Confusion of tongues.
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Attitude to Death↗
Biomedical subjects
E Berman
Publications and source records attributed to E Berman.
Optical spectroscopy and scintillation mechanisms of CexLa1-xF3.
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Journal Article↗
All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.
OBJECTIVE: To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia. DESIGN: Phase II evaluation and comparison with historical control patients. SETTING: Tertiary care cancer referral center. PATIENTS: Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again. RESULTS: 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior. CONCLUSIONS: All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.
Adolescent↗
Comparative activity of tamoxifen and N-desmethyltamoxifen in human multidrug resistant leukemia cell lines.
Tamoxifen (Tmx) is one of a number of agents that can reverse the multidrug resistant (MDR) phenotype in vitro; it is unique, however, in that both the parent compound and the main metabolite, N-desmethyltamoxifen (NDMTmx), have long plasma half-lives, 7 and 14 days, respectively. To determine whether NDMTmx was as active as the parent compound in restoring sensitivity to daunorubicin (DNR) in vitro, we performed uptake and retention studies in the MDR-positive human leukemia cell lines CEM-VLB and HL-60/RV+ using laser flow cytometry to quantitate intracellular DNR concentration. Cells incubated with DNR and NDMTmx 10 microM demonstrated increased intracellular DNR levels that were very similar to those obtained with DNR and Tmx 10 microM. Cellular retention of DNR was also measured after incubation with Tmx 10 microM or NDMTmx 10 microM and resuspension in fresh medium containing Tmx or NDMTmx in order to stimulate in vivo conditions. Washout curves in both cell lines were similar with both Tmx and NDMTmx. Finally, clonogenic experiments were performed to determine whether Tmx and NDMTmx demonstrated the same degree of cytotoxicity. The combination of Tmx 10 microM plus DNR and that of NDMTmx 10 microM plus DNR each resulted in > 80% growth inhibition. These results suggest that NDMTmx is as active as Tmx in restoring sensitivity to DNR in vitro, a finding which may have important implications in clinical trials that assess the ability of Tmx to reverse the MDR phenotype.
Daunorubicin↗
Concomitant administration of chlorambucil limits dose intensity of fludarabine in previously treated patients with chronic lymphocytic leukemia.
Fifteen patients with chronic lymphocytic leukemia (CLL) were treated in a phase I-II study of chlorambucil with an escalating dose of fludarabine. The study was designed to identify a maximum tolerated dose (MTD) of fludarabine given in conjunction with a constant dose of chlorambucil. Patients were eligible for study if they had Rai intermediate or high-risk disease which had relapsed from or was refractory to conventional treatment. The initial cohort of patients received fludarabine 10 mg/m2/d days 1-5 and chlorambucil 20 mg/m2 days 1 and 15. Cycles were repeated every 28 days. Unacceptable toxicity was encountered in this cohort. The protocol was then modified to give chlorambucil 20 mg/m2 on day 1 (only). At this chlorambucil dose, cohorts of three patients were treated with fludarabine 10, 15, and 20 mg/m2/d x 5 days. The predominant toxicity was thrombocytopenia with 73% experiencing grade > or = 3 toxicity. The dose-limiting non-hematologic toxicity was infection. We identified an MTD of fludarabine of 15 mg/m2/d x 5 days when given with chlorambucil 20 mg/m2 for this group of patients. One patient achieved a CR and three patients achieved a PR for a total response rate of 27%. We conclude that concomitant administration of chlorambucil limits the dose intensity of fludarabine which can be administered to previously treated patients with CLL.
Aged↗
Steroidogenic assessment using ovary culture in cycling rats: effects of bis(2-diethylhexyl)phthalate on ovarian steroid production.
In vitro ovary culture in rats was used to characterize ovarian steroidogenesis and to evaluate changes produced by in vivo exposure to bis(2-diethylhexyl)phthalate (DEHP). Steroid profiles [progesterone (P4), estradiol (E2), and testosterone (T)] from cultures of minced ovary were obtained in untreated immature and mature rats, and from mature rats treated with DEHP. A 1-h incubation without human chorionic gonadotropin (hCG) was used to produce an initial steroidogenic profile. Three 1-h incubations with hCG were used to produce a stimulated steroid profile. A combination of initial and stimulated ovarian steroid profiles was shown to correctly identify the stage of the cycle in all untreated rats, using multivariate statistical analysis. Separately, initial or stimulated ovarian steroid profiles correctly identified the stage of the cycle in more than 90% of the rats. The statistical analysis using a combination of variables (multivariate) indicated that DEHP-treated rats were significantly different (P < 0.001) from sham-treated rats. In fact, the alteration caused by DEHP in the in vitro ovarian steroidogenic profile was most apparent in rats during diestrus and estrus. In DEHP-treated rats in diestrus, ovarian steroidogenesis appeared to shift to the production of more T and more E2 than in untreated rats in diestrus. The change seen in steroid profiles in DEHP-treated rats in estrus is to decreased E2 production. The steroid profile from ovary culture in conjunction with vaginal cytology was very useful in correctly identifying in vivo DEHP-treated rats, and will be a useful in vitro technique in the evaluation of ovarian toxicants in cycling females.
Analysis of Variance↗
Parental and relationship representations and experiences of depression in college students.
Young adults' descriptions of their parents and their relationships with their parents were used to reexamine the relations between object representation and depressive experience. One hundred eight students completed (a) four open-ended descriptions, including two written descriptions of the parents (mother and father, separately), and two written descriptions of the relationships with the parents; and (b) the Depressive Experience Questionnaire. Each of the four open-ended descriptions was rated on seven scales. Factor analysis yielded four distinct factors from the 28 dimensions of the descriptions. These factors were related to: (a) the degree of elaboration and investment, (b) the structural level of the descriptions, (c) the affective tone of the description of the father, and (d) the affective tone of the description of the mother. Significant differences and interactions were found regarding the interplay between the specific significant other represented (father or mother) and the specific framework of representation (parent description or relationship description). Measures derived from parents' and relationship descriptions significantly predicted depressive experiences of self-criticism and dependency. The results indicate the advantages of a joint exploration of the representation of distinct significant others (mother and father) and the use of two modes of relatedness (describe parent and describe relationship with parent) in the process of personality assessment.
Adolescent↗
A review of idarubicin in acute leukemia.
Since the introduction of the anthracycline idarubicin for the treatment of acute myelogenous leukemia, clinicians have questioned whether it offers significant benefit over the standard anthracycline, daunorubicin. While the three prospectively randomized US trials that compared these two agents in adults with newly diagnosed disease differed somewhat, all reported an improved remission incidence in patients on the idarubicin arm, and two reported improved survival. Overall survival curves, however--albeit better on the idarubicin arm--are still depressingly low. Nonetheless, even if the compound represents only an incremental improvement, it gives more patients the opportunity for more intensive postinduction therapy, such as bone marrow transplantation, or innovative approaches to eradicating minimal residual disease, such as the use of recombinant interleukin-2. This article describes the mechanism of action and pharmacology of idarubicin and reviews the results of clinical studies to date in both acute myelogenous leukemia and acute lymphoblastic leukemia.
Adult↗
Severe toxicity limits intensification of induction therapy for acute lymphoblastic leukemia.
Fourteen adult patients with newly-diagnosed acute lymphoblastic, leukemia (ALL), and lymphoblastic lymphoma, were treated with a dose-intense induction regimen. This regimen was designed to increase the fraction of patients achieving an early complete remission, in an attempt to increase the fraction of patients who are long-term disease-free survivors. The induction regimen included vincristine, prednisone, intermediate-dose cytarabine (Ara-C), and idarubicin, all given during the first week of therapy. This combination led to significant hepatic, gastro-intestinal, infectious, and neurologic toxicity. There was unacceptable treatment-related mortality (29%). After the first eight patients, the study was modified, omitting the Ara-C from the induction phase. Gastrointestinal morbidity was less in the cohort treated without Ara-C; however, infectious morbidity persisted at unacceptable levels and this program was terminated as too toxic to administer. There were nine complete remissions, three early deaths, and two patients with resistant disease. There have been six relapses, three of which occurred in patients who, because of protracted grade III/IV toxicity, were no longer receiving chemotherapy. With a minimum follow-up of 20 months, only three patients are still alive. We conclude that this combination of vincristine, prednisone, Ara-C, and idarubicin, is too toxic to be used as induction therapy for adult patients with ALL and lymphoblastic lymphoma.
Adult↗
Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute lymphocytic leukemia.
Although the mechanisms of resistance to methotrexate (MTX) are known in experimental tumors made resistant to this drug, little information is available regarding acquired resistance to MTX in patients. A competitive displacement assay using the fluorescent lysine analogue of MTX, N-(4-amino-4-deoxy-N10-methylpteroyl)-N epsilon-(4'-fluorescein-thiocarbamyl)-L-lysine (PT430), was developed as a sensitive method of detection of transport resistance to MTX in cell lines, as well as in blast cells from patients with leukemia. Rapid uptake of PT430 at high concentrations (20 mumol/L) in leukemic blasts resulted in achievement of steady-state levels within 2 hours. Subsequent incubation with the folate antagonists, MTX and trimetrexate (TMTX), which differ in the mode of carrier transport, produced characteristic patterns of PT430 displacement. Flow cytometric analysis of the mean fluorescence intensity in the human CCRF-CEM T-cell lymphoblastic leukemia cell line and its MTX-resistant subline clearly identified the presence of transport deficiency in the resistant subline. Analysis of blasts from 17 patients with leukemia, nine with no prior chemotherapy and eight previously treated with chemotherapy, found evidence of MTX transport resistance in two of the four patients who were treated with MTX and considered to be clinically resistant to the drug. The finding that blast cells of some patients with leukemia considered clinically resistant to MTX is due to decreased MTX transport has important implications for clinical use of this drug and for new drug development.
Adolescent↗
Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemia cells.
We examined the effect of daunorubicin (DNR), the new anthracycline derivative idarubicin (IDR), and verapamil on two leukemia cell lines that displayed the multidrug resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular anthracycline content. The vinblastine-resistant human lymphoblastic leukemia cell line CEM-VBL demonstrated minimal DNR uptake; simultaneous incubation with verapamil and DNR increased intracellular DNR uptake fourfold. IDR uptake was 10 times more rapid in these cells and simultaneous incubation with IDR and verapamil resulted in only a 1.2-fold increase of intracellular IDR. Similar results were observed in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Intracellular retention of DNR and IDR was also measured in each cell line. In CEM-BVL cells, 38% of the original DNR concentration remained after a 2-hour resuspension in fresh medium compared with 71% of the original IDR concentration. In HL-60/RV+ cells, 36% of the DNR concentration remained compared with 51% of the IDR concentration. After incubation of CEM-VBL and HL-60/RV+ cells with DNR for 1 hour followed by resuspension in fresh medium plus verapamil, intracellular DNA retention increased 5- and 5.2-fold, respectively. However, incubation of these cells for 1 hour with IDR followed by resuspension in fresh medium plus verapamil resulted in only a 1.6- and 2.4-fold increase in intracellular IDR retention. Lastly, clonogenic experiments were performed to correlate intracellular anthracycline content with cytotoxicity. DNR alone had a minimal effect on the clonogenic growth of CEM-VBL cells, whereas the combination of DNR plus verapamil resulted in approximately 80% growth inhibition. However, incubation of these cells with IDR alone resulted in greater than 95% growth inhibition. These results suggest that IDR may be more effective than DNR in leukemia cells that display the MDR phenotype.
Cell Division↗
High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia.
We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.
Adult↗
Reasons that patients with acute myelogenous leukemia do not undergo allogeneic bone marrow transplantation.
BACKGROUND: Numerous reports suggest that allogeneic bone marrow transplantation prolongs the survival of adult patients with acute myelogenous leukemia (AML) in first remission. However, it is unclear how many such patients actually undergo this procedure. METHODS: We reviewed the case records of 350 consecutive adult patients with AML treated with chemotherapy at a single institution from 1979 (when the policy of offering allogeneic transplantation to all such patients in first remission was introduced) through 1990. The criteria for exclusion before transplantation included age greater than 40 and, beginning in 1984, a diagnosis of acute promyelocytic leukemia. RESULTS: One hundred forty-two patients (41 percent of the study population) were 40 years of age or under. HLA testing was performed for 120 of these patients (85 percent). Sixty-seven patients (47 percent) had an HLA-identical sibling as a potential donor. One hundred three patients (73 percent) entered remission during treatment according to one of five chemotherapy protocols. Of the 52 patients who both entered remission and had an HLA match, 30 underwent transplantation while they were in first remission. These 30 patients constituted 21 percent of all study patients 40 years old or under, 29 percent of all patients 40 or under who entered remission, 45 percent of all patients with an HLA match, 58 percent of all patients who had both a remission and a match, and 9 percent of all patients treated according to a protocol. Among patients with a match who did not undergo transplantation, those with primary refractory disease were the largest subgroup. CONCLUSIONS: These findings suggest that allogeneic bone marrow transplantation is performed in less than 60 percent of adult patients with AML who are potentially eligible for the procedure.
Adult↗
New drugs in acute myelogenous leukemia: a review.
Numerous clinical trials in adult patients with newly diagnosed acute myelogenous leukemia indicate that the survival rate is approximately 20%. A limited number of favorable prognostic features have been identified; patients who present with specific cytogenetic abnormalities such as t(15;17), t(8;21) and inv (16) tend to have survival rates approaching 40%. However, such patients constitute only a small proportion of the total denominator and it has therefore been a major focus of scientific endeavor to develop new drugs for the treatment of this disease. A wide variety of agents have undergone preliminary testing in this regard and include both natural substances such as homoherringtonine, a drug that has demonstrated modest complete remission rates in this disease and all-trans retinoic acid, a compound that has revolutionized the treatment of acute promyelocytic leukemia. This review will put in perspective some of the newer drugs for the treatment of acute myelogenous leukemia and allow for some conclusions to be drawn as to their impact in the treatment of this disease.
Amsacrine↗
The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene.
The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
Alanine Transaminase↗
Comparison of open and blind histopathologic evaluation of hepatic lesions.
This paper explores the controversy among scientists on whether microscopic evaluation of tissue slides should be done in an open or blind fashion. Definitions are given and discussed that provide a better focus to the problem. An experiment was conducted in which hepatocellular degeneration and necrosis in rats were assessed both openly and blindly. The results indicate that 'simple bias' is present when the slides are read openly. Valid comparisons among treatment groups are possible in the presence of simple bias, provided appropriate control groups have been incorporated into the experimental design.
Animals↗
Prophylactic and therapeutic treatment of ascites in broiler chickens.
1. This work examined the effect of using three different feeding regimens in the prophylaxis and treatment of ascites in fastgrowing broilers stressed by exposure to cold (less than 10 degrees C), itself a potent inducer of ascites. 2. Broilers were exposed to cold in tiered cages in a semi-open poultry shed from the age of 24, 29 or 34 d and from day 35 they were given one of three types of food (pellets, pellets with high energy content, mash). Total mortality and mortality with ascites were recorded and erythrocyte packed cell volume (PCV) and relative weight of the right ventricle were measured (both reliable indices of ascites development). 3. Despite relatively low ambient temperatures and consequent high mortality from ascites, the mash diet was effective both in preventing ascites (prophylaxis) and in treating existing ascites.
Animal Feed↗
Hepatotoxic interactions of ethanol with allyl alcohol or carbon tetrachloride in rats.
To assess whether potential toxic interactions occur between ethanol and allyl alcohol or carbon tetrachloride following subacute, concurrent chemical exposure, male Fischer 344 rats, approximately 70 d of age, were given ethanol at 0, 0.05, 0.1, 0.2, or 0.5 ml/kg in corn oil daily by gavage for 14 d (ETOH group), or the same levels of ethanol with 21 mg allyl alcohol/kg (ALAC group), or the same levels of ethanol with 20 mg carbon tetrachloride/kg (CCL4 group). Hepatic response was assessed 24 h after the last dose. Interactions were evaluated by comparing the ETOH group with either the ALAC group or the CCL4 group using multivariate analysis of variance procedures. No statistically significant interaction was seen between the ETOH group and the ALAC group at the dosages used. Although an interaction between ethanol and carbon tetrachloride given simultaneously was not statistically significant, a small interactive effect on weight gain from d 0 to termination was apparent (p = .057). Exposure to ethanol alone resulted in a concentration-dependent decrease in absolute and relative liver weight, with a threshold between 0.05 and 0.1 ml/kg. There was no histopathological evidence of hepatic damage with ethanol alone, and no effect on hepatic cytochrome P-450 and glutathione levels or on serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALK). Exposure to allyl alcohol alone resulted in significant increases in absolute and relative liver weights, liver glutathione, and periportal hepatocellular vacuolar degeneration. Exposure to carbon tetrachloride alone resulted in significant increases in absolute and relative liver weight, serum levels of ALT, AST, and ALK, and centrilobular hepatocellular vacuolar degeneration and necrosis. These observations indicate that subacute, concurrent exposure of ethanol with carbon tetrachloride or allyl alcohol at ethanol levels comparable to those reported in gavage vehicles did not result in interactive toxicity.
1-Propanol↗