More on Myb in myelofibrosis: molecular analyses of MYB and EP300 in 55 patients with myeloproliferative disorders.
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Base Sequence↗
Biomedical subjects
Andrew P Grigg
Publications and source records attributed to Andrew P Grigg.
Genetic heterogeneity of granulocytes for the JAK2 V617F mutation in essential thrombocythaemia: implications for mutation detection in peripheral blood.
AIMS: The molecular pathogenesis of essential thrombocythaemia (ET) is heterogeneous. We aimed to determine the relative sensitivity of four separate molecular assays used to detect the presence of the JAK2 V617F mutation in peripheral blood from patients with essential thrombocythaemia and related myeloproliferative disorders. METHODS: Purified granulocytes from 60 patients were analysed for the presence of the JAK2 V617F mutation by direct sequencing, denaturing high-performance liquid chromatography (DHPLC), allele-specific polymerase chain reaction (PCR) and allele-specific enrichment. Clinical data were collected for all patients and correlated with assay results. RESULTS: Direct sequencing and DHPLC were relatively insensitive assays for mutation detection, together identifying only 53% of the JAK2 V617F positive cases of ET. Allele-specific PCR and allele-specific enrichment were significantly more sensitive assays and were able to identify additional ET patients that were positive for the JAK2 V617F mutation in only a minority of circulating granulocytes. Enrichment for the mutation was demonstrated in blood platelets from two of these patients. CONCLUSIONS: The observed biological difference in circulating granulocyte involvement by the JAK2 V617F clone necessitates a sensitive molecular assay for the diagnostic investigation of thrombocytosis.
Adult↗
Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia.
BACKGROUND: We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia. METHODS: A total of 809 patients with essential thrombocythemia who were at high risk for vascular events received low-dose aspirin plus either anagrelide or hydroxyurea. The composite primary end point was the actuarial risk of arterial thrombosis (myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or peripheral arterial thrombosis), venous thrombosis (deep-vein thrombosis, splanchnic-vein thrombosis, or pulmonary embolism), serious hemorrhage, or death from thrombotic or hemorrhagic causes. RESULTS: After a median follow-up of 39 months, patients in the anagrelide group were significantly more likely than those in the hydroxyurea group to have reached the primary end point (odds ratio, 1.57; 95 percent confidence interval, 1.04 to 2.37; P=0.03). As compared with hydroxyurea plus aspirin, anagrelide plus aspirin was associated with increased rates of arterial thrombosis (P=0.004), serious hemorrhage (P=0.008), and transformation to myelofibrosis (P=0.01) but with a decreased rate of venous thromboembolism (P=0.006). Patients receiving anagrelide were more likely to withdraw from their assigned treatment (P<0.001). Equivalent long-term control of the platelet count was achieved in both groups. CONCLUSIONS: Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events.
Adult↗
Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies.
Whether the addition of rituximab to fludarabine and cyclosphosphamide (FC) increases early or late infection risk remains poorly defined. This retrospective analysis of 160 patients treated with FC+/-rituximab found no evidence of increased infection among patients receiving FC+rituximab, providing some evidence of safety for the continued exploration of this regimen.
Adult↗
A comparison of pegfilgrastim and filgrastim.
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Aged↗
A new model for predicting infectious complications during fludarabine-based combination chemotherapy among patients with indolent lymphoid malignancies.
BACKGROUND: Fludarabine-containing combination chemotherapy regimens are increasingly used in the treatment of indolent lymphoid malignancies, with the associated risk of infection being the major toxicity. Predictors of infection during fludarabine-containing combination therapy are poorly defined and optimal strategies for infection prophylaxis are not known. The authors analyzed their experience with patients treated with the fludarabine-mitoxantrone (FM) or fludarabine-cyclophosphamide (FC) regimens to develop a predictive model for infections. METHODS: Ninety-two patients with indolent lymphoid malignancies were treated with FM (n = 29) or FC (n = 63). Baseline variables including age, gender, regimen, disease histology, previous therapy, time from diagnosis to current treatment, performance status, renal function, absolute neutrophil count (ANC), lymphocyte count, and immunoglobulin G levels were examined retrospectively for their association with risk of infectious complications during or within 4 weeks of therapy. RESULTS: Six risk factors were associated with infectious complications: age > 60 years, > or = 3 previous therapies, previous fludarabine exposure, time from diagnosis to current treatment of > 3 years, performance status > or = 2, and baseline ANC < 2.0 x 10(9)/L. Compared with patients with 0-2 risk factors, patients with > or = 3 risk factors had higher infection rates (26% vs. 7% per cycle, P < 0.0001), more Grade 4 neutropenia (41% vs. 8% per cycle, P < 0.0001), and more neutropenic sepsis (15% vs. 1% per cycle, P < 0.0001). CONCLUSIONS: Infection risk during fludarabine-containing combination chemotherapy was predicted with a model comprising six baseline risk factors. Patients predicted to be at high risk of infection were an appropriate group for consideration of prophylactic strategies.
Adult↗
Fatal anerobic bacteremia after hematopoietic stem cell transplant.
We describe 3 cases of fatal but clinically unsuspected anerobic bacteremia amongst hematopoietic stem cell transplant (HSCT) recipients treated empirically for fever and neutropenia with third or fourth generation cephalosporins. All patients had diarrhea but none had classical findings of neutropenic enterocolitis. HSCT recipients with fever, neutropenia and gastrointestinal tract symptoms such as abdominal pain or diarrhea or with septic shock despite broad spectrum antibiotics should receive an antimicrobial agent with anerobic activity.
Adult↗
Graft-versus-host disease, donor chimerism, and organ toxicity in stem cell transplantation after conditioning with fludarabine and melphalan.
Hematopoietic stem cell transplantation may be used to induce a graft-versus-tumor effect against a range of malignancies. Pretransplantation conditioning regimens vary considerably in their degree of myelosuppression and immunosuppression, which may result in marked differences in the rate of T-cell engraftment and, as a consequence, the onset and severity of graft-versus-host disease (GVHD). We have examined the development of T-cell chimerism and the onset of GVHD following fludarabine and melphalan conditioning in 39 patients undergoing stem cell allografts from matched-sibling donors. Cyclosporin and short-course methotrexate were used as GVHD prophylaxis. Fatal regimen-related toxicity occurred in 4 patients. Rapid T-cell engraftment was found in all but 1 of the patients assessed, with more than 90% donor T-cell chimerism at 1 month posttransplantation. Of the evaluable patients, 43% developed grade 2-4 acute GVHD and 87% developed chronic GVHD (70% extensive). Overall, the combination of fludarabine and melphalan is intensely immunosuppressive, leads to rapid T-cell engraftment and results in substantial toxicity and GVHD, particularly in heavily pretreated patients.
Adult↗
Primary adrenal lymphoma.
Primary adrenal lymphoma is a rare extranodal lymphoma with characteristic clinical features including a high incidence of bilateral involvement, predominantly diffuse large B-cell histology, and a low incidence of extra-adrenal disease at diagnosis. Patients are most commonly older men presenting with fever, lumbar pain, and/or symptoms of adrenal insufficiency. Prolonged disease-free survival appears uncommon, which may reflect a publication bias and/or the presence of additional adverse prognostic factors at diagnosis in most patients. Given the rarity of this disease, no prospective chemotherapy studies have been reported. Unresolved therapeutic issues include the optimal chemotherapy regimen (with vs. without monoclonal antibody), the role of bilateral adrenalectomy and/or adjuvant radiation therapy, and the need for central nervous system prophylaxis, given recent reports raising the possibility of a high risk of parenchymal or meningeal relapse. Multicenter collaborative retrospective reviews and prospective trials are needed to address these issues.
Adrenal Gland Neoplasms↗
Cisplatin, fludarabine, and cytarabine: a novel, pharmacologically designed salvage therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin's lymphoma.
BACKGROUND: Based on in vitro synergism, the combination of cytarabine (ara-C) and cisplatin is the basis of many salvage regimens for patients with aggressive non-Hodgkin lymphoma (NHL). However, patients with previously refractory disease are significantly less likely to respond, stimulating the search for novel salvage regimens. In vitro, fludarabine enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C incorporation into DNA and inhibiting repair of platinum/DNA adducts, suggesting that the combination of cisplatin, fludarabine, and ara-C (PFA) may have clinical utility. METHODS: A Phase-II study of a 96 hour continuous infusion of cisplatin with two timed-sequential couplets of fludarabine and ara-C together with granulocyte colony stimulating factor was performed in 45 patients with previously refractory, histologically aggressive or mantle cell NHL. RESULTS: Patients had predominantly diffuse large cell and/or immunoblastic NHL or its variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of patients had previously refractory disease, with a median International Prognostic Index score of 3. A median of 2 cycles per patient were delivered (range, 1-4 cycles) with significant myelosuppression; there were medians of 2 days of neutropenia < 0.5 x 10(9)/L (range, 0-12 days) and 3 days of thrombocytopenia < 20 x 10(9)/L (range, 0-24 days). This was more severe in older patients and was cumulative with successive cycles. Thirty-five percent of cycles were complicated by infections, nausea and emesis were prominent, but other nonhematologic toxicity was mild. Peripheral blood progenitor cells were mobilized adequately after the first cycle, but collections were impaired after more prolonged therapy. The overall response rate was 48% (7% of patients had complete responses, and 41% of patients had partial responses), with one toxic death due to tumor-lysis syndrome. Patients with mantle cell lymphoma were more likely to respond than patients with other histologies (88% vs. 39%, respectively; P = 0.019), although three of eight patients had relapsed rather than refractory disease. The median remission duration was 4 months, with 28% of potentially eligible patients able to proceed to subsequent high dose therapy. The actuarial 2 year survival rates were 20% +/- 6% overall and 50 +/- 18% for patients with mantle cell lymphoma. CONCLUSIONS: Given the adverse outlook for these patients, the results are promising, particularly for patients with mantle cell lymphoma, and suggest that the addition of fludarabine as a potential biochemical modulator may enhance the activity of cisplatin and ara-C. This is associated with significant cumulative (but manageable) myelosuppression. This paradigm, in which a nucleoside analogue is used to inhibit the repair of platinum/DNA adducts, also may be applicable for the treatment of patients with other types of platinum-sensitive tumors.
Adolescent↗
Aplastic anemia as a late complication of thymoma in remission.
Thymoma has many auto-immune associations, including aplastic anemia and myasthenia gravis. The pathophysiologic relationship between thymoma and its auto-immune sequelae are yet to be fully elucidated, but are thought to be as a result of the production of auto-reactive T cell clones by the thymic epithelium. We report a case in which aplastic anemia did not develop until sometime after remission from thymoma had been induced. This observation suggests that auto-reactive T cells may be produced by the thymoma but not induce clinical auto-immune disease until a later time, even after eradication of thymoma has been achieved.
Anemia, Aplastic↗