a Gynecologic Oncology Group phase II trial of ip cisplatin and recombinant alpha-interferon.

The Gynecologic Oncology Group conducted a phase II trial of intraperitoneal (ip) cisplatin plus recombinant human alpha-interferon in patients with small-volume persistent/recurrent ovarian cancer. This study was based on the known single agent activity of the drugs administered by the ip route and experimental evidence of cytotoxic synergy between the agents. In 18 evaluable patients, only 1 partial response was observed (5.5% response rate). In an effort to explain these disappointing findings, patients were retrospectively divided into two groups; those with favorable disease (documented response to systemic platinum and absence of surgical findings of diffuse carcinomatosis at laparotomy prior to initiation of ip therapy) or unfavorable disease (no evidence of response to systemic platinum and/or laparotomy findings of diffuse carcinomatosis before ip treatment). The favorable patient population would be predicted to have a far greater chance of responding to local therapy, but only 3 of the evaluable patients fell into this category. In the 15 unfavorable patients, only 1 partial response was observed (7% response rate). We conclude that patients who have failed to demonstrate a response to systemic cisplatin or carboplatin or who have diffuse carcinomatosis at second-look laparotomy are poor candidates for second-line ip cisplatin-based therapy, even if they are considered to have small-volume residual disease (each individual tumor nodules less than 0.5-1 cm). Such patients should be considered for alternative therapeutic strategies.

Adult↗
PubMed1992

Presence of interleukin 10 (IL-10) in the ascites of patients with ovarian and other intra-abdominal cancers.

Typically, ovarian cancer remains restricted to the peritoneal cavity. Because of this unique localization, the study of ovarian cancer is particularly suitable for immune analysis and for the development of immunotherapy. Here we report that peritoneal fluid from patients with ovarian or other intra-abdominal cancers contained significantly elevated levels of interleukin 10 (IL-10) (542 +/- 77 pg/ml, N = 35), compared with peritoneal fluid from patients with benign gynecological conditions (34.2 +/- 7.5 pg/ml, N = 63) (P < 0.001). Peritoneal fluid IL-10 levels did not correlate with histology, tumor stage, grade, or prognosis. IL-10 levels were also elevated in the serum of patients with intra-abdominal cancer (1353 +/- 906, N = 8). Established ovarian cancer cell lines (N = 5) did not produce any detectable IL-10. Investigation of the cell surface phenotype of the cells in the peritoneal cavity indicated the presence of significant amounts of activated immune cells. The presence of cytokines such as IL-10 in the peritoneal cavity of ovarian cancer bearing patients could be important in the growth and development of cancer, more specifically, in relation to host immune responsiveness.

Antigens, CD↗
PubMed1992

Improving adherence to screening follow-up among women with abnormal Pap smears: results from a large clinic-based trial of three intervention strategies.

In a large randomized trial involving over 2,000 women with abnormal cervical cytology (pap smear), three clinic-based interventions were tested as strategies to increase return rates for screening follow-up: 1) a personalized follow-up letter and pamphlet; 2) a slide-tape program on pap smears; and 3) transportation incentives (bus passes/parking permits). The three interventions were evaluated using a 2 x 2 x 2 factorial design. Results of this study confirm a high rate of loss to screening follow-up (i.e., no return visits) among women with abnormal pap smears (29% overall), with substantial variability among the 12 participating clinics (13% to 42/%). For the sample as a whole, both transportation incentives and the combined intervention condition of personalized follow-up and slide-tape program had a significant positive impact on screening follow-up. However, transportation incentives emerged as the dominant intervention condition among patient subgroups that can be characterized as more disadvantaged socioeconomically and at higher risk of developing cervical cancer, including patients receiving care from the county health department (odds ratio (OR) = 1.51; P less than .05); patients without health insurance (OR = 1.77; P less than .01); and patients with more severe pap smear results (OR = 1.71; P less than .05). In contrast, among patient subgroups that can be characterized as relatively more advantaged and at lower risk of developing cervical cancer, only the combined intervention condition of personalized follow-up and slide-tape program was associated with a higher patient return rate. Subgroups reflecting this pattern included patients seen in noncounty clinics (OR = 4.54; P less than .05) and patients with less severe pap smear results (OR = 5.16; P less than .01). The implications of these findings are discussed in terms of designing clinic-based interventions to improve screening follow-up.

Adolescent↗
PubMed1992

Early-stage squamous cell and adenocarcinoma of the cervix.

Articles on early-stage squamous cell and adenocarcinoma of the cervix published between August 1990 and July 1991 are reviewed. A new monoclonal antibody used to distinguish endocervical from endometrial differentiation is described, as well as a histochemical means of distinguishing in situ from invasive adenocarcinoma. In vitro and in vivo studies of cell lines immortalized with human papillomavirus DNA are described with a discussion of the mechanism of the development of malignancy. An animal model to test and develop an anti-human papillomavirus vaccine is presented. The epidemiology of adenocarcinoma is also reviewed, and the development of invasive carcinoma after conservative therapy or conization for dysplasia is discussed. Computed tomography scanning has been found to be no more accurate than examination for staging of early cervical cancer. Several studies in the review period have evaluated risk factors for recurrent disease in patients treated for early-stage cervical cancer, including a prospective surgical pathologic study by the Gynecologic Oncology Group. The optimal treatment of early stage I adenocarcinoma of the cervix is discussed, comparing the efficacy of primary surgical therapy with the efficacy of radiation therapy. The risk of ovarian metastases in patients with early-stage cervical cancer is very low for both squamous cell and adenocarcinoma. The surgical technique and efficacy of laparoscopic pelvic lymphadenectomy for patients with early-stage cervical cancer are discussed. Lateral transposition of the ovaries at the time of radical hysterectomy for cervical cancer has significant potential benefits but also risks. Finally, surveillance methods that detect recurrent cervical cancer after treatment for early-stage disease are discussed.

Adenocarcinoma↗
PubMed1992

Biologic and immunologic therapy of ovarian cancer.

Conventional cytotoxic chemotherapy fails to cure the majority of patients with advanced-stage ovarian cancer, in spite of encouraging initial antitumor responses. With the emergence of drug resistance in refractory tumors, new biologic and immunologic treatment strategies are needed. Small-volume residual peritoneal disease remains an attractive target for therapeutic trials; however, even in this optimal circumstance, few regimens have yet achieved a high frequency of pathologically confirmed complete remissions. Considerable progress has been made in understanding the impact of growth factors and their receptors on tumor growth regulation and modulation of response to chemotherapy. Better characterization of the antigens recognized by monoclonal antibodies, as well as sequencing of the antibodies themselves, has permitted the rational design of therapeutic reagents that take full advantage of molecular biology techniques for production and conjugation. Important limitations of preclinical models for prediction of host toxicity are recognized, and the reasons for treatment failure in situ, as well as strategies to prevent serious dose-limiting toxicities, are being explored. Further developments in cytokine biology, adoptive cellular therapy, monoclonal antibody conjugation, and molecular biology will continue to provide a growing array of reagents for critical evaluation.

Adjuvants, Immunologic↗
PubMed1991

Assessment of current International Federation of Gynecology and Obstetrics staging of vulvar carcinoma relative to prognostic factors for survival (a Gynecologic Oncology Group study).

Analysis of 588 patients with vulvar carcinoma delineated four risk groups by the proportional hazards model. Groin node status (laterality and number positive) and lesion diameter were the only two important independent prognostic factors. The 5-year relative survival rates were 98%, 87%, 75%, and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter less than or equal to 2 cm), low (one positive groin node and lesion diameter less than or equal to 2 cm or negative groin nodes and fewer than two lesions less than or equal to 8 cm diameter), intermediate (negative groin nodes and lesion diameter greater than 8 cm diameter, one positive groin node and lesion diameter greater than 2 cm, or two unilaterally positive groin nodes and lesion diameter less than or equal to 8 cm), and high (three or more positive groin nodes or two bilaterally positive groin nodes), respectively. Applying the International Federation of Gynecology and Obstetrics staging (1988) to these data discriminated risk of death (caused by recurrent vulvar cancer); the 5-year rates were 98%, 85%, 74%, and 31% for stages I, II, III, and IV, respectively. However, within International Federation of Gynecology and Obstetrics stage III there were 47 low-, 95 intermediate-, and 28 high-risk patients with relative survivals of 95%, 74%, and 34%, respectively. Overall, this assessment validates current International Federation of Gynecology and Obstetrics vulvar carcinoma staging, but further refinements are warranted in stage III.

Carcinoma, Squamous Cell↗
PubMed1991

Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer.

Interleukin-6 is a pleiotropic cytokine with a wide range of effects, including induction of B-cell and cytotoxic T-cell differentiation, and induction of acute phase reactant production by hepatocytes. Interleukin-6 also can act as an autocrine growth factor in malignancy. Various cell types produce interleukin-6, including T and B cells, monocytes, fibroblasts, and some solid tumor cells. In previous work we detected the production of substantial amounts of interleukin-6 by human ovarian cancer cells, including the ovarian cancer cell lines CAOV-3, OVCAR-3, and SKOV-3, and several primary ovarian tumor cultures. In this study we retrospectively examined 90 separate serum specimens for interleukin-6 in 36 patients with epithelial ovarian cancer. The mean serum interleukin-6 concentration of those ovarian cancer patients with macroscopic disease (n = 57) was 0.26 +/- 0.04 U/ml (mean +/- SEM). Healthy adult donors have interleukin-6 serum levels of 0.12 +/- 0.03 U/ml. Sixteen of 21 ovarian cancer patients with macroscopic disease (76%) had elevated (greater than 0.20 U/ml) levels of serum interleukin-6, with levels approaching 1 U/ml in some patients (p less than 0.01). Of those nine patients with bulky tumor (residual greater than 2 cm), eight (89%) had an elevated interleukin-6 level (mean, 0.31 +/- 0.05), while eight of 12 (66%) with minimal residual disease (less than 2 cm) had elevated levels. Only two of 15 (13%) patients who were in clinical remission and who had microscopic disease had elevated values. Of the 36 patients, 22 were CA 125 negative (less than 35 U/ml), and of these, four had elevated interleukin-6 levels. Of the 14 patients with an elevated CA 125 level, 12 (86%) had elevated interleukin-6 levels. In those 16 patients in whom serial levels of interleukin-6 were measured, rising levels were found over a 3 to 4 month interval in nine (56%); this correlated with tumor progression. Furthermore, the subsequent survival of patients was shown to correlate with the level of interleukin-6, such that patients whose levels were elevated greater than 0.20 U/ml interleukin-6 survived a mean of 12.5 months, compared with 27.2 months for patients with normal levels (p less than 0.001). These data support the concept that interleukin-6 may be a useful tumor marker in some patients with epithelial ovarian cancer, as it correlates with the tumor burden, clinical disease status, and survival.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed1991

A phase I-II trial of intraperitoneal cisplatin and alpha-interferon in patients with persistent epithelial ovarian cancer.

A toxicity, dose, and schedule study of intraperitoneal (ip) cisplatin and alpha-interferon was conducted as a salvage therapy for patients with persistent, advanced epithelial ovarian cancer after primary systemic therapy with cisplatin-combination chemotherapy. Twenty-four patients were entered into this prospective, nonrandomized phase I-II trial conducted at two institutions following a uniform protocol. Cisplatin doses were escalated from 45 to 90 mg/m2, and alpha-interferon doses were escalated from 10 to 50 x 10(6) IU. At protocol entry, 4 (16%) patients had microscopic residual disease at second-look laparotomy, 5 (21%) had minimal residual disease less than 5 mm, 7 (30%) had residual disease 5-20 mm, and 8 (33%) had bulky residual disease greater than 20 mm. Toxicity was acceptable overall. Hematopoietic toxicity included a grade 3 total white cell count in 12% of courses when the cisplatin dose was equal to or greater than 60 mg/m2. Renal toxicity was modest with grade 2 toxicity in 20% of courses with a cisplatin dose greater than 60 mg/m2. Gastrointestinal toxicity, especially nausea and vomiting was seen in most courses; however, it was grade 3 and dose-limiting in greater than 30% of courses with cisplatin 75-90 mg/m2. General malaise, fever, flu-like symptoms, chills, and myalgias were seen in most courses, but it was dose-limiting (grade 3) toxicity in 6-11% of cycles when the dose of interferon was 25-50 x 10(6) IU. There was no grade 4 toxicity. Thus, the maximum tolerated dose (MTD) of the combination is 60 mg/m2 cisplatin and 25 x 10(6) IU interferon. Eighteen patients were evaluable for response, 15 of whom had responded to prior cisplatin therapy and 3 had not. Of the 10 patients evaluable for clinical response, one patient (10%) achieved a complete response (CCR), and one (10%) had a partial response (PCR). The progression free interval (PFI) and survival were 11 months and 19 months, respectively, for the CCR patient, 6 and 11 months, respectively, for the PCR patient, and the mean survival for nonresponders was 8 months. The other 8 patients underwent a reassessment laparotomy: 2 (25%) achieved a complete pathologic response (CPR), and 3 (38%) had a partial pathologic response (PPR). Both pathologic responses were in patients with minimal residual disease less than 5 mm.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1991

Fine-needle aspiration cytology accuracy with palpable gynecologic neoplasms.

From 1984 to 1988, 62 fine-needle aspirations (FNA) were performed on palpable lesions in 59 gynecologic oncology patients at the UCLA Medical Center. Sites of aspiration included abdomen, cervix, vagina, superficial lymph nodes, and pelvic masses. Confirmatory open biopsy (41) or adequate clinical follow-up (17) was obtained in 55 patients (58 aspirates). FNA correctly established the diagnosis of malignancy in 19 of 26 (73%) biopsied patients. The predictive value for a positive test was 100%, and the predictive value for a negative test was 82%. Initial surgical biopsy had been incorrectly benign in 4 of these patients who were shown subsequently to have malignant tumors by FNA and clinical findings. In 7 patients, FNA failed to diagnose the malignancy found by open biopsy. Two of the false-negative FNAs were insufficient and five were in masses where palpation was inadequate. In 17 patients who were followed clinically without open biopsy, FNA correctly predicted the subsequent clinical course in 15 (88%). There were no false-positive FNA diagnoses obtained when cytologic results were correlated with both clinical outcome and surgical biopsy. Aspiration cytology has a specificity of 100% and a sensitivity of 65%. A negative FNA obtained from a clinically suspicious lesion should be followed by a repeat aspiration or surgical biopsy.

Abdominal Neoplasms↗
PubMed1991

Concurrent cisplatin and 5-fluorouracil chemotherapy and radiation therapy for advanced-stage squamous carcinoma of the vulva.

A phase II trial of concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy and radiation therapy (CT + RT) was conducted for the primary treatment of 12 patients with retrospective surgical FIGO stages III-IV squamous carcinoma of the vulva. Eight patients were stage III and four were stage IV. Chemotherapy was used as a radiation sensitizer and it was administered in two 5-day cycles 28 days apart. Cisplatin, 50 mg/m2/day iv on Days 1 and 2 or 100 mg/m2 on Day 1 or 2, plus continuous-infusion 5-FU, 1000 mg/m2/day for 4-5 days commencing on Days 1 and 28 of external-beam radiation therapy, are given. The pelvic radiation to a dose of 4400-5400 cGy is administered AP and PA to treat the primary tumor, the groin nodes, and the iliac vessels to the level below the common iliac nodes. Complete tumor responses were seen in 8 of 12 (67%) patients. Responses were observed in 6 of 8 (75%) stage III patients and 2 of 4 (50%) stage IV patients. Partial response were observed in 3 patients, and 1 patient had persistent disease. At the completion of concurrent chemoradiation therapy, radical vulvectomy or excision was used in 3 patients and posterior exenteration in 1. With a median follow-up of 37 months (range, 7-60 months), 10 patients are alive and free of disease, and 2 patients died at 12 and 15 months. There were no treatment-related deaths and no grade 4 toxicity. The morbidity included moist desquamation of the vulva in all patients, with grade 2 toxicity in 10 and grade 3 in 2. One patient had a deep venous thrombosis that responded to anticoagulation therapy. These data support the use of concurrent cisplatin and 5-FU chemotherapy and radiation therapy as an alternative to primary radical surgery to treat advanced-stage squamous carcinoma of the vulva.

Aged↗
PubMed1991

Adnexal torsion. An unusual cause of abdominal pain in postmenopausal women.

Adnexal torsion is a rare cause of abdominal pain in older women. Because the presenting symptoms and signs are vague, the diagnosis is not often considered. Lower abdominal pain with nausea and vomiting are usual in patients with torsion. Ultrasonography or computed tomography are useful diagnostic tests. Two case reports of older patients with adnexal torsion are presented to emphasize the diagnostic features of this entity, including lower abdominal pain, nausea and vomiting, and abdominal mass. Although the condition is uncommon, adnexal torsion should be considered in the differential diagnosis of acute abdominal pain.

Abdominal Pain↗
PubMed1990

Resistance of human ovarian cancer cells to tumor necrosis factor and lymphokine-activated killer cells: correlation with expression of HER2/neu oncogenes.

Since overexpression of HER2/neu oncogenes in breast cancer cells is associated with resistance to the cytotoxic effect of tumor necrosis factor (TNF), we investigated whether this correlation also existed for ovarian cancer targets. Nine continuously cultured human ovarian cancer lines were studied and compared to 3 breast cancer lines. Three of the ovarian and 1 breast cancer line demonstrated amplified HER2/neu genes by Southern analysis, increased HER2/neu RNA by Northern analysis, and marked immunoperoxidase staining for HER2/neu protein. The other 8 lines contained unamplified genes and undetectable RNA and protein. All 4 overexpressed lines were relatively resistant to the cytotoxic effects of TNF. Interestingly, they were also resistant to lymphokine-activated killer cells. In contrast, 7 of 8 nonexpressed lines showed sensitivity to TNF and all 8 were sensitive to lymphokine-activated killer cells. There was no difference in sensitivity to lysis by hydrogen peroxide or peptide defensins between over- and nonexpressed lines. These data indicate that expression of HER2/neu oncogenes may impart a proliferative advantage in tumor cells due to induction of resistance to several different cytotoxic mechanisms.

Blotting, Northern↗
PubMed1990

Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures.

We examined the production and utilization of interleukin 6 (IL-6), a multifunctional cytokine with diverse biological effects, by both ovarian cancer cell lines and primary ovarian tumor cultures. We have found that epithelial ovarian cancer cell lines (CAOV-3, OVCAR-3, and SKOV-3) constitutively produce varying amounts of IL-6. This molecule is biologically active as determined by the proliferation of an IL-6-dependent hybridoma cell line, MH60.BSF-2, and is detectable by an IL-6 enzyme-linked immunosorbent assay. By cytoplasmic immunoperoxidase staining, greater than 98% of the cells produce at least some IL-6, with variation in the staining intensity between individual cells. The ovarian cancer cell-produced protein has a molecular weight of approximately 24,000, and exhibits some molecular weight heterogeneity, with Mr 27,000 and 28,000 minor forms of IL-6. The levels of IL-6 produced by ovarian cancer cells can be modulated by other inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma. Our results suggest that IL-6 is not an autocrine growth factor for these established ovarian tumor cell lines, because the addition of either exogenous IL-6 or antibodies to IL-6 did not affect the cellular proliferation of the cell lines. We also found significant levels (greater than 3 ng/ml) of IL-6 in ascitic fluids of ovarian cancer patients and in the supernants of primary cultures from freshly excised ovarian tumors. The production of IL-6 by epithelial ovarian cancer cells may prove to be a useful diagnostic tool and aid in investigation of the host immune response to ovarian cancer.

Cell Division↗
PubMed1990

Phase II study of N-methylformamide (N-MF) (NSC 3051) in patients with advanced epithelial ovarian cancer. A Gynecologic Oncology Group study.

Forty-four patients with advanced, measurable, epithelial carcinoma of the ovary were treated with 97 courses of N-methylformamide (N-MF) at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Forty-one patients had prior surgery and had received one prior chemotherapy regimen. Only seven patients had received any prior radiation therapy. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. Three partial responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One major toxicity was a syndrome consisting of some combination of myalgias, arthralgias, pleuritic pain, abdominal pain, peripheral neuropathy, anorexia, lethargy, and declining performance status (pain-lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was as common a reason as hepatic toxicity for discontinuation of N-MF. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The low level of clinical activity and the unpleasant adverse effects in this population of patients with previously treated ovarian cancer makes it unlikely that this drug will play any significant role in treatment of epithelial ovarian cancer.

Adult↗