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Biomedical subjects

C N Coleman

Publications and source records attributed to C N Coleman.

At least 145 records · Page 8Linked to original sources
PubMed1985

Cutaneous malignant melanoma after Hodgkin's disease.

Eight cutaneous malignant melanomas occurred in 6 of 1405 patients with Hodgkin's disease, although the expected incidence rate was 0.77 (relative risk, 8; 95% confidence interval, 3 to 17). One melanoma was a thin, level II lesion less than 0.76 mm thick; the rest were mostly bulky, deeply invasive lesions despite close clinical surveillance. The melanomas spread aggressively; 3 of 6 patients died within 1 to 3 years. Two of the six patients developed a second primary malignant melanoma 1 year after the first. Two of six patients had biopsy-proven dysplastic nevus syndrome, a known precursor to cutaneous malignant melanoma, and an additional 3 patients had clinical evidence of dysplastic nevus syndrome. Histologically, the malignant melanomas showed a sparse inflammatory infiltrate, an abnormal host response seen previously in cutaneous melanomas developing in immunosuppressed patients. Dysplastic nevi may identify patients at highest risk who require modified medical management.

Adult↗
PubMed1984

The effect of postoperative and primary radiation therapy on delivered dose of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy in breast cancer.

The dose of adjuvant chemotherapy for breast cancer may be an important factor in the success of the treatment program. In a retrospective analysis, the authors determined whether patients who were irradiated either postoperatively (N = 29) or as part of primary treatment (N = 13) received a lower dose of adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy than patients who were not irradiated (N = 42). The 84 evaluable patients received either cyclical or weekly CMF. Radiation therapy included the chest wall or breast and regional lymph nodes. The mean percentage of maximum chemotherapy dose delivered (59.9% versus 73.5%; P less than 0.001), mean percent prescribable or theoretical maximum dose (83.1% versus 91.3%; P less than 0.001), and mean leukocyte count (3.9 versus 4.5; P less than 0.01) during therapy were statistically significantly lower in irradiated patients. The lower delivered chemotherapy dose in irradiated patients was not related to the radiation dose to the thoracic spine. The authors conclude that radiation therapy to the chest wall or breast and regional lymph nodes reduces the dose of adjuvant CMF that can be delivered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

The current status of drug development of hypoxic cell radiosensitizers and their potential role in gynecologic oncology.

Both laboratory and clinical data suggest that hypoxia contributes to the failure of radiotherapy to achieve local control of bulky gynecologic tumors. As part of a Phase I trial of hypoxic cell radiosensitizers, 19 women at Stanford University with advanced (n = 6) or recurrent (n = 13) pelvic neoplasms were treated with radiotherapy plus desmethylmisonidazole. Complete or partial response occurred in 42% of patients with some patients achieving local control for over 1 year. It is unknown if the sensitizer added to the results of radiotherapy alone. A Phase I trial of a theoretically superior sensitizer, SR-2508, is soon to begin. It is anticipated that the dose-limiting neurotoxicity seen with misonidazole and desmethylmisonidazole will either be eliminated or will occur at a much higher total dose of drug. Many patients with gynecologic tumors could potentially benefit from participation in the new drug trials.

Adult↗
PubMed1984

The effect of vitamin B6 on the neurotoxicity and pharmacology of desmethylmisonidazole and misonidazole: clinical and laboratory studies.

The clinical usefulness of misonidazole (MISO) and desmethylmisonidazole (DMM) is severely limited by neurotoxicity. Based on theoretical considerations and on laboratory data suggesting that pyridoxine (PN) decreased MISO toxicity in mice, we attempted to ameliorate the clinical neuropathy of DMM using oral PN. Pharmacokinetic analysis suggested interaction of PN and DMM but no protection against neuropathy was observed. Serial experiments with C3H and BALB/c mice were done using various forms of vitamin B6 (PN, pyridoxal, pyridoxal phosphate) administered orally and i.p. and the nonspecific adsorbing agent activated charcoal. No consistent protection was observed. A slower rate of drug delivery (dose/day) allowed a larger cumulative dose of MISO to be given, a result paradoxical to that seen in the clinic. Dexamethasone did not alter MISO toxicity in mice, contrary to the clinical findings. We conclude that vitamin B6 is not useful in preventing clinical neurotoxicity of MISO or DMM. Furthermore, this mouse model of neurotoxicity assessment has produced results inconsistent with those seen clinically.

Animals↗
PubMed1984

Clinical trials with hypoxic cell sensitizers: time to retrench or time to push forward?

Results of world-wide clinical trials with misonidazole are discussed. An attempt is made to assess the reasons for the lack of positive results and the cost-benefit analysis is critically reviewed. The data on the clinical investigations of the second generation misonidazole analogues SR-2508 and RO-03-8799 are presented. Emphasis is placed on future work such as tumor selection for clinical trials, reduction of drug toxicity and methods to increase the drug radiosensitizing properties. Because of the large amount of knowledge, experience, productivity and good scientific clinical data accummulated with nitroimidazoles over the past five years, it is recommended that this is the time to push forward with the work on the newest, more efficient compounds.

Clinical Trials as Topic↗
PubMed1984

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508.

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.

Drug Evaluation↗
PubMed1984

Inhibition of cis-diamminedichloroplatinum secretion by the human kidney with probenecid.

The renal handling of cis-diamminedichloroplatinum (CP) was investigated by measuring the renal clearance of creatinine, inulin, and free platinum in ten cancer patients. Free platinum clearances exceeded the glomerular filtration rate in all time periods. For example, at 1 to 2 hr, the mean clearance of free platinum was 224 +/- 32 (S.E.) ml/min compared to a mean creatinine clearance of 94 +/- 15 ml/min or a mean inulin clearance of 94 +/- 17 ml/min (p less than 0.01), indicating secretion of CP or a metabolite. Seven additional cancer patients were treated with probenecid prior to CP. Fractional platinum clearances, calculated as a ratio of free platinum clearance to creatinine clearance, were reduced significantly in the probenecid-treated group (158 +/- 17%) compared to controls (270 +/- 57%) (p less than 0.03). Fractional platinum clearances, calculated as a ratio of free platinum clearance to inulin clearance, were also significantly reduced in the treated group (154 +/- 14%) compared to controls (271 +/- 47%) (p = 0.04). These results suggest that cisplatin is secreted by the human kidney, and this can be inhibited by probenecid. Such maneuvers may be helpful in improving the therapeutic index of this important chemotherapeutic agent.

Cisplatin↗
PubMed1984

The treatment of malignant histiocytosis.

Twenty-four consecutive cases of malignant histiocytosis (MH) treated at Stanford Medical Center between 1973 and 1983 have been reviewed. Most patients presented with systemic symptoms (91%) and advanced disease (stage IV, 80%). Multiple organ involvement was common. In six cases, pathologic tissue was further characterized by frozen section immune histochemistry, using a panel of monoclonal antibodies known to react with monocytes and macrophages, as well as a variety of hematopoietic cells. One case expressed a mature monocyte/macrophage phenotype; three cases were considered null cell or primitive lesions; and two cases were identified as probable T cell lymphomas. Seven patients underwent splenectomy. Two patients died prior to any treatment. Twenty-two patients were treated with CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) +/- bleomycin (B), +/- midcycle high-dose methotrexate (HD-MTX) with leucovorin rescue. Seven patients received prophylactic intrathecal MTX. Of 22 evaluable patients, there was a 68% complete response rate (CR), a 23% partial response rate (PR), and a 9% no response rate (NR). Median duration of CR was 30+ months; median duration of PR was 2.4 months. Median survival for patients attaining a CR has not been reached v 3 months for the PR and NR groups. For all 24 patients, median survival was 2 years, with a 5-year actuarial survival of 40%. Multivariate analysis revealed that a platelet count less than 150,000 (P Cox = .005) and the dose of drug delivered (P Cox = .057) were the most important prognostic factors. Prophylactic intrathecal MTX therapy and splenectomy did not influence survival. Although MH is an aggressive disease with a poor prognosis, it is potentially curable. Systematic and aggressive treatment should further improve the outcome.

Adolescent↗
PubMed1983

Phase I trial of intravenous L-phenylalanine mustard plus the sensitizer misonidazole.

Misonidazole (MISO), a hypoxic cell radiosensitizer, has been shown in vivo to enhance tumor cell killing by melphalan (LPAM) with little or no enhancement of normal tissue injury. A Phase I trial was conducted using MISO p.o. 2 hr before i.v. LPAM. The highest doses used were the single maximum tolerated doses of MISO, 4 g/sq m, and LPAM, 0.6 mg/kg. Thirty-five patients were entered; 30 were evaluable for assessment of hematological toxicity, which was predicted to be the dose-limiting toxicity. The median age was 60 years (range, 28 to 72 years). Mild to moderate nausea and vomiting occurred in 80% of patients. Five developed serious hematological toxicity defined as nadir white blood cell count less than 1000/cu mm, platelets less than 20,000/cu mm or 4-week posttreatment white blood cell count less than 2000/cu mm, platelets less than 50,000/cu mm. Four of the toxicities occurred at the LPAM dose of 0.6 mg/kg but were independent of MISO dose. One patient died of infection. Two patients whose tumor demonstrated an objective response to therapy and 10 others with disease stabilization received additional courses. Four patients developed mild MISO neuropathy. Pharmacokinetic studies demonstrated that MISO did not appear to affect the pharmacokinetics of LPAM in plasma. Both LPAM and MISO can be given safely at their individual maximum tolerated dose. This combination will proceed to Phase II trials.

Adult↗
PubMed1982

CT of irradiated solid tumor metastases to the brain.

Twenty patients with solid tumor metastases to the brain, demonstrated by CT scanning, had follow-up scans after radiation therapy of the metastatic focus. Nine patients (45%) showed no evidence of the metastasis on the initial follow-up scans. Another 10 patients (50%) showed some improvement in the size, enhancement, or surrounding edema of the lesion. Only one patient showed progression in spite of therapy. The CT scan identified those patients who achieved longer survival and/or longer time intervals before brain relapse. However, CT scans must be interpreted with caution in patients still on corticosteroid treatment. Additionally, other non-tumoral conditions may mimic tumor recurrence. Radiation therapy offered palliation in patients with brain metastases, and in some instances, sterilized patients of their metastatic brain involvement.

Adult↗
PubMed1982

Functional hyposplenia after splenic irradiation for Hodgkin's disease.

We previously reported a patients who developed fulminant pneumococcal sepsis 12 years after successful treatment for Hodgkin's disease, which included splenic irradiation. We have since evaluated splenic size and function in 25 patients who had received splenic irradiation 5 to 16 years previously either for Hodgkin's disease (n = 19) or non-Hodgkin's lymphoma (n = 6). Mean maximum splenic diameter as measured on a 99mTc-sulfur colloid liver-spleen scan was 6.2 cm in the irradiated group and 9.7 cm in a control group (p less than 0.001). The mean percentage of erythrocytes containing pits when observed with interference phase microscopy was 13.0% in the irradiated group, which was significantly different (p less than 0.001) from the levels found in each of the control groups: normal subjects, 0.9%; unstaged and untreated lymphoma patients, 0.6%; and patients after splenectomy, 33.7%. Patients who have had splenic irradiation should be considered at risk of developing overwhelming pneumococcal sepsis.

Adolescent↗
PubMed1982

The management of stage I--II Hodgkin's disease with irradiation alone or combined modality therapy: the Stanford experience.

At Stanford University, between 1968 and 1978, 230 patients with pathologic stage I--II Hodgkin's disease were treated on prospective clinical trials with either irradiation alone or irradiation followed by 6 cycles of adjuvant combination chemotherapy. The actuarial survival at 10 yr was 84% for patients in either treatment group. Freedom from relapse at 10 yr was 77% among patients treated with irradiation alone and 84% after treatment with combined modality therapy [p(Gehan) = 0.09]. Freedom from second relapse at 10 yr was 89% and 94%, respectively [p(Gehan) = 0.56]. Several prognostic factors were evaluated in order to identify patients at high risk for relapse or with poor ultimate survival after initial treatment with irradiation alone. Systemic symptoms, histologic subtype, age, and limited extranodal involvement (E-lesions) did not affect the prognosis of patients and failed to identify patients whose survival could be improved by the routine use of combined modality therapy. Patients with large mediastinal masses (mediastinal mass ratio greater than or equal to 1/3) had a significantly poorer freedom from relapse when treated with irradiation alone than when treated initially with combined modality therapy [45% versus 81% at 10 yr, p(Gehan) = 0.03). The 10-yr survival of these patients, however, was not significantly different (84% versus 74%). The implications of these observations on the management of patient with early stage Hodgkin's disease are discussed.

Adult↗
PubMed1982

Adverse effects of cancer therapy. Risk of secondary neoplasms.

Due to the long latency period for solid tumor induction (median 12-13 years), the radiation-induced malignancies now being observed are mostly related to the era of kilovoltage irradiation. Some tumors, such as thyroid cancer, have very low, if any, threshold dose for tumor induction. Sarcomas appear to require higher doses (approximately 100 rads) for induction. Controversy exists as to whether high doses of irradiation are less carcinogenic than lower doses due to greater cell killing at high doses. Acute leukemia has been induced by either irradiation alone or chemotherapy alone. Current intensive therapy protocols using combinations of chemotherapy and radiotherapy, or prolonged chemotherapy, are more leukemogenic, with the 4-year actuarial risk of leukemia in the range 4-17%. Immunosuppression due to various disease states or treatments had been accompanied by malignant tumors, often lymphomas in unusual sites such as the central nervous system. Unusual non-Hodgkin's lymphomas have recently been observed in patients treated for Hodgkin's disease, suggesting that some secondary neoplasms in cancer patients are related to immunosuppression.

Antineoplastic Agents↗
PubMed1981

Splenic injury caused by therapeutic irradiation.

Splenic irradiation in the course of therapy for lymphoma can result in functional deficit, sometimes as severe as that caused by splenectomy, placing the patient at risk for fatal infection. We examined 33 spleens obtained at necropsy from patients irradiated for lymphomas (mainly Hodgkin's disease) and compared them with 18 nonirradiated spleens from similar patients. One to 8 years after a mean radiation dose of 3899 rads, fractionated over 5-6 weeks, most irradiated spleens were small (average weight 75 g) and had thick, wrinkled capsules, often with focal hemorrhage. There was collapse of the parenchyma, with close apposition of trabeculae and mild to severe diffuse fibrosis of the red pulp. Lymphocyte depletion was obvious in more than 50% of the specimens. The most consistent alteration was myointimal proliferation of arteries. Significant intimal thickening was seen only in the irradiated specimens. Similar myointimal changes were found in the veins of three cases. While none of these changes is specific, their combination appears to be characteristic of delayed radiation injury to the spleen.

Adult↗
PubMed1981

Lymphoblastic lymphoma in adults: results of a pilot protocol.

Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.

Adolescent↗
PubMed1980

Thyroid carcinoma after high-dose external radiotherapy for Hodgkin's disease: report of three cases.

Three patients (two female and one male), who had received mantle irradiation for Hodgkin's disease eight, ten, and twelve years previously, developed papillary thyroid carcinoma. The radiation doses to the necks overlying the site of thyroid cancers were 3000, 4000, and 4100 rads, respectively. It has been stated that there is no risk of developing thyroid cancer with such high doses of external irradiation but apparently this complication will be encountered in a small number of patients.

Adult↗