Pregnancy in chronic myeloid leukemia patients treated with alpha interferon.
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Adult↗
Biomedical subjects
R Pandita
Publications and source records attributed to R Pandita.
Chromosome aberrations in de novo acute myeloid leukemia patients in Kuwait.
Cytogenetic analysis was successfully performed at the time of diagnosis in 45 patients with de novo acute myeloid leukemia, including 10 children and 35 adults. In approximately 73% of AML patients (35 patients) clonal chromosome abnormalities were detected at the time of diagnosis. Twelve patients (22.8%) had apparently normal karyotypes. Recurring aberrations found in 22 of patients with abnormal karyotypes included t(15;17)(q22;q11), t(8;21)(q22;q22), inv(16)(p13q22), trisomy 8, monosomy 7 and del(5q). The highest frequency of chromosome changes was observed in AML-M3. The occurrence of the classical cytogenetic abnormalities was not a ubiquitous phenomenon. In 11 patients previously not described miscellaneous clonal chromosomal abnormalities were detected. Clonal chromosomal abnormalities detected in AML have shown correlations between specific recurrent chromosomal abnormalities and clinico-biological characteristics of the patients, therefore have been repeatedly shown to constitute markers of diagnostic and prognostic significance. Moreover, ongoing cytogenetic analysis can identify new nonrandom chromosome aberrations in AML and contribute to the identification of novel genes involved in the development of cancer, which can lead to better understanding of the disease pathogenesis.
Acute Disease↗
Sequential standard dose mitoxantrone and cytosine arabinoside for newly diagnosed adult acute myeloblastic leukemia.
Twenty one adult patients with previously untreated acute myeloblastic leukemia (AML) were treated with sequential mitoxantrone and standard dose cytosine arabinoside remission induction therapy. The median age was 33 years (range 17-56 years). Complete remission (CR) was achieved in 80% (17/21 cases) and 76% (16/21 cases) achieved CR after one course of induction therapy. The median duration of disease free survival was 9 months with an actuarial disease free survival of 22% at 43 months. The non-hematological toxicity was acceptable. We conclude that sequential mitoxantrone and cytosine arabinoside combination therapy is an effective antileukemic regimen which produces high CR rates in previously untreated adult patients with AML.
Adolescent↗
Isolation and characterization of a human gene containing a nuclear localization signal from the critical region for velo-cardio-facial syndrome on 22q11.
Velo-cardio-facial syndrome (VCFS) and DiGeorge syndrome are congenital disorders characterized by craniofacial anomalies, conotruncal heart defects, immune deficiencies, and learning disabilities. Both diseases are associated with similar hemizygous 22q11 deletions, indicating that haploinsufficiency of a gene(s) in 22q11 is responsible for their etiology. We describe here a new gene called NLVCF, which maps to the critical region for VCFS on 22q11 between the genes HIRA and UFD1L. NLVCF encodes a putative protein of 206 amino acids. The coding region encompasses four exons that span a genomic interval of 3.4 kb. Coding sequence analysis revealed that NLVCF is a novel gene that contains two consensus sequences for nuclear localization signals. The Nlvcf mouse homolog is 75% identical in amino acid sequence and maps to the orthologous region on mouse chromosome 16. The human NLVCF transcript is 1.3 kb in size and is expressed at varying levels in many fetal and adult tissues. Whole-mount in situ hybridization showed that Nlvcf is expressed in most structures of 9.5-dpc mouse embryos, with especially high expression in the head as well as in the first and second pharyngeal arches. NLVCF and HIRA are divergently transcribed, and their start codons lie approximately 1 kb apart in both humans and mice. Interestingly, the two genes exhibit a similar expression pattern in mouse embryos, suggesting that they may share common regulatory elements. The pattern of expression of NLVCF and its localization in the critical region suggest that NLVCF may contribute to the etiology of VCFS.
Amino Acid Sequence↗
Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients.
Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects. Many VCFS patients have hemizygous deletions for a part of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology. Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement. To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11. We found that 83% had a deletion and >90% of these had a similar approximately 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method. The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. In some cases, we were able to map the chromosome breakpoints within a single cosmid. A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.
Abnormalities, Multiple↗
Bilateral osteonecrosis of the head of the femur complicating acute promyelocytic leukemia: a sequel to treatment of retinoic acid syndrome with dexamethasone.
The complication of 'retinoic acid syndrome' occurs in 25-30% of patients with acute promyelocytic leukemia (APL) treated with all-transretinoic acid (ATRA). Early dexamethasone therapy has reduced mortality from this complication. No long-term sequel of the syndrome or its treatment with dexamethasone has been described. We report a patient with APL treated with ATRA who developed avascular necrosis of both femoral heads following treatment of retinoic acid syndrome with short-duration, high-dose dexamethasone.
Adult↗
Recent trends in the incidence of lymphomas in Kuwait.
All cases of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) reported to the Kuwait Cancer Registry between 1980-1989 were analyzed. Age specific and age standardized incidence rates were calculated for Kuwaiti and non-Kuwaiti males and females for the two periods of 1980-1984 and 1985-1989, and compared to detect short term changes. The study of 153 cases of HD and 325 cases of NHL in 1980-1984 and 213 cases of HD and 338 cases of NHL in 1985-1989 showed that HD incidence was stable in the two periods, the mixed cellularity subtype frequency and incidence declined, while the frequency and the incidence of nodular sclerosis increased significantly in the second period. These changes were most significant in the non-Kuwaiti males. The NHL incidence declined significantly in the 1985-1989 period. The incidence of low grade and intermediate grade NHL declined in the period of 1985-1989. The high grade NHL frequency increased, however, the annual incidence rate increase was not significant. The change in the HD subtypes may probably be related to the improvement in the socio-economic condition. The higher proportion of high grade lymphomas may be related to the population structure in Kuwait and is not related to the acquired immunodeficiency syndrome.
Adolescent↗
Both type I and type II interferons down-regulate human tumor necrosis factor receptors in human hepatocellular carcinoma cell line Hep G2. Role of protein kinase C.
It is well known that interferon-gamma (IFN-gamma; type II) potentiates various responses of human tumor necrosis factor (TNF) in a wide variety of cells and that this potentiation is accompanied by the up-regulation of TNF receptor synthesis. In the present studies we examined the regulation of TNF receptors by type I and type II IFNs in a hepatocellular carcinoma cell line, HEP G2. Exposure of these cells to IFN-gamma led to a decrease in TNF receptor number (4029 vs. 2719 sites/cell) without any change in the receptor affinity (0.96 nM vs. 1.1 nM). The effect was time and dose-dependent. Like IFN-gamma, IFN-alpha and IFN-beta (type I) down-modulated the TNF receptors on these cells. The effect of IFNs on the TNF receptors was inhibited by staurosporin, a protein kinase C (PK-C) inhibitor. Furthermore, by the use of receptor-specific antibodies, we found that the IFN-dependent decrease was primarily due to the p60 form of the TNF receptor. Our results presented are the first to demonstrate that IFNs can also down-modulate TNF receptors in certain cells and that this effect is mediated through PK-C.
Alkaloids↗
Inhibition by all-trans-retinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages.
Besides their growth-inhibiting and differentiation-inducing properties, retinoids have been shown to exert immunomodulatory and anti-inflammatory functions by mechanisms that are not well understood. Tumor necrosis factor-alpha (TNF), a cytokine produced by mononuclear phagocytes, has been shown to be an important mediator of endotoxin-induced septic shock, cachexia, bone resorption, and inflammation. Nitric oxide may also have a role in septic shock, hypotension, and vasodilatation. In this study, we examined the effects of retinoids on the production of TNF and nitric oxide by murine peritoneal macrophages. Of the various retinoids studied, all-trans-retinoic acid (RA) was most potent; it almost completely inhibited the production of TNF by macrophages activated with endotoxin and interferon-gamma. The inhibitory effect was dependent on the dose and duration of RA exposure to macrophages. RA also blocked phorbol ester-induced TNF production in a macrophage cell line (RAW 264.7). Besides TNF, the retinoid suppressed the production of nitric oxide from activated peritoneal macrophages. The importance of these results in relation to controlling various harmful effects of cytokines released by activated macrophages is discussed.
Animals↗
Febrile neutropenia in cancer patients in Kuwait: microbial spectrum and outcome.
A sample of 100 consecutive febrile neutropenic episodes in cancer patients in Kuwait was studied. Acute leukaemias (44%) and lymphomas (29%) were the most frequent underlying cancers; 21 bacteraemis (gram-positive 10, gram-negative 9, polymicrobial 2) were encountered. Staphylococcous epidermidis and Escherichia coli were the commonest organisms. Urinary tract infection occurred in 30% of the microbiologically documented cases. A total of 84 episodes responded to therapy and 9 of the 14 deaths were secondary to infection.
Adolescent↗
The epidemiology of leukemia in Kuwait.
This study reports the occurrence of leukemia subtypes in Kuwait between 1979 and 1989. The cases were analyzed by age, sex, Kuwaiti and non-Kuwaiti nationality status. Of the total 723 cases, acute lymphoblastic leukemia (ALL) was the most frequent (44.2%), exhibited a peak incidence in the 0-4 years age group and was also the most common leukemia of childhood (90.5%). Acute myeloblastic leukemia (AML) constituted 32.4% of leukemia and showed a progressive increase in incidence with age. Chronic myeloid leukemia (CML) constituted 14.8% and chronic lymphocytic leukemia (CLL) 8.6% of all cases. The incidence, age and sex distribution of ALL, AML and CML was similar to that in the developed Western countries while the lesser frequency of CLL was similar to that in the Orient. This pattern of leukemia subtypes may be related to the population structure consisting of the predominantly young in Kuwait, and the peak incidence of ALL in the very young to the socio-economic conditions.
Adolescent↗
Acute tumor lysis syndrome in acute lymphoblastic leukemia and Burkitt's lymphoma: experience in a single centre in Kuwait.
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Adolescent↗
Human immunodeficiency virus (HIV) infection associated with acute myeloblastic leukemia in a low HIV prevalence area.
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Adolescent↗
Trisomy 4 and de novo acute myelomonocytic leukemia in a Kuwaiti patient.
Trisomy 4 is a rare but specific karyotypic abnormality associated with primary and secondary acute myeloblastic leukemia (AML). We report such an occurrence in a Kuwaiti patient with de novo acute myelomonocytic leukemia and its disappearance on achievement of complete remission.
Antineoplastic Combined Chemotherapy Protocols↗
Splenic lymphoma with villous lymphocytes. Report of first 2 cases from the Middle East.
Two cases of splenic lymphoma with villous lymphocytes (SLVL) were diagnosed on the basis of marked splenomegaly, circulating villous lymphocytes, serum IgM monoclonal paraprotein and bone marrow infiltration. Immunological studies confirmed the B cell phenotype (CD19+, CD20+, CD22+ and CD5- and CD25-). Ultrastructural studies revealed characteristic uneven villi with polar predisposition. Interferon-alpha therapy in 1 patient did not result in any clinical or hematological improvement. This is the first report of SLVL from the Middle East.
B-Lymphocytes↗
Effectiveness of moderate dose combination chemotherapy in Burkitt's lymphoma.
Twenty-five evaluable pediatric patients with histologically proven Burkitt's lymphoma were treated with moderate dose combination chemotherapy consisting of cyclophosphamide, vincristine, methotrexate and cytosine arabinoside (COMA regime) without central nervous system prophylaxis. Complete remission was achieved in 94.1% (16/17) of patients with Stage I, I R, II and III A disease, with disease-free survival of more than 3 years. This protocol was attended by minimal chemotherapeutic toxicity. This combination chemotherapy was ineffective in more advanced disease (Stages III B, IV), major cause of failure being progressive disease with central nervous system involvement. This study showed the effectiveness of moderate dose chemotherapy without CNS prophylaxis in early stage Burkitt's lymphoma including Stage III A and needs for aggressive chemotherapy with CNS prophylaxis in more advanced disease.
Adolescent↗
Induction of chromosomal rearrangement by tumor necrosis factors produced by primary B lymphoblastoid cells derived from cancer patients.
We have previously reported the isolation of the cytotoxic factors, tumor necrosis factor-alpha (TNF-alpha), from monocytes and lymphotoxin or TNF-beta, from an established human B lymphoblastoid cell line. In the current study, we examined the production of cytotoxic factors by primary lymphoid cells derived from patients with different malignancies and correlated it with the chromosomal abnormalities in producer cells. Lymphoid cell lines were established from 78 untreated patients with breast carcinoma, 2 with cervical carcinoma, 24 with colon carcinoma, 12 with prostate carcinoma, 3 with melanoma, and the remaining from asymptomatic family members. Lymphoid cells from all 119 patients and their asymptomatic family members constitutively produced as much as 240 units/ml of TNF-beta in vitro. In contrast, TNF-alpha was produced by lymphoid cells from only 6 patients; a related cytokine with similar biological properties to TNF-beta. Sixty-five of these 119 samples were also analyzed for chromosomal abnormalities by standard cytogenetic technique. The production of TNFs was accompanied with varying degrees of chromosomal abnormalities in the cells from all patients. These included both structural and numerical abnormalities. We also examined the direct effect of TNF-beta on the induction of chromosomal abnormalities in growing cultures of both T and B lymphocytes. Our preliminary results indicate that treatment of lymphocytes with this cytokine induced chromosomal rearrangements in a dose-dependent manner. Thus, we provide for the first time both indirect and direct evidence that a soluble mediator such as TNF-beta can induce chromosomal alterations commonly associated with different types of tumors.
B-Lymphocytes↗
Interferon-gamma induces cell surface expression for both types of tumor necrosis factor receptors.
Interferons are known to potentiate various biological effects of tumor necrosis factor (TNF). Recently, two different types of TNF receptors with molecular masses of 60 kDa (p60) and 80 kDa (p80), primarily expressed by epithelial cells and myeloid cells, respectively, have been identified. In the present report, we examined the effect of interferon-gamma (IFN-gamma) on each type of TNF receptor. Our results indicate that IFN-gamma induces TNF receptors on both myeloid (e.g. HL-60) and epithelial cells (e.g. HeLa). Furthermore, by using antibodies specific to each type of receptor, we demonstrate that both TNF receptors are equally inducible by IFN-alpha, IFN-beta and IFN-gamma. Thus, the increase in TNF receptors by interferons may play a role in their synergistic cellular response.
Cell Line↗