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Biomedical subjects

M Hamblin

Publications and source records attributed to M Hamblin.

13 recordsLinked to original sources
PubMed2001

Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients.

Adult T-cell leukaemia lymphoma (ATLL) is an aggressive disease caused by the human T-lymphotropic virus 1 (HTLV-I) with a short survival. Responses to interferon alpha (IFN-alpha) and zidovudine (AZT) have been documented but not with long-term follow-up. We treated 15 ATLL patients with IFN and AZT. Eleven patients had acute ATLL, two had lymphoma and two smouldering ATLL, with progression. The main features were: organomegaly (14), skin lesions (10), high white blood cell (WBC) count (11) and hypercalcaemia (9). Eleven patients had previously received chemotherapy and one had received an autograft. At the time of the study, seven patients had progressive disease and eight were in partial or complete clinical remission. Responses (PR) lasting 2+ to 44+ months were seen in 67%; 26% did not respond (NR) and one patient was not evaluable. Hypercalcaemia predicted a poor outcome but differences were not significant. Eight of the 15 patients have died 3-41 months from diagnosis. Median survival for the 15 patients was 18 months. Survival of the NR ranged from 4 to 20 months; six PR patients are alive 8-82 months from diagnosis. The differences in survival between NR (median: 6 months) and PR (55% of patients alive at 4 years) were statistically significant (P = 0.002). In conclusion, IFN and AZT improves the outcome of ATLL patients and helps maintain responses.

Adult↗
PubMed1999

High dose methyl prednisolone in refractory chronic lymphocytic leukaemia.

We treated 14 patients with advanced, resistant chronic lymphocytic leukaemia (CLL) including three with >10% prolymphocytes (CLL/PL) with high dose methyl prednisolone (HDMP). All patients had stage C CLL or bulky stage B disease. There were 11 males and 3 females with a median age of 58.5 years (range: 49-69). Six out of eleven CLL patients had a partial response as defined by the NCI guidelines, no patient had a complete remission. The mean duration of PR was 19.6 months with a median of 8 months (range 6-78). Seven patients have died including the 5 non-responders. None of the 3 patients with CLL/PL had a measurable response. Previous treatments included chlorambucil, fludarabine, deoxycoformycin, anthracycline containing regimens such as CHOP and Campath-1H. HDMP was given at a dose of 1 g/m2 for five days, at monthly intervals for one to seven courses depending on the response. H2 antagonists and antimicrobial prophylaxis were given concurrently. Acyclovir prophylaxis was given if there was a recent history of herpes infection. HDMP was generally well tolerated. Side effects included fluid retention, hyperglycaemia, bradycardia (1 patient), herpes simplex (1), and pneumonia (1) in a patient with a previous history of recurrent chest infection and pneumonia. These results suggest that HDMP may be beneficial in the treatment of refractory CLL but is of no value in CLL/PL.

Aged↗
PubMed1999

Outcome of biphenotypic acute leukemia.

BACKGROUND AND OBJECTIVE: Although biphenotypic leukemia is now a defined entity, outcome of this rare form of acute leukemia has not been well documented. We present the first comprehensive study analyzing induction and consolidation therapy of biphenotypic leukemia and correlate outcome to prognostic factors. DESIGN AND METHODS: In this retrospective study, the incidence of biphenotypic leukemia was found to be 3.6% from 693 adult and pediatric acute leukemias referred to our center for treatment over the last 8 years. Of these, 15 were B-lymphoid/myeloid, 8 were T-lymphoid/myeloid, one was T/B lymphoid and one had trilineage differentiation. RESULTS: Induction of remission in de novo cases was achieved in 70% of patients and relapse of disease occurred in 15%. The use of combined lymphoid and myeloid drugs for induction resulted in a high incidence of early deaths (25%). The overall probability of survival at 2 years was 39.4%. Patients with secondary disease had a uniformly poor outcome with low remission rates and high relapse rates. INTERPRETATION AND CONCLUSIONS: Prognosis was most strongly related to the presence of the Philadelphia chromosome (p=0.03) and age under 15 years (p=0.01). We conclude that patients with biphenotypic leukemia should have risk stratification with treatment tailored to their prognostic factors.

Acute Disease↗
PubMed1997

Sequential development of myelodysplasia and acute myeloid leukemia but with no karyotypic evolution after autografting in a patient with Philadelphia positive acute lymphoblastic leukemia.

A woman with Philadelphia chromosome-positive c-ALL with +8 and i17q in addition underwent an unpurged blood stem cell autograft after 200mg/m2 melphalan in first relapse. Maintenance therapy with 6-mercatopurine was started following the autograft. Moderate pancytopenia developed after 4 months, and myelodysplasia (refractory anemia) was diagnosed which rapidly evolved into AML. The cytogenetic findings remained unchanged. She also developed CNS disease, but the blasts in the cerebrospinal fluid were lymphoid in character on immunophenotyping. She then received palliative treatment until death. The remarkable features here are the evolution into myelodysplasia and AML with retention of the original complex karyotype, and subsequent coexistence of lymphoid disease in the CNS and myeloid disease systemically. It is possible that the lineage switch and development of myelodysplasia in this case may have been secondary to treatment, but persistence of the original cytogenetic clone makes this unlikely. This may have been the result of some unusual effect of the treatment on the original clone, or expansion of a small unidentified myeloid clone present originally which gained a proliferative advantage due to the ALL-type treatment. This case confirms the aggressive and polymorphic nature of Ph+ ALL which may be the result of origin from an early progenitor cell (stem cell disease).

Acute Disease↗
PubMed1996

Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors.

We have evaluated the effect of in vivo Campath-1G on engraftment and GVHD in 23 patients with severe aplastic anaemia transplanted from HLA-identical sibling donors. In 14 patients Campath 1g was given pre-transplant for up to 9 days in an attempt to overcome graft rejection (group 1). In nine patients Campath-1G was given pre-transplant, but also continued post-transplant until day +5 to reduce GVHD (group 2). There were three patients with late graft failure in group I following initial neutrophil engraftment, and four cases of grade II+ GVHD. In group II, two patients had early graft failure (no take), and there were no cases of acute GVHD out of seven evaluable patients. One patient in group I developed chronic GVHD of the liver, and two patients (one in each group) had transient localised chronic GVHD. PCR of short tandem repeats was used to evaluate chimaeric status in 13 patients. Of 11 patients with initial neutrophil engraftment, only one had 100% donor haemopoiesis at all times. The remaining patients had either transient mixed chimaerism or persistence of recipient (< 20%) cells. We conclude that in vivo Campath-1G is associated with a high incidence of mixed chimaerism which tips the balance away from GVHD but towards graft rejection.

Adolescent↗
PubMed1996

T cell-depleted allogeneic bone marrow transplantation from a partially HLA-mismatched unrelated donor for progressive chronic lymphocytic leukemia and fludarabine-induced bone marrow failure.

A 49-year-old man with a 3-year history of chronic lymphocytic leukemia (CLL, stage B at diagnosis) responded well to four course of fludarabine, but developed marrow failure and prolonged pancytopenia lasting 9 months following the fifth course. Fludarabine therapy could not be continued due to pancytopenia, eventually resulting in disease progression. Bone marrow transplantation from an unrelated donor mismatched at one DRB1 locus and both DQB1 loci was performed as salvage therapy. The marrow was depleted of T cells with Campath-1G. Pre-transplant immunosuppression was enhanced with 600 cGy total lymphoid irradiation and Campath-1G infusions in addition to 120 mg/kg cyclophosphamide and 1200 cGy fractionated total body irradiation. Cyclosporine alone was used as post-transplant immunosuppression. Neutrophils reached 0.5x10(9)/1 on day 14 and platelets 50 x 10(9)/1 on day 40. No acute graft-versus-host disease was seen. Bulk disease detected on CT scanning prior to BMT was found to have disappeared 10 weeks after BMT. The marrow showed residual disease (5% CD5+/CD19+ cells) 9 weeks after transplantation, which had decreased markedly at 13 (0.5%) and 26 (0.4%) weeks. The patient is currently alive and well 10 months after BMT with no clinically detectable disease. We conclude that BMT from an unrelated donor is a feasible treatment option in advanced CLL.

Antineoplastic Agents↗
PubMed1996

Transfusion requirements after bone marrow transplantation from HLA-identical siblings: effects of donor-recipient ABO incompatibility.

Transfusion requirements of 477 patients with hematologic malignancies undergoing BMT from HLA-identical siblings were studied. The median (range) number of red cells transfused in the first, second and third months were 4 (0-32), 1 (0-39), and 0 (0-22) respectively, and the number of random donor platelet concentrates 32.5 (0-196), 0 (0-220) and 0 (0-135). On multivariate analysis, diagnosis other than acute leukemia, conditioning regimen other than cyclophosphamide-TBI, cyclosporine-methotrexate GVHD prophylaxis, and occurrence of acute GVHD increased platelet requirements significantly in the first month. Diagnosis other than acute leukemia, donor-recipient ABO incompatibility, conditioning regimen other than cyclophosphamide-TBI, and age over 18 years increased red cell requirements significantly in the first month. Platelet requirements in the second month and red cell requirements in the second and third months were increased significantly by the occurrence of acute GVHD, a diagnosis other than acute leukemia, and a conditioning regimen other than cyclophosphamide-TBI. Platelet requirements in the third month were influenced only by acute GVHD. We conclude that ABO incompatibility does not influence platelet requirements after allogeneic BMT. It affects red cell requirements in the first month along with the diagnosis, conditioning regimen, and age. However, other factors outweigh the influence of ABO-incompatibility on red cell requirements beyond the first month.

ABO Blood-Group System↗
PubMed1996

Idarubicin, high-dose cytarabine, and etoposide for induction of remission in acute leukemia.

Between 1990 and 1944, 52 newly diagnosed patients with primary (n = 47) or therapy-related (n = 5) acute myeloid leukemia (AML) under the age of 55 years received an induction chemotherapy protocol (designated BF12) consisting of idarubicin ([IDA] 5 mg/m2), high-dose cytarabine ([HD-Ara-C] 2 mg/m2 per 12 hours, 3-hour infusion), and etoposide ([VP-16] 100 mg/m2, 1-hour infusion) on each of 5 consecutive days. Thirty-seven of 51 assessable patients (72.5%), including all five patients with therapy-related AML, attained remission with one cycle. The overall remission rate was 78.4%. Total therapy of AML, with BF12 followed by two courses of consolidation therapy and allogeneic or unpurged autologous bone marrow transplantation (BMT) in first remission, has resulted in actuarial 3-year survival of 49.9% of consecutive unselected patients with newly diagnosed primary AML (minimum follow-up period, 1 year). Twenty-five patients have received BF12 for relapsed acute leukemia, including 13 relapsing after BMT. Five patients died of toxicity and were not assessable for response. Of the remaining 20 patients, five were refractory, two attained partial remissions, and 13 (65%) achieved complete remission (CR). Four of the 13 patients relapsing after BMT died of toxicity, four were refractory, and five of nine assessable patients (56%) attained CR. We conclude that the combination IDA/HD-Ara-C/VP-16 is highly effective in the treatment of newly diagnosed AML and relapsed acute leukemia.

Acute Disease↗
PubMed1990

Co-occlusion and persistence of a baculovirus mutant lacking the polyhedrin gene.

A co-occlusion process was evaluated as a commercially and ecologically acceptable strategy for the development of genetically improved baculovirus insecticides. Coinfection of Spodoptera frugiperda (IPLB-SF-21) tissue culture cells with Autographa californica nuclear polyhedrosis virus (AcMNPV) and an AcMNPV mutant (Ac-E10) lacking the polyhedrin gene resulted in occlusion of both virus types within polyhedra. The amount of occluded Ac-E10 virions in progeny polyhedra populations during serial passage in Trichoplusia ni larvae was evaluated. Maintenance of the mutant in progeny polyhedra required polyhedra inocula containing equal numbers of the two virus types at a high dose. A significant reduction in occluded mutant nucleocapsids occurs with inoculum levels below a 100% lethal dose. At inoculum levels below a 30% lethal dose, the majority of fourth-instar larvae were infected with only one type of virus. The commercial application and ecological advantages of the co-occlusion process are discussed.

Journal Article↗
PubMed1981

Dopamine receptors: subtypes, localization and regulation.

Receptor binding studies with a variety of dopaminergic ligands have confirmed behavioral and biochemical findings that the central nervous system and peripheral nervous system contain several dopamine receptor subtypes. These subtypes can be discriminated on the basis of their agonist-antagonist pharmacological specificities, linkage to adenylate cyclase, cellular location, regulation by guanine neucleotides and ions, and involvement in several human diseases. Although questions remain unanswered, progress is rapidly being made in equating the subgroupings arrived at by these different experimental approaches. Dopamine receptors are regulated by a number of factors. Acutely, guanine nucleotides and some ions regulate agonist but not antagonist binding and are essential for receptor coupling with adenylate cyclase. Chronically, changes in the level of dopaminergic stimulation modulate the number of at least some receptor subtypes, resulting in "up or down regulation." An increase in receptor number appears central to the pathology of Parkinson's disease, tardive dyskinesia, and perhaps schizophrenia. Animal models indicate that it may be possible to exploit inherent capabilities for receptor modulation in clinical therapy. The therapeutic precedents set by the indentification of distinct subtypes of adrenoreceptors. histamine, and cholinergic receptors portends and exciting future for dopamine receptor research.

Adenylyl Cyclases↗
PubMedDate not supplied

Regulation of 5-HT2 and 5-HT1C serotonin receptor levels. Methodology and mechanisms.

Both the 5-hydroxytryptamine2 (5-HT2) and 5-HT1c receptors may be regulated by a large number of endogenous and exogenous factors. The 5-HT2 receptors, for example, may be decreased by acute and chronic treatment with many antipsychotic agents, some antidepressants, and receptor-specific agonists. Similar to the 5-HT2 receptor, the 5-HT1c receptors may be decreased by acute and chronic treatment with the antidepressant mianserin. The 5-HT2 receptors appear to increase during perinatal development and are reported to be elevated in the frontal cortex and hippocampus of victims of suicide; the 5-HT1c receptors display supersensitivity following ablation of serotonergic terminals with 5,7-dihydroxytryptamine. The molecular details responsible for these changes remain unknown, though with the recent cloning of the cDNAs for the 5-HT2 and 5-HT1c receptors the occasion is particularly favorable for mechanistic studies aimed at determining how these alterations occur. Preliminary information suggests that developmentally induced alterations in 5-HT2 and 5-HT1c receptors may be due to transcriptional regulation while changes caused by mianserin treatment might be due to posttranslational processes (e.g., proteolysis, internalization, phosphorylation, covalent alterations). Insights into the molecular means by which 5-HT receptors are regulated could have profound influences on our understanding of pharmacologic, developmental, and psychopathologic processes.

Animals↗