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Biomedical subjects

R M Simon

Publications and source records attributed to R M Simon.

At least 37 records · Page 2Linked to original sources
PubMed1987

Cardiotoxicity in patients treated with mitoxantrone: Southwest Oncology Group phase II studies.

A model describing the development of cardiotoxicity as a function of cumulative dose of a drug and other covariates is presented. Methods are given for testing and illustrating a cumulative dose effect. Also, equations for estimation of the probability of developing cardiotoxicity in the presence or absence of competing risks are given. The methods are illustrated for mitoxantrone by means of data obtained from Southwest Oncology Group studies.

Dose-Response Relationship, Drug↗
PubMed1986

The pathologic and clinical heterogeneity of lymphocyte-depleted Hodgkin's disease.

Patients with Hodgkin's disease of the lymphocyte-depleted subtype (LDHD) have been said to have a poor prognosis. However, reports of this subtype are complicated by the fact that the histologic diagnosis of LDHD is often not straightforward, and its distinction from aggressive non-Hodgkin's lymphomas (NHL) can be difficult. We have reviewed our patients with LDHD at the National Cancer Institute (NCI) in light of an additional decade of experience with neoplastic and non-neoplastic conditions mimicking Hodgkin's disease. Of 198 patients who received MOPP (mechlorethamine, vincristine, procarbazine, prednisone) treatment at the NCI for Hodgkin's disease between 1964 and 1976, 43 (22%) were originally classified as LDHD. The initial diagnostic biopsies from 39 of these patients were reviewed and revealed ten with NHL, nine with LDHD, and 13 with nodular sclerosing Hodgkin's disease of the lymphocyte-depleted subtype (NSLD). The other seven patients had Hodgkin's disease without a lymphocyte-depleted component. The NHL patients were further subclassified as diffuse, large-cell (two cases) and large-cell, immunoblastic (eight cases). The pathologic review was done without knowledge of clinical features which were examined after review in the three major subgroups. Of ten patients with NHL, only three had a complete remission (CR), and median survival was 7 months. Nine of the NHL patients presented with features that are unusual for patients with Hodgkin's disease, such as bulky abdominal disease, epitrochlear lymphade-nopathy, or hypercalcemia. CRs were attained by 67% and 85% of patients in the LDHD and NSLD groups, respectively: median survival had not been reached in either group with a median of 14 years of follow-up. Lymphocyte-depleted Hodgkin's disease, adequately treated, is in our limited group of patients no worse than other histopathologic subtypes of Hodgkin's disease. The erroneous inclusion of patients with high-grade NHLs into this subtype of Hodgkin's disease may be one reason for earlier literature reports of its more aggressive nature. The diagnosis of LDHD should be made cautiously, particularly in patients with clinical features that are unusual for Hodgkin's disease at presentation.

Adolescent↗
PubMed1986

Efficiency of antitumor screening relative to activity criteria.

Well over 100,000 compounds have been screened by the National Cancer Institute (NCI) in mouse leukemia P388 in the search for new leads toward antineoplastic agents. The protocol for screening requires confirmation testing of compounds showing initial activity. By activity criteria being varied for initial and confirmation testing, it is possible to improve the efficiency of screening. The experimental variability of P388 screening was first determined by analysis of outcomes from 90 tests on each of 21 compounds of varied activity. By application of these results to NCI P388 data for 31,428 compounds adequately tested on a daily times five schedule, the consequences of using different activity thresholds were estimated. The results here may apply to those of other similar large-scale screening programs.

Animals↗
PubMed1986

Antiemetic studies: a methodological discussion.

Methodological issues encountered in reviewing the antiemetic literature are discussed. Variables affecting antiemetic assessment include those relating to the patient, the emetic stimulus, and the differences in action of the antiemetic drugs. Study design questions including the desirability of randomization, double blinding, use of controls, and stratifications for factors such as previous exposure to chemotherapy and strength of the emetic stimulus are discussed. From a statistical viewpoint a parallel subject design with adequate sample size is recommended. The problems of standardizing the evaluation of nausea and vomiting are considered and simple ordinal scales grading severity are suggested. The patient's overall assessment of tolerance of therapy is of primary importance.

Antiemetics↗
PubMed1985

Application of a human tumor colony-forming assay to new drug screening.

The applicability of a human tumor colony-forming assay to drug screening was investigated in terms of feasibility, validity, and potential for discovering new antitumor drugs. Feasibility was addressed in a pilot study during which basic methods, appropriate assay quality controls, and a standardized protocol for screening were developed. Considerable variability was noted in the availability and colony growth of different tumor types. The majority of the evaluable experiments utilized breast, colorectal, kidney, lung, melanoma, or ovarian tumors. For many tumor types, little evidence of growth was observed, or only rare specimens formed colonies. Colony-forming efficiencies ranged from 0.05 to 0.11% for the six most useful tumors listed above. A set of quality control measures was developed to address technical problems inherent in the assay. Testing of standard agents in the pilot study established that most of these agents could be detected as active. However, it also identified three assay limitations: compounds requiring systemic metabolic activation are inactive; medium constituents may block the activity of certain antimetabolites; and compounds without therapeutic efficacy may be positive in the assay. The assay categorized nontoxic clinically ineffective agents as true negatives with 97% accuracy. Of 79 compounds which were negative in the current National Cancer Institute prescreen (leukemia P388), 14 were active in the assay. Several demonstrated outstanding in vitro activity and are structurally unrelated to compounds already in development or in clinical trials. A subset of these active compounds were found to lack activity in a P388 in vitro colony-forming assay. This indication of differential cytotoxicity to human tumor cells makes this subset of compounds particularly interesting as antitumor drug leads. The demonstrated sensitivity to most standard agents, discrimination of nontoxic compounds, reproducibility of survival values within assays and between laboratories, and evidence of ability to identify active compounds which were negative in the in vivo prescreen suggest that the human tumor colony-forming assay may be a valuable tool for antitumor drug screening. However, because of technical limitations inherent in the current assay methodology, this must be confined to selected tumor types and limited to screening on a moderate scale.

Antineoplastic Agents↗
PubMed1984

CT of the liver and spleen with EOE-13: review of 225 examinations.

EOE-13 is an experimental liver-spleen-specific computed tomographic (CT) contrast agent developed at the National Institutes of Health. Experience with this agent in 225 clinical examinations is described. On average, use of EOE-13 increases the attenuation of normal liver by 32.5 H and that of normal spleen by 52.3 H. Tumors in these organs increase only 2.6 H, making them more easily detectable. Most of the iodine in EOE-13 appears to clear from the liver and spleen by 24 hr after injection. No deaths or permanent morbidity have been observed. The complication rate is 3.6%. EOE-13 is valuable for the detection of hepatic and splenic tumors.

Adult↗
PubMed1983

An autopsy study of histologic progression in non-Hodgkin's lymphomas. 192 cases from the National Cancer Institute.

Histologic slides were reviewed from 192 autopsies of patients with non-Hodgkin's lymphomas admitted to the National Cancer Institute (NCI) from 1953 to 1975. Each autopsy was classified according to the systems of Rappaport and Lukes-Collins. Comparisons with the initial diagnosis were made. The initial histologic diagnoses of the autopsied population were similar in distribution to other published series of non-Hodgkin's lymphomas. Of the 56 cases which initially demonstrated nodular patterns of growth, the following distribution was found at autopsy: 25%, no lymphoma; 6%, nodular lymphoma; 32%, diffuse histiocytic (large cell) lymphoma (DHL); 21%, diffuse undifferentiated (non-Burkitt's) lymphoma (DUL); and 16%, the remaining diffuse morphologies. Of the 136 patients with initial diagnosis of diffuse lymphoma, the following distributions were observed at autopsy: 20%, no lymphoma; 0%, nodular lymphoma; 31%, diffuse histiocytic (large cell) lymphoma; 12%, diffuse undifferentiated (non-Burkitt's) lymphoma; 9%, Burkitt's tumor; 14%, diffuse poorly differentiated lymphocytic lymphoma; and 14%, the remaining diffuse morphologic types. One hundred and thirty-four cases which were initially diagnosed as follicular center cell type within the Lukes-Collins classification gave the following distribution at autopsy: 21%, no lymphoma; 25%, small noncleaved type; 17%, large noncleaved type; 23%, non-follicular center cell lymphomas (17% immunoblastic B); and the remaining 13% were distributed among the other follicular center cell types. This autopsy review demonstrates the rarity of nodular (follicular) lymphomas at autopsy, and the predominance of the diffuse histiocytic or "transformed" type. This study provides a comparison of the rate of histologic progression of lymphomas in the same patient population at autopsy with a previously published study of progression during life.

Adolescent↗
PubMed1983

Limiting dilution analysis of Epstein-Barr virus-induced immunoglobulin production by human B cells.

The Epstein-Barr virus (EBV) is a herpes virus that has the capacity to infect human B cells and to induce them to secrete immunoglobulin (Ig). In the current experiments, Poisson analysis of limiting dilution cultures has been used to study the activation of human peripheral B cells by the B95-8 strain of EBV. Under the culture conditions used, 0.2-1% of peripheral blood B cells were activated by EBV to secrete IgM or IgG. In addition, when multiple replicate cultures containing limited numbers of B cells were tested for IgM and for IgG production, the precursors for IgM and IgG segregated independently; thus, individual B cell precursors matured into cells secreting IgM or IgG but not both classes of Ig. Additional experiments using limiting dilutions of EBV were undertaken to study the viral requirements for B cell activation. These studies indicated that B cell activation by EBV to produce Ig was consistent with a "one-hit" model and inconsistent with a "two-hit" model. Taken together, these results indicate that infection by one EBV virion is sufficient to induce a precursor peripheral blood B cell to secrete Ig and that only one isotype of Ig is then secreted.

Antibody Formation↗
PubMed1982

Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute.

A retrospective review was performed of 473 consecutive patients with malignant lymphoma referred to the National Cancer Institute. All patients had their clinical and pathologic material reviewed and where necessary reclassified. Using a modification of the Rappaport system, 180 (38.1%) patients had a nodular lymphoma, 293 (61.9%) had a diffuse lymphoma. Nodular lymphoma patients usually presented with lymphadenopathy; diffuse lymphoma patients often presented with extranodal disease, particularly those patients with poorly differentiated lymphocytic, "histiocytic", and Burkitt's lymphoma. Median age for all patients was 46 years, but was lower for diffuse poorly differentiated lymphocytic, diffuse undifferentiated, and Burkitt's lymphoma patients. Women were more likely to have a nodular rather than diffuse lymphoma. P less than 0.05. Analyzed by clinical staging, most nodular lymphoma patients had CS III (66.1%) disease, while most diffuse lymphoma patients had either CS III (31.1%) or CS IV (38.9%) disease. Analyzed by pathologic staging, most nodular lymphoma patients had PS III (34.8%) or PS IV (49.4%) disease, most diffuse lymphoma patients had PS IV (56.3%) disease. Only 7% of all lymphoma patients had PS I disease, only 14.9% were PS II. Systemic symptoms were more likely to be found in diffuse lymphoma and/or advanced stage patients.

Burkitt Lymphoma↗
PubMed1982

Malignant lymphoma. II Prognostic factors and response to treatment of 473 patients at the National Cancer Institute.

Treatment results were reviewed in 473 consecutively staged and treated patients at the National Cancer Institute over a 22-year period from 1953 to 1975. Responses correlated with histologic pattern and stage of disease. Complete responses to radiotherapy were frequent in CS I (86%) or PS I (91%). CS II (70%) or PS II (69%) nodular lymphoma patients. Similar treatment regimens were less effective in diffuse lymphoma patients, CS I (53%) or PS I (57%) and CS II (50%) or PS II (51%). Using chemotherapy or combined modality approaches, complete responses were obtained in a high proportion of advanced nodular disease patients, CS III (51%) or PS (59%), CS IV (44%), or PS IV (46%). With the introduction of combination chemotherapy and/or modern radiotherapeutic techniques, 52% CS III and 63% PS III, and 47% CS IV and 46% PS IV patients achieved a complete response. Patients with nodular lymphoma tend to have higher complete response rates and longer survivals than their counterparts with diffuse histologic types (P less than 0.05). Patients with nodular lymphocytic lymphoma had a better survival than those with mixed or "histiocytic" histologic types (P less than 0.03). Patients with diffuse well differentiated lymphocytic lymphoma survived significantly longer than patients with other diffuse histologic types (P less than 0.05). Percentage and prominence of nodularity were not of prognostic significance in those patients with combined nodular and diffuse patterns of disease. When compared by histologic type, patient sex did not appear to be an important prognostic factor. The presence of B-symptoms was associated with a poorer survival in patients with nodular disease (P less than 0.05) and in patients with diffuse disease (P less than 0.001). Over the years of this study, survival appears to have improved in each histologic subtype except DPDL.

Drug Therapy, Combination↗
PubMed1982

Sample size requirements for comparing time-to-failure among k treatment groups.

Clinical trials are commonly undertaken to compare three or more treatment groups. In this paper sample size requirements are provided for the k group comparative clinical trial in which time-to-failure is the measure of treatment efficacy. Time-to-failure is assumed to have an exponential distribution and so these results generalize those of George and Desu. When the alternative hypothesis specifies only the magnitude of the largest difference among the treatment groups, a particularly simple expression is obtained. It is shown that heuristic use of sample size formulae or tables for comparing two treatment groups is not adequate for obtaining sufficient power and properly accounting for the multiple comparisons possible with k greater than or equal to 3 treatment groups.

Clinical Trials as Topic↗
PubMed1982

Influence on retrolental fibroplasia of intramuscular vitamin E administration during respiratory distress syndrome.

The effect of vitamin E administered during the acute phase of therapy for respiratory distress syndrome (RDS) on the development of retinopathy of prematurity (ROP) was evaluated in a randomized double-masked study. One hundred neonates received either vitamin E or placebo intramuscularly within the first 24 hours of birth and at 24, 48, and 168 hours respectively. Additional doses were given twice weekly while the infant remained in an oxygen-enriched environment and could not tolerate feedings and vitamin supplements. Parenteral vitamin E-treated infants had significantly increased serum vitamin E levels compared to placebo-treated infants. Most placebo-treated patients attained normal serum vitamin E levels during the second week of life because of nutritional sources of vitamin E. Infants in both groups had RDS of similar severity. Seventy-four infants, 37 vitamin E-treated and 37 placebo-treated, survived longer than 10 days and had ophthalmologic examinations. Active changes of Stage I and Stage II ROP were noted in 17 of those patients; 9 (24.3%) vitamin E-treated and 8 (21.6%) placebo-treated patients (P = 0.572). No infants developed severe cicatricial changes, and their retinal findings regressed. The incidence of risk factors associated with ROP development occurred equally in the vitamin E-treated and placebo-treated infants that developed ROP. Thus, vitamin E-administration as described in this study did not result in any further reduction in the incidence of the active stages of ROP over that seen with standard neonatal care, which included daily oral Vitamin E supplements.

Clinical Trials as Topic↗
PubMed1981

Natural history of malignant lymphomas with divergent histologies at staging evaluation.

The pathology and medical records of 515 patients with malignant lymphomas treated at the National Cancer Institute have been reviewed to determine the frequency and natural history of patients who have different histologic diagnoses in various tissue sites at their initial staging evaluation. Of the 101 patients who had multiple tissue sites biopsied, 33 patients had different histologic diagnoses. Eighteen patients had a nodular pattern in one site and a diffuse pattern in another. The final stage and treatment of these 18 patients were similar to that of the 27 patients with multiple identical nodular biopsies and 41 patients with multiple identical diffuse biopsies. However, the 56% complete response rate for patients with both a nodular pattern and a diffuse pattern was intermediate between that achieved in patients with identical nodular biopsies (70%) and identical diffuse biopsies (30%). Median survival for these three groups was as follows: identical nodular biopsies, 53 months; both a nodular and a diffuse pattern, 37 months; and identical diffuse biopsies, 12 months. These results demonstrate that patients with different histologic diagnoses in various sites at staging evaluation are not uncommon and have a unique natural history that should be considered in planning treatment.

Biopsy↗
PubMed1981

Anterior segment and retinal pigmentary abnormalities in arteriohepatic dysplasia.

Arteriohepatic dysplasia (AHD, Alagille's syndrome) is presumed to be one of the six known familial intrahepatic cholestatic syndromes, all of which present with neonatal jaundice or failure to thrive, or both. Accurate early diagnosis of the proper syndrome is important, as arteriohepatic dysplasia has a good prognosis, whereas the other syndromes usually lead to death in infancy or early adulthood. Posterior embryotoxon was found in all five of our patients and may be one of the hallmarks of this syndrome. Axenfeld's anomaly was present in three of five patients, and retinal pigmentary abnormalities were found in four of five patients. Variable abnormalities were found in the cardiovascular system, bones, central nervous system, kidneys, endocrine system, and body habitus. Inheritance may be autosomal dominant as vertical transmission was documented in one family. Liver function improves during the first five years of life so that only the ocular and skeletal signs may be present in adults.

Abnormalities, Multiple↗
PubMed1981

A prospective randomized study of adjuvant parenteral nutrition in the treatment of diffuse lymphoma: effect on drug tolerance.

Total parenteral nutrition (TPN) has been suggested as a useful addition to chemotherapy of malignant disease in the hope of decreasing drug toxicity and increasing drug tolerance. In this study, 17 of 36 patients given chemotherapy for advanced diffuse lymphoma were randomly selected to receive TPN. The dose of the chemotherapeutic agents to be administered was decreased according to predetermined toxicity guidelines. A comparison of drug dosage in the group receiving TPN and the group receiving standard nutrition is a measure of drug tolerance in these patients. Drug dosage was evaluable in 15 TPN and 18 standard nutrition patients. No difference in tolerance of any specific drug or total drug dose occurred when all patients in both groups were compared. Similar comparisons in subgroups of malnourished patients and responding patients also revealed no difference. A cycle-by-cycle analysis demonstrated no difference in any phase of therapy. The wbc count, platelet count, and albumin level, on the first day of each cycle, the nadir during cycles and the day of nadir were compared in TPN and standard nutrition patients. No differences were found. This study does not suggest improved drug tolerance in lymphoma patients as a result of TPN support. Further controlled studies are needed to determine which groups of cancer patients might benefit from TPN and how these benefits occur.

Antineoplastic Agents↗
PubMed1980

Advanced ovarian cancer: correlation of histologic grade with response to therapy and survival.

In order to determine the prognostic and therapeutic importance of histologic grade for patients with advanced ovarian cancer, the pathologic specimens from 82 patients with Stage III-IV disease (as defined by the International Federation of Gynecologists and Obstetricians (F.I.G.O.)) were reviewed and graded by two methods. A system based on cytologic detail using both the degree of anaplasia and the number of undifferentiated cells, (modified Broders' Grades 1--4) was found to be particularly useful because it identified four groups with different survival outcomes as well as an apparent differential response to chemotherapy. Specifically, the overall improvement of survival in patients with Stage III-IV disease observed in a prospective study of combination chemotherapy was related primarily to an increased survival of patients with Grade 2 and 3 lesions. Survival in Grade 1 patients was markedly better than for Grade 4 patients, but in neither case did survival appear to be influenced by the choice of chemotherapy. These observations suggest that prospective clinical trials assessing the efficacy of chemotherapy should employ cytologic grades as a separate stratification factor since chemotherapy for advanced disease may have to be tailored, in part, to the histologic grade.

Anaplasia↗