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A Rahemtulla

Publications and source records attributed to A Rahemtulla.

At least 19 recordsLinked to original sources
PubMed2006

LACE-conditioned autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma: treatment outcome and risk factor analysis in 67 patients from a single centre.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit.

Adolescent↗
PubMed2006

Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: a single-centre experience in 211 patients.

High-dose therapy with autologous stem cell therapy (ASCT) has become the treatment of choice for eligible patients with myeloma. We analysed retrospectively the prognostic influence of pre-transplant characteristics and transplant modalities on response and survival in 211 myeloma patients who were transplanted in our centre between 1994 and 2004. All patients received peripheral blood stem cell support after conditioning with melphalan alone (183 patients), or melphalan and total blood irradiation (28 patients). We evaluated the influence of age, type of multiple myeloma, status prior and post ASCT, previous treatment regimens, time of ASCT from diagnosis, year of autograft, dose of re-infused CD34(+) cells, plasma cell infiltration and beta2-microglobulin at diagnosis on overall survival (OS) and event-free survival (EFS) to define patients with better prognosis. Median OS and EFS from transplantation were 50.9 and 20.1 months, respectively. Median OS from diagnosis was 68.8 months. Transplant-related mortality was 1.4%. Lower beta2-microglobulin levels, achievement of complete remission (CR) post transplant and lower plasma cell infiltration at diagnosis and transplant correlated with longer EFS and OS, whereas CR at transplant and low international prognostic index at transplant correlated with better EFS. Higher CD34(+) cell dose correlated with improved OS. We conclude that ASCT is safe and effective and the outcome is independent of age, time from diagnosis, previous treatment and conditioning regimen.

Adult↗
PubMed2006

Long-term outcome of high-dose melphalan and autologous stem cell transplantation for AL amyloidosis.

Light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which amyloidogenic monoclonal light chains deposit in various tissues resulting in organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10-14 months. Several phase II studies report haematological and clinical remission in up to 50% of patients after high-dose melphalan and autologous stem cell transplantation. We analysed retrospectively the long-term outcome of 19 patients treated in this way between August/1996 and December/2001. We observed a relatively high treatment-related mortality of 26%, but 12 patients (63%) were high-risk candidates. Eight patients (42%) surviving longer than 100 days achieved haematological remission and long-term survival, whereas 6 (32%) obtained no clear benefit from high-dose therapy. However, 62% of patients survived beyond 2 years and the median survival from transplant was 48 months (range 0-104 months).

Adult↗
PubMed2005

Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: patterns of residual leukaemia and prognostic factors for cytogenetic relapse.

We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of 'residual' disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.

Adolescent↗
PubMed2005

The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio.

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.

Adult↗
PubMed2005

Analysis of outcome following allogeneic haemopoietic stem cell transplantation for myeloma using myeloablative conditioning--evidence for a superior outcome using melphalan combined with total body irradiation.

We have undertaken a retrospective multicentre analysis of 139 patients (median age 44.4 years) undergoing allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma using myeloablative conditioning. The majority of patients received total body irradiation (TBI) combined with either melphalan (56.9%) or cyclophosphamide (28.5%). Overall, transplant-related mortality (TRM) was 37.9% at 1 year and was not significantly different for patients receiving melphalan/TBI compared with cyclophosphamide/TBI. The overall complete remission (CR) rate, including patients in CR at the time of transplant, was greater for patients receiving melphalan/TBI (64.7%) compared with cyclophosphamide/TBI (47.2%)(P = 0.085). A significantly higher proportion of patients with continuing disease at the time of transplant achieved CR post-transplant following melphalan/TBI conditioning compared with cyclophosphamide/TBI (52.9% and 33.4% respectively, P = 0.009). Relapse/progression rates at 5 years were significantly lower for melphalan/TBI (36.7%) compared with cyclophosphamide/TBI (80.8%, P < 0.0001) and remained significant in multivariate analysis. This resulted in an overall survival at 5 years of 44.1% and 28.1% for melphalan/TBI and cyclophosphamide/TBI, respectively (P = 0.059). These results demonstrate that the type of conditioning for sibling allogeneic HSCT for myeloma has a major effect on transplant outcome.

Adult↗
PubMed2004

Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.

Cell Line, Tumor↗
PubMed2004

Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma.

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.

Adult↗
PubMed2003

Autologous stem cell transplantation in multiple myeloma: improved survival in nonsecretory multiple myeloma but lack of influence of age, status at transplant, previous treatment and conditioning regimen. A single-centre experience in 127 patients.

High-dose therapy with autologous stem cell transplantation (ASCT) has become the treatment of choice for symptomatic eligible patients with multiple myeloma (MM). We report our centre experience and analyse retrospectively the prognostic influence of pretransplant characteristics and transplant modalities on response and survival. A total of 127 MM patients (median age: 55.2 years) were transplanted between 1994 and 2001. In all, 69 patients had IgG, 28 IgA, 23 light chain, one IgD and six non secretory MM. At the time of autograft, 6% of patients were in complete remission (CR), 73% in partial remission (PR), 12% showed minor response to previous treatment and 9% had stable or refractory disease. Prior to autograft, 79% of cases had received only one line of chemotherapy and 21% two or more lines. All patients received PBSC support after conditioning with 200 mg/m(2) melphalan alone (100 patients) or melphalan and TBI (27 patients). We evaluated the influence of age (using as cutoff value the ages of 55, 60 and 65 years), type of MM, status pre- and post-ASCT, number of lines of previous regimens, time of ASCT from diagnosis, year of autograft, dose of reinfused CD34+ cells, plasma cell infiltration and beta(2)-microglobulin at diagnosis on overall (OS) and progression-free survivals (PFS) to define patients with better prognosis. Following ASCT, 15% of patients were in CR and 81% in PR, while only two patients progressed. Median OS and PFS from transplantation were 50.4 and 23.5 months, respectively. Median OS from diagnosis was 79.7 months. Transplant-related mortality was 2.3%. Low levels of beta(2)-microglobulin and the achievement of CR post-transplant correlated with longer PFS (P<0.03 and P<0.01, respectively). The median PFS was 36.1, 23.9, 21.1 and 16.4 months for nonsecretory, IgG, IgA and light chain subtypes, respectively. Age was not an important prognostic factor at a cutoff value of 55 or 60 years. We conclude that ASCT is a safe and effective procedure even in resistant cases. The outcome was independent of age, time from diagnosis, previous treatment and conditioning regimen, but there was a tendency for better survival in the nonsecretory patients.

Age Factors↗
PubMed2003

Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors.

Allogeneic haemopoietic stem cell transplantation (SCT) is the only curative option for severe bone marrow (BM) failure in patients with Fanconi anaemia (FA). We have developed a non total body irradiation (TBI) conditioning protocol consisting of fludarabine (120-150 mg/m(2)), low dose of cyclophosphamide (40 mg/kg) and antilymphocyte globulin (45 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin alone for sibling allografts but also included Campath-1 H (days 1-5 post SCT) for the unrelated allografts. We have performed two sibling and two unrelated BM transplants with a follow-up of 11-51 months. All patients experienced minimal toxicity and were discharged from hospital 28-32 days post SCT. Neutrophil and platelet engraftment occurred from days 11 to 19 and 15 to 34, respectively. All patients achieved stable full donor haemopoiesis with normalisation of the peripheral blood count despite one of them having myelodysplasia (MDS) with 8% blasts prior to the SCT. The only site of acute GVHD was in the skin (grade I-II) and only one patient progressed to limited chronic GVHD. This protocol is associated with reduced toxicity and prompt engraftment in FA patients with AA and/or MDS undergoing SCT using sibling or unrelated donors.

Adolescent↗
PubMed2003

Disseminated Aspergillus terreus infection arising from cutaneous inoculation treated with caspofungin.

A case of disseminated Aspergillus terreus infection in a patient with prolonged neutropenia after stem cell transplant for myeloma is reported. The isolate was resistant to amphotericin B in vitro, and the patient was successfully managed with surgical debridement and the recently licensed antifungal agent caspofungin. There are many challenges associated with treating invasive aspergillosis, particularly that due to A. terreus, and the early use of caspofungin should be considered.

Amphotericin B↗
PubMed2001

Critical role for IL-4 in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

Blockade of the CD40-CD154 pathway can inhibit CD4(+) T cell activation but is unable to prevent immune responses mediated by CD8(+) T cells. However, even in the absence of CD8(+) T cells, inhibition of the CD40-CD154 pathway is insufficient to prevent the development of transplant arteriosclerosis. This study investigated the mechanisms of transplant arteriosclerosis in the absence of the CD40 pathway. C57BL/6 CD40(-/-) (H2(b)) recipients were transplanted with MHC-mismatched BALB/c (H2(d)) aortas. Transplant arteriosclerosis was evident in both CD40(-/-) and CD40(+/-) mice (intimal proliferation was 59 +/- 5% for CD40(-/-) mice vs 58 +/- 4% for CD40(+/-) mice) in the presence or absence of CD8(+) T cells (intimal proliferation was 46 +/- 7% for CD40(-/-) anti-CD8-treated mice vs 50 +/- 10% for CD40(+/-) anti-CD8-treated mice), confirming that CD8(+) T cells are not essential effector cells for the development of this disease. In CD40(-/-) recipients depleted of CD8(+) T cells, the number of eosinophils infiltrating the graft was markedly increased (109 +/- 24 eosinophils/grid for CD40(-/-) anti-CD8-treated mice vs 28 +/- 7 for CD40(+/-) anti-CD8-treated mice). The increased presence of eosinophils correlated with augmented intragraft production of IL-4. To test the hypothesis that IL-4 was responsible for the intimal proliferation, CD8 T cell-depleted CD40(-/-) recipients were treated with anti-IL-4 mAb. This resulted in significantly reduced eosinophil infiltration into the graft (12 +/- 5 eosinophils/grid for CD40(-/-) anti-CD8(+), anti-IL-4-treated mice vs 109 +/- 24 for CD40(-/-) anti-CD8-treated mice), intragraft eotaxin, CCR3 mRNA production, and the level of intimal proliferation (18 +/- 5% for CD40(-/-) anti-CD8(+)-, anti-IL-4-treated mice vs 46 +/- 7% for CD40(-/-) anti-CD8-treated mice). In conclusion, elevated intragraft IL-4 production results in an eosinophil infiltrate and is an important mechanism for CD8(+) T cell-independent transplant arteriosclerosis in the absence of CD40-CD154 costimulation.

Animals↗
PubMed2001

Selective silencing of full-length CD80 but not IgV-CD80 leads to impaired clonal deletion of self-reactive T cells and altered regulation of immune responses.

Co-stimulation provided by the B7 family of proteins underpins the development of protective immunity. There are three identified members of this family: CD80, its splice variant IgV-CD80 and CD86. It has hitherto been difficult to analyze the expression and function of IgV-CD80 since there are no appropriate reagents capable of distinguishing it from CD80. We have generated mice, by gene targeting, the lack CD80 whilst maintaining expression of IgV-CD80. Mutant animals did not delete T cells bearing mammary tumor virus-reactive TCR as efficiently as wild-type animals. We also demonstrate the importance of IgV-CD80 in the responses of recently activated cells and reveal a role for CD80 in sustaining T cell responses. CD86, whilst critical to primary T cell activation, made only a minor contribution to re-activation of normal cells.

Animals↗
PubMed2001

Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment.

The mechanism of T cell lineage commitment remains controversial; to examine it we deleted the CD4-silencer element in the germ line of a mouse using a combination of gene targeting and Cre/LoxP-mediated recombination. We found that these mice were unable to extinguish CD4 expression either in immature thymocytes or mature CD8+ cytotoxic T cells (CTLs), which resulted in the development of major histocompatibility complex class II-restricted double-positive CTLs in the periphery. This finding strongly supports a stochastic over an instructive mechanism of coreceptor down-regulation.

Animals↗
PubMed2001

Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.

Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-kappa B (NF-kappa B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-kappa B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-alpha and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-kappa B activation and chemokine production, enhancing liver injury. TNF-alpha and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences.

Animals↗
PubMed2001

Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration.

We investigated the potential of dietary saturated fatty acids to reverse alcoholic liver injury despite continued administration of alcohol. Five groups (six rats/group) of male Wistar rats were studied. Rats in groups 1 and 2 were fed a fish oil-ethanol diet for 8 and 6 weeks, respectively. Rats in groups 3 and 4 were fed fish oil and ethanol for 6 weeks before being switched to isocaloric diets containing ethanol with palm oil (group 3) or medium-chain triglycerides (MCTs, group 4) for 2 weeks. Rats in group 5 were fed fish oil and dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, nuclear factor-kappaB (NF-kappaB) activation, and mRNAs for cyclooxygenase-2 (Cox-2) and tumor necrosis factor-alpha (TNF-alpha). Endotoxin in plasma was determined. The most severe inflammation and fibrosis were detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, activation of NF-kappaB, and mRNAs for Cox-2 and TNF-alpha. After the rats were switched to palm oil or MCT, there was marked histological improvement with decreased levels of endotoxin and lipid peroxidation, absence of NF-kappaB activation, and reduced expression of TNF-alpha and Cox-2. A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis, inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased activation of NF-kappaB and reduced levels of TNF-alpha and Cox-2.

Aniline Hydroxylase↗