Biomedical subjects
C J Cohen
Publications and source records attributed to C J Cohen.
The inhibition of receptor-mediated and voltage-dependent calcium entry by the antiproliferative L-651,582.
L-651,582, 5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4- carboxamide, an antiproliferative and antiparasitic agent previously shown to affect 45Ca2+ uptake into mammalian cells, inhibits both receptor-mediated and voltage-dependent calcium entry in well characterized in vitro systems. Indo 1 fluorescence measurements of cytosolic calcium levels indicate that the drug has no effect on the initial transient release of internal stores of calcium stimulated by fMet-Leu-Phe in rat polymorphonuclear leukocytes. It does decrease the levels maintained subsequently, however, indicating blockage of calcium influx through receptor-operated channels. L-651,582 also blocks the stimulation of leukotriene B4 (LTB4) production by fMet-Leu-Phe with an IC50 = 0.5 micrograms/ml equal to that for calcium entry inhibition. The LTB4 inhibition is likely due to calcium entry inhibition since L-651,582 does not inhibit calmodulin or enzymes producing arachidonate metabolites. L-651,582 also inhibits potassium-stimulated 45Ca2+ influx into GH3 cells with an IC50 of 0.5 microgram/ml, indicating a block of voltage-gated L-type calcium channels. Patch voltage clamp measurements of current through L- and T-type calcium in guinea pig atrial cells also indicate that L-651,582 is a calcium antagonist. Block of L-type calcium channels is voltage-dependent, and the apparent dissociation constant for the high affinity state is 0.2 micrograms/ml. The IC50 for block of T-type calcium channels is 1.4 micrograms/ml. The inhibition of cellular proliferation and the production of arachidonate metabolites by L-651,582 may be the result of the nearly equipotent block of receptor-operated and voltage-gated calcium channels.
A phase II trial of adjuvant cisplatin and doxorubicin in stage I epithelial ovarian cancer.
We have treated 26 patients with Stage I ovarian cancer with platinum-based chemotherapy. Patients received 50 mg/m2 cisplatin and 50 mg/m2 doxorubicin every 21 days for six cycles. Eighteen patients had complete surgical staging defined as total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and aortic node sampling, omentectomy, and cytology. Eight patients had all of the above with the exception of node sampling. The overall median follow-up for the group is 43+ months. Three patients had grade 1 tumors with positive washings or capsule invasion and are disease free with a median follow-up of 53+ months. Of 23 patients with grade 2-3 tumors, 22 are alive and free of disease with a median follow-up of 42+ months. There has been 1 recurrence, at 18 months, in a patient who had complete staging and a grade 2 tumor. The patient recurred with carcinomatosis, documented by laparoscopy. There was no significant hematologic, neurologic, or renal toxicity encountered in any patient. Adjuvant combination chemotherapy is beneficial for selected patients with early-stage ovarian cancer who are at high risk for failure after surgical treatment alone.
Induction chemotherapy followed by radical surgery in cervical cancer.
To evaluate the therapeutic potential of cytotoxic therapy in patients with squamous cell carcinoma of the cervix, 28 patients with disease clinically localized to the pelvis were treated with chemotherapy followed by radical pelvic surgery. Treatment consisted of cis-platinum 50 mg/m2, mitomycin C 10 mg/m2, vincristine 1.0 mg/m2, and bleomycin 10 U IM given as a course (over 21 days) of induction chemotherapy followed by radical hysterectomy and pelvic and aortic lymphadenectomy in 26 patients and total pelvic exenteration in 2 patients. The stage distribution of the patients in the study was 4 stage IB, 6 stage IIA, 7 stage IIB, 1 stage IIIA, 11 stage IIIB, and 1 stage IVA. Two patients with stage IIIB cancer were found, at the time of laparotomy, to have carcinomatosis and were excluded from the final evaluation in this study. All patients achieved a clinical and histologic response to chemotherapy. There were 35% complete and 65% partial responses. After chemotherapy, at the time of surgery, 4 patients were found to be histologically free of disease, and the incidence of surgically documented nodal disease after chemotherapy was found to be 32%. There was no significant hematologic or pulmonary toxicity. Induction chemotherapy is well tolerated and may be beneficial in the management of some patients with cervical cancer who are at high risk for failure with conventional treatment.
Recurrent cervical squamous cell carcinoma in an ovary following ovarian conservation and radical hysterectomy.
This is the second reported case of an ovarian recurrence of Stage I squamous cell carcinoma of the cervix. It occurs following radical hysterectomy, chemotherapy, and radiotherapy. The issue of ovarian conservation is addressed.
Primary prophylaxis for Pneumocystis carinii pneumonia in HIV-infected people with CD4 counts below 200/mm3: a cost-effectiveness analysis.
We developed a decision-analytic model to assess the effectiveness and costs of dapsone, trimethoprim-sulfamethoxazole, or aerosolized pentamidine as initial prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected people without prior symptoms AIDS and with CD4 counts less than 200/mm3. Each strategy increased life expectancy by about 18% compared with no prophylaxis; annual per-person costs were $440, $700, and $1,680 for dapsone, trimethoprim-sulfamethoxazole, and aerosolized pentamidine, respectively. These cost differences make a strategy beginning with dapsone most cost effective, with an incremental cost-effectiveness ratio of $13,400 per life year saved compared with no prophylaxis. Aerosolized pentamidine was substantially less cost effective, but the incremental cost effectiveness ratios were highly dependent on estimates for quality of life, efficacy, toxicity, and compliance. We conclude that, based on currently available data, initial prophylaxis with either dapsone or trimethoprim-sulfamethoxazole is most cost effective. For every 100,000 people treated, starting prophylaxis with trimethoprim-sulfamethoxazole or dapsone--with crossover to aerosolized pentamidine if oral therapy is not tolerated--may save between $98 million and $124 million per year.
Long-term effects of a lifestyle modification exercise program on the fitness of sedentary, obese children.
We studied the effects of a lifestyle modification and exercise program on the fitness of 12 sedentary and obese children who were physician-referred into a 1-month YMCA lifestyle modification program. These variables were measured at entry, at the program's conclusion, and 1 and 4 months following conclusion: weight (lbs), sum of 2 skinfolds (mm), number of sit-ups, 9-minute run (total distance in yds), sit-and-reach for flexibility (cm). Total serum cholesterol (mg/dl) was measured only at entry and 4 months following conclusion. We found a NS decrease in weight (124 to 117 lbs) and sum of skinfolds (54 to 40 mm); a significant (p less than 0.01) increase in sit-ups (23 to 35); a significant (p less than 0.05) increase in 9 minute run distance (1201 to 1419 yds); no change in flexibility; and a NS decrease in total serum cholesterol (178 to 155 mg/dl). It was concluded that, while good changes were made, a longer period of time would be required to significantly reduce weight, sum of skinfolds, and total serum cholesterol.
The concept of uterine preservation with ovarian malignancies.
A 30-year-old woman with bilateral, recurrent, borderline papillary serous cystadenocarcinoma of the ovary was treated with bilateral oophorocystectomy and omentectomy with uterine preservation. Ten years later, through induction of an artificial endometrial cycle and ovum donation, she conceived twins and delivered two healthy infants. Staging exploratory laparotomy at the time of cesarean delivery was negative for malignancy. This case illustrates the value of uterine preservation for cases in which classical teaching has indicated hysterectomy with bilateral salpingoophorectomy.
Ovarian intraepithelial neoplasia demonstrated in patients with stage I ovarian carcinoma.
Retrospective review of sections of ovary from 50 patients with stage I, grade 1-3, epithelial ovarian carcinoma was performed to assess presence of cellular and nuclear atypia in noncancerous tissue adjacent to the primary tumor; ovarian tissue from 50 patients undergoing incidental oophorectomy was reviewed as well. Atypia was more common in cancer patients, and finding the combination of nuclear atypia, defined as presence of pleomorphism or irregular chromatin distribution, with cellular atypia, defined as presence of stratification or loss of polarity, allowed separation of cancer and control groups with 98% sensitivity and 100% specificity. Presence of nuclear and cellular atypia was used to define ovarian intraepithelial neoplasia (OIN). If OIN is demonstrated to precede ovarian carcinoma, then it may offer insights into the development of ovarian cancer and may eventually increase the feasibility of screening for this disease.
Clinical features of advanced ovarian mixed mesodermal tumors and treatment with doxorubicin- and cis-platinum-based chemotherapy.
Records of 15 patients with stage III and IV malignant mixed mesodermal tumors of the ovary treated between 1977 and 1988 were reviewed. All patients had primary surgery; 13 were given postoperative chemotherapy including doxorubicin and cis-platinum. Median survival for patients receiving chemotherapy is 16 months; 62% were alive at 12 months and 31% at 24 months. Progression-free responses were seen in 85% of treated patients and 55% of these recurred. All recurrences involved the pelvis and were predominantly mesenchymal. Serum CA-125 values accurately reflected tumor presence in 82% of tested patients. Cytoreductive surgery followed by treatment including doxorubicin- and cis-platinum-based chemotherapy is effective in treatment of disseminated ovarian mixed mesodermal tumors, but additional components must be added to achieve durable responses and consistently prolonged survivals.
Therapeutic and metabolic effects of high (greater than 1 g/m2) systemic cumulative doses of cis-platinum in patients with ovarian carcinoma.
Adverse effects requiring discontinuation of cis-platinum therapy are usually noted after administration of 600 mg/m2 cis-platinum. Metabolic and therapeutic effects of high (greater than 1 g/m2) cumulative lifetime doses of cis-platinum were reviewed for 20 patients treated with multiple courses of chemotherapy for metastatic, recurrent ovarian carcinoma. Median survival in this selected group is 65 months. Common abnormalities included anemia, hypomagnesemia, and elevated renal functions. No patient required cessation of treatment because of metabolic changes and in no case did the abnormality compromise the patient's activities of daily living. We conclude that, in selected patients, repeated treatment, regardless of cumulative dose, with cis-platinum-based chemotherapy can be well tolerated and may be of therapeutic benefit.
Clinical features and treatment outcome of patients with epithelial carcinoma of the ovary metastatic to the central nervous system.
Involvement of the central nervous system with carcinoma of the ovary is being noted with increasing frequency. We report on six patients who presented with central nervous system metastases between 2-61 months after diagnosis. Five patients had elevated serum CA 125 values at the time of diagnosis of central nervous system disease and presenting symptoms, and findings on neurologic examination generally correlated with computed tomography-documented lesions. Eighty-three percent of our patients were symptomatically relieved with a course of 30 Gy given to the whole brain; however, there were no long-term survivors (range 2-24 months). Survival did not appear prolonged in the four patients who received systemic chemotherapy as well as whole-brain irradiation.
Immune complexes in ovarian carcinoma.
Immunodiagnostic screening may improve the survival of ovarian carcinoma by earlier detection and follow-up during treatment. Presently, several ovarian cancer-associated antigens are being utilized to monitor treatment response; a specific and precise test for screening is not currently available. The present study was designed to investigate the presence and clinical significance of circulating immune complexes (IC) in patients with ovarian carcinoma using a polyethylene glycol (PEG) assay. If this assay were to prove clinically useful in patients with ovarian carcinoma, its potential as a screening test would then be evaluated. Serum was obtained from 38 patients with advanced ovarian carcinoma preoperatively, postoperatively, and prior to the administration of a combination chemotherapy regimen containing cisplatin. Five patients had values greater than or equal to 0.10. This test identified only 12.5% of the patients with active disease. Serial sampling failed to reveal any correlation with disease status. Our experience does not support the usefulness of IC levels in studying or treating patients with ovarian carcinoma.
Schedule and dosage modification of a cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin combination chemotherapy regimen for refractory ovarian cancer.
A cyclophosphamide, hexamethylmelamine, doxorubicin and cisplatin (CHAP II) regimen produced median survival of 15 and 17 months. All patients had prior chemotherapy, 26 with cisplatin in the former group, and 27 without cisplatin in the latter group. Treatment employed both a novel sequential schedule of cisplatin (usually in the evening) 24 h before cyclophosphamide-doxorubicin and novel stepwise escalation, first of doxorubicin, then of hexamethylmelamine until either nadir white blood counts fell to 1000-1500/mm3 or platelets to 75,000-100,000/mm3. Compared to prior Mount Sinai experience: (i) survival was significantly improved; (ii) with and without prior cisplatin, response rates approached a significant improvement, 12% and 29% complete and 24% and 35% partial. Five of seven additional patients with progression during unmaintained remission also responded, two with pathologically complete remissions. Findings suggest: (i) the importance of maximum dose intensity in ovarian cancer treatment; (ii) the responsiveness of patients failing first line treatment to dose intensive treatment; (iii) the possible importance of schedule, and sequential or circadian timing of cisplatin, and other drugs; (iv) and testing revised clinical criteria of resistance to drugs.
Nimodipine block of calcium channels in rat vascular smooth muscle cell lines. Exceptionally high-affinity binding in A7r5 and A10 cells.
Calcium channel currents were studied in the A10 and A7r5 cell lines derived from rat thoracic aorta muscle cells. The whole-cell variation of the patch voltage clamp technique was used. Results with each cell line were nearly identical. Two types of Ca channels were found in each cell line that are similar to the L-type and T-type Ca channels found in excitable cells. Nimodipine block of the L-type Ca channels in both cell lines is more potent than in previously studied tissues. The kinetics of nimodipine block are accounted for by a model that postulates 1:1 drug binding to open Ca channels with an apparent dissociation constant (KO) of 16-45 pM. In A7r5 cells, the rate of onset of nimodipine block increases with the test potential, in quantitative agreement with the model of open channel block. The apparent association rate (f) is 1.4 x 10(9) M-1 s-1; the dissociation rate (b) is about 0.024 s-1. In anterior pituitary cells (GH4C1 cells), KO is 30 times larger; b is only twice as fast, but f is 15 times slower. The comparative kinetic analysis indicates that the high-affinity binding site for nimodipine is similar in both GH4C1 and A7r5 cells, but nimodipine diffuses much faster or has a larger partition coefficient into the plasmalemma of A7r5 cells than for GH4C1 cells. Unusually high-affinity binding was not observed in earlier 45Ca flux studies with A10 and A7r5 cells. The model of open channel block accounts for the discrepancy; only a small fraction of the Ca channels are in the high affinity open state under the conditions used in 45Ca flux studies, so an effective binding constant is measured that is much greater than the dissociation constant for high-affinity binding.
Point mutations or polymorphisms? A sequence analysis of the enhancer 3' to the A gamma-globin gene.
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Modulation and intensification of a cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin ovarian cancer regimen.
For 61 patients with stage III-IV carcinoma of the ovary, chemotherapy consisted first of cisplatin 50 mg/m2 on day 1, cyclophosphamide 500 mg/m2 on day 3, doxorubicin 50 mg/m2 on day 3, and hexamethylmelamine 100 mg/m2 on days 4-15 every 4 weeks. The dosages of doxorubicin and hexamethylmelamine were increased by 60 and 100%, respectively, until the nadir white blood cell counts fell to 1.0 x 10(9)/L. This regimen was less neurotoxic and nephrotoxic than other intensive treatments and produced better therapeutic effects than did the immediate preceding Mount Sinai regimens: 1) The overall median survival was 43 months and progression-free survival was 25 months; 2) the greatest benefit occurred among patients under 50 years of age; 3) regression of large tumors increased in frequency, with 33% of tumors 2-6 cm and 16% of tumors larger than 6 cm converted to either pathologically proved remission or microscopic disease; and 4) for the first time, partial surgical debulking producing residual tumors less than 6 cm in size improved early survival.
Continuous infusion fluoropyrimidines as salvage therapy for patients with advanced ovarian carcinoma.
A major challenge facing those caring for patients with ovarian carcinoma is inducing remission following the failure of first-line treatment. Toward this end, we have examined the efficacy of continuous infusion fluoropyrimidines. During a 2-year period, nine patients with recurrent ovarian carcinoma received treatment with continuous infusion 5-fluorouracil (5-FU) or 5-fluorouracil-deoxyribose as single agents or in combination with other drugs. Eight patients were evaluable, with responses obtained with each treatment regimen. Myelotoxicity was mild, with only 3 episodes of grade 4 toxicity out of 70 total cycles of chemotherapy. Mucositis was moderate to severe, tending to be the dose-limiting adverse effect. Continuous infusion 5-FU in these combinations appears to be active with very acceptable toxicity in heavily pretreated patients.