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Biomedical subjects

B U Sevin

Publications and source records attributed to B U Sevin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Surgery for the treatment of locally recurrent disease.

BACKGROUND AND METHODS: Total pelvic exenteration is a salvage procedure done in the effort to eliminate completely pelvic cancer. Low colorectal anastomosis and continent urinary diversion are two new procedures that allow complete pelvic evisceration without the need for external appliances. From 1984 through 1994, 67 patients have undergone rectosigmoid colectomy and low-colorectal anastomosis. Sixteen patients underwent surgery as part of a total pelvic exenteration for recurrent cervical cancer, and 51 patients underwent surgery for either primary or recurrent ovarian carcinoma as part of an optimal debulking procedure. Between 1988 and 1995, 55 patients have received continent urinary diversion with the Miami Pouch. Fifty-two patients underwent surgery for recurrent cervical cancer, two patients for advanced vulvar cancer, and one patient for a vesico-vaginal fistula. All of the patients with recurrent cervical cancer had previously received radiation therapy for gynecologic cancer. RESULTS: Of the 16 patients with recurrent cervical cancer who had a low colorectal anastomosis, 14 had a temporary colostomy. Of these 14 patients, eight had a colostomy takedown and have maintained fecal continence. Of the 51 patients with ovarian cancer who had a low colorectal anastomosis, all achieved fecal continence. With the Miami Pouch, a urinary continence rate of 86% was obtained. Twenty-four (44%) patients had early complications, including ureteral obstruction, ureterocolonic anastomotic leak, reservoir cutaneous fistula, small bowel obstruction, and pyelonephritis. Nineteen (35%) patients had late complications, including ureteral reflux, urinary incontinence, difficult catheterizations, and reservoir stones. There was a perioperative mortality rate of 5%. CONCLUSIONS: Low-colorectal anastomosis is an attractive alternative to permanent colostomy, allowing all patients who had the protective colostomies taken down to achieve fecal continence. Continent urinary diversion with the Miami Pouch is also a worthwhile procedure because of its high continence rate. Although survival advantage for either procedure has not been proven, the quality of life of patients undergoing such procedures has been substantially improved because of the avoidance of external appliances. This has been achieved with acceptable morbidity and mortality rates.

Anastomosis, Surgical↗
PubMed1995

Prognostic factors of early stage cervical cancer treated by radical hysterectomy.

BACKGROUND: This study was performed to identify pathologic and clinical features that best correlate with lymph node metastasis and disease free survival among patients with Stage I and II cervical cancer treated by radical hysterectomy. METHODS: Three hundred-seventy patients with complete clinical information and pathologic material, including cone and cervical biopsies, were selected for analysis. Of these patients, 301 with clinical stages I and II disease were the subject of this paper. The results of patients with microinvasive carcinoma of the cervix, as defined by the Society of Gynecologic Oncologists (depth of invasion < or = 3 mm and no lymph node vascular space invasion), were reported previously and excluded from this analysis. Patients with small cell carcinoma of the cervix were found to have a very poor prognosis (disease free 5-year survival of 36%) and were also excluded from this analysis (Sevin BU, Nadji M, Metkoch MW, Lu Y, Averette HE. Unpublished data, 1995). Variables studied were patient age, weight, race, marital status, and economic status; tumor size; depth of invasion; lymph node-vascular space involvement; cell type; tumor grade; lymph node metastasis; and number of lymph nodes removed. The influence of these variables on survival was examined by univariate analysis with use of Cox's regression model and the log rank test for comparison of survival curves. RESULTS: Factors that predict disease free survival, ranked by degree of significance, were depth of invasion, tumor size, lymph node-vascular space invasion, number of positive nodes, tumor volume, clinical stage, and tumor extension to the vagina or surgical margins. CONCLUSIONS: Radical hysterectomy and bilateral lymphadenectomy is standard therapy for patients with Stage IB and IIA carcinoma of the cervix. A variety of surgically defined risk factors predict 5-year disease free survival, and many of these factors are related. Identification of independent risk factors requires a multivariate analysis of data.

Adult↗
PubMed1995

Paclitaxel: a radiation sensitizer of human cervical cancer cells.

Paclitaxel is an exciting chemotherapeutic agent active in a variety of malignant tumors. This study was designed to explore the radiosensitizing potential of paclitaxel in human cervical cancer cell lines. The cell lines ME180, SiHa, and MS751 were evaluated. Experiments were performed in the proliferative phase of growth. Paclitaxel doses were treated at 0.01x, 0.02x, 0.03x, 0.04x, and 0.05x peak plasma concentration (PPC) in ME180 and 0.001x, 0.002x, 0.003x, 0.004x, and 0.005x PPC in SiHa and MS751. Radiation (RT) doses of cobalt-60 were 0, 2, 4, 6, 8, and 10 Gy. In the combination group RT was given 48 hr after paclitaxel treatment. To allow for median effect analyses, combination doses were kept at a fixed ratio: 0.01x/2 Gy, 0.02x/4 Gy, 0.03x/6 Gy, 0.04x/8 Gy, and 0.05x/10 Gy for ME180 and 0.001x/2 Gy, 0.002x/4 Gy, 0.003x/6 Gy, 0.004x/8 Gy, and 0.005x/10 Gy in MS-751 and SiHa. Adenosine triphosphate bioluminescence was performed on Day 7 after treatment and compared to untreated controls. Dose-response data were fit to the linear quadratic model and mean inactivation dose D was calculated. Data analysis with t test was performed. The median effect principle was used to evaluate the nature of the interaction between the two therapeutic modalities. Paclitaxel increased radiation cytotoxicity in all three cell lines. Mean inactivation D values for RT versus combination were 6.70 (+/- 0.15) and 4.33 (+/- 0.43) (P = 0.004) in ME180, 6.08 (+/- 0.70) and 4.54 (+/- 0.093) (P = 0.033) in MS751, and 7.03 (+/- 0.46) and 5.97 (+/- 0.51) (P = 0.034) in SiHa. The interaction of paclitaxel and RT was found to be supraadditive in ME180 and SiHa and subadditive in MS751. We conclude that paclitaxel has modest radiation-sensitizing effects in cervical cancer cell lines and that further clinical trials should be considered.

Cell Survival↗
PubMed1995

A correlation of cell cycle perturbations with chemosensitivity in human ovarian cancer cells exposed to cytotoxic drugs in vitro.

To test the association between cytotoxicity and in vitro cell cycle perturbations we systematically studied cell cycle perturbations after exposing human ovarian cancer cells to nine commonly used cytotoxic agents. Three principal patterns of cell cycle alterations were observed: a sequential S-G2/M block after exposure to the non-phase-specific agents cis-platinum, 4-hydroperoxy-cyclophosphamide, and mitomycin C (Group I); an isolated G2/M block after exposure to the G2/M phase-specific drugs etoposide and vincristine and the non-phase-specific agent doxorubicin (Group II); and an isolated S block following exposure to the S phase-specific agents 5-fluorouracil, methotrexate, and cytosine arabinoside (Group III). Overall, there was no direct correlation between the degree of cell cycle perturbations and chemosensitivity. However, when the three subgroups of non-phase-specific agents, S phase-specific agents, and G2/M-specific agents were analyzed separately, positive correlations between the magnitude of cell kinetic alterations and chemosensitivity were observed. Cell kinetic alterations appeared to precede cytotoxicity.

Antineoplastic Agents↗
PubMed1995

Combination anti-gene therapy targeting c-myc and p53 in ovarian cancer cell lines.

Gene therapy clinical trials targeting p53 and other genes are underway in nongynecologic cancer systems. To explore the potential for antigene therapy in gynecologic oncology, we examined the in vitro effects of oligonucleotides targeting c-myc and p53 in the ovarian cancer cell lines CAOV-3, SKOV-3, and BG-1. The ATP cell viability assay was used to measure growth effects after 6-day treatments with 27-mer antisense phosphorothioate oligodeoxyribonucleotides (oligos) targeting the Puf/nm23 binding region of c-myc and promoter/ATG region of p53. A random sequence of the p53 27-mer was used as a control, and an untransformed fibroblast cell line was used for comparison. IC50 was defined as the oligo concentration required for 50% growth reduction compared to untreated controls. Synergistic vs antagonistic effects of oligo combinations were quantitated by combination indexes (CI) as calculated from median effect parameters by the methods of Chou and Talalay. Mean +/- SE IC50's of c-myc and p53 antisense oligos in CAOV-3 and SKOV-3 ranged from 1.0 +/- 0.2 to 9.7 +/- 1.3 microM. The IC50's of c-myc oligos were consistently lower than corresponding p53 oligos in all cell lines (P < 0.034, t test). The fibroblast cell line was sensitive to anti-c-myc and combination anti-c-myc/p53 oligos (IC50 = 1.5 +/- 0.6 and 1.4 +/- 0.2 microM, respectively), but not to anti-p53 oligos alone (IC50 > 16 microM). Nonspecific toxicity was observed at concentrations of 16 microM for all cell lines except in BG-1, where maximal growth stimulation occurred at this concentration with anti-p53 oligos. Growth stimulation was also observed in BG-1 with anti-c-myc and anti-c-myc/p53 combinations at intermediate doses, with inhibition at higher doses. While c-myc/p53 combinations in CAOV-3 were synergistic (CI < 0.8), they were antagonistic in SKOV-3 (CI > 3.2). Phosphorothioate oligos directed against c-myc and p53 in different cell lines were shown to have both antiproliferative and stimulatory activity, as single agents and in combination, at concentrations that are achievable in vivo. Because of the complex patterns of effects, further in vitro studies are warranted before considering clinical trials with these agents in gynecologic cancers.

Base Sequence↗
PubMed1995

[Value of the adenosine triphosphate chemosensitivity assay for pre-therapeutic determination of the chemosensitivity of breast cancer cells in cell culture].

UNLABELLED: This presentation gives a summary of the chemosensitivity test results in breast cancer using the ATP-Cell-Viability Assay (ATP-CVA). Other assays and test systems for chemosensitivity testing are also evaluated. Our results with the ATP-CVA in breast cancer cell lines showed that this test system is a reproducible and reliable tool in the screening of new drugs. Our results with drug combinations showed that with the ATP-CVA and the "median effect principle" synergistic and antagonistic effects can be reliably calculated. The application of the ATP- CVA in fresh human breast cancer made it possible to test tumor chemosensitivity in individual patients. We found an evaluability rate of the ATP-CVA of 95% in 116 patients. The chemosensitivity profiles of the tested tumors revealed a big heterogeneity of chemosensitivity results for single and drug combinations. The 22 in vitro/in vivo correlations from patients with metastatic breast cancer treated with at least three cycles of chemotherapy showed a sensitivity of the ATP-CVA of 92% and a specificity of 89%. CONCLUSIONS: These data are encouraging and further investigations on chemosensitivity testing of fresh tumours are currently ongoing in a prospective study at the University of Zurich.

Adenosine Triphosphate↗
PubMed1995

In vitro chemosensitivity of paclitaxel and other chemotherapeutic agents in malignant gestational trophoblastic neoplasms.

This is the first report on the ATP cell viability assay as a chemosensitivity test system for gestational trophoblastic neoplasms (GTN). We obtained chemosensitivity profiles in two established trophoblastic cell lines and four fresh tumors. Ten drugs were tested in vitro in the two cell lines JAR and JEG-3. The IC50 values of the 10 chemotherapeutic agents tested were very similar for both cell lines. The three most active drugs in these cell lines were VP-16, paclitaxel and vincristine. This is the first report on the activity of paclitaxel in trophoblastic cell lines. We furthermore evaluated this assay for chemosensitivity testing in four fresh malignant GTN tumors: one placental site trophoblastic tumor, one chorocarcinoma and two invasive moles. The placental site trophoblastic tumor specimen revealed to be rather chemoresistant in vitro whereas the other three tumors were chemosensitive. From our cell line data we conclude that the ATP cell viability assay is a practicable assay for chemosensitivity testing of GTN cell lines and gives repeatable results. However, the value of this assay for fresh GTN chemosensitivity testing needs to be defined.

Adenosine Triphosphate↗
PubMed1995

[Do cell cycle changes of human ovarian carcinoma cells after exposure to cytostatic drugs in vitro correlate with cytotoxicity?].

OBJECTIVES: Is there a correlation between cell cycle perturbations and cytotoxicity in ovarian cancer cells exposed to cytotoxic drugs in vitro? METHODS: We tested the association between cytotoxicity and in vitro cell cycle perturbations after exposure of human ovarian cancer cells to seven cytotoxic agents. RESULTS: Three principal patterns of cell cycle alterations were observed; a sequential S-G/M block after exposure to the non phase-specific agents cis-platinum, 4-hydroperoxy-eyclophosphamide, and mitomycin C (Group I); an isolated G2/M block after exposure to the G2/M phase-specific drugs etoposide and vincristine (Group II); and an isolated S block following exposure to the S phase-specific agents 5-fluorouracil and cytosine arabinoside (Group III). Overall, there was no direct correlation between the degree of cell cycle perturbations and cytotoxicity. However, when the three subgroups of phase non-specific agents, S phase-specific agents, and G2/M specific agents were analyzed separately, positive correlations between the magnitude of cell kinetic alterations and cytotoxicity were observed. CONCLUSIONS: Cell kinetic alterations appeared to precede cytotoxicity. The experimental model may be particularly useful to study cell kinetic effects after high-dose chemotherapy since, in contrast to conventional chemotherapy, the magnitude of cell kinetic perturbations after this kind of treatment is significantly increased.

Antineoplastic Agents↗
PubMed1994

National survey of ovarian carcinoma XII. Epithelial ovarian malignancies in women less than or equal to 25 years of age.

BACKGROUND: Epithelial ovarian carcinoma in women less than or equal to 25 years of age is a rare entity. This study used the database of the National Survey of Ovarian Carcinoma to analyze the disease and survival in women less than or equal to 25 years of age. METHODS: Tumor registries of 1230 hospitals were asked to enter the first 25 patients with histologically confirmed ovarian carcinoma from January 1 to December 31, 1983 and from January 1 to December 31, 1988. Data for a total of 12,136 patients were collected. Survival analysis and long-term evaluations were available on patients diagnosed with cancer in 1983. Chi-square analysis was used to compare the frequencies of operations performed in 1983 and 1988. RESULTS: Of 12,136 patients with epithelial ovarian carcinoma, 135 (1.1%) were less than or equal to 25 years of age. The majority of patients had early disease with the following distributions: stage I, 58.5%; stage II, 8.9%; stages III and IV, 28.9%. More patients had early-grade lesions with the following distributions: borderline, 21.5%; Grade 1, 27.4%; Grade 2, 11.1%; Grade 3, 6.7%; and unknown grade, 33.3%. Optimal cytoreduction was achieved in 77% of patients. During the 5-year study period, there was a significant change in the patterns of care toward more conservative surgery. In particular, unilateral salpingooophorectomy increased significantly from 38.2 to 59.7% (P = 0.0237), whereas hysterectomy decreased proportionally from 54.4 to 29.9% (P = 0.0039). The overall 5-year survival rate was 87.3% with the following divisions: stage I, 96.7%; stage II, 90.0%; stage III, 78.5%; and stage IV, 76.4%. Regarding histologic grade, 5-year survival rates were: borderline, 91.6%; Grade 1, 93.7%; Grade 2, 85.7%; Grade 3, 33.3%. CONCLUSION: Young patients with epithelial ovarian carcinoma appeared to have favorable stage and histologic grade. These factors combined with good performance status and optimal cytoreduction resulted in improved survival from cancer.

Adult↗
PubMed1994

A multivariate analysis of clinicopathologic factors for predicting outcome in uterine sarcomas.

This study involved a comprehensive review of the histologic slides of 62 patients who were diagnosed with uterine sarcoma from 1978 through 1988 at a single institution. In addition, DNA content (ploidy level) could be determined from the H & E slides of these tumors using image analysis. Also, 42 of these cases had retrievable cell blocks on which DNA analysis was performed by means of flow cytometry. A linear regression analysis found a high degree of correlation (r = 0.8) between the measurement of the DNA index of these tumors by these two techniques. All cases were retrospectively restaged using the newly adopted FIGO surgical staging criteria which found the following distribution: 22 (35.5%) Stage I, 10 (16.1%) Stage II, 12 (19.4%) Stage III, and 18 (29%) Stage IV. A multivariate analysis of 60 evaluable patients using the Cox proportional hazard model found that surgical staging was the most significant prognostic factor with respect to the endpoint of overall survival (P = 0.00004). Both patient age at diagnosis and mitotic index were independent from surgical staging in predicting outcome. Furthermore, there was a trend suggesting that DNA index also had prognostic value. Of particular interest was that patients with diploid tumors (DNA index, 0.9-1.1) had a 5-year overall survival of 72% and did not approach median survival; however, hyperdiploid tumors (DNA index > 1.1) and hypodiploid tumors (DNA index < 0.9) were associated with median survivals of 18 and 12 months, respectively. In conclusion, this study supports the use of surgical staging of patients with uterine sarcomas in order to optimally determine their chance for survival. Further biologic investigations which may result in identifying those patients who could benefit from adjunctive treatment are recommended.

Adult↗
PubMed1994

Complications of the ileocolonic continent urinary reservoir (Miami pouch).

Urinary diversion via the continent ileocolonic reservoir has been performed at our institution since February 1988. During a 4-year period, 39 patients have received this procedure as an alternative to other forms of cutaneous urinary diversion at the time of exenteration. We analyze our data in terms of early and late (beyond 6 weeks) complications resulting directly from the operation or from this form of urinary diversion. A total of 18 patients (46%) suffered early complications resulting in an operative mortality rate of 7% (3 of 39 patients). One or more late complications occurred in six patients (15%). Only one patient required reoperation for a postoperative complication. With ongoing experience, problem areas have been identified that have led us to make modifications in technique. We review our experience with the incidence of early and late complications in terms of management and ultimate prevention.

Humans↗
PubMed1994

Evaluation of paclitaxel (taxol), cisplatin, and the combination paclitaxel-cisplatin in ovarian cancer in vitro with the ATP cell viability assay.

This study evaluates the in vitro sensitivities of 42 ovarian cancer specimens to the new anticancer agent Paclitaxel (taxol, Tx), cisplatin (DDP), and the combination Tx-DDP with the adenosine triphosphate cell viability assay (ATP-CVA). In vitro response is defined by > or = 50% ATP decrease compared to untreated controls 6-7 days after drug treatment with 20% of the peak plasma concentration (PPC). Response rates were 12% to Tx, 19% to DDP, and 27% to Tx + DDP. The mean IC50's of Tx, DDP, and the combination Tx-DDP were (2.6x, 1.0x, and 0.38x PPC, respectively). The mean inhibition of cell viability was significantly greater with drug combinations compared to single drugs. In 7/11 tumors synergistic effects and in 2/11 additive effects were found between Tx and DDP. We conclude that based on ATP-CVA in vitro results, Tx-DDP shows significantly better activity compared to each of the single drugs in ovarian cancer.

Adenosine Triphosphate↗
PubMed1994

Comparison of paclitaxel and docetaxel (Taxotere) in gynecologic and breast cancer cell lines with the ATP-cell viability assay.

The in vitro effects of paclitaxel (Tx) and docetaxel (Taxotere, Txt) are compared in this study using the adenosine triphosphate cell viability assay (ATP-CVA) in 14 cancer cell lines. Eleven cell lines were sensitive and three were partially sensitive to paclitaxel. Nine cell lines were sensitive, three were partially sensitive and two were resistant to docetaxel. Mean IC50s were 3.7-660 ng/ml paclitaxel and 5.4-540 ng/ml docetaxel. In five sensitive cancer cell lines docetaxel was more active than paclitaxel, and in six sensitive cell lines paclitaxel was more active than docetaxel on a concentration basis. Two cell lines were sensitive to paclitaxel and resistant to docetaxel. In one cell line the two compounds had similar activities. In the ATP-CVA, paclitaxel and docetaxel are very active and are partially non-cross-resistant.

Adenocarcinoma↗
PubMed1994

Fine-needle aspiration cytology of palpable lesions of the lower female genital tract.

During January 1978 through May 1989, 232 fine-needle aspirations of palpable lesions of the vulva, vagina, inguinal area, and perineum were performed on 209 women. Five samples were considered inadequate for cytologic evaluation. Eighty-seven (38.3%) aspirates were interpreted as malignant, 80 of which were further classified into specific cell types. Most malignant neoplasms represented metastases from other gynecologic organs. Of the 140 (61.7%) nonmalignant aspirates, only 28 (20%) could be categorized into specific pathologic disorders. The false-positive and false-negative rates were 0 and 4.6%, respectively. We conclude that, because of its safety, simplicity, and accuracy, fine-needle aspiration cytology represents a valuable diagnostic tool in the evaluation of palpable lesions of the lower female genital tract. This technique is particularly helpful in the assessment of primary, metastatic, or recurrent malignant neoplasms of this region.

Adenocarcinoma↗
PubMed1994

[Quantitative determination of dose-response relations of taxol and cisplatin in ovarian cancer cells with a bioassay in comparison with cytomorphology].

The dose-response relations of the cytotoxic drugs taxol and cisplatin and their combination were analyzed in an ovarian cancer cell line (BG-1). The chemosensitivity profiles were obtained with 5 concentrations using the ATP cell viability assay (ATP-CVA). Furthermore, the cytomorphologic changes were analyzed. Our findings demonstrate that the ATP-CVA is able to determine the fraction of surviving cells and has proved to be an effective tool to measure cytotoxicity. At the same time we were able to analyze the cytomorphologic changes. The implications of these results for the practice of gynecologic oncology are discussed.

Antineoplastic Combined Chemotherapy Protocols↗