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Biomedical subjects

R A Larson

Publications and source records attributed to R A Larson.

At least 127 records · Page 7Linked to original sources
PubMed1989

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q).

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL-3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

Chromosome Deletion↗
PubMed1989

Chromosomal sensitivity of lymphocytes from individuals with therapy-related acute nonlymphocytic leukemia.

A small fraction of those individuals exposed to cytotoxic chemotherapy or radiation for the treatment of a primary malignant disease will develop a second malignancy some time later. Although exposure to the cytotoxic agents is believed to be the causative factor, the reason only certain individuals develop the second malignancy is unknown. Some studies have suggested that these individuals might be predisposed to cancer because of an inherent sensitivity to the alkylating agents used in cancer therapy. We have reported that these individuals with therapy-related acute nonlymphocytic leukemia (t-ANLL) have reduced endogenous levels of the repair protein O6-alkylguanine alkyltransferase (AGT). To further investigate the etiology of this disease, alkylation-induced sister-chromatid exchange (SCE) formation in individuals who developed second malignancies, was compared to other patient groups and normal controls. Peripheral blood lymphocytes from patients with (1) t-ANLL, (2) primary forms of acute nonlymphocytic leukemia (ANLL de novo), (3) patients with primary malignancies at risk of developing secondary disease, and (4) unexposed, healthy controls were treated in vitro with N-methyl-N'-nitro-nitrosoguanidine or mitomycin C. Baseline and mutagen-induced frequencies of SCEs were determined. These studies failed to detect any increased sensitivity in those patients who developed second malignancies as compared to controls or patients with de novo forms of the same disease. Also, no correlation between sensitivity to the alkylating agent N-methyl-N'-nitro-nitrosoguanidine and endogenous levels of the AGT repair protein was found. These results suggest that t-ANLL patients are not sensitive to SCE induction by either MNNG or MMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1989

Der(5)t(5;7)(q11.2;p11.2): a new recurring abnormality in malignant myeloid disorders.

Complete or partial monosomy for the long arm of chromosomes 5 and/or 7 is frequently observed in malignant cells from patients with a therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute nonlymphocytic leukemia (t-ANLL). Partial monosomy is usually the result of a chromosomal deletion; however, unbalanced translocations have also been observed. We have identified one such translocation in three patients who had either t-ANLL or a primary MDS. The genetic consequences of this translocation [-5,-7,+der(5)t(5;7)(q11.2;p11.2)] are partial monosomy for the long arm of chromosome 5 and complete monosomy for the long arm of chromosome 7. Thus, this rearrangement may represent a new, recurring abnormality that is associated with malignant myeloid disorders.

Aged↗
PubMed1989

Sanguinarine, a phototoxic H2O2-producing alkaloid.

Sanguinarine chloride, a quaternary salt of a benzophenanthrene alkaloid, was phototoxic to catalase-deficient strains of Escherichia coli but not to Trichoplusia ni (cabbage looper moth larvae), an insect with high levels of catalase activity. Chemical analyses confirm that sanguinarine is an efficient producer of H2O2. This differential toxicity suggests that the mode of phototoxic action involves production of H2O2 which could be detoxified in many organisms by catalase.

Alkaloids↗
PubMed1989

The t(2;5)(p23;q35): a recurring chromosomal abnormality in Ki-1-positive anaplastic large cell lymphoma.

In lymphoid neoplasms, nonrandom cytogenetic abnormalities correlate with clinical, morphologic and immunophenotypic features. A subtype of non-Hodgkin's lymphoma, which expresses the Ki-1 antigen (CD30) and has distinct morphologic and clinical features, has recently been described. We now report the association of a reciprocal translocation involving the short arm of chromosome 2 (band p23) and the long arm of chromosome 5 (band q35), t(2;5)(p23;q35), with Ki-1 positive anaplastic large cell lymphoma. Rearrangement of the genes that are located at the breakpoints on chromosomes 2 and 5 may be a critical step in the pathogenesis of this lymphoma.

Adolescent↗
PubMed1989

Clinicopathologic manifestations and breakpoints of the t(3;5) in patients with acute nonlymphocytic leukemia.

Acquired chromosomal rearrangements in acute nonlymphocytic leukemia (ANLL) have been linked to specific clinicopathologic features that suggest new disease subtypes. In this collaborative study, we report five patients with ANLL and a t(3;5) in their leukemic cells. At diagnosis, four of the patients had a t(3;5) as their sole karyotypic anomaly; the remaining patient had additional structural and numerical abnormalities. Careful cytogenetic analysis indicated that the breakpoints of this rearrangement are 3q25.1 and 5q34, in contrast to the various breakpoints reported in earlier studies (3q21----3q25 and 5q31----5q35). The karyotypic, morphologic, and clinical characteristics of this group, as well as those of 14 previously reported patients with the t(3;5), were compared to identify any features that might warrant consideration of a specific syndrome. The available information indicates a worldwide distribution and a nearly equal male:female ratio for patients with this translocation. The median age of the group, 37 years, was younger than that of all patients with ANLL, 49 years. A preceding myelodysplastic syndrome was observed in three patients. The limited numbers of observations on leukocyte count, hemoglobin level, and platelet count precluded meaningful comparison with data for ANLL patients in general. Although each FAB morphologic subtype, except M3, occurred in patients with a t(3;5), the frequency of M6 was much greater than expected. Bone marrows from each of the five patients we report showed increased numbers of megakaryocytes; trilineage dysplasia was observed in the marrow of each of the four patients for whom it could be assessed. Taken together, these findings suggest that the t(3;5) may affect cells capable of differentiation into multiple lineages.

Adolescent↗
PubMed1988

A recurring chromosome rearrangement, dic(16;22), in acute nonlymphocytic leukemia.

A dicentric chromosome, dic(16;22), resulting in the loss of 16q and 22p was seen in bone marrow cells from two patients with acute myelomonocytic leukemia and one patient with a therapy-related myelodysplastic syndrome that evolved to leukemia. Review of the clinical findings and of the bone marrow morphology failed to reveal any distinctive features in common among these patients. The dic(16;22) may be a new, rare, recurring abnormality associated with malignant myeloid disorders.

Aged↗
PubMed1988

Disseminated cutaneous and peritoneal hyalohyphomycosis caused by Fusarium species: three cases and review of the literature.

Three recent cases of hyalohyphomycosis caused by Fusarium sp. illustrate differing aspects of infections produced by these organisms. One patient was undergoing continuous ambulatory peritoneal dialysis when peritonitis developed caused by Fusarium moniliforme. Removal of the catheter and amphotericin B were used in successful management. In a neutropenic patient on therapy for leukemia, multiple persistent infections occurred including JK diptheroids, and Candida albicans sepsis. Finally, numerous florid skin lesions caused by Fusarium oxysporum developed even while the patient was receiving amphotericin B and he died. In a second neutropenic patient on treatment for leukemia, sinus and cutaneous lesions developed due to Fusarium. These resolved on amphotericin B therapy following the return of circulating neutrophils. The literature on Fusarium infections and aspects of the biology of the organism are reviewed.

Acute Disease↗
PubMed1988

Recurrent fungal pneumonias in patients with acute nonlymphocytic leukemia undergoing multiple courses of intensive chemotherapy.

The records of 40 consecutive patients with newly diagnosed acute nonlymphocytic leukemia (ANLL) were reviewed to determine the risk of recurrent fungal pneumonia during multiple episodes of chemotherapy-induced granulocytopenia. Fungal pneumonias were diagnosed as proven or probable using defined pathologic, microbiologic, radiologic, and clinical criteria. Sixteen patients died without a complete remission; of these, all 11 who underwent autopsy were found to have invasive fungal pneumonia. The 24 patients who achieved a complete remission received one to nine (median, four) additional courses of intensive chemotherapy for remission consolidation and/or relapse, and experienced 132 episodes of severe granulocytopenia. Seven patients never had a pulmonary infection despite 34 granulocytopenic episodes. However, fungal pneumonia complicated 32 (33 percent) of 98 granulocytopenic episodes in the other 17 patients. Fifteen of the patients who achieved a complete remission had at least one episode of fungal pneumonia; 12 received further chemotherapy, and nine (75 percent) of these had a subsequent fungal pneumonia. In all, 17 (52 percent) of 33 subsequent granulocytopenic episodes experienced by patients with a prior fungal pneumonia were complicated by another fungal pneumonia. All four patients with a probable fungal pneumonia diagnosed antemortem who subsequently underwent autopsy were found to have invasive fungal disease. It would appear that patients with ANLL who have had one episode of fungal pneumonia are at high risk for recurrence during subsequent episodes of granulocytopenia. Empiric or even prophylactic amphotericin B therapy may be warranted for such patients.

Acute Disease↗
PubMed1988

Role of cloned carotenoid genes expressed in Escherichia coli in protecting against inactivation by near-UV light and specific phototoxic molecules.

Genes controlling carotenoid synthesis were cloned from Erwinia herbicola and expressed in an Escherichia coli strain. Carotenoids protect against high fluences of near-UV (NUV; 320 to 400 nm) but not against far-UV (200-300 nm). Protection of E. coli cells was not observed following treatment with either psoralen or 8-methoxypsoralen plus NUV. However, significant protection of cells producing carotenoids was observed with three photosensitizing molecules activated by NUV (alpha-terthienyl, harmine, and phenylheptatriyne) which are thought to have the membrane as an important lethal target. Protection of carotenoid-producing cells against inactivation was not observed with acridine orange plus visible light but was seen with toluidine blue O plus visible light.

Acridine Orange↗
PubMed1988

Psychosocial symptomatology, personal growth, and development among young adult patients following the diagnosis of leukemia or lymphoma.

Leukemias and lymphomas, especially Hodgkin's disease, are common cancers in young adults. Young adulthood is also a critical period for psychological and social development. The occurrence of cancer can interfere with the development of independence, self-image, and life goals of young adult patients. Young adult patients with leukemia or lymphoma, especially those with less favorable prognoses, experience areas of significant personal growth and maturation during their illness and treatment. Close family and social supports report as much psychosocial stress, and in many cases more stress, than the patients themselves, but similar patterns of personal growth are rarely seen.

Adult↗
PubMed1988

Short remission durations in therapy-related leukemia despite cytogenetic complete responses to high-dose cytarabine.

Seventeen patients with therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute nonlymphocytic leukemia (t-ANLL) were treated with single-agent high-dose cytarabine (HDAC; 1 to 3 g/m2 every 12 hours for 12 doses). The initial neoplasm was still present in eight patients when t-MDS/t-ANLL developed. Fifteen of the 16 patients with chromosomal abnormalities in bone marrow cells had loss or rearrangement of chromosomes 5 and/or 7. One patient had a t(15;17), and one had inadequate material for cytogenetic analysis. Twelve patients had normal metaphase cells (3% to 71%). Indications for HDAC therapy were progressive pancytopenia in 13 patients or rising blast count in four. Five patients died of marrow hypoplasia following therapy. Four others had refractory t-ANLL and died within the subsequent 5 months. Only one of ten patients with a poor performance status (PS greater than or equal to 2 using the ECOG scale) achieved a complete remission, but all seven patients with a good performance status (PS less than or equal to 1) had a complete remission. Hematologic remissions were achieved in 8 patients (47%) after one (6 patients) or two (2 patients) induction courses and were confirmed by recovery of a 100% normal marrow karyotype in six of the seven patients who were retested. Patients in remission received one to four consolidation courses with HDAC alternating with cytarabine/doxorubicin, but seven relapsed within 8 months (median remission duration, 5 months). In every case, the original chromosomal abnormality reappeared at relapse. HDAC has a high response rate for good-performance patients with t-MDS/t-ANLL, but complete remissions are short even when confirmed cytogenetically and consolidated intensively.

Adult↗
PubMed1988

Specific chromosomal abnormalities in acute nonlymphocytic leukemia correlate with drug susceptibility in vivo.

Specific chromosomal abnormalities are independent predictors of response to therapy in acute nonlymphocytic leukemia (ANLL) de novo. In a series of 149 patients with ANLL, we sought to determine whether the t(8;21), t(15;17), t(9;11) or other abnormalities of the long arm of chromosome 11, inv(16) or t(16;16), inv(3) or t(3;3), trisomy 8, and abnormalities of chromosome 5 (-5/5q-) or of chromosome 7 (-7/7q-) identify differences in susceptibility to chemotherapy drugs in vivo. The immediate outcome of the first cycle of remission induction chemotherapy was analyzed for patients in each cytogenetic subgroup as an index of the drug susceptibility of the leukemia cells in vivo. Patients with t(8;21), inv(16), t(16;16), or 11q abnormalities had high rates of complete remission after initial therapy (60-100%), whereas patients with -7/7q- or -5/5q- had low initial response rates (0-36%), suggestive of drug resistance in vivo. In general, cytogenetic groups with high initial complete remission rates ("drug sensitive") also had long disease-free survivals; those groups with low initial remission rates ("drug resistant") had short remission durations even if these patients eventually achieved complete remission with further therapy. Patients with acute promyelocytic leukemia (APL), all of whom had the t(15;17), were the exception; despite low initial remission rates, they had long disease-free survivals, possibly due to a more rapid cytotoxic effect of chemotherapy on the clonogenic APL cells than on the more numerous malignant promyelocytes. We conclude that the prognostic importance of specific chromosomal abnormalities in ANLL resides in part in differing susceptibilities to chemotherapy.

Acute Disease↗
PubMed1987

High-performance liquid chromatographic assay for mitoxantrone in plasma using electrochemical detection.

A sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of mitoxantrone in plasma using electrochemical detection. Bisantrene was chosen as the internal standard. A reversed-phase, 10-microns muBondapak C18 analytical column (30 cm X 3.9 mm) with an isocratic mobile phase of 28% acetonitrile in 80 mM sodium formate buffer (pH 3.0) was used. The eluent was monitored by both electrochemical detection at an applied potential of +0.75 V vs. Ag/AgCl and visible absorbance at 660 nm. Only electrochemical detection was able to quantitate the internal standard and provided ten times higher sensitivity than visible absorbance for mitoxantrone with a detection limit as low as 0.1 ng/ml. Calibration curves in the range 0.1-1000 ng/ml showed good linearity (r = 0.998) and precision (coefficient of variation less than 10%). This HPLC method utilized a reproducible and inexpensive liquid-liquid extraction procedure. Using methylene chloride, the extraction efficacy of mitoxantrone from plasma was 85.3% with a coefficient of variation less than 2.1%. This new assay was then applied to measure mitoxantrone concentrations in plasma obtained from two leukemic patients receiving 12 mg/m2 mitoxantrone as a 1-h infusion.

Chromatography, High Pressure Liquid↗
PubMed1987

Assignment of CSF-1 to 5q33.1: evidence for clustering of genes regulating hematopoiesis and for their involvement in the deletion of the long arm of chromosome 5 in myeloid disorders.

The CSF-1 gene encodes a hematopoietic colony-stimulating factor (CSF) that promotes growth, differentiation, and survival of mononuclear phagocytes. By using somatic cell hybrids and in situ hybridization, we localized this gene to human chromosome 5 at bands q31 to q35, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the CSF-1 gene was found to be deleted in the 5q- chromosome of a patient with refractory anemia who had a del(5)(q15q33.3) and in that of a second patient with acute nonlymphocytic leukemia de novo who had a similar distal breakpoint [del(5)(q13q33.3)]. The gene was present in the deleted chromosome of a third patient, with therapy-related acute nonlymphocytic leukemia, who had a more proximal breakpoint in band q33 [del(5)(q22q33.1)]. Hybridization of the CSF-1 probe to metaphase cells of a fourth patient, with acute nonlymphocytic leukemia de novo, who had a rearrangement of chromosomes 5 and 21 [ins(21;5)(q22;q31.3q33.1)] resulted in labeling of the breakpoint junctions of both rearranged chromosomes; this suggested that CSF-1 is located at 5q33.1. Thus, a small segment of chromosome 5 contains GM-CSF (the gene encoding the granulocyte-macrophage CSF), CSF-1, and FMS, which encodes the CSF-1 receptor, in that order from the centromere; this cluster of genes may be involved in the altered hematopoiesis associated with a deletion of 5q.

Adult↗