IGHV gene insertions and deletions in chronic lymphocytic leukemia: "CLL-biased" deletions in a subset of cases with stereotyped receptors.

Nucleotide insertions/duplications or deletions in immunoglobulin heavy chain genes have been found in 24/760 patients (3.15%) with chronic lymphocytic leukemia (CLL). In 21/24 cases, the inserted/duplicated or lost nucleotides occurred in multiples of 3; therefore, the original reading frame was maintained and a potentially intact receptor was coded. The pattern and location of insertions/duplications or deletions in CLL and their restriction to mutated IGHV rearranged genes strongly suggests that they resulted from somatic hypermutation. Their incidence in CLL is consistent with previous reports in normal, auto-reactive and neoplastic human B cells, thus seemingly indicating that these modifications generally arise without any particular disease-specific associations. A striking exception to this rule was identified in CLL IGHV3-21-expressing cases: one amino acid was deleted from the CDR2 region in 16/63 (25.4%) mutated CLL IGHV3-21 sequences (including public database-derived IGHV3-21 CLL cases + the present series) vs. only 2/257 (0.78%) public database-derived mutated non-CLL IGHV3-21 sequences; 15/16 CLL IGHV3-21 sequences carrying this deletion belonged to a subset with unique, shared HCDR3 and light chain CDR3 motifs. This finding further supports the idea of selective antigenic pressures playing a pathogenetic role in some CLL cases.

Myocardial infarction under the age of 36: prevalence of thrombophilic disorders.

It has been suggested that thrombotic tendency increases the risk of myocardial infarction (MI). To investigate the association between the risk of MI at a young age and genetic thrombogenic disorders (G20210A mutation in the prothrombin gene, G1691A mutation in the factor V gene and deficiencies of protein C, protein S and antithrombin III) we conducted a case-control study among 70 survivors of MI who had experienced the event before the age of 36 and 260 healthy subjects. The G20210A mutation in the prothrombin gene was found more often in young patients with MI than among controls (11.4 versus 3.1%). The odds ratio (OR) for MI for carriers versus non-carriers was 4 (95% confidence interval [CI], 1.5 to 11.3). The adjusted OR for major cardiovascular risk factors (smoking, hypecholesterolaemia, diabetes mellitus, hypertension and obesity) was 4.3 (95% CI, 1.3 to 14). The simultaneous presence of both G20210A mutation in the prothrombin gene and smoking further increased the risk of MI compared with nonsmokers and non-carriers (OR, 58; 95% CI, 11.4-294). The G1691A mutation in factor V gene was not associated with an increased relative risk for MI (OR, 0.87; 95% CI, 0.26 to 2.5). Finally, there was no significant difference in the prevalence of deficiencies of protein C, protein S and antithrombin III between cases and controls. In conclusion, our data indicate that the G20210A mutation in the prothrombin gene was the only genetic prothrombotic risk factor associated with the risk of developing MI under the age of 36 years.

Prognostic impact of DNA ploidy pattern, S-phase fraction (SPF), and proliferating cell nuclear antigen (PCNA) in patients with primary gastric lymphoma.

BACKGROUND: DNA ploidy, S-phase fraction (SPF), and proliferating cell nuclear antigen (PCNA) are considered to be significant prognostic factors in non-Hodgkin lymphomas. However, reports on their prognostic importance in gastric lymphoma patients are relatively lacking. METHODS: In the present study, we retrospectively studied the above-mentioned parameters in 29 patients with primary gastric lymphoma; 11/29 had B-low grade mucosa associated lymphoid tissue lymphoma (B-MALT), while 18/29 had diffuse large B-cell lymphoma (DLBCL), according to WHO classification. Proliferative activity was studied by staining against PCNA; in addition, the prognostic significance of DNA ploidy and SPF, as determined by flow cytometry, were investigated and compared to the results of the PCNA stainings. RESULTS: Seven out of 29 patients were found to have aneuploid tumors; DNA index values were >1 for all aneuploid lymphomas. There was no difference in DNA aneuploidy in MALT vs. DLBCL. The mean percentage of SPF was 11.4. SPF was found significantly lower in MALT vs. DLBCL (P < 0.05). The mean percentage of PCNA positive tumor cells was 52.6. PCNA protein expression was significantly lower in MALT vs. DLBCL (P < 0.0001). There was a significant positive correlation between PCNA score and SPF (P < 0.01, by Spearman analysis). DNA ploidy had no impact on survival in the present study. Both SPF and PCNA expression were important prognostic factors in the univariate analysis; however, in the multivariate analysis, the only independent prognostic factor for survival was PCNA expression. CONCLUSIONS: These findings indicate that SPF and PCNA are significant prognostic factors in patients with primary gastric lymphomas. However, in the present study, DNA ploidy had no impact on survival in patients with primary gastric lymphomas.

Prognostic value of C-reactive protein, fibrinogen, interleukin-6, and macrophage colony stimulating factor in severe unstable angina.

BACKGROUND: Inflammatory process plays an important role in the pathogenesis of acute coronary syndromes. HYPOTHESIS: The study was undertaken to evaluate whether admission levels of C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6). and macrophage colony stimulating factor (MCSF) can predict short-term prognosis in patients with unstable angina. METHODS: C-reactive protein, fibrinogen, IL-6, and MCSF were measured on admission in 141 consecutive patients, aged 59 +/- 10 years, with unstable angina (Braunwald class IIIb). Patients were divided into two groups according to their in-hospital outcome: Group 1 comprised 77 patients with a complicated course (2 died, 15 developed nonfatal myocardial infarction, and 60 had recurrence of angina), and Group 2 comprised 64 patients with an uneventful course. RESULTS: Admission median levels of CRP (8.8 vs. 3.1 mg/l, p = 0.0002). fibrinogen (392 vs. 340 mg/dl, p = 0.008), IL-6 (8.8 vs. 4.5 pg/ml, p = 0.03), and MCSF (434 vs. 307 pg/ml, p = 0.0001) were higher in Group I than in Group 2. The MCSF levels were an independent risk factor for in-hospital events, with an adjusted odds ratio for eventful in-hospital outcome of 3.3 (95% confidence interval 1-10.9, p = 0.04), and correlated with levels of IL-6 (r(s) = 0.52, p = 0.0001), CRP (r(s) = 0.43, p = 0.0001), and fibrinogen (r(s) = 0.25, p = 0.004). CONCLUSIONS: These findings suggest that among the studied inflammatory indices only increased admission levels of MCSF are strongly and independently related with adverse short-term prognosis in patients with severe unstable angina.

Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients.

Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count < 10% (RAEB-I), and 27 with RAEB and blast count between 11-20% (RAEB-II). rHuEpo was given subcutaneously at a dose of 150 U/kg thrice weekly, for a minimum of 26 weeks. Response to treatment was evaluated after 12 and 26 weeks of therapy. The overall RR was 45.1%; the RR for RA, RARS, RAEB-I and RAEB-II were 48.3%, 58.4%, 33.8% and 13% respectively. A significant increase in RR was observed at week 26 in RA, RARS and RAEB-I patients, as the response probability increased with treatment duration. The RR was higher in the good cytogenetic prognostic group and serum Epo level of > 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21.7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.