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Vikram Mathews

Publications and source records attributed to Vikram Mathews.

14 recordsLinked to original sources
PubMed2006

Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice.

Secondary malignancies are a serious adverse consequence of alkylator chemotherapy. The risk of developing an alkylator-associated malignancy is influenced by genetic background, although the relevant genetic factors are poorly understood. To screen for novel susceptibility factors, we established a mouse model of alkylator-induced malignancy. We exposed mice from 20 inbred strains to the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). ENU was a potent carcinogen in many of the strains tested, inducing 140 tumors in 240 ENU-treated mice (66% incidence of at least one tumor in evaluable mice), compared with a background incidence of 8% spontaneous tumors in 240 strain-, age-, and sex-matched control mice (relative risk, 8.4; P < 0.0001). A wide variety of tumor histologies were noted, including epithelial carcinomas, soft tissue sarcomas, and hematopoietic tumors. Cancer susceptibility was a heritable trait for the most common tumor types, lung adenocarcinoma (H(2) = 0.25), T cell lymphoma (H(2) = 0.19), and myeloid malignancies (H(2) = 0.10). Quantitative trait locus mapping identified regions on chromosomes 3, 6, 9, and 15 containing candidate genes associated with lung adenoma, lung carcinoma, and lymphoma susceptibility. This novel mouse model recapitulates many features of human alkylator-associated cancer and supports the hypothesis that susceptibility to this syndrome is influenced by inherited polymorphisms that could be used to make informed clinical treatment decisions.

Alkylating Agents↗
PubMed2006

Infections in children undergoing allogeneic bone marrow transplantation in India.

We studied the clinical profile of infections among 221 pediatric patients who underwent 230 allogeneic transplants between 1986 and June 2004. All patients developed febrile neutropenia. There were 283 documented infections, which included bacterial (36.9%), viral (45.7%), fungal (11.1%) and other infections (6.3%) including tuberculosis. Bacterial and fungal infections were more common in the first 30 days following BMT, while viral infections were more common >30 days after BMT. Bacterial pathogens were predominantly gram-negative organisms (72.7%), when compared with gram-positive organisms (27.3%). Common gram-negative organisms included NFGNB, Pseudomonas, Escherichia coli and Klebsiella while coagulase negative Staphylococci was the main gram-positive organism. Bacteremia (61.2%) was the main source positive cultures and was mainly because of gram-negative organisms (81%), predominantly NFGNB and Pseudomonas. Exactly 103/221(43.7%) transplants had 128 documented viral infections commonly because of Cytomegalovirus, Herpes group of viruses and transfusion related hepatitis. Thirty of 221 (13.5%) of transplants had 30 documented fungal infections with the majority being because of aspergillus (90%). Tuberculosis was seen in 1.7% of transplants while catheter infections were seen in 21 patients (9.1%). Infection related mortality was seen in 12% predominantly because of CMV or fungal infections. A sub group analysis (pre-1998 vs. post-1998) revealed higher incidences of gram-negative infections, bacteremia and bacterial infection related mortality in the pre-1998 era when compared with the recent times. The profile and mortality of infections in this series from India is not significantly different from reports from the West.

Adolescent↗
PubMed2006

Mutations in coagulation factor XIII A gene in eight unrelated Indians. Five novel mutations identified by a novel PCR-CSGE approach.

Factor XIII deficiency is a rare autosomal (1:2,000,000) recessive disorder of blood coagulation usually attributed to mutations in the coagulation factor XIII (FXIII) A gene. We have studied the molecular basis of FXIII deficiency in eight unrelated South Indian patients. Their diagnosis was based on clinical history, normal plasma clotting times and increased solubility of fibrin clot in 5 mol/l urea. Genomic DNA was screened for FXIII A gene defects by a novel PCR and CSGE strategy. Mutations were identified in all these patients. Five of these were novel mutations occurring in four patients. These included a novel c.210T > G transversion in homozygosity in exon 3 predicting a Tyr69X in the beta-sandwich domain in one patient. Another patient was compound heterozygote for a novel c.791C > T transition predicting a Ser263Phe in the core domain and a novel c.2045-1G > A transition at the acceptor splice junction of intron 14. Two novel frame shifts were also identified in two patients in a homozygous condition. One of them resulted from a single base 'G' duplication (c.892_895dupG) at codons Ser290/Ala291fs affecting the core domain and the other was due to a single base 'A' duplication (c.1642_1644dupA) and at codonTyr547fs affecting barrel-1 domain. The remaining four patients had the previously reported Arg260His, Ser413Leu, and Val414Phe (n = 2) missense mutations in the core domain. The novel mutations identified were considered to be disease causative by studying the nature of mutation, the degree of conservation of the mutated aminoacid among transglutaminases of different species and by molecular modeling. Apart from describing a significant number of novel mutations, this report is the first study from Southern India to describe FXIII A gene mutations.

Adolescent↗
PubMed2005

Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity.

Arsenic trioxide, as a single agent, has proven efficacy in inducing molecular remission in patients with acute promyelocytic leukemia (APL). There is limited long-term outcome data with single-agent As2O3 in the management of newly diagnosed cases of APL. Between January 1998 to December 2004, 72 newly diagnosed cases of APL were treated with a regimen of single-agent As2O3 at our center. Complete hematologic remission was achieved in 86.1%. At a median follow-up of 25 months (range: 8-92 months), the 3-year Kaplan-Meier estimate of EFS, DFS, and OS was 74.87% +/- 5.6%, 87.21% +/- 4.93%, and 86.11% +/- 4.08%, respectively. Patients presenting with a white blood cell (WBC) count lower than 5 x 10(9)/L and a platelet count higher than 20 x 10(9)/L at diagnosis (n = 22 [30.6%]) have an excellent prognosis with this regimen (EFS, OS, and DFS of 100%). The toxicity profile, in the majority, was mild and reversible. After remission induction, this regimen was administered on an outpatient basis. Single-agent As2O3, as used in this series, in the management of newly diagnosed cases of APL, is associated with responses comparable with conventional chemotherapy regimens. Additionally, this regimen has minimal toxicity and can be administered on an outpatient basis after remission induction.

Adolescent↗
PubMed2005

Surgery for hemophilia in developing countries.

Surgical interventions in patients with hemophilia (PWH) in the developing world are difficult in the setting of limited availability of factor concentrates. Although the adequacy of international guidelines for factor concentrate prophylaxis for PWH undergoing surgery has been established, frequently it is not practical in the developing world. These recommendations were not established based on large clinical trials and fail to define the safe lower limit of factor concentrate prophylaxis for surgery. The need to define these lower limits is essential in the developing world so that the limited resources may be used optimally for the cohort of PWH. There are limited data from the developing world with regard to PWH undergoing surgical procedures. In this article, we outline experience from our institution, a tertiary referral center for hemophilia care in India. We trace the basis on which our current factor concentrate prophylaxis regimen (which is lower than that recommended internationally) was established. In our experience our low-dose protocols are effective, reduce factor consumption by one third, and are not associated with a significantly increased risk of delayed hemorrhage. We hope that this experience will form a framework on which guidelines can be established for developing countries.

Blood Coagulation Factors↗
PubMed2005

Dapsone for chronic idiopathic thrombocytopenic purpura in children and adults--a report on 90 patients.

Data on 90 patients (55 adults and 35 children) with chronic idiopathic thrombocytopenic purpura (ITP) and a platelet count of <50 x 10(9)/L treated with dapsone at a dose of 1-2 mg/kg/d are presented. A response was observed in 57 (63.3%) patients. The average time for response was 3.5 months (range 1-9) and the average duration of treatment with dapsone was 10.4 months (range 4-14). Overall response rates of 65.7% and 61.8% were observed in children and adults respectively. Side effects requiring discontinuation of therapy were observed in three (2%) patients. These results demonstrate that dapsone is an effective, inexpensive and well-tolerated treatment for chronic ITP, in both children and adults and could be considered for patients who fail steroid therapy.

Adolescent↗
PubMed2004

Effects of pretransplantation treatment with rituximab on outcomes of autologous stem-cell transplantation for non-Hodgkin's lymphoma.

PURPOSE: To analyze the effects of preautografting treatment with rituximab (R) on stem-cell mobilization, post-transplantation complications, engraftment, disease-free survival, and overall survival in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Single-institution retrospective comparative outcome analysis in a cohort of 273 relapsed chemosensitive NHL patients of whom 127 (47%) received R pretransplantation. RESULTS: R was administered a median of 3 months before autologous transplantation. When compared to the nonrituximab group, R patients were older (56 v 50 years; P < .001), and had delays in post-transplantation platelets recovery (39 v 27 days; P = .001). Pretransplantation R did not affect stem-cell mobilization, post-transplantation early complications, duration of hospitalization, or mortality rates at days 30 and 100. In contrast to patients with low-grade NHL, both disease-free and overall survival rates were significantly better when R was included in the pretransplantation salvage therapy for patients with intermediate-grade NHL. CONCLUSION: In this large, single-center retrospective analysis, pretransplantation treatment with R was associated with improved survival in patients with intermediate-grade NHL, at the price, however, of a delay in platelet engraftment.

Adult↗
PubMed2004

Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice.

The t(8;21)(q22;q22) translocation, present in 10-15% of acute myeloid leukemia (AML) cases, generates the AML1/ETO fusion protein. To study the role of AML1/ETO in the pathogenesis of AML, we used the Ly6A locus that encodes the well characterized hematopoietic stem cell marker, Sca1, to target expression of AML1/ETO to the hematopoietic stem cell compartment in mice. Whereas germ-line expression of AML1/ETO from the AML1 promoter results in embryonic lethality, heterozygous Sca1(+/AML1-ETO ires EGFP) (abbreviated Sca(+/AE)) mutant mice are born in Mendelian ratios with no apparent abnormalities in growth or fertility. Hematopoietic cells from Sca(+/AE) mice have markedly extended survival in vitro and increasing myeloid clonogenic progenitor output over time. Sca(+/AE) mice develop a spontaneous myeloproliferative disorder with a latency of 6 months and a penetrance of 82% at 14 months. These results reinforce the notion that the phenotype of murine transgenic models of human leukemia is critically dependent on the cellular compartment targeted by the transgene. This model should provide a useful platform to analyze the effect of AML1/ETO on hematopoiesis and its potential cooperation with other mutations in the pathogenesis of leukemia.

Animals↗
PubMed2004

Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation.

Hepatic venoocclusive disease (HVOD) in bone marrow transplantation (BMT) is attributed to toxicity of cytoreductive agents, especially busulfan and cyclophosphamide, in the conditioning therapy. Busulfan, as well as the metabolites of cyclophosphamide, are conjugated with glutathione (GSH), catalyzed by enzymes of the glutathione S-transferase (GST) family. To assess the impact of polymorphisms of the GST genes, GSTM1 and GSTT1, on the risk of HVOD, we evaluated 114 consecutive patients with beta-thalassemia major undergoing BMT. There was a significantly increased incidence of HVOD in patients with the GSTM1-null genotype compared with those with the GSTM1-positive genotype (46.5% vs 18.3%; P =.001). Pharmacokinetic analysis in these patients showed that the clearance of busulfan was higher and first-dose steady-state concentration was lower among those with HVOD (0.403 +/- 0.06 vs 0.33 +/- 0.071 L/h/kg, Student t test P value =.000 01; and 508 +/- 125 vs 656 +/- 255 ng/mL, t test P value =.001, respectively). We conclude that the GSTM1-null genotype predisposes to HVOD, and the sinusoidal endothelial cells and hepatocyte damage may be mediated by metabolites of busulfan through depletion of the cellular GSH pool.

Adolescent↗
PubMed2004

Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury.

Endothelial progenitor cells (EPCs) are detectable in the blood and bone marrow throughout life. These cells contribute to new blood vessel formation (neovascularization) in physiological states such as wound healing and in pathological states such as tumor angiogenesis. We hypothesized that bone marrow-derived EPCs could play a role in the response to pancreatic islet cell injury. We used a murine model of experimentally induced beta-cell injury followed by transplantation with genetically marked bone marrow cells. Bone marrow-derived cells were detectable throughout the pancreas after transplantation. Whereas the total number of bone marrow-derived cells in the pancreas decreased over time, the frequency of endothelial cells (of both donor and recipient origin) increased after transplantation in the animals in which beta-cell injury had been induced. There was no evidence in this model that bone marrow-derived cells differentiated into insulin-expressing cells. This study provides evidence that bone marrow-derived EPCs are recruited to the pancreas in response to islet injury. EPC-mediated neovascularization of the pancreas could in principle be exploited to facilitate the recovery of non-terminally injured beta-cells or to improve the survival and/or function of islet allografts.

Animals↗
PubMed2004

Stem cell transplantation in acute myelogenous leukemia in first remission: what are the options?

Most newly diagnosed patients with acute myeloid leukemia (AML) in first remission will relapse without additional consolidation therapy. The options for consolidation therapy include repeated cycles of high-dose cytosine arabinoside-based chemotherapy and autologous or allogeneic stem cell transplantation (SCT). Chemotherapy alone is associated with the highest risk of relapse, but it has the lowest treatment-related mortality (TRM). Allogeneic SCT has the lowest risk of relapse with the highest TRM, whereas autologous SCT has an intermediate risk of relapse and TRM. Cytogenetic status of patients with AML is the single most important prognostic factor. However, it is increasingly recognized that this factor alone is inadequate for risk stratification. Based on cytogenetic stratification, a good-risk group of patients in first complete remission (CR1) would benefit most from high-dose consolidation chemotherapy. The risks of a SCT outweigh the benefit in this group. In the unfavorable-risk group, an allogeneic sibling SCT in CR1 would be acceptable, whereas the outcomes with chemotherapy alone or with an autologous SCT are dismal. Based on minimal data, a matched-unrelated donor SCT for this group of patients should be recommended. In the intermediate-risk group, strategies are evolving and the use of additional prognosticators will help in decision making. Autologous or allogeneic sibling SCT is a reasonable option in a subset of patients within this group at a high risk of relapse. There are insufficient data to recommend a haploidentical or cord blood transplant for patients with AML in CR1.

Hematopoietic Stem Cell Transplantation↗
PubMed2003

Enhanced green fluorescent protein targeted to the Sca-1 (Ly-6A) locus in transgenic mice results in efficient marking of hematopoietic stem cells in vivo.

OBJECTIVE: Hematopoietic stem cells are important clinically, both as targets of disease and as reagents for cellular therapy. Studies in hematopoietic stem cell biology have been hampered by difficulties in purifying and manipulating these cells. To facilitate these studies, we sought to develop a system for targeting genes of interest to the hematopoietic stem cell compartment in transgenic mice. MATERIALS AND METHODS: We used Sca-1, a glycosyl phosphatidylinositol-anchored protein expressed on the surface of all hematopoietic stem cells in commonly used inbred mouse strains. We created a mutant Sca-1 allele in which the enhanced green fluorescent protein (EGFP) cDNA is integrated into the Sca-1 locus by homologous recombination in embryonic stem cells. RESULTS: EGFP protein is detectable in all hematopoietic tissues of mice heterozygous for the mutant Sca-1 allele. Growth and development of these mice are normal. No adverse effects of long-term, high-level EGFP expression were noted. Sca-1 positive cells coexpress EGFP in all tissues and lineages examined, as predicted by the targeting strategy. Sca-1 and EGFP expression are coordinately up-regulated in splenocytes from mutant mice. The Lin(-)EGFP(+) bone marrow population contains all progenitor activity in Sca-1(+)(/EGFP) mice. The Lin(-)EGFP(+) bone marrow cells are equivalent to Lin(-)Sca-1(+) cells in long-term repopulation and serial transplantation assays. CONCLUSION: The hematopoietic stem cell compartment appears to be targeted in Sca-1(+)(/EGFP) mutant mice. This system should be useful for studying the normal biology of hematopoietic stem cells and for targeting other genes to this cellular compartment.

Animals↗
PubMed2002

Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience.

Arsenic trioxide (As(2)O(3)) has been found effective in the treatment in the treatment of acute promyelocytic leukemia (APML). Most studies with As(2)O(3) involve patients with APML who have relapsed following standard therapy. Between January 1998 and July 2000, 14 patients were recruited for an ongoing trial of As(2)O(3) in the treatment of newly diagnosed APML. Arsenic trioxide was administered at a dose of 10 mg/day until complete remission (CR) was achieved. Afterward, a consolidation course and a maintenance schedule consisting of As(2)O(3) as a single agent were administered over 6 months. There were 3 early deaths related to intra-cerebral hemorrhage: two on day 3 and one on day 4. Of the 11 evaluable patients, one died on day 21 secondary to uncontrolled sepsis, while the remaining 10 (91%) have attained CR. The average time to CR was 52.3 days (range: 34-70 days). One patient developed an isolated central nervous system (CNS) relapse and subsequently went into a second CR following therapy with triple intrathecal chemotherapy, cranial irradiation, and an additional 4-week course of systemic As(2)O(3). This patient, as well as the remaining nine, has continued to remain in CR at a median follow up of 15 months (range: 2-33 months). Eight out of 10 patients achieved molecular remission at variable periods during their consolidation and maintenance schedules. One patient developed an ATRA syndrome and was administered daunorubicin (40 mg/day) for 2 days. The side effects with this therapy were minimal and did not require cessation of therapy in any patient. There was no significant hepatic toxicity. In our experience, arsenic trioxide is effective in inducing and maintaining remission in patients with APML with minimal side effects. The optimal regimen and total dose required need to be defined.

Adolescent↗