Exposure to myelotoxic agents and myelodysplasia: case–control study and correlation with clinicobiological findings

To better define the role of exposure to myelotoxic agents in the genesis of myelodysplastic syndrome (MDS), we carried out (a) a case–control study for the determination of the relative risk (RR) of developing MDS, including 178 consecutive patients and 178 sex- and age-matched controls; (b) a study of clinicobiological features in MDS arising after occupational exposure to myelotoxic agents and in MDS in ‘non-exposed’ patients. The definition of the ‘exposure’ status was based on a predetermined questionnaire, with calculation of an ‘exposure’ index (hours/day × days/year × years). Cumulative exposure to pesticides or to organic solvents, for >2400 h, was recorded in 48 and 25 MDS patients, respectively, compared to 27 and four controls (P < 0.00001; RR 3.74; 95% confidence interval 2.02–5.37). Older age and an excess of refractory anaemia with ringed sideroblasts and refractory anaemia with excess of blasts was noted among ‘exposed’ MDS-patients (group 1), compared to non-exposed MDS-patients (group 2). 68.3% patients in group 1 had clonal chromosome changes, compared with 43.2% patients in group 2. Complex karyotypes, ?7/7q?, ?5/5q?, +8, 7p and 17p aberrations were seen more frequently in group 1, whereas a normal karyotype, isolated 5q? or 20q? occurred more frequently in group 2. The association of exposure to myelotoxic agents with older age at presentation and with unfavourable chromosome changes accounted for the shorter survival observed in ‘exposed’ patients. These data show that occupational exposure to pesticides and organic solvents in our region resulted in an increased RR of developing MDS and that a distinct cytogenetic profile was associated with MDS in ‘exposed’ patients. These findings provide strong indirect evidence that these agents may play a role in the pathogenesis of MDS, preferentially targeting some of the chromosome regions which are frequently involved in therapy-related myeloid neoplasias.     

Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis

Immunophenotypic studies, fluorescence in situ hybridization (FISH) and conventional karyotyping were used to define the clinicobiological significance of 14q32 translocations involving the immunoglobulin gene locus (14q32/ IGH ) in 252 chronic lymphocytic leukaemia (CLL) patients. The following regions were studied: 13q14, centromere 12, 6q21; 11q22/ ATM ; 17p13/ TP53 , 14q32/ IGH . Patients were classified as group 1 (favourable, i.e. 13q-single or normal), group 2 (intermediate risk, i.e. +12, 6q-, 1–2 anomalies), group 3 (unfavourable, i.e. 17p-, 11q-, complex karyotype), or group 4 (14q32/ IGH translocation). Endpoints were treatment-free survival (TFS) and overall survival (OS). One hundred and ten patients were included in group 1, 99 in group 2, 25 in group 3 and 18 in group 4. 14q32/ IGH translocation partners were identified in eight cases ( BCL2 in five cases, BCL11A , CCND3 and CDK6 in one case each). group 4 showed shorter TFS versus groups 2 and 1 (25% patients treated at 2 months vs. 12 ( P  = 0·02) and 20 months ( P  = 0·002), respectively) and shorter OS (25% patients dead at 18 months versus 50 ( P  = 0·0003) and >60 months ( P  < 0·0001) respectively. The 14q32/ IGH translocation maintained prognostic significance at multivariate analysis on TFS ( P  = 0·025) and OS ( P  < 0·001), along with advanced stage and CD38⁺. These findings show that the 14q32/ IGH translocation predicts for an unfavourable outcome in CLL and that this cytogenetic subset might be included as a separate entity in a hierarchical cytogenetic classification of CLL.     

Stress echocardiography versus myocardial SPECT for risk stratification of patients with coronary artery disease

PURPOSE OF REVIEW: Diagnostic testing using noninvasive imaging has become an integral part of risk stratification in patients with coronary artery disease. It is important to understand the integral strengths and weaknesses between the different modalities of stress testing and to apply accurately the type of test the clinical scenario demands. RECENT FINDINGS: There have been tremendous advances made in the field of cardiac imaging. Both myocardial perfusion imaging and stress echocardiographic techniques continue to evolve and play an important role in the assessment of patients with coronary artery disease. SUMMARY: In this review the authors discuss the relative merits of both stress echocardiography and myocardial single photon emission computed tomographic imaging for diagnosis and risk stratification of patients with coronary artery disease.     

Relation between contractile reserve and improvement in left ventricular function with beta-blocker therapy in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Beta blockers improve left ventricular (LV) ejection fraction but patient responses are heterogenous. We investigated the role of contractile reserve (CR) in predicting beta-blocker response in ischemic and nonischemic cardiomyopathy. Resting and low-dose dobutamine echocardiograms were recorded in 32 patients with heart failure (LV ejection fraction 相似文献   

Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: Clinical and biologic correlations

To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis. © 2015 Wiley Periodicals, Inc.     

Secondary chromosome changes in mantle cell lymphoma: cytogenetic and fluorescence in situ hybridization studies.

To better define the incidence and nature of secondary chromosome anomalies in mantle cell lymphoma (MCL) carrying the t(11:14)/BCL1 rearrangement, cytogenetic and fluorescence in situ hybridization studies (FISH) were performed in 42 patients (39 classical histology, 3 blastoid variant), using 6q21, 9p21/p16, 13q14, 17p13/p53 and chromosome-12-specific probes. Karyotypes from 89 cases published in 5 recent series including patients diagnosed in a homogeneous fashion were reviewed. In our series, FISH confirmed the interpretation of the karyotype in all cases and disclosed cryptic chromosome deletions in a sizeable fraction of cases. One patient (2.4% of total) was found with a cryptic 9p21 deletion by FISH. Two cases (4.8%) had a 6q21 deletion at CCA and at FISH; +12 was found in three cases by CCA plus nine by FISH (28.6%); 13q14 deletion was found in six cases by CCA plus 16 by FISH (52.4%), 17p13 deletion in three cases by CCA plus 8 by FISH (26.2%). In 131 patients (42 present series plus 89 in the literature) secondary chromosome aberrations seen by conventional cytogenetic analysis in more than 5 cases included deletions/translocations (del/t) 6q15-23 [15 cases]; -13 [14 cases]; del/t 1p21-31 [12 cases]; +3q [11 cases]; del/t 17p [9 cases]; 8p translocations and del(Y) [8 cases each]; -20 [7 cases]; 13q14 deletion, del/t 11q22-23, del/t 9q, del(10)(q22q24), -20, -21, -22 and -X [6 cases each]. We arrived at the following conclusions: i) though no secondary anomaly is specific for MCL, there is a distinct profile of recurrent chromosome lesions in MCL with 1p21-31 deletions, 8p translocations, 11q22-23 anomalies having a strong association with CD5+ B-cell lymphomas of low-to-intermediate grade histology; ii) FISH enabled the detection of cryptic chromosome 12, 13q and 17p rearrangements in a sizeable fraction of cases; iii) 9p21/p16 deletions did not occur at a high incidence in this series, possibly because of the low number of cases with blastoid variant.