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Biomedical subjects

M A Cornbleet

Publications and source records attributed to M A Cornbleet.

At least 37 records · Page 2Linked to original sources
PubMed1989

Phase I study of methylacetylenic putrescine, an inhibitor of polyamine biosynthesis.

In a phase I clinical trial, nine patients with advanced malignancies not amenable to alternative therapy received alpha-methyl-delta-acetylenic putrescine (MAP), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC). MAP was given orally in increasing doses to successive groups of three patients as follows: 375 mg, 750 mg and 1500 mg/day, given as three equally divided doses for 4 weeks. Doses of 375 and 750 mg/day were well tolerated, with no detectable toxicity. Of three patients receiving 1500 mg/day, two experienced moderate to severe myelosuppression; one of these also became anuric, requiring the discontinuation of therapy after 9 days. Both effects were reversible after treatment was stopped. No objective responses were observed, with five patients having stable disease and four, progressive disease during the study period. In the seven patients in whom it could be calculated, the plasma elimination half-life t1/2 of MAP measured on the last day of treatment was between 3.9 and 9.2 h in six patients (mean, 5.6 h) and 26.1 h in the seventh. Mean steady-state trough concentrations of MAP were 2.3 mumol after the 375 mg/day dose, 7.1 mumol after 750 mg/day and 16.6 mumol after dosing with 1500 mg/day for 4 weeks, the levels after each treatment schedule being sufficient to inhibit ODC as demonstrated by increases in the urinary excretion of decarboxylated S-adenosylmethionine (dc-SAM). MAP treatment was associated with mean maximal increases in the urinary excretion of dc-SAM of 2.6-, 9.3- and 17.9-fold after 375, 750 and 1500 mg/day for 4 weeks, respectively, but no consistent changes in the urinary excretion of the polyamines, putrescine, spermidine or spermine were observed. Thus, the 24-h urinary excretion of dc-SAM may be used as a conveniently accessible marker of ODC inhibition in cancer patients.

Adult↗
PubMed1987

Phase I study of TCNU, a novel nitrosourea.

TCNU is a chloroethyl nitrosourea based on the endogenous amino acid taurine. This paper reports its first evaluation in man. Eighty-four patients with refractory cancer received 12 dose escalations from 10-150 mg/m2 TCNU administered orally every 6 weeks. Clinical side-effects were predominantly gastro-intestinal but dose-limiting toxicity was thrombocytopenia. Pharmacokinetic monitoring with an HPLC assay sensitive to the nanogram range demonstrated unchanged TCNU in plasma for up to 8 h following administration. The mean half-life was 60 min. Clinical responses were seen in melanoma (four patients), lung cancer (two squamous, one small cell) and one patient each with renal and stomach cancer. These responses, together with the unusual pharmacokinetic profile of TCNU, warrant exploration in disease-orientated phase II studies at a recommended dose of 130 mg/m2 p.o. q 5 weeks.

Adolescent↗
PubMed1987

Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast.

One hundred fifteen patients with metastatic carcinoma of the breast were treated in a randomized trial of mitoxantrone (Novantrone, Lederle Laboratories, Pearl River, NY) combined with vincristine and prednisolone (VMP) or doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) combined with vincristine and prednisolone (VAP). In 100 evaluable patients, the objective response rates were 35% for VMP and 61% for VAP, the complete response rates being 6% and 13%, respectively. In responding patients, median time to progression was 6.2 months for VMP and 7.9 months for VAP. The median survival whether measured from primary diagnosis, first metastasis, or from the start of chemotherapy was similar for both regimens. Toxicity, particularly alopecia, was appreciably lower in the VMP treated patients, but subclinical cardiotoxicity was seen within the scheduled dosage for both combinations. We conclude that VAP is clearly more active, but clinically more toxic than VMP. There is no survival advantage conferred by the more toxic combination. Cardiac toxicity is a potential hazard with either drug combination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Optimising antiemesis in cancer chemotherapy: efficacy of continuous versus intermittent infusion of high dose metoclopramide in emesis induced by cisplatin.

Thirty three untreated patients being given cisplatin received metoclopramide (7 mg/kg) for antiemesis by either continuous or intermittent infusion in a random order. Each patient received intravenous dexamethasone in addition. High pressure liquid chromatography was used to measure plasma concentrations of metoclopramide. The two regimens were evaluated for antiemetic efficacy and the incidence of side effects. The intermittent metoclopramide regimen resulted in peak and trough plasma concentrations of metoclopramide with accumulation at eight hours, while the loading dose and continuous infusion resulted in mean plasma concentrations greater than 0.85 micrograms/ml (2.8 mumol/l) throughout the eight hour period. The continuous infusion was associated with a significant improvement in nausea and vomiting and reduction in diarrhoea. Major control of emesis (two episodes or fewer) was achieved in 27 patients receiving continuous metoclopramide compared with 18 receiving intermittent metoclopramide.

Adult↗
PubMed1986

Adult neuroblastoma. Report of three cases and review of the literature.

Adult neuroblastoma is an uncommon malignancy. The authors report three additional cases and review the 39 reported cases in the world literature. Presentation in the abdomen is the most common; a high rate of lower limb presentation is also observed. Incidence is equal between sexes with median age of presentation of 34 years. Survival is greatest after surgical intervention (median, 20.5 months) compared with no surgery (median, 12.5 months). Chemotherapy may benefit individual patients but does not have a major impact on survival. Radiotherapy is indicated for localized, inoperable primaries or painful metastases. The survival rates of this group of patients parallels that of childhood neuroblastoma, Stage III-IV.

Adult↗
PubMed1986

Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes.

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

Adolescent↗
PubMed1985

cis-Platinum and vindesine in combination in the treatment of non-small cell lung cancer.

Sixty-three patients with advanced non-small cell carcinoma of the bronchus were treated with a combination of cis-platinum and vindesine. All patients had measurable disease and were of good performance status; none had received prior chemotherapy or radiotherapy. Thirty-three per cent of patients responded, with five patients achieving complete remission. Median duration of response was 4 months, with a median survival of 14 months in the responsers, compared with 6.5 months in the whole group and 4.8 months in the nonresponders. Severe toxicity was encountered, with alopecia, gastrointestinal toxicity and neurotoxicity common. Myelosuppression and renal toxicity were not dose-limiting. Thus the activity of this drug combination is confirmed, but severe toxicity precludes its widespread use in clinical practice.

Adenocarcinoma↗
PubMed1985

Cisplatin combination chemotherapy for advanced germ-cell testicular tumours.

Thirty-six patients with advanced non-seminomatous germ-cell testicular tumours and two patients with advanced seminomas were treated with cisplatin-containing combination chemotherapy. Thirty-four patients received cisplatin 100 mg/m2 iv, vinblastine 0.3 mg/kg iv and bleomycin 30 mg iv (PVB) and three patients received this combination with etoposide (VP16-213) 120 mg/m2 iv on 3 consecutive days substituted for vinblastine (BEP). One patient received cisplatin and bleomycin only. All 35 evaluable patients with non-seminomatous tumours responded; 22 patients (61%) achieved a complete response (CR); 16 of these (73%) are alive with no evidence of disease at follow-up ranging from 18 to 55 months (median 36). Of 13 patients achieving a partial response (PR), 11 have died of progressive disease at 7 to 30 months (median 11) and two are alive with disease which has continued to regress following chemotherapy. Of 32 patients who received adequate chemotherapy, 16 (50%) are alive and disease-free and three (9%) are alive with evidence of disease. The chances of achieving a CR were reduced in those patients with bulky disease or high levels of AFP or beta hCG at presentation but not in those who had received prior radiotherapy. Toxicity was considerable, including alopecia and nausea or vomiting in all patients, and haematological toxicity, neurotoxicity, hearing loss and dyspnoea in a substantial number of patients.

Adult↗
PubMed1985

Cis-platin and methotrexate in the treatment of transitional cell carcinoma of the urinary tract.

Nineteen patients with recurrent or metastatic transitional cell carcinoma of the urinary tract were treated with a 3-weekly combination of methotrexate 200 mg/m2 as a 24-h infusion with folinic acid rescue and cis-platin 100 mg/m2. An objective response rate of 68% was obtained, with 4 patients (21%) achieving complete remission. Pulmonary disease and lymph node metastases were particularly sensitive to this therapy. The median duration of response was 21 weeks with a median survival of 54 weeks in the responding patients. This regimen warrants further investigation in the treatment of invasive bladder carcinoma.

Aged↗
PubMed1985

Pathologic stages IA and IIA Hodgkin's disease: results of treatment with radiotherapy alone (1968-1980).

Between Jan 1, 1968, and Dec 31, 1980, 108 previously untreated patients with Hodgkin's disease pathologic stages (PSs) IA (29 patients) and IIA (79 patients) initially received radiotherapy alone. One postoperative death (due to pulmonary embolus) (0.9%) occurred, with one serious complication (0.9%). Between 1968 and 1973, patients were randomized to receive either involved field radiation treatment (RTIF) or extended field radiation treatment (RTEF). Since 1973 all patients have received RTEF, 4,000 cGy in four to five weeks, with a median follow-up of 7.4 years. Complete remission (CR) was achieved in 102 patients (94.4%), with no significant difference according to treatment or stage. Of the complete responders, 25 patients relapsed: 5/15 RTIF and 20/87 RTEF (P = .6). Twenty-one of 25 relapsing patients achieved a second CR. Disease free survival rates at five and ten years constituted: PS IA, 78.6% for both; PS IIA, 74.8% and 73.1% (P = .6); RTEF, 76.7% for both; RTIF, 73.3% and 66.7% (P = .7). Eighteen patients have died: eight of recurrent lymphoma, two of pulmonary embolus, one each of myocardial infarction, pulmonary fibrosis, and acute nonlymphocytic leukemia (ANLL) (following salvage chemotherapy), and one of diffuse histiocytic lymphoma (DHL). Four patients died in remission of unrelated causes. Actuarial survival rates at five and ten years constituted: PS IA, 95.7% and 72.4%; PS IIA, 89.6% and 81.4% (P = .3); RTIF, 93.7% for both; RTEF, 90.7% and 71.2% (P = .2). Age, sex, number of sites, and mediastinal involvement did not influence the outcome. Acute toxicity was modest and more frequent among those receiving RTEF (P = .08). Chronic toxicity (onset more than 30 days after completion of treatment) was identified in 16 patients: 1/16 RTIF; 15/92 RTEF (P = .5). Three patients developed a second malignancy: one carcinoma of the cervix in situ; one ANLL (following salvage chemotherapy); and one DHL of the stomach. At least 75% of patients with PS IA and IIA Hodgkin's disease were cured by radiation alone, with a risk of secondary malignancy following radiation alone of 0.9%. Since the majority of relapsing patients were successfully salvaged by chemotherapy, radiation alone appears to be the initial treatment of choice in this group of patients.

Actuarial Analysis↗
PubMed1984

Phase II trial of vindesine and VP16-213 in the palliation of poor-prognosis patients and elderly patients with small cell lung cancer.

Forty-three previously untreated patients, all of whom had poor-prognosis small cell lung cancer and/or were greater than 65 years old, received treatment with vindesine and VP16-213. Thirteen patients had limited disease and 30 extensive disease. Response rates (CR + PR) of 86% (CR 29%) and 66% (CR 17%) were seen in patients with limited and extensive disease, respectively. Time to relapse was short in those responding (4-4.5 months), and most responders required additional treatments. The overall toxicity was minimal and patient compliance was high. This combination is useful for the palliative treatment of small cell lung cancer when aggressive chemotherapy is inappropriate.

Adult↗
PubMed1984

Mitoxantrone for the treatment of advanced breast cancer: single-agent therapy in previously untreated patients.

Mitoxantrone (dihydroxyanthracenedione) is a substituted anthraquinone with a similar spectrum of activity to adriamycin in experimental tumours. One hundred and thirty-four patients with advanced breast cancer and no prior chemotherapy for advanced disease were treated with mitoxantrone (14 mg/m2 i.v. q 3 weeks), of whom 99 are presently evaluable for response and all for toxicity. Six patients achieved a complete response and 29 a partial response, the overall response rate being 35% (95% confidence limits, 25-45%). Median time to treatment failure was greater than 46 weeks. Mitoxantrone was well tolerated, myelosuppression being the dose-limiting toxicity. The most frequent nonhaematological toxicities were nausea and vomiting (40%), but these were rarely severe. Total alopecia occurred in only 6 patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174-256 mg/m2. Mitoxantrone offers comparable efficacy and less acute toxicity than the most active currently available single agents in advanced breast cancer.

Adult↗
PubMed1984

Emesis due to cancer chemotherapy: results of a prospective, randomised, double-blind trial of varying doses of metoclopramide in the management of cis-platinum-induced vomiting.

A randomised, double-blind prospective trial was conducted to determine the relative anti-emetic efficacy of three dose levels of metoclopramide in cancer patients receiving combination chemotherapy including cis-platinum. With consecutive courses of chemotherapy, 60 patients received doses of either 3,5 or 10 mg/kg metoclopramide (50, 54 or 55 courses respectively) in a randomly assigned sequence. Major control of emesis (less than or equal to 2 vomits) was achieved in 38% of 159 patient treatments. There were no significant differences in either anti-emetic efficacy or the incidence of side-effects between the three doses used. It is concluded that while metoclopramide is an effective anti-emetic for patients receiving cisplatinum therapy, no advantage accrues to the use of doses in excess of 3 mg/kg (total dose).

Adolescent↗