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Biomedical subjects

J E Karp

Publications and source records attributed to J E Karp.

At least 91 records · Page 5Linked to original sources
PubMed1988

Asynchronous antigen expression in B lineage acute lymphoblastic leukemia.

Cell surface phenotypes of 113 B lineage acute lymphocytic leukemia (ALL) cases, defined by the presence of HLA-DR and at least one B-cell-specific antigen (either CD19, CD20, or CD22), were compared with antigen-defined stages of normal B lymphocyte development. The cases were first evaluated for expression of HLA-DR, CD19, CD34, CD10, CD20, and CD22 by indirect one-color immunofluorescence. Pairwise comparisons of cell surface marker expression were performed for each leukemic sample: no correlations were observed for paired antigen expression on the leukemic samples using antigens expressed either early or late during normal B lymphoid development. Complete immunophenotypes of the cases were then compared with normal B-cell developmental stages. Sixteen different complete immunophenotypes were observed on the leukemias that were not found in normal marrow; at least 78% of the cases demonstrated such "asynchronous" combinations of B lymphoid-associated differentiation antigens. Several samples were subsequently studied by two-color immunofluorescence, and the presence of doubly labeled cells with "asynchronous" antigen combinations was confirmed. These results indicate that the majority of B lineage leukemias exhibit "developmental asynchrony," as compared with normal marrow B cells. The data further suggest that ALL cases do not accurately represent cells arrested at the stage where the leukemogenic event occurred. Rather, ALL appears to be a disease in which there may be maturation of leukemic blasts; but this maturation is "asynchronous" when compared with the normal developmental process.

Adult↗
PubMed1987

Remission of rheumatoid arthritis with the successful treatment of acute myelogenous leukemia with cytosine arabinoside, daunorubicin, and m-AMSA.

We describe 2 patients in whom a sustained remission of longstanding rheumatoid arthritis occurred with treatment for acute myelogenous leukemia (cytosine arabinoside, daunorubicin, and m-AMSA), even though both illnesses had been refractory to therapy with standard disease-modifying agents. These 2 patients represent the first successful treatment of rheumatoid disease using such an approach.

Amsacrine↗
PubMed1987

Favorable outcome of invasive aspergillosis in patients with acute leukemia.

During a 2-year period, 15 of 110 patients (14%) admitted for intensive therapy of acute leukemia associated with prolonged deep granulocytopenia developed documented invasive aspergillosis (IA). Antemortem diagnosis was accomplished in 14, and 13 of 15 (87%) survived the infection. Because of the high success rate, we reviewed the courses of the 15 patients to assess factors associated with this favorable outcome. Eleven presented with pulmonary IA; early symptoms occurred at a mean 21.6 days of granulocytopenia (less than 100/muL) and included refractory fever in 14 and pulmonary signs or symptoms in 11. Primary necrotic chest wall lesions associated with Hickman catheters developed in four at a mean 11 days of granulocytopenia, followed by pulmonary involvement. All 15 patients had chest radiographs during granulocytopenia, with 14 (93%) demonstrating pulmonary infiltrates and/or nodules at a mean 20.6 days of aplasia. Nine patients had lung computerized tomography (CT) scans, revealing nodular infiltrates in one patient and a characteristic zone of low attenuation surrounding a mass-like infiltrate in seven other patients, which was found to be diagnostic of IA. Subsequent CT scans performed during and following bone marrow recovery showed progression to cavitation followed by either complete resolution or minimal pulmonary scarring. Eleven patients developed IA during empiric amphotericin B (Amp-B) therapy (0.5 mg/kg/d) for fever refractory to antibacterial antibiotics. Fourteen patients received high-dose Amp-B (1.0 to 1.5 mg/kg/d), which was started within a mean of 2.2 days of first clinical findings; 13 survived. Ten patients received 5-fluorocytosine in addition to high dose amp-B. Survival was similar regardless of presentation, as 91% with primary pulmonary IA and 75% presenting with chest wall lesions survived. All 13 surviving patients had complete granulocyte recovery at a mean 33.8 days. Nephrotoxicity (creatinine greater than 2.0 mg/dL) was observed in seven patients during therapy for IA, but was transient in all seven. We conclude IA can be successfully treated in the deeply granulocytopenic patient provided that it is recognized and treated early, and provided that antifungal therapy is aggressive and is continued until granulocyte recovery occurs.

Acute Disease↗
PubMed1987

Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management.

Over 80 percent of patients with invasive pulmonary aspergillosis (IPA) undergoing intensive antileukemic chemotherapy in a recent two-year period survived the pulmonary infection as a result of early diagnosis and aggressive therapy with high-dose amphotericin B and 5-fluorocytosine. CT played an important role in establishing the early diagnosis of IPA and affected management. Since our original communication describing the CT findings of IPA, we have added ten new cases, each subsequently substantiated by lung biopsy (two), autopsy (two), and/or positive cultures of sputum or extrapulmonary sites (seven). The CT halo sign, or zone of lower attenuation surrounding a pulmonary mass, was present in eight of nine patients with early CT scans obtained during bone marrow aplasia. Characteristic CT progression from multiple fluffy masses to cavitation or air crescent formation suggested IPA in five of seven patients with serial CT scans. CT directly affected patient management in seven of ten cases. Scan findings were one criterion for increasing to high-dose amphotericin B or for adding 5-fluorocytosine. CT characteristics of healing IPA lesions were similar to resolving pulmonary infarcts and were used to monitor disease activity in patients on long-term amphotericin B and prior to retreatment chemotherapy.

Acute Disease↗
PubMed1987

Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial.

We evaluated the effect of norfloxacin, 400 mg given orally every 12 hours, on the prevention of bacterial infections in 68 adult patients who had acute leukemia throughout prolonged courses of granulocytopenia (median, 32 days). Gram-negative infections were documented in 13 of the 33 patients receiving placebo, but only in 4 of the 35 patients receiving norfloxacin; no effect on the frequency of gram-positive or fungal infections was noted. Norfloxacin administration resulted in the suppression of gastrointestinal tract colonization by aerobic bacteria without the development of norfloxacin resistance. Patients receiving norfloxacin developed first infectious fevers later than did those receiving placebo, had more rapid resolution of that fever after systemic antibiotic treatment, and spent less time febrile. Therefore, although no difference was seen in survival duration, we found that the prophylactic administration of oral norfloxacin led to decreases in overall morbidity and gram-negative infections, was well tolerated, and did not predispose to the development of multiply drug-resistant bacteria.

Acute Disease↗
PubMed1987

Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia.

To define the relationship between leukemic cell growth, intracellular metabolism of 1-B-D-arabinofuranosylcytosine (ara-C), and the clinical response to timed sequential induction therapy with ara-C in adult acute myelogenous leukemia (AML), growth kinetic and biochemical pharmacologic determinants were examined in AML bone marrow populations. Leukemic blasts from 45 previously untreated patients obtained prior to therapy were cultured in vitro in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). Cell populations cultured in HSA demonstrated both increased proliferation, as measured by both [3H]dThd incorporation into DNA and [3H]dThd leukemic blast labeling index, and greater [3H] ara-C leukemic blast labeling index relative to cells maintained in APS. HSA-cultured marrow cells from the 31 patients who achieved complete remission with ara-C-containing therapy demonstrated enhanced intracellular formation of ara-C 5'-triphosphate over three hours and retention of this active form during one subsequent hour in drug-free medium relative to cells maintained in APS. In contrast, cells from the 14 nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. These studies of human AML marrow cells identify behavior patterns of ara-C activation and net metabolism in the kinetically perturbed, proliferative state that may discriminate clinical sensitivity from clinical resistance to ara-C-based timed sequential therapy. Sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and pharmacologic parameters, while refractory cells demonstrate uncoupling of these determinants in the growth-stimulated state. These in vitro measurements may further serve as a template for prediction of clinical outcome to timed sequential therapy with ara-C, where both pharmacologic and cytokinetic determinants of response are intrinsic to the success of the designed drug scheduling.

Arabinofuranosylcytosine Triphosphate↗
PubMed1987

An in vitro model to predict clinical response in adult acute myelogenous leukemia.

The relationship between in vitro leukemic cell growth kinetics, intracellular biochemical pharmacology of 1-beta-D-arabinofuranosylcytosine (ara-C), and clinical response to ara-C-containing timed sequential therapy was examined in leukemic marrow populations from 62 adults with acute myelogenous leukemia (AML). Leukemic blasts from 45 previously untreated and 17 relapse patients were obtained before therapy, and cultured in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). While all cell populations cultured in HSA demonstrated increased proliferation, only growth-stimulated cohorts from those patients achieving complete remission with ara-C-based therapy demonstrated enhanced intracellular drug activation and active drug retention relative to cells maintained in APS, whereas cells from nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. In this in vitro model system, sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and net pharmacologic parameters, while refractory cohorts evince uncoupling of these determinants in the growth-stimulated state. This model identifies behavior patterns that may discriminate clinical sensitivity from clinical resistance and may serve to predict clinical outcome to timed sequential therapy with ara-C.

Adult↗
PubMed1987

Relationship of the hematopoietic cycle to the combined activities of a stimulator and a short-lived inhibitor.

Substances that circulate in the blood following drug-induced bone marrow aplasia produce a biphasic curve of DNA synthesis in cells in liquid and semisolid cultures which reflect relative concentrations of these growth regulators of hematopoiesis. This net effect magnified by induced marrow failure in human, rat, and mouse is a sinusoidal curve that is the reciprocal of the WBC. Generated in the bone marrow, humoral stimulating activity (HSA) produces peak growth of colonies in agar (CFU-GM) during the proliferative phase of bone marrow recovery, whereas humoral inhibitory activity (HIA), present at the time of marrow maturation, suppresses colony growth. Split femurs from rats given cyclophosphamide (CY) and killed at regular intervals condition media that affect DNA synthesis in a fashion similar to that of HSA-HIA in the rats' sera. In Dexter cultures, HSA is derived from the adherent rather than the hematopoietic cell, whereas HIA is produced by that nonadherent cell. Animals treated with a lethal dose of busulfan (BU) produce large amounts of HSA in vivo until death. Those transplanted with adherent bone marrow cells depleted of hematopoietic cells on day 1 after BU also die, whereas those given nonadherent marrow cells survive and generate HIA at the time of bone marrow recovery. HSA and media conditioned by bone marrow stromal cells causes an increase in spleen colonies (CFU-S), as does HIA. These studies support the contention that the net effect of putative regulators of hematopoiesis, measured in the drug-perturbed state, consist of a constantly present stimulator emanating from bone marrow stroma, and a variable inhibitor produced by maturing hematopoietic bone marrow cells.

Animals↗
PubMed1986

Empiric use of vancomycin during prolonged treatment-induced granulocytopenia. Randomized, double-blind, placebo-controlled clinical trial in patients with acute leukemia.

Because gram-positive infections cause morbidity following intensive antileukemic chemotherapy, the effects of vancomycin versus placebo were evaluated in a randomized, double-blind, placebo-controlled trial in 60 adult patients with acute leukemia and first infectious fever during prolonged (mean of 32 days) granulocytopenia. Gram-positive sepsis was associated with first fever in 17 (28 percent) of the 60 patients. None of 31 patients randomly assigned to receive vancomycin demonstrated gram-positive infection, whereas 16 of 22 patients randomly assigned to receive placebo subsequently had gram-positive infection (seven had sepsis, and nine had local infections; p less than 0.005). All patients with gram-positive infection were then given vancomycin, and all showed prompt clinical responses. The predominant gram-positive organism causing infection was beta-lactam-resistant Staphylococcus epidermis (19 of 44 isolates). Patients randomly assigned to receive vancomycin had more rapid resolution of first infectious fever and fewer total febrile days during the granulocytopenic course than did patients randomly assigned to receive placebo. Although vancomycin had no effect on the presence or absence of documented fungal infection, patients treated with vancomycin received empiric amphotericin B for recurrent or persistent fever later (mean of 14 days after initial antibiotic coverage was begun) than did patients receiving placebo (mean of 9.9 days; p less than 0.005), and thus received fewer total days of empiric amphotericin B therapy (mean of 16.3 days) than did patients given placebo (mean of 24.6 days; p less than 0.01). These data demonstrate that empiric use of vancomycin reduces the morbidity of gram-positive infections following intensive antileukemic therapy and decreases the need for empiric use of toxic amphotericin B.

Adult↗
PubMed1986

Increased incidence of fungemia caused by Candida krusei.

Candida krusei colonized 12.4% of 868 patients undergoing episodes of therapy-induced granulocytopenia over a 9-year period. The gastrointestinal tract was most frequently colonized, followed by the respiratory tract and urinary tract. Ten patients developed systemic infections with C. krusei; all 10 had two or more positive blood cultures. Nine of the 10 patients were colonized with C. krusei, and 6 were receiving systemic antifungal agents at the time of development of the infection. Seven patients died within 1 month of C. krusei sepsis; systemic candidiasis was seen in the autopsies of the four patients on whom autopsies were performed. Therefore, C. krusei should be recognized as an emerging pathogen in select patient populations.

Adult↗
PubMed1986

Association of reduced total iron binding capacity and fungal infections in leukemic granulocytopenic patients.

Serum total iron-binding capacity (TIBC) was measured serially on 70 patients with acute leukemia throughout the period of chemotherapy-induced granulocytopenia. Fungal infections were documented in 13 of these patients (18.6%), while 41 patients (58.6%) had clinically suspected fungal infections and 16 (22.9%) had no evidence of fungal infections during the granulocytopenia. Documented fungal infection occurred in patients with the greatest reduction in TIBC (P less than .015). Early reduction in TIBC also correlated with a greater risk for occurrence of fungal infection, and the earliest institution of amphotericin B (Amp-B) (P less than .004). Effective antifungal therapy was further associated with a return of TIBC levels toward normal. These data demonstrate that altered iron metabolism during granulocytopenia is associated with the development of fungal infections in compromised patients. Serial monitoring of TIBC, along with other clinical and mycologic findings, may prove useful in developing strategies for predicting patients at risk for developing a fungal infection and directing the appropriate use of empiric therapy with Amp-B.

Acute Disease↗
PubMed1986

Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion.

Most studies using high-dose cytarabine (ara-c) for the therapy of acute leukemia have employed intermittent short infusions. In this study, we have evaluated the pharmacology and toxicity of high-dose ara-c by 72-hour continuous infusion. Plasma ara-c concentrations varied from 3.6 microM at the starting dose of 4 g/m2/72 hours to 22.6 microM at 18 g. Plasma clearance appeared to decrease progressively at doses greater than 10 g, suggesting that the route of elimination was saturable. CSF ara-c concentrations ranged from 1.2 microM at 4 g to 4.1 microM at 18 g; the ratio of CSF to plasma ara-c decreased progressively from 0.33 at 4 g to 0.18 at 18 g. The toxic effects were significant and included myelosuppression, nausea, and vomiting in all patients. No single dose-limiting toxicity was identified. Further dose escalation was precluded by combined organ system effects, which included hepatic, pulmonary, renal, and gastrointestinal toxic effects. Attempts to incorporate a 72-hour infusion of ara-c into a combination chemotherapy regimen should proceed cautiously with a starting dose of 6 g/m2/72 hours.

Acute Disease↗
PubMed1986

Drug induced host factors which stimulate growth of residual leukemia in Lewis x Brown Norway F1 (LEW-BN) rats.

Antitumor synergism occurs with two drugs in sequence when the second drug is given at the time of maximal regrowth of residual leukemia and peak humoral stimulatory activity (HSA). To determine if this enhancement relates to a host derived HSA, studies were conducted in Lewis x brown Norway F1 rats bearing brown Norway myelocytic leukemia. A significant cure rate was observed in rats treated initially with 1-beta-D-arabinofuranosylcytosine and then given injections of 10(6) leukemia cells and treated with a second 2-day course of 1-beta-D-arabinofuranosylcytosine in every-8-h s.c. injections in the 6-day period after the initial drug. No effect on survival of the initial drug or of the second drug given at intervals after day 6 was noted. This result is consistent with the efficacy of treatment at the time of peak HSA and tumor growth. The direct effect of HSA on tumor sensitivity to 1-beta-D-arabinofuranosylcytosine was evaluated by 18-h incubations of leukemia and HSA, followed by bioassay. Increased survival and high cure rates were observed when compared with cultured cells in normal serum. These studies support the notion that host derived factors operative during drug induced aplasia stimulate tumor growth and thereby, if the drugs are properly timed, increase sensitivity to cycle active agents.

Animals↗
PubMed1986

Infection management during antileukemia treatment-induced granulocytopenia: the role for oral norfloxacin prophylaxis against infections arising from the gastrointestinal tract.

Aerobic gram negative bacterial infections occur commonly in patients with acute leukemia undergoing intensive chemotherapy-induced bone marrow aplasia, and often arise from the gastrointestinal (GI) tract. The value of oral prophylactic norfloxacin (400 mg every 12 hours) in preventing bacterial infections was determined for 68 adults with acute leukemia by a prospective, randomized, double-blind, placebo-controlled trial. The efficacy of norfloxacin administered prophylactically throughout the course of intensive therapy and deep (less than 100 mm/3), prolonged (median 32 day) granulocytopenia against infections arising from the GI tract was demonstrated by its impact on the clinical manifestations of infection, microbiologically documented gram negative bacterial infections, overall antibiotic management, and GI colonization. Although there was no difference with respect to survival, norfloxacin decreased overall morbidity associated with gram-negative infections, was well tolerated, did not impinge on systemic antibacterial or antitumor therapy, and did not predispose to the development of bacteria resistant either to itself or to multiple other antibiotics. The advantages of norfloxacin relative to other oral agents used for GI prophylaxis and the potential beneficial effects of norfloxacin or overall medical cost are discussed. Oral norfloxacin achieves the goals of GI prophylaxis by effectively suppressing early infection arising from the GI tract and inhibiting GI colonization by multiply resistant pathogens that could give rise to late-onset infections during profound chemotherapy-induced bone marrow aplasia.

Acute Disease↗
PubMed1986

Growth response of residual leukemia after initial drug therapy.

Clinical trials with laboratory correlates were conducted in patients with acute leukemia to determine if relationships exist between drug dose and growth of surviving leukemia cells. The therapeutic design was based on findings in the leukemic rat that relate the initial dose of drug and tumor kill to the magnitude of residual tumor proliferation and sensitivity to a second drug. Patients with acute myelocytic leukemia received cytarabine, either 2 or 6 g/m2/72 h by continuous infusion. The presence and magnitude of change between initial and residual tumor after treatment, as measured by change in labeling indices, depended on the "priming" dose of drug. The amount of perturbation correlated with clinical response to cytarabine given at the time of induced proliferation. With results which parallel the rat data, the direct relationship of initial drug dose and proliferation of residual tumor is demonstrated in humans, and lends support to the design of our clinical trials of timed sequential therapy.

Acute Disease↗
PubMed1985

Transient idiopathic hyperammonaemia in adults.

Transient severe hyperammonaemia developed in the absence of serious liver dysfunction in three patients being treated for acute leukaemia. The onset of the biochemical disturbance was abrupt and led rapidly to acute encephalopathy, fatal in two cases. In the third patient, prompt initiation of aggressive haemodialysis and intravenous sodium benzoate and sodium phenylacetate infusion successfully controlled plasma ammonium levels until they spontaneously resolved. The cause of the disorder remains to be determined, but urinary nitrogen partition studies suggest temporary impairment of ureagenesis in a catabolic setting as a major pathophysiological feature of this disorder. The absence of liver disease, the normal mitochondrial ultrastructure seen in two cases, and the plasma aminoacid profiles observed serve to distinguish this disorder from others such as Reye's syndrome.

Acute Disease↗
PubMed1984

Human histocompatibility antigens and survival in acute myelocytic leukemia.

Several previous reports have suggested an association between human histocompatibility antigens (HLA) and survival in acute myelocytic leukemia (AML). The authors have retrospectively analyzed the records of 104 consecutive newly diagnosed patients with AML treated on the Leukemia Service of the Johns Hopkins Oncology Center from March 1978 through May 1982 who had HLA typing performed to further evaluate this point. The authors have been unable to demonstrate a statistically significant association of HLA phenotype with the ability to achieve a complete response (CR), length of CR, survival of the total group of treated patients, or survival of only those patients achieving a CR (P less than 0.05). The available evidence does not strongly support a significant influence of HLA on survival in AML.

Acute Disease↗