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Biomedical subjects

R S Benjamin

Publications and source records attributed to R S Benjamin.

At least 127 records · Page 7Linked to original sources
PubMed1985

Doxorubicin-induced congestive heart failure in adults.

The prognosis of doxorubicin-induced congestive heart failure (CHF) is reported to be poor. To define the clinical course of doxorubicin-induced CHF, the authors reviewed their experience with 43 patients with this diagnosis. The median age of the total group was 55 years (range, 23-69); the median cumulative dose of doxorubicin was 450 mg/m2 (range, 200 mg/m2-1150 mg/m2). A majority of the patients had a diagnosis of breast cancer. The median survival of the whole group estimated by means of a Kaplan-Meier plot was 112 weeks. Twelve of 43 patients (28%) died of CHF, 7 of them (16%) because of fulminant failure in less than 8 weeks and the remaining 5 because of a more protracted course with recurrent episodes of cardiac decompensation. Twenty-five of the 43 patients (58%) achieved complete control of CHF. In the remaining 6 patients (14%), CHF had improved but was not completely controlled at the time of death, which was secondary to progressive tumor. Treatment consisted of standard therapy with digitalis and diuretics. Survival was significantly shorter in patients who presented with class IV dyspnea and in those who developed CHF less than 4 weeks after administration of the last dose of doxorubicin. The authors conclude that in a majority of patients, doxorubicin-induced CHF is easily treatable and frequently controlled with digitalis and diuretics.

Adult↗
PubMed1985

Evaluation of mitoxantrone cardiac toxicity by nuclear angiography and endomyocardial biopsy: an update.

Sixty-six patients who underwent endomyocardial biopsy for detection of mitoxantrone (Novantrone; dihydroxyanthracenedione) cardiac toxicity were evaluated. All but one had breast cancer, 29 had received prior doxorubicin and 29 of the 37 patients who had not had prior doxorubicin received it or another anthracycline subsequently. Endomyocardial biopsy was carried out initially after four courses of chemotherapy with increasing intervals thereafter. Although cardiac ejection fraction was determined before each course of chemotherapy, our data are limited to cardiac ejection fractions from our own institution which were repeated approximately every four courses. Endomyocardial biopsy changes consisting of dilatation of the sarcoplasmic reticulum with vacuole formation, and myofibrillar dropout are similar to the early changes of anthracycline cardiomyopathy. While there was a slight suggestion of increasing biopsy grade with increasing mitoxantrone dose, no significant changes in cardiac ejection fraction could be associated, regardless of prior doxorubicin therapy. We concluded that mitoxantrone does show morphologic evidence of cardiac toxicity; however, the structural changes are minor and are haemodynamically insignificant. Determination of how much mitoxantrone treatment may contribute to the deterioration of pre-existing doxorubicin damage must await the outcome of longer follow-up.

Adult↗
PubMed1985

A phase II trial of PCNU in patients with malignant melanoma and central nervous system metastases.

Twelve patients with malignant melanoma metastatic to the central nervous system (CNS) were treated with PCNU. All patients had prior chemotherapy and/or radiation therapy and had progressive brain metastases, documented by computerized tomography. PCNU was given as a single intravenous infusion of 90-110 mg/m2 every 6-8 weeks. There was one partial response and four patients had stable disease. Although no episodes of sepsis or bleeding occurred, seven of 17 courses led to significant granulocytopenia or thrombocytopenia. Nonhematopoietic toxicities were mild. These results indicate that systemic PCNU is unlikely to be more effective than other currently used chemotherapy in patients with malignant melanoma and CNS metastases.

Brain Neoplasms↗
PubMed1985

Detorubicin--an active anthracycline in untreated metastatic melanoma.

A phase II study of detorubicin, the semisynthetic 14-diethoxyacetoxy ester of daunorubicin, was conducted in 42 patients with metastatic melanoma. The drug was administered in a dose range of 120 to 180 mg/m2 and repeated at 3-week intervals. One clinical complete remission (soft tissue) and seven partial responses (three visceral and four soft tissue) were observed among the 22 patients who had undergone no prior chemotherapy, a complete and partial response rate of 36%. The duration of response varied from 2 to 27 months with a median of 10 months. There were also four (19%) minor responses (one visceral and three soft tissue). In contrast, among the 20 patients who had undergone prior chemotherapy treatment, only three patients showed a minor response. General toxicities were acceptable and were similar to those of Adriamycin (Adria Laboratories, Columbus, Ohio). Cardiac toxicity was evaluated by cardiac biopsy and radionuclide scan. Cardiac biopsy changes were identical to those observed with Adriamycin and were progressive with cumulative dose. One patient had a high-grade biopsy at a cumulative detorubicin dose of 1,420 mg/m2. Similarly, a trend of decreasing ejection fraction with cumulative dose was noted. Only one patient developed congestive heart failure at a cumulative dose of 1,290 mg/m2, that was well compensated with digoxin and diuretics. In contrast to Adriamycin, detorubicin has shown activity in previously untreated patients with metastatic melanoma.

Adult↗
PubMed1985

Pharmacokinetic and biochemical studies on acivicin in phase I clinical trials.

Acivicin pharmacokinetics were studied in Phase I patients receiving i.v. treatment on single-dose or daily x5 (daily times five doses) regimens repeated every 3 weeks. In 14 patients, the time course of plasma concentrations was characterized by a biexponential equation with a terminal (elimination-phase) half-life of 9.92 +/- 3.91 h (mean +/- SD), distribution phase half-life of 0.32 +/- 0.28 h, total body clearance of 1.69 +/- 0.48 liters/h/m2, and volume of distribution of 21.79 +/- 2.94 liters/m2. Acivicin kinetics appeared to be dose-independent over the range of 8.5-150 mg/m2/day. Urinary excretion of intact acivicin in nine patients ranged from 2-42% in the first 24 h following administration; interpatient variability in urinary excretion was large, but daily urinary recovery within patients on the daily x5 schedule was quite consistent. Measurements of acivicin effects on the activity of carbamyl phosphate synthetase II (CPS II) were conducted using leukocytes and/or malignant ascites of three colon cancer patients. Acivicin given to one patient at 8.5 mg/m2/day on the daily x5 schedule caused a 70% reduction in leukocyte CPS II activity within 5 h after therapy was initiated. Leukocyte CPS II activity remained suppressed at this level over the 5-day dosing regimen. In this patient, CPS II activity in malignant ascitic cells had decreased by 75% on day 4 of the daily x5 regimen. On the single dose schedule, treatment of two patients with 100 mg/m2 caused leukocyte CPS II activity to decrease by greater than 90% within 4 h of treatment with gradual recovery over the next 2 days.

Antibiotics, Antineoplastic↗
PubMed1985

Radioimmunoimaging in malignant melanoma with 111In-labeled monoclonal antibody 96.5.

A radiolabeled monoclonal antibody (96.5) reactive with an Mr 97,000 antigen found on over 80% of melanoma cell lines and tissue extracts was examined for its ability to detect malignant melanoma metastases in vivo. For imaging purposes, it was conjugated with diethyltriaminepentaacetic acid and subsequently labeled with 111In by chelation. Thirty-one patients with metastatic melanoma received single injections of monoclonal antibody 96.5 at concentrations ranging from 0.5 to 20 mg and at specific activities of 111In ranging from 0.125 to 4 mCi/mg. Total-body scans were performed at various time intervals following administration. No serious side effects were observed. Of a total of 100 previously documented metastatic sites, 50 imaged for a specificity of 50%. The number of sites imaged increased significantly as the amount of antibody administered increased relative to the average radiation dose. Considerable background uptake of isotope was observed in blood pool and other organs with gradual acquisition of label in tumor sites by 48 to 72 h. Hence, tumor imaging of melanoma using 111In-labeled monoclonal antibody 96.5 appeared feasible, especially at antibody doses above 2 mg.

Adult↗
PubMed1985

Pharmacokinetics of 111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma.

Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111In-labeled chelate complex unattached to antibody. Analysis of the 111In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.

Animals↗
PubMed1984

Intracarotid infusion of cis-diamminedichloroplatinum in the treatment of recurrent malignant brain tumors.

Thirty-five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug-related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.

Adult↗
PubMed1984

A phase II trial of 2,5,-diaziridinyl 3,6-bis (carboethoxy amino) 1,4-benzoquinone (AZQ, NSC 182986) in recurrent primary brain tumors.

Forty-one patients with recurrent primary malignant brain tumors were treated with 2,5-diaziridinyl 3,6-bis (carboethoxyamino), 1,4-benzoquinone (AZQ) at an initial dose of 6-8 mg/m2/day X 5 days. Courses were repeated monthly upon recovery of myelosuppression. Six of 25 evaluable patients (24%) showed definite tumor regression, and 7 (28%) showed disease stability as determined by monthly CT scans and neurologic examination. For all patients receiving one course of AZQ, the response rate was 16% (6 of 37 patients) and the stable disease rate 19%. The estimated median time to tumor progression with AZQ was 54 weeks for the responding patients and 36 weeks for the stable patients. Toxicity consisted of myelosuppression, primarily thrombocytopenia, which was delayed and cumulative. Other toxicities were uncommon. Further clinical trials in patients with malignant primary brain tumors, including combination studies with other drugs, are indicated.

Adolescent↗
PubMed1984

Central nervous system pharmacology of Baker's antifolate (NSC139105) in man.

Radiolabelled Baker's Antifolate (BAF) was administered to 6 patients undergoing surgical resection of intracerebral tumors. Levels of radioactivity in resected tumor and edematous brain adjacent to tumor were generally higher than levels in concurrent plasma samples and were generally comparable to levels in temporalis muscle. Levels in tumor cyst fluid were far lower than concurrent plasma levels and levels in surrounding tumor. Chromatography was performed on tumor from 2 patients and revealed that only a small proportion of the radioactivity represented unchanged BAF. The major metabolite present in tissues was 1 000 times less potent as an inhibitor of dihydrofolate reductase than was BAF. Five patients had cerebrospinal fluid (CSF) sampled following administration of tracer doses of radiolabelled BAF. Radioactivity levels were far lower in CSF than in plasma. Levels of radioactivity in the CSF were also far lower than levels in tumor and brain samples from other patients and were slightly lower than tumor cyst fluid levels. Two patients had CSF collected after they received therapeutic doses of BAF. In these patients, both CSF and plasma were assayed using a dihydrofolate reductase inhibition assay. As with tracer dose studies, CSF concentrations of BAF were substantially lower than were concurrent plasma concentrations. Thus it appears that only very low concentrations of BAF are attainable in human CSF and intracerebral tumor, although a metabolite which is a very weak inhibitor of dihydrofolate reductase attains high concentrations in tumor.

Antineoplastic Agents↗
PubMed1984

Human tissue distribution of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (NSC 141549, AMSA).

Concentrations of AMSA were determined by HPLC in autopsy tissue samples from five patients who had received the drug antemortem. Relative organ concentrations of AMSA varied from patient to patient; however, concentrations were generally highest in gallbladder, liver, and kidney, while low levels were generally but not invariably found in lung, testicle, muscle, fat, spleen, bladder, pancreas, colon, prostate, and brain. One patient with ventricular fibrillation and seizures had high tissue AMSA concentrations in myocardium, but low concentrations in brain. Another patient with seizures during treatment had high brain concentrations of AMSA. Relative organ concentrations were similar to those found in mice, except that mice have high AMSA concentration in their spleens whereas our patients did not, even when the spleen was infiltrated with leukemic cells. High tissue concentrations of AMSA were still present 2 weeks after treatment. AMSA concentration was lower in a renal oncocytoma (1.1 micrograms/g) than in surrounding kidney (2.4 micrograms/g).

Adult↗
PubMed1984

Phase-I trial of intracarotid BCNU and cisplatin in patients with malignant intracerebral tumors.

Eighteen patients with progressive or recurrent intracerebral malignant neoplasms after cranial radiation therapy were entered in a phase-I trial of intracarotid bis-chloroethylnitrosourea (BCNU) and cisplatin. Thirty-six courses of varying doses of BCNU and cisplatin were infused intraarterially via a percutaneous, trasfemoral approach. Courses were repeated every 4-6 weeks upon patients' recovery from toxicity. Intraarterial cisplatin or BCNU alone was administered if the blood counts were still subnormal. CT scans and neurologic examinations were performed monthly. Major toxic effects included ipsilateral retinal (amaurosis) in 4 patients and neurologic toxicity in 2 patients (minor focal seizure, reversible obtundation in one patient, and transient hemiparesis in one patient). One patient was infused by a catheter inserted into the supraclinoid internal carotid artery and had no further visual deterioration and no major side effects. Tumor regression was observed in patients previously treated with radiation and/or systemic chemotherapy, including 4 of 9 who had recurrent malignant gliomas, and 2 of 9 who had metastatic tumors. Recommended dose for phase-II trials is BCNU 100 mg/m2 and cisplatin 60 mg/m2 every 4-6 weeks. Retinal and neurologic toxicity are possible side effects.

Adult↗
PubMed1984

Phase II evaluation of PALA in patients with refractory metastatic sarcomas.

The efficacy of PALA was evaluated in 22 patients with metastatic soft tissue and bone sarcomas. The 20 evaluable patients had received a median of three prior chemotherapeutic regimens, including an adriamycin combination, to which eight had shown response. PALA was administered at 2-week intervals. Sixteen patients received 6 g/m2 over 1 hour intravenously as their initial dose, while six patients received 5 g/m2. The major side effects were skin rash, stomatitis, diarrhea, nausea, and vomiting. Significant myelosuppression was not seen. Two patients had stabilization of disease for periods of 10 and 13 weeks. At the dose and schedule used in this trial, PALA was not effective against advanced adult sarcoma.

Adult↗
PubMed1984

A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.

One hundred fifty-eight patients receiving Adriamycin underwent 226 transjugular biopsy procedures. The specimens were evaluated by electron microscopy for evidence of drug-related cardiotoxicity. Ejection fraction determinations using echocardiographic or nuclear techniques at rest were available for 69% and 81% of the patients, respectively. Analysis of the data revealed a correlation between cumulative Adriamycin dose and biopsy grade (p less than 0.02). No similar relationship existed between cumulative Adriamycin dose and ejection fractions obtained at rest or between biopsy grades and ejection fractions. In patients who underwent serial endomyocardial biopsies and serial ejection fraction determinations, the correlation between changes in biopsy grade and ejection fraction was poor. A change in resting ejection fraction detected by either method did not reliably predict a change in biopsy grade. The poor correlation between ejection fractions and biopsy grades could be due in part to the sensitivity and specificity of the Adriamycin-related structural changes in contrast to the wider range of disease processes that can affect myocardial function, and to the fact that structural changes often precede the ejection fraction abnormalities. The greater sensitivity and specificity of the biopsy grade should prove useful in reducing the risks associated with evaluating new anthracyclines and potential myocardial protectors of Adriamycin toxicity.

Biopsy↗
PubMed1984

Increased therapeutic index of weekly doxorubicin in the therapy of non-small cell lung cancer: a prospective, randomized study.

One hundred patients with non-small cell lung cancer were entered into a randomized evaluation of two schedules of doxorubicin combined with ftorafur, cyclophosphamide, and cisplatin (FACP). Doxorubicin was given either weekly at 20 mg/m2, or every three weeks (standard) at 60 mg/m2. Fifty-two patients were randomized to the FACP/weekly doxorubicin arm and 48 patients to the FACP/standard doxorubicin arm. The FACP/weekly doxorubicin regimen was associated with higher complete and partial remission rates (31% versus 19%), longer response duration (median, 33 versus 21 weeks), and longer survival duration for responders (median, 58 versus 50 weeks). These differences were not significant. Less neutropenia (p = 0.01) and less infectious morbidity (p = 0.05) were observed in the FACP/weekly doxorubicin arm. Twenty-eight patients underwent 35 endomyocardial biopsies to assess doxorubicin-induced cardiotoxicity. Sixteen biopsies were performed in 12 patients receiving cumulative doxorubicin doses ranging from 250 to 1,190 mg/m2 within the FACP/weekly doxorubicin arm. Nineteen biopsies were performed in 16 patients receiving cumulative doxorubicin doses ranging from 250 to 540 mg/m2 within the FACP/standard doxorubicin regimen. The FACP/weekly doxorubicin regimen was associated with significantly lower cardiotoxicity scores (p = 0.01). This study indicates that weekly administered doxorubicin is as effective and less cardiotoxic than the standard schedule.

Adenocarcinoma↗
PubMed1984

Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule.

A Phase I trial of tricyclic nucleoside phosphate (1,4,5,6,8-pentaazaacenaphthylene-3-amino-1, 5-dihydro-5-methyl-1-beta-D-ribofuranosyl 5'-phosphate ester; NSC 280594) was conducted using a 5-day continuous infusion schedule. Thirty-seven patients with advanced cancer were entered on the study, of whom 33 patients were evaluable for response and toxicity. Dose levels ranged from 10 mg/sq m/day X 5 days to 40 mg/sq m/day X 5 days. Initially, courses were repeated every 3 to 4 weeks. As cumulative toxicity became manifested, the interval between courses was changed to every 6 weeks. Major toxicities included hyperglycemia, hepatotoxicity, and thrombocytopenia. Patients with a prior history of diabetes mellitus, extensive radiation therapy, or significant liver metastases were prone to severe toxicity. Other toxicities noted were nausea and vomiting, abdominal discomfort, anemia, and reduction in serum calcium, phosphorus, and albumin levels. Rare side effects included hypertriglyceridemia, hyperamylasemia, diarrhea, and stomatitis. Antitumor activity observed include improvement in s.c. metastases in a patient with papillary thyroid carcinoma, stabilization of disease in a patient with mesothelioma, and mixed responses in three patients (colon cancer, sarcoma, and tonsillar squamous cell cancer). Recommended schedule for Phase II studies is 20 mg/sq m/day for 5 days every 6 weeks.

Acenaphthenes↗
PubMed1983

Hepatic arterial chemotherapy and occlusion for palliation of primary hepatocellular and unknown primary neoplasms in the liver.

Eighteen patients with malignant liver disease were treated with hepatic arterial infusion (HAI) of floxuridine (FUDR), Adriamycin (doxorubicin), and mitomycin C (FUDRAM). Twelve of the patients had primary hepatocellular carcinoma and six had metastatic liver carcinoma originating from an unknown primary site. One complete remission and seven partial remissions (greater than or equal to 50% reduction in tumor size) were observed among 12 hepatocellular cancer patients, while only one partial remission was achieved among six patients with unknown primary liver neoplasms. When arterial occlusion was added to HAI of FUDRAM, a prolongation of median survival to 14 months as opposed to six months in patients with an intact arterial tree was observed (P = 0.02). Arterial occlusion had its effect on survival particularly among patients who failed to respond to HAI of FUDRAM. Thus, among nonresponding patients, the addition of arterial occlusion resulted in a median survival of 10.5 months while median survival in those without arterial occlusion was six months (P = 0.08). With procedure-related morbidity being minimal, we conclude that arterially administered FUDRAM offers a notable palliation to patients with primary hepatocellular carcinoma. In patients with unknown primary liver neoplasms and those with hepatocellular cancer who fail HAI of FUDRAM, arterial occlusion can offer additional palliation.

Adult↗