Clonal evolution in B-lineage acute lymphoblastic leukemia by contemporaneous VH-VH gene replacements and VH-DJH gene rearrangements

B-cell acute lymphoblastic leukemia (B-ALL), more frequently than any other B-lineage neoplasm, exhibits oligoclonal Ig heavy chain (IgH) gene rearrangement in 15% to 43% of all cases studied. To study the molecular processes that promote multiple IgH rearrangements, a comprehensive sequence analysis of a B-ALL case was performed in which seven clonal IgH gene rearrangements were identified. The genetic profiles suggested that a single leukemic progenitor clone evolved into several subclones through dual processes of variable (VH) to preexisting diversity-joining (DJH) gene segment rearrangement and VH to VH gene replacement. Predominant IgH-V usage and the uniquely rearranged clonotype-specific VHDJH region gene sequences were identified using a novel DNA-based gene amplification strategy. Polymerase chain reaction (PCR) was directed by an IgH-J generic primer and a complement of family-specific IgH-V primers that defined the major B-cell IgH-V gene usage. Clonality of rearranged VHDJH bands was substantiated by high resolution denaturant gel electrophoretic analysis. Sequence patterns of the amplified VHDJH fragments segregated into two groups defined by common DJH sequences. Partial N region homology at the VHD junction as well as shared DJH sequences firmly established VH to VHDJH gene replacement as a mechanism generating clonal evolution in one group. In the second subset, oligoclonality was propagated by independent VH gene rearrangements to a common DJH precursor. The contributions of all clonal Ig-VHDJH repertoires for each group was approximately 50% and reflected a symmetric distribution of leukemic subclones generated by either process. Thus, oligoclonal rearrangements evolved by two independent, yet seemingly contemporaneous molecular genetic mechanisms. All seven clones displayed nonfunctional Ig-VHDJH recombinations. These observations may have relevance to the recombinatorial opportunities available during normal B-cell maturation.     

Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia

Because a close relationship has been established between mixed cryoglobulinemia and hepatitis C virus (HCV) infection, the clinical, histologic, and virologic findings of 31 patients affected by mixed cryoglobulinemia have been determined. HCV infection was investigated by the presence of anti-HCV antibodies and by polymerase chain reaction (PCR) amplification of the 5' untranslated region (5'UTR), and the genotype of HCV was also determined according to Okamoto et al (J Gen Virol 73:673, 1992). A bone marrow (BM) biopsy was performed in all patients, and liver and kidney biopsies were performed when indicated. The prevalence of anti-HCV antibodies was high (83.9%); polymerase chain reaction amplification of the 5' untranslated region was positive in 26 subjects (83.9%), and Core region amplification in 26 of 27 subjects (96.2%). A high prevalence of genotype II was found (76.6%). Chronic liver disease was present in 15 (48%) patients. BM biopsy specimens showed the presence of low-grade non-Hodgkin's lymphomas in 12 cases (38.7%), whereas, in 11 patients (35.5%), the BM infiltration was not monoclonal (reactive). Mixed cryoglobulinemia is closely associated with HCV infection. Apparently, only 1 patient was not infected by the virus. Several HCV genotypes are involved in the pathogenesis of mixed cryoglobulinemia. The disease is associated with a high prevalence of low-grade non-Hodgkin's lymphomas.     

Ofuji papuloerythroderma evolving to cutaneous T-cell lymphoma

Ofuji papuloerythroderma is an uncommon entity of unknown aetiology, characterized by a pruritic eruption of widespread, red–brown, flat papules that leads to spare skin folds. A number of cases have been described associated with tumour pathology, mainly cutaneous T‐cell lymphomas. We report a new case of Ofuji papuloerythroderma evolving to cutaneous T‐cell lymphoma in an 85‐year‐old woman who had been previously diagnosed with papuloerythroderma 7 years previously.     

Approach to the patient with metabolic acidosis: Newer concepts

Summary: A new classification for patients with metabolic acidosis is provided: a pathophysiological classification. to recognize an overproduction of acids which results in a hydrogen ion (H⁺) gain the number of new anions retained in the body is added to those excreted in the urine when the cation accompanying them was not H⁺ or ammonium (NH₄⁺). the first tools are to recognize new anions that were added during the overproduction of acids. the nature of these anions can be recognized by assessing their fractional excretion. the second set of tools focuses on an assessment of NH₄⁺ in the urine using urine anion and osmolar gaps. the clinical approach suggested focuses on detecting an emergency (severity of H⁺ accumulation, toxic alcohols and/or dyskalaemias). the second step analyzes the expected responses to acidaemia; here the focus is on the P_CO2 in vital organs and the rate of excretion of ammonium. the principles used for diagnosis and treatment of metabolic acidosis are illustrated by a case example.