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Biomedical subjects

James N George

Publications and source records attributed to James N George.

At least 19 recordsLinked to original sources
PubMed2007

Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases.

BACKGROUND: Patients with disseminated malignancy who present with microangiopathic hemolytic anemia and thrombocytopenia may be misdiagnosed as thrombotic thrombocytopenic purpura (TTP), resulting in inappropriate plasma exchange treatment, a procedure with major risk, and delay of appropriate chemotherapy. PURPOSE: To assess clinical features that may distinguish occult disseminated malignancy from TTP. PATIENTS AND METHODS: We report the 17-year experience of The Oklahoma TTP-Hemolytic-Uremic Syndrome (HUS) Registry (1989-2005) and a systematic review of previously published case reports. RESULTS: Ten of 351 patients in the Oklahoma Registry who were initially diagnosed with TTP and treated with plasma exchange were subsequently discovered to have disseminated malignancy. Only one patient had a history of cancer. In these 10 patients, neurologic abnormalities, hematocrit, platelet count, and serum creatinine were not different from the 133 concurrent patients with idiopathic TTP. Patients with disseminated malignancy had a longer duration of symptoms, more frequent presence of respiratory symptoms, higher lactate dehydrogenase levels, and more often failed to respond to plasma exchange treatment. Diagnosis of malignancy was made by bone marrow biopsy in six patients but not until autopsy in two patients. A systematic literature review identified 19 additional patients, reported from 1965 to 2005, in whom TTP or HUS was initially suspected and systemic malignancy was subsequently discovered. Fourteen different malignant disorders were diagnosed in these 29 patients. CONCLUSIONS: Occult disseminated malignancy may mimic TTP. A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with TTP have atypical clinical features or fail to respond to plasma exchange.

Adult↗
PubMed2007

Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group.

BACKGROUND AND OBJECTIVES: There are no widely accepted criteria for the definition of hematopoietic stem cell transplant -associated microangiopathy (TAM). An International Working Group was formed to develop a consensus formulation of criteria for diagnosing clinically significant TAM. DESIGN AND METHODS: The participants proposed a list of candidate criteria, selected those considered necessary, and ranked those considered optional to identify a core set of criteria. Three obligatory criteria and four optional criteria that ranked highest formed a core set. In an appropriateness panel process, the participants scored the diagnosis of 16 patient profiles as appropriate or not appropriate for TAM. Using the experts' ratings on the patient profiles as a gold standard, the sensitivity and specificity of 24 candidate definitions of the disorder developed from the core set of criteria were evaluated. A nominal group technique was used to facilitate consensus formation. The definition of TAM with the highest score formed the final PROPOSAL RESULTS: The Working Group proposes that the diagnosis of TAM requires fulfilment of all of the following criteria: (i) >4% schistocytes in blood; (ii) de novo, prolonged or progressive thrombocytopenia (platelet count <50 x 109/L or 50% or greater reduction from previous counts); (iii) sudden and persistent increase in lactate dehydrogenase concentration; (iv) decrease in hemoglobin concentration or increased transfusion requirement; and (v) decrease in serum haptoglobin. The sensitivity and specificity of this definition exceed 80%. INTERPRETATION AND CONCLUSIONS: The Working Group recommends that the presented criteria of TAM be adopted in clinical use, especially in scientific trials.

Bone Marrow Transplantation↗
PubMed2006

An evaluation of cyclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura.

We present the results of two consecutively performed cohort studies that evaluated the clinical effects of corticosteroids or cyclosporin as an adjunct to plasma exchange (PE) for the treatment of an acute episode of thrombotic thrombocytopenic purpura (TTP). In comparing 12 corticosteroid-treated patients with eight cyclosporin-treated patients, none of the cyclosporin-treated patients suffered an exacerbation or recurrence of TTP in the first 30 d after discontinuing PE compared with 6/10 (60%) of the corticosteroid-treated patients (P = 0.042). These data suggest that cyclosporin may have advantages over corticosteroids as an adjunct to PE therapy in the initial treatment of idiopathic TTP.

ADAM Proteins↗
PubMed2006

AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP.

BACKGROUND: Most current treatments for chronic immune thrombocytopenic purpura (ITP) act by decreasing platelet destruction. In a phase 1-2 study, we administered a thrombopoiesis-stimulating protein, AMG 531, to patients with ITP. METHODS: In phase 1, 24 patients who had received at least one treatment for ITP were assigned to escalating-dose cohorts of 4 patients each and given two identical doses of AMG 531 (0.2 to 10 microg per kilogram of body weight). In phase 2, 21 patients were randomly assigned to receive six weekly subcutaneous injections of AMG 531 (1, 3, or 6 microg per kilogram) or placebo. The primary objective was to assess the safety of AMG 531; the secondary objective was to evaluate platelet counts during and after treatment. RESULTS: No major adverse events that could be attributed directly to AMG 531 occurred during the treatment period; 4 of 41 patients had transient post-treatment worsening of thrombocytopenia. In phase 1, a platelet count that was within the targeted range (50,000 to 450,000 per cubic millimeter) and at least twice the baseline count was achieved in 4 of 12 patients given 3, 6, or 10 mug of AMG 531 per kilogram. Overall, a platelet count of at least 50,000 per cubic millimeter was achieved in 7 of 12 patients, including 3 with counts exceeding 450,000 per cubic millimeter. Increases in the platelet count were dose-dependent; mean peak counts were 163,000, 309,000, and 746,000 per cubic millimeter with 3, 6, and 10 microg of AMG 531 per kilogram [corrected], respectively. In phase 2, the targeted platelet range was achieved in 10 of 16 patients treated with 1 or 3 mug of AMG 531 per kilogram per week for 6 weeks. Mean peak counts were 135,000, 241,000, and 81,000 per cubic millimeter in the groups that received the 1-mug dose, the 3-mug dose, and placebo, respectively. CONCLUSIONS: AMG 531 caused no major adverse events and increased platelet counts in patients with ITP. (ClinicalTrials.gov number, NCT00111475 [ClinicalTrials.gov].).

Adrenal Cortex Hormones↗
PubMed2006

Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the Transfusion Medicine/Hemostasis Clinical Trials Network with a systematic review of rituximab therapy for immune-mediated disorders.

The rationale for immunosuppressive therapy of thrombotic thrombocytopenic purpura (TTP) was established by observations that TTP may be caused by autoantibodies to ADAMTS13. Patients with high-titer autoantibodies to ADAMTS13 may have a higher mortality, and survivors may require prolonged plasma exchange therapy in spite of adjunctive glucocorticoid treatment. More intensive immunosuppressive therapy with rituximab may provide benefit for many of these patients. The Transfusion Medicine/Hemostasis Clinical Trials Network is developing a randomized, clinical trial to test the hypothesis that addition of rituximab to standard treatment of TTP with plasma exchange and glucocorticoids will decrease initial treatment failure rates as well as subsequent relapses over the following 3 years. To provide the background data for this clinical trial, a systematic review of all published reports on rituximab treatment of immune-mediated disorders was performed. Twelve articles have reported 27 patients treated with rituximab for TTP, with benefit described in 25 (93%) of the patients. Additional reports have described rituximab treatment of 37 other immune-mediated disorders, with clinical response in most patients. These observations from small uncontrolled case series provide the background and rationale for a randomized clinical trial to establish the role of rituximab in the management of patients with TTP.

Humans↗
PubMed2006

Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 mug/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.

Adult↗
PubMed2005

Recent advances in the treatment of chronic refractory immune thrombocytopenic purpura.

We define chronic refractory immune thrombocytopenic purpura (ITP) as ITP with persistent thrombocytopenia following treatment with glucocorticoids and splenectomy. Chronic refractory ITP is uncommon, occurring in fewer than 10% of all adult patients with ITP diagnoses. The goal of treatment is only to achieve a safe platelet count with minimal treatment-related risk. A safe platelet count may be considered to be as low as 10,000/microL, because the risk for major bleeding in otherwise healthy subjects is great only when the platelet count is less than 10,000/microL. Observation without specific treatment is appropriate for patients with moderate thrombocytopenia and no clinically important bleeding symptoms. For patients with chronic refractory ITP who require treatment, there is no consensus for what therapies to use or the sequence in which to use them. For patients with severe and symptomatic thrombocytopenia, the use of anti-CD20 (rituximab) and immunosuppressive agents, alone or in combination, may be most effective. The mechanism of all current therapies is to decrease the accelerated platelet destruction brought about by immunosuppression. An alternative approach, the stimulation of platelet production with thrombopoietic agents, has been successful in investigational studies and may provide a new management option.

Antibodies, Monoclonal↗
PubMed2005

The role of ADAMTS13 in the pathogenesis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

The identification, characterization, and clinical observation of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains) have provided important insights into the pathogenesis of thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is a plasma enzyme essential for postsecretion proteolytic processing of von Willebrand factor (VWF). Absence of ADAMTS13 is associated with the occurrence of abnormally large multimers of VWF and is also associated with the occurrence of TTP. Initial assumptions that absent ADAMTS13 was itself the etiology of TTP have been tempered by subsequent observations that ADAMTS13 activity can be severely deficient without clinical abnormalities and that patients can have characteristic clinical features of TTP without severe ADAMTS13 deficiency. A current interpretation of these observations is that ADAMTS13 deficiency is a major risk factor for the development of TTP, but it is neither always necessary nor sufficient to cause TTP. This interpretation is consistent with other vascular and thrombotic disorders in which multiple risk factors and associated conditions contribute to the etiology of acute events.

ADAM Proteins↗
PubMed2004

Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications.

Splenectomy has been a standard treatment for adult patients with idiopathic thrombocytopenic purpura (ITP) for more than 50 years. However, the durability of responses, the ability to predict who will respond, and the frequency of surgical complications with splenectomy all remain uncertain. To better interpret current knowledge we systematically identified and reviewed all 135 case series, 1966 to 2004, that described 15 or more consecutive patients who had splenectomy for ITP and that had data for 1 of these 3 outcomes. Complete response was defined as a normal platelet count following splenectomy and for the duration of follow-up with no additional treatment. Forty-seven case series reported complete response in 1731 (66%) of 2623 adult patients with follow-up for 1 to 153 months; complete response rates did not correlate with duration of follow-up (r = -0.103, P = .49). None of 12 preoperative characteristics that have been reported consistently predicted response to splenectomy. Mortality was 1.0% (48 of 4955 patients) with laparotomy and 0.2% (3 of 1301 patients) with laparoscopy. Complication rates were 12.9% (318 of 2465) with laparotomy and 9.6% (88 of 921 patients) with laparoscopic splenectomy. Although the risk of surgery is an important consideration, splenectomy provides a high frequency of durable responses for adult patients with ITP.

Adult↗
PubMed2004

Management of adult patients with persistent idiopathic thrombocytopenic purpura following splenectomy: a systematic review.

BACKGROUND: Treatment of chronic refractory idiopathic thrombocytopenic purpura is a dilemma because many patients have minimal symptoms, response to treatment is uncertain, and treatments may have serious adverse effects. PURPOSE: To determine the effectiveness of treatments for adult patients with idiopathic thrombocytopenic purpura who have not responded to splenectomy. DATA SOURCES: English-language reports from 1966 through 2003 that were retrieved from MEDLINE and Reference Update and bibliographies of retrieved articles. STUDY SELECTION: Articles reporting 5 or more total patients were reviewed to select eligible patients. Patients were eligible for inclusion if they were more than 16 years of age, had idiopathic thrombocytopenic purpura for more than 3 months, had a previous splenectomy, and had a platelet count less than 50 x 10(9) cells/L. DATA EXTRACTION: Patients were assessed for platelet count response, bleeding complications, duration of follow-up, and death. Complete remission was defined as a normal platelet count with no treatment for more than 3 months and for the duration of follow-up. DATA SYNTHESIS: 90 articles with 656 patients treated with 22 therapies met selection criteria. Azathioprine, cyclophosphamide, and rituximab had the most reported complete responses, but they were reported in only 41 to 109 patients. Reported complete response rates ranged from 17% to 27%, but 36% to 42% of patients had no response with these 3 treatments. Most reports described only platelet count responses; bleeding outcomes were reported in only 63 patients (10%). Only 111 (17%) of the 656 eligible patients had pretreatment platelet counts of less than 10 x 10(9) cells/L. No treatment method was reported in more than 20 patients. CONCLUSIONS: Evidence for the effectiveness of any treatment for patients with idiopathic thrombocytopenic purpura and persistent severe thrombocytopenia after splenectomy is minimal. Potentially effective treatments must be evaluated by randomized, controlled trials to determine both benefit and safety.

Adult↗
PubMed2004

Use of erythropoietin in cancer patients: assessment of oncologists' practice patterns in the United States and other countries.

PURPOSE: To assess physician use of erythropoietin in cancer patients before publication of the American Society of Clinical Oncology/American Society of Hematology guidelines. METHODS: Questionnaires about erythropoietin use in practice and 12 hypothetical clinical scenarios involving patients with cancer were mailed to 2000 oncologists/hematologists in the United States and 19 other countries. Response rates were 30% in the United States and 25% internationally. Data on erythropoietin use for ovarian cancer were obtained from one clinical trial. Multivariate regression models assessed predictors of erythropoietin prescription. RESULTS: Most physicians selected a hemoglobin level < or =10 g/dL as an upper threshold for erythropoietin use (36% to 51% of U.S. physicians and 21% to 32% of foreign physicians). Frequent erythropoietin use (defined as use in at least 10% of cancer patients) was higher in the United States than elsewhere (adjusted odds ratio [OR] = 5.8; 95% confidence interval [CI]: 2.5 to 13.4). Among U.S. physicians, those who said they used erythropoietin frequently were more likely to be in fee-for-service than managed care settings (OR = 2.2; 95% CI: 1.3 to 3.7). Those who reported never using erythropoietin practiced in countries that had lower annual per capita health care expenditures, lower proportions of privately funded health care, and a national health service (P <0.05 for all comparisons). Of 235 ovarian cancer patients who received topotecan, 38% (45/118) of U.S. patients and 2% (2/117) of European patients who developed grade 1 anemia (hemoglobin level between 10 and 12 g/dL) were treated with erythropoietin (P <0.01). CONCLUSION: Financial considerations and a hemoglobin level <10 g/dL appear to influence erythropoietin use in the United States, whereas financial considerations alone determine erythropoietin use abroad.

Anemia↗