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David P Steensma

Publications and source records attributed to David P Steensma.

At least 19 recordsLinked to original sources
PubMed2007

A history of the kidney in plasma cell disorders.

BACKGROUND: The kidneys are commonly injured in plasma cell dyscrasias. METHODS: We reviewed the pertinent medical literature related to the historical development of clinical nephrology and diagnostic renal pathology; early case reports of patients with plasma cell disorders; and historical descriptions of multiple myeloma, amyloidosis, and the renal disorders that are associated with these conditions. RESULTS: Medieval uroscopists recognized proteinuria, and in 1827 Richard Bright first linked proteinuria to both dropsy (edema) and the autopsy finding of chronically diseased, scarred kidneys. In the 1840s, Henry Bence Jones and William Macintyre described a peculiar form of proteinuria in a middle-aged English grocer with fragile, tumor-riddled bones; this proteinuria became known as 'Bence Jones type'. It was initially believed that Bence Jones proteins were harmless to the kidney, but after 1899 (when myeloma cast nephropathy was recognized), investigators observed numerous renal injury patterns associated with plasma cell dyscrasias. Gross observations of 'waxy degeneration' or 'lardaceous change' in organs including the kidney yielded to the misnomer 'amyloid' in 1854, when iodine staining suggested to Rudolf Virchow that the strange material present in these conditions was a form of starch or cellulose. During the 20th century, biochemists and physicians carefully studied patients with myeloma, in order to better define the nature and structure of normal and pathological immunoglobulins. CONCLUSION: Historical understanding of the kidney in plasma cell disorders reflects developments in understanding of the anatomy and physiology of the kidneys in health and in disease.

Amyloidosis↗
PubMed2006

Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria.

Congenital erythropoietic porphyria (CEP), an autosomal recessive disorder, is due to mutations of uroporphyrinogen III synthase (UROS). Deficiency of UROS results in excess uroporphyrin I, which causes photosensitization. We evaluated a 3-year-old boy with CEP. A hypochromic, microcytic anemia was present from birth, and platelet counts averaged 70 x 10(9)/L (70,000/microL). Erythrocyte UROS activity was 21% of controls. Red cell morphology and globin chain labeling studies were compatible with beta-thalassemia. Hb electrophoresis revealed 36.3% A, 2.4% A(2), 59.5% F, and 1.8% of an unidentified peak. No UROS or alpha- and beta-globin mutations were found in the child or the parents. The molecular basis of the phenotype proved to be a mutation of GATA1, an X-linked transcription factor common to globin genes and heme biosynthetic enzymes in erythrocytes. A mutation at codon 216 in the child and on one allele of his mother changed arginine to tryptophan (R216W). This is the first report of a human porphyria due to a mutation in a trans-acting factor and the first association of CEP with thalassemia and thrombocytopenia. The Hb F level of 59.5% suggests a role for GATA-1 in globin switching. A bone marrow allograft corrected both the porphyria and the thalassemia.

Amino Acid Sequence↗
PubMed2006

Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed sideroblasts).

BACKGROUND: For most cases of idiopathic acquired sideroblastic anemia (IASA), the molecular pathogenesis is unknown, despite the consistent morphological signature of abundant pathological ringed sideroblasts with their characteristic iron-engorged mitochondria. Moderately elevated free erythrocyte protoporphyrin (FEP) levels have been described in IASA, suggesting that the activity of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis (incorporation of ferrous iron into protoporphyrin), might be diminished in erythroid progenitor cells from IASA patients. METHODS: We confirmed FEP elevation in IASA, then pursued a candidate gene approach that included screening the gene encoding ferrochelatase, FECH, for promoter and coding region mutations and mRNA expression changes in bone marrow from 37 patients with IASA. RESULTS: The analytical techniques employed detected mutations in a test cohort of previously undiagnosed patients with biochemical evidence for erythropoietic protoporphyria, a condition resulting from germline mutations in FECH, but somatic missense mutations of FECH and its promoter were not observed in IASA patients. FECH was modestly overexpressed in progenitor cells from patients with IASA, compared with MDS patients without sideroblasts and healthy controls. In addition, we analyzed ABCB7 and PUS1, genes implicated in congenital sideroblastic anemia syndromes, but again found no coding mutations in acquired cases. CONCLUSION: We conclude that acquired mutations in the factors currently known to cause inherited sideroblastic anemias are uncommon in IASA.

ATP-Binding Cassette Transporters↗
PubMed2006

MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.

Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

Adult↗
PubMed2006

Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer.

PURPOSE: To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. PATIENTS AND METHODS: Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. RESULTS: Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. CONCLUSION: After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.

Adult↗
PubMed2006

A novel mutation in the last exon of ATRX in a patient with alpha-thalassemia myelodysplastic syndrome.

We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene (CGA-->TGA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.

Aged↗
PubMed2006

Are myelodysplastic syndromes "cancer"? Unexpected adverse consequences of linguistic ambiguity.

Myelodysplastic syndromes (MDS) are clonal, neoplastic disorders of hematopoietic tissue that convey a guarded prognosis, but physicians vary in whether they refer to MDS as a "cancer" when discussing the diagnosis with patients. Because of past ambiguity about whether MDS is truly a malignancy, confusion about MDS terminology is widespread. Additionally, patients who carry one of the dubious cancer-specific health insurance policies are usually not eligible for financial benefits when they receive a diagnosis of MDS. Likewise, patients with MDS who have been led to believe they do not have a form of cancer by their primary physician may become upset when seeing another health care provider who does refer to MDS in this way. Here, I discuss evidence supporting broader consideration of MDS as a form of malignant neoplasia - i.e., cancer - as well as some of the relevant practical issues.

Disease Progression↗
PubMed2006

JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?

Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.

Animals↗
PubMed2006

C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders.

C-terminal somatic mutations in nucleophosmin (NPM), a nucleolar shuttling protein that binds p53 and p19(Arf), were recently described in karyotypically normal acute myeloid leukaemia (AML). We analysed primary marrow samples from 150 patients with various chronic myeloid disorders for mutations in the NPM1 gene encoding NPM. NPM1 mutations (tetranucleotide duplication) were detected in three patients, all of whom had chronic myelomonocytic leukaemia (CMML) and a short (<1 year) survival, with rapid progression to overt AML. All other patients were NPM1-wild type in the region analysed. In conclusion, C-terminal NPM mutations are uncommon in chronic myeloid neoplasia, but if present may represent an evolving leukaemic clone.

Base Sequence↗
PubMed2006

Pure red cell aplasia associated with thymoma: clinical insights from a 50-year single-institution experience.

Acquired pure red cell aplasia (PRCA) is a rare disorder of erythropoiesis that can develop in association with a thymoma. Optimal management of this subgroup is unclear, and there have been few series reporting long-term clinical outcomes. Here, we report features of 13 patients treated for PRCA associated with thymoma over 50 years at our institution. Surgical resection of the thymoma was insufficient for normalisation of erythropoiesis in all cases. T-cell gene rearrangement studies did not routinely demonstrate a clonal process, and ciclosporin and anti-thymocyte globulin were effective adjuvant treatments. However, treatment-related morbidity was high, with frequent infectious complications.

Adjuvants, Immunologic↗
PubMed2006

Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis.

PURPOSE: It is widely accepted that an increased serum endogenous erythropoietin (Epo) level in a patient presenting with an elevated red cell mass makes a diagnosis of clonal polycythemia vera (PV) extremely unlikely. However, until the recent description of the constitutively activating V617F point mutation of the Janus 2 tyrosine kinase (JAK2)--a high-frequency molecular marker that is extremely specific for clonal chronic myeloproliferative disorders--distinction of PV from secondary erythrocytosis or other conditions has often been difficult. The purpose of this study was to use JAK2 V617F analysis to re-evaluate the validity of elevated Epo levels as a PV-exclusion criterion in patients with hepatic vein thrombosis [Budd-Chiari syndrome (BCS)]. PATIENTS AND METHODS: We reviewed clinical data from 30 patients at our institution who presented with erythrocytosis and BCS. We isolated myeloid cells from fresh or archival bone marrow samples from four patients with BCS and an elevated serum Epo level, and analyzed them for the presence of the JAK2 V617F mutation. RESULTS: All four samples were positive for JAK2 V617F, confirming the presence of a clonal hematopoietic disorder consistent with PV. CONCLUSION: In the presence of BCS, elevated serum Epo levels do not exclude the diagnosis of PV.

Adult↗
PubMed2006

JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology.

In early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests.

Base Sequence↗
PubMed2006

The myelodysplastic syndromes: diagnosis and treatment.

The myelodysplastic syndromes (MDSs) are common, acquired, clinically challenging hematologic conditions that are characterized by bone marrow failure and a risk of progression to acute leukemia. These disorders can arise de novo, especially in elderly patients or, less often, as a consequence of prior chemotherapy or radiotherapy for an unrelated disease. The MDS classification systems were revised recently and updated. These refined classification and prognostic schemes help stratify patients by their risk of leukemia progression and death; this knowledge can help clinicians select appropriate therapy. Although many treatments for MDS have been proposed and evaluated, at present, only hematopoietic stem cell transplantation offers any real hope for cure, and no available therapy beyond general supportive care offers benefit to more than a minority of patients. However, recent clinical trials enrolling patients with MDS have reported encouraging results with use of newer drugs, including lenalidomide, decitabine, and darbepoetin alfa. Other exciting treatment regimens are being tested. Here, we present a contemporary, practical clinical approach to the diagnosis and risk-stratified treatment of MDS. We review when to suspect MDS, detail how to evaluate patients who may have a form of the condition, explain key features of treatments that are currently available in the United States, and summarize a general, common-sense therapeutic approach to patients with MDS.

Biopsy↗