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Biomedical subjects

C J Cohen

Publications and source records attributed to C J Cohen.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pelvic exenteration in gynecologic oncology: Experience at the Mount Sinai Center, 1975-1992.

Thirty-nine patients underwent pelvic exenteration for gynecologic malignancies at The Mount Sinai Medical Center between 1975 and 1992. Surgical techniques, morbidity, survival, and other variables for patients so treated in two periods, 1975-1984 and 1985-1992, were compared. The primary cancer included squamous cell carcinoma of the cervix, 27; adenocarcinoma of the cervix, 1; squamous cell carcinoma of the vagina, 4; adenocarcinoma of the endometrium, 4; squamous cell carcinoma of the vulva, 2; and adenocarcinoma of the rectum, 1. Median survival was 23.1 months, with a median follow-up of 18 months. Survival was significantly related to status of the lymph nodes (p 0.0004) and surgical margins (p 0.0038). There were two postoperative mortalities, one due to pulmonary embolus and another to myocardial infarction. The ability in the second period analyzed, 1985-1992, to integrate a continent urinary reservoir and supralevator exenteration without colostomy yet not induce increased morbidity or decreased survival, has not been previously reported.

Adult↗
PubMed1994

Type III omega-agatoxins: a family of probes for similar binding sites on L- and N-type calcium channels.

The peptide omega-agatoxin-IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta is the only known agent that blocks L-type and N-type Ca channels with equal high potency (IC50 < or = 1 nM). From the same venom, we have purified and sequenced a family of peptides which are homologous to omega-Aga-IIIA but vary over 100-fold in their relative affinity for L-type versus N-type Ca channels. One of these, omega-Aga-IIIB, is 76 amino acids long and identical to omega-Aga-IIIA in 66 positions. We identified two other similar peptides, omega-Aga-IIIC and omega-Aga-IIID, as well as one single amino acid variant of omega-Aga-IIIA and two of omega-Aga-IIIB. The type III omega-agatoxins exhibit similar but distinct activities on voltage-gated Ca channels. omega-Aga-IIIA, omega-Aga-IIIB, and omega-Aga-IIID are nearly indistinguishable in their actions at the insect neuromuscular junction (no effect at 0.1 microM), on atrial T-type Ca channels (no effect at 0.5 microM), and in two assays for synaptosomal Ca channels: they are nearly equipotent inhibitors of 125I-omega-conotoxin GVIA binding to rat brain synaptic membranes (IC50 = 0.17-0.33 nM) and blockers of the K(+)-induced 45Ca2+ influx into chick brain synaptosomes (omega-Aga-IIIB, 1.2 nM; omega-Aga-IIIA, 2.4 nM). In contrast, omega-Aga-IIIA is a better blocker of locust Ca channels (IC50 approximately 10-50 nM) than is omega-Aga-IIIB. Finally, although omega-Aga-IIIA, omega-Aga-IIIB, and omega-Aga-IIID all block atrial L-type Ca channels, omega-Aga-IIIA is over 100-fold more potent. Thus, although type III omega-agatoxins appear to recognize a binding site common to L- and N-type Ca channels, omega-Aga-IIIB and omega-Aga-IIID identify differences between the two channels.

Agatoxins↗
PubMed1994

The stapled continent ileocecal urinary reservoir in the surgical management of gynecologic malignancy.

Total cystectomy at the time of radical pelvic surgery for gynecologic malignancies is not uncommon. Many techniques have been developed for urinary diversion including the continent ileocecal urinary reservoir. Twenty-nine patients underwent construction of a continent ileocecal urinary reservoir during the reconstructive phase of an exenterative procedure or for the relief of urinary tract fistula between 1990 and 1993. All procedures were performed using the mechanical stapling devices using metal staples. The right and proximal transverse colon were mobilized to a length of 24 cm. The ileum was divided 8 cm proximal to the ileocecal valve and plicated using the stapling technique. The colonic segment was opened on its antimesenteric border and the reservoir was created by stapling in a fashion to reapproximate the distal ends to each other. The ureters were stented and implanted without tunneling. A large Malecot drain was placed in all the pouches for irrigation of the colonic mucosa in the postoperative period. The ileal stoma was fixed to the anterior abdominal wall as was the anterior surface of the pouch. Operative time ranged from 50 to 150 min for the pouch construction. All patients underwent retrograde contrast study of the pouch 7-10 days postoperatively to verify lack of anastomatic leaks. After recovery, all patients successfully self-catheterized the pouch three to five times daily without difficulty. Of the 29 patients, 17 (59%) had received prior radiation as part of therapy. All patients remained continent at the end of observation. One developed a fistula to the perineum after intraoperative placement of 125I seeds on the pelvic wall. One patient developed pouch stones; endoscopic evaluation of this pouch revealed no evidence of stones at the staple lines and metabolic workup demonstrated hypocitremia as the etiology for the stones. Mean reservoir volume was 550 ml. Mean follow-up is 15.8 months; 5 have expired due to recurrent disease and 19 (83%) remain alive. Only two patients have been admitted for urosepsis due to reflux pyelonephritis. The stapled continent ileocecal reservoir offers benefits to patients undergoing total cystectomy. Using the mechanical stapling devices decreases the operative time and has not resulted in stone formation or pouch leakage. The complications of the procedure are acceptable.

Adult↗
PubMed1994

Growth factor expression in normal peritoneum of patients with gynecologic carcinoma.

Both epidermal growth factor receptor (EGFR) and HER-2/neu (neu) have been found to be of prognostic importance in epithelial ovarian and endometrial carcinoma, but alterations in proto-oncogene expression of normal tissues of patients with gynecologic malignancies are unknown. Patients (118) undergoing laparotomy for gynecologic indications (78 ovarian cancer, 11 endometrial cancer, 19 benign gynecologic disease, 10 other cancers) had biopsies of normal peritoneum for quantitative assessment of neu and EGFR concentrations. Patients undergoing exploration for gynecologic malignancy were found to have significantly higher median neu expression in the peritoneal biopsies than patients with benign gynecologic disease (P = 0.002). Most patients in this study were found to have ovarian cancer, and median peritoneal neu expression was found to be significantly higher in patients with ovarian cancer versus benign ovarian masses (P = 0.0008) or any benign gynecologic disease (P = 0.004). No significant alteration of unbound EGFR was found in peritoneal biopsies of any of the groups of patients. No associations were found for a history of breast cancer, presence of ascites, or menopausal status with alteration of neu or EGFR expression in normal peritoneum. These findings of altered expression of neu in normal tissues of patients with ovarian cancer are suggestive of the presence of proto-oncogene alterations in loco-regional tissues of the peritoneum, such as might be seen if a paracrine influence existed between tumor and peritoneal cells. Alternatively, the alterations may represent subtle alterations of proto-oncogene expression of germ-line tissues.

Biomarkers, Tumor↗
PubMed1994

Screening for ovarian cancer: the role of noninvasive imaging techniques.

In spite of diagnostic and therapeutic improvements the Surveillance Epidemiology and End Results Program data suggest that the overall cure rate for patients with ovarian cancer is 39%. Because of the dramatic difference in cure between patients with local disease (80% to 90%) and those with distant disease (15% to 25%), screening to find early ovarian cancer or its precursors is desirable. Transvaginal ultrasonography is the most efficient, accurate, and least expensive of the imaging modalities (transabdominal ultrasonography, computed tomography, magnetic resonance imaging, radioimmunoscintigraphy) for this purpose. To date, 10,000 women have been screened in three large programs; 11 cancers were detected (10 stage I, one occult stage IIIB) and all have apparently been cured. Doppler flow imaging and morphology index values improve the accuracy of transvaginal ultrasonography. A cost analysis suggests that screening costs are not yet less than treatment costs if there is to be universal screening of 27 million women at risk in the United States. However, for a population with a lifetime risk for ovarian cancer of 1%, screening will save five lives per 2000 patients screened.

Female↗
PubMed1994

Dictyostelium discoideum mutants with conditional defects in phagocytosis.

We have isolated and characterized Dictyostelium discoideum mutants with conditional defects in phagocytosis. Under suspension conditions, the mutants exhibited dramatic reductions in the uptake of bacteria and polystyrene latex beads. The initial binding of these ligands was unaffected, however, indicating that the defect was not in a plasma membrane receptor: Because of the phagocytosis defect, the mutants were unable to grow when cultured in suspensions of heat-killed bacteria. The mutants exhibited normal capacities for fluid phase endocytosis and grew as rapidly as parental (AX4) cells in axenic medium. Both the defects in phagocytosis and growth on bacteria were corrected when the mutant Dictyostelium cells were cultured on solid substrates. Reversion and genetic complementation analysis suggested that the mutant phenotypes were caused by single gene defects. While the precise site of action of the mutations was not established, the mutations are likely to affect an early signaling event because the binding of bacteria to mutant cells in suspension was unable to trigger the localized polymerization of actin filaments required for ingestion; other aspects of actin function appeared normal. This class of conditional phagocytosis mutant should prove to be useful for the expression cloning of the affected gene(s).

Animals↗
PubMed1994

Dictyostelium discoideum mutants with temperature-sensitive defects in endocytosis.

We have isolated and characterized temperature-sensitive endocytosis mutants in Dictyostelium discoideum. Dictyostelium is an attractive model for genetic studies of endocytosis because of its high rates of endocytosis, its reliance on endocytosis for nutrient uptake, and tractable molecular genetics. Endocytosis-defective mutants were isolated by a fluorescence-activated cell sorting (FACS) as cells unable to take up a fluorescent marker. One temperature-sensitive mutant (indy1) was characterized in detail and found to exhibit a complete block in fluid phase endocytosis at the restrictive temperature, but normal rates of endocytosis at the permissive temperature. Likewise, a potential cell surface receptor that was rapidly internalized in wild-type cells and indy1 cells at the permissive temperature was poorly internalized in indy1 under restrictive conditions. Growth was also completely arrested at the restrictive temperature. The endocytosis block was rapidly induced upon shift to the restrictive temperature and reversed upon return to normal conditions. Inhibition of endocytosis was also specific, as other membrane-trafficking events such as phagocytosis, secretion of lysosomal enzymes, and contractile vacuole function were unaffected at the restrictive temperature. Because recycling and transport to late endocytic compartments were not affected, the site of the defect's action is probably at an early step in the endocytic pathway. Additionally, indy1 cells were unable to proceed through the normal development program at the restrictive temperature. Given the tight functional and growth phenotypes, the indy1 mutant provides an opportunity to isolate genes responsible for endocytosis in Dictyostelium by complementation cloning.

Adenosine Triphosphate↗
PubMed1994

Isolation of myocardial L-type calcium channel gating currents with the spider toxin omega-Aga-IIIA.

The peptide omega-agatoxin-IIIA (omega-Aga-IIIA) blocks ionic current through L-type Ca channels in guinea pig atrial cells without affecting the associated gating currents. omega-Aga-IIIA permits the study of L-type Ca channel ionic and gating currents under nearly identical ionic conditions. Under conditions that isolate L-type Ca channel currents, omega-Aga-IIIA blocks all ionic current during a test pulse and after repolarization. This block reveals intramembrane charge movements of equal magnitude and opposite sign at the beginning of the pulse (Q(on)) and after repolarization (Q(off)). Q(on) and Q(off) are suppressed by 1 microM felodipine, saturate with increasing test potential, and are insensitive to Cd. The decay of the transient current associated with Q(on) is composed of fast and slow exponential components. The slow component has a time constant similar to that for activation of L-type Ca channel ionic current, over a broad voltage range. The current associated with Q(off) decays monoexponentially and more slowly than ionic current. Similar charge movements are found in guinea pig tracheal myocytes, which lack Na channels and T-type Ca channels. The kinetic and pharmacological properties of Q(on) and Q(off) indicate that they reflect gating currents associated with L-type Ca channels. omega-Aga-IIIA has no effect on gating currents when ionic current is eliminated by stepping to the reversal potential for Ca or by Cd block. Gating currents constitute a significant component of total current when physiological concentrations of Ca are present and they obscure the activation and deactivation of L-type Ca channels. By using omega-Aga-IIIA, we resolve the entire time course of L-type Ca channel ionic and gating currents. We also show that L- and T-type Ca channel ionic currents can be accurately quantified by tail current analysis once gating currents are taken into account.

Agatoxins↗
PubMed1993

Feasibility of intraoperative administration of chemotherapy for gynecologic malignancies: assessment of acute postoperative morbidity.

In order to assess the acute effects of the intraoperative administration of intraperitoneal (IP) carboplatin with and without intravenous (IV) doxorubicin in patients with gynecologic malignancies, 25 patients were treated at the conclusion of their surgical procedure. Twenty-three had epithelial ovarian cancer and 2 had advanced endometrial cancer. Twelve patients received IP carboplatin and IV doxorubicin at the conclusion of their primary cytoreduction. The remaining 13 received IP carboplatin alone and consisted of 4 reassessment laparotomies for ovarian cancer, 7 secondary cytoreductions, 1 minilaparotomy for the placement of an IP catheter, and 1 second-look laparoscopy. The median age of the 25 patients was 59 years. Eight patients underwent bowel resections with anastomoses; 2 had ureteral resections and ureteroneocystostomies, 1 required a splenectomy, and 1 underwent a partial hepatic resection. There were no mortalities. Three of the 13 patients who received the IP carboplatin alone had postoperative fevers with no infectious source, which did not delay discharge. No other morbidity was noted in this group. However, 7 patients who received IV doxorubicin along with the IP carboplatin developed severe leukopenia requiring antimicrobial and colony-stimulating factor support. One patient required reexploration for postoperative hemorrhage and also developed a pulmonary embolus. One woman developed postoperative pneumonia. The median hospital stay for the 25 patients was 9 days. Intraoperative chemotherapy can be administered with tolerable immediate adverse effects.

Adult↗
PubMed1993

Morphometric differentiation between responsive tumor cells and mesothelial hyperplasia in second-look operations for ovarian cancer.

We developed a procedure based on computerized image analysis to establish objective criteria for the differential diagnosis between mesothelial hyperplasia and cancer in peritoneal tissue samples obtained at second-look operations for ovarian cancer. The tumor tissue after chemotherapy was classified as "nonresponsive" if it was found by histologic criteria to be roughly similar to the tumor before chemotherapy and as "responsive" if it was found to be different (small clusters of bland-looking cells with no mitotic activity). Eighty-five samples of tissue had been classified previously by a pathologist into one of the four following groups: ovarian tumor prior to chemotherapy, "responsive" tumor, "nonresponsive" tumor, or mesothelial hyperplasia. Cell profiles of the tissue samples were studied by computerized image analysis using 21 morphometric descriptors derived from the manual tracings of tumor nuclei, including nuclear perimeter, nuclear area, maximal chord, circularity factor, and standard deviations of these descriptors. Size distribution curves of nuclear areas and maximal chords were included in the analysis. A multivariate discriminant analysis confirmed the separation into the four diagnostic groups, accomplished with consideration of the physical descriptors alone, except for some overlapping between groups 1 and 3. The separation between carcinoma and mesothelial hyperplasia was clear in all cases.

Cell Nucleus↗
PubMed1993

Secondary cytoreduction for ovarian cancer following cisplatin therapy.

PURPOSE: This study was undertaken to evaluate the efficacy of secondary surgical cytoreduction in the management of ovarian cancer. PATIENTS AND METHODS: The cases of 100 patients with recurrent or progressive epithelial ovarian cancer whose initial treatment had been cytoreduction followed by cytotoxic therapy with a cisplatin-based regimen were reviewed. All 100 patients underwent surgery, after recurrence or progression was documented preoperatively, by gynecologic oncologists at the Mount Sinai Medical Center, New York, NY, between 1980 and 1991 with the intention of performing radical tumor reduction. RESULTS: Sixty-one patients had a secondary cytoreduction that left residual disease less than 2 cm in diameter. The median survival, determined from the date of the secondary cytoreduction to the date of death or last follow-up, is 27.1 months in the optimally treated group and 9.0 months for the 39 patients whose surgery was suboptimal (P = .0001). Other variables associated with statistically significant longer survival, and a significantly higher probability of achieving a successful secondary cytoreduction, included age < or = 55 years at the time of secondary cytoreduction, interval from initial diagnosis to secondary cytoreduction of more than 12 months, residual disease at initial staging laparotomy of less than 2 cm, and a complete clinical response to a cisplatin-based front-line regimen. Multivariate analysis confirms the survival benefit provided by a successful secondary cytoreduction when adjusted for the above variables. There was one postoperative mortality. Ten percent of the successfully cytoreduced patients and 18% of the unsuccessfully cytoreduced patients experienced some degree of postoperative morbidity. CONCLUSION: These data justify the performance of secondary cytoreductive surgery for patients who develop gross recurrent or progressive ovarian cancer following cisplatin therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Phase II trial of etoposide, carboplatin, and ifosfamide as salvage therapy in advanced ovarian carcinoma.

A phase II study combining etoposide with carboplatin and ifosfamide as salvage therapy in advanced ovarian cancer was undertaken. Objective responses were achieved in 37.5% of 16 evaluable patients with a mean progression-free interval of 8.6 months. Stable disease was present in 25% of patients; in 37.5% of patients the disease progressed on salvage. Based on original response to front-line therapy, patients were classified as being platinum-sensitive (group I) or platinum-refractory (group II). Clinical response to salvage therapy was seen in 44.5% of group I patients, but in only 28.6% of group II patients. This difference was not statistically significant. When a more precise definition of platinum sensitivity was applied, clinical responses were seen in 54.5% of group I patients, but no responses were noted among group II patients (p < 0.05). Platinum sensitivity appeared to be an important factor in achieving a response with this regimen. This combination was well tolerated, myelotoxicity being the dose-limiting toxicity encountered. No life-threatening, nonhematologic toxicities were seen. One death occurred secondary to nadir sepsis. The combination of etoposide, carboplatin, and ifosfamide is an active salvage regimen in patients with advanced ovarian carcinoma; however, severe myelotoxicities and inability to produce long-term responses underscore the need for continued trials to find a more durable salvage regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Two types of endometrial papillary neoplasm. A morphometric study.

Fourteen cases of Papillary Endometrial Carcinoma (EC) were analyzed by Interactive Computerized Morphometry. Seven cases were diagnosed as well differentiated adenocarcinomas with papillary features (PF) and belonged to a group of EC with associated adenomatous hyperplasia (AH). Seven cases were diagnosed as uterine papillary serous carcinomas (PA) and belonged to a group of EC without associated AH. Two morphometric procedures were used. DRAW for the characterization of individual nuclei (area, perimeter, chord) and NU-MEAS for tissue architectural features (crowding and stratification). Using a stepwise discriminant multifactorial analysis, both methods proved to be accurate for the two diagnostic categories, as shown by the 100% posterior probabilities and by the two diagnostic categories, as shown by the 100% posterior probabilities and by the distances between group means. A doubtful case was analyzed and classified using a K-nearest neighbor procedure, compared to the individual case in the database. The distinction between the two types of papillary EC is important for the differential diagnosis of the two lesions. Well differentiated adenocarcinoma with papillary features is seen usually in the context of a well-differentiated adenocarcinoma, in a group of patients known to have estrogen-related less aggressive tumors. Uterine papillary serous carcinoma was described to have a biological behavior similar to that of papillary ovarian carcinoma and is encountered in a group of patients with more invasive and less differentiated EC2. Computerized interactive morphometry is a valuable method to use for the accuracy of this differential diagnosis in doubtful cases.

Adenocarcinoma↗
PubMed1992

Block of T-type Ca channels in guinea pig atrial cells by antiarrhythmic agents and Ca channel antagonists.

Myocardial cells have two types of Ca channels commonly called T-type and L-type. Whole cell Ca channel currents in guinea pig atrial myocytes can be separated and quantitated by analyzing channel closing kinetics after a brief depolarization (tail current analysis). L-type Ca channels deactivate rapidly when the membrane is repolarized and T-type Ca channels deactivate relatively slowly. Ca channel block by the therapeutically useful Ca channel antagonists is voltage dependent, so it is desirable to study block of both channel types over an extended voltage range. Tail current analysis allows this and was used to study block of both types of Ca channels under identical conditions. Amiodarone, bepridil, and cinnarizine block T-type Ca channels more potently than L-type Ca channels when binding equilibrates at normal diastolic potentials (approximately -90 mV). None of these drugs is a selective blocker of T-type Ca channels because block of L-type Ca channels is enhanced when cells are almost completely depolarized. Although weak block of T-type Ca channels by 1,4-dihydropyridines has usually been reported, we found that felodipine blocks these channels with high affinity. When most T-type Ca channels are inactivated, the apparent dissociation constant (KI) is 13 nM. Felodipine also blocks T-type Ca channels in GH3 cells (a cell line derived from rat anterior pituitary), but KI = 700 nM. Thus, T-type Ca channels in different cell types are pharmacologically distinct. Felodipine can block L-type Ca channels in atrial cells more potently than T-type Ca channels, but block of L-type Ca channels is potent only at depolarized potentials; block of both channel types is comparable at normal diastolic membrane potentials. Felodipine and the 1,4-dihydropyridines isradipine and (-)-202-791 are approximately equipotent at blocking T-type Ca channels, but differ substantially in potency for block of L-type Ca channels. Block of T-type Ca channels may account for some of the pharmacological effects of 1,4-dihydropyridines and for the antiarrhythmic activity of amiodarone and bepridil.

Animals↗
PubMed1992

Tamoxifen and endometrial cancer.

Tamoxifen is a nonsteroidal antiestrogen employed frequently in the treatment of breast cancer. An association between this drug and endometrial neoplasia has been reported. We report on 11 postmenopausal women with breast cancer who developed endometrial cancer while undergoing tamoxifen therapy and recommend aggressive investigation of vaginal bleeding in all women being treated with this agent.

Adenocarcinoma↗
PubMed1992

High affinity block of myocardial L-type calcium channels by the spider toxin omega-Aga-toxin IIIA: advantages over 1,4-dihydropyridines.

The peptide omega-agatoxin IIIA (omega-Aga-IIIA) from venom of the funnel web spider Agelenopsis aperta blocks L-type Ca2+ channels in neurons and myocardial cells with high affinity. We report that omega-Aga-IIIA also blocks whole-cell Ca2+ channel currents in guinea pig atrial myocytes. Although other high affinity blockers of L-type Ca2+ channels are available (such as the 1,4-dihydropyridines), omega-Aga-IIIA is a valuable pharmacological tool; omega-Aga-IIIA is the only known ligand that blocks L-type Ca2+ channels with high affinity at all voltages (IC50 approximately 1 nM) and it causes little or no block of T-type Ca2+ channels, unlike the 1,4-dihydropyridines. We use omega-Aga-IIIA to selectively eliminate L-type Ca2+ currents and we show that felodipine blocks T-type Ca2+ currents. Consequently, the toxin is better than dihydropyridines for separating ionic currents through voltage-dependent Ca2+ channels and defining their physiological function.

Agatoxins↗