Selected Genetic Polymorphisms Associated with Hypoxia and Multidrug Resistance in Monoclonal Gammopathies Patients.

BACKGROUND: Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, including hypoxia-inducible factors (HIFs). Activation of HIF-1α is associated with increased expression of P-glycoprotein and multidrug resistance in cancer cells. In this retrospective study, we analyzed candidate single-nucleotide polymorphisms (SNPs) in HIF-1α and HIF-1ß associated with risk of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). PATIENTS AND METHODS: Genotypes of SNPs associated with hypoxia were determined in an independent cohort of monoclonal gammopathies (MG) (275 MM and 228 MGUS patients) and in 219 cancer-free controls by real time polymerase chain reaction allelic discrimination. RESULTS: When MM patients were compared to controls, protective role of CG genotype compared to CC in HIF-1ß (rs2228099) for MM development was observed (OR = 0.65; CI 0.45-0.95; p = 0.026). Even after adjustment for patients' age and body mass index (BMI), there were significantly lower odds (OR = 0.55; p = 0.045) of developing MM patients of CG genotype in comparison to CC genotype. Log-rank test confirmed association of GT haplotype (rs11549467, rs2057482) in HIF-1α with better overall survival (median 41.8 months; (CI 35.1-48.5)) for "none GT" and median 93.8 months (CI 31.3-156.4) for "at least one GT" haplotype (p = 0.0500). Further, significant associations between SNPs in MDR1 and outcome of MM were found in 110 MM patients that underwent bortezomib-based treatment. CONCLUSION: Our study showed a genetic predisposition for risk of MG development and/or outcome of MM patients; nevertheless, further studies are needed to confirm our initial analysis.

Can we predict clinical cardiotoxicity with cardiac biomarkers in patients after haematopoietic stem cell transplantation?

The long-term prognosis of patients after haematopoietic stem cell transplantation (HSCT) has greatly improved. Cardiac complications represent unresolved and potentially life-threatening conditions in these patients. We prospectively examined 37 consecutive patients with a median age of 28 years who underwent allogeneic HSCT. Biomarkers of cardiac injury were measured serially before the conditioning regimen, the first day after HSCT and then 14, 30, 90 and 180 days after HSCT. Echocardiography was performed before and 1 month after HSCT. Eleven patients (30%) had persistently increased NT-proBNP values, 14 patients (38%) had only transient elevations and 12 (32%) had no changes in NT-proBNP concentrations for a period exceeding 14 days after HSCT. Elevated NT-proBNP values at day 14 after HSCT remained an independent predictor of cardiotoxicity during the first 6 months after HSCT (P < 0.01). Patients with persistent elevations in NT-proBNP also had significant elevations in hs-cTnT concentrations (P < 0.01). Only patients with persistently increased NT-proBNP had a significant worsening in systolic and some diastolic echocardiographic parameters, and we observed in this group the highest values of both cardiomarkers during the 6-month period. Forty-five percent of these patients developed clinical manifestation of cardiotoxicity. Elevations in NT-proBNP concentrations at day 14 after HSCT can predict patients at risk of developing cardiac events during the first 6 months after HSCT. Simultaneous elevations of both cardiomarkers (NT-proBNP and hs-cTnT) persisting 14 days after HSCT had a sensitivity of 83% and a specificity of 80.69%.

Serial measurements of cardiac biomarkers in patients after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Previous therapy with anthracyclines (ANT) and conditioning regimen followed by hematopoietic stem cell transplantation (HSCT) represents a high risk for development of cardiotoxicity. The aim of this study was to assess subclinical myocardial damage after HSCT using echocardiography and cardiac biomarkers--high sensitive cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and to identify patients at risk of developing clinical cardiotoxicity. PATIENTS AND METHODS: Thirty-seven patients who were treated with allogeneic HSCT for hematologic diseases at median age of 28 years at time of HSCT were studied. Conditioning regimen included either chemotherapy without total body irradiation (TBI) or combination of chemotherapy with TBI. Twenty-nine (78.3%) patients were pretreated with ANT therapy. Cardiac biomarkers were serially measured before conditioning regimen and at days 1, 14 and 30 after HSCT. Cardiac systolic and diastolic functions were assessed before conditioning regimen and 1 month after HSCT by echocardiography. RESULTS: The changes in plasma NT-proBNP and hs-cTnT levels during the 30 days following the HSCT were statistically significant (P < 0.01 v.s. P < 0.01). Persistent elevations of NT-proBNP and hs-cTnT simultaneously for a period exceeding 14 days after HSCT were found in 29.7% patients. Serum concentrations of cardiomarkers were significantly elevated in ANT group compared to non-ANT group. These observations were underscored by the echocardiographic studies which did reveal significant changes in systolic and diastolic parameters. Five of 37 (13.5%) patients developed clinical manifestation of cardiotoxicity. CONCLUSIONS: Elevations in both cardiac biomarkers were found before clinical signs of cardiotoxicity developed. Persistent elevations in NT-pro-BNP and hs-cTnT concentrations simultaneously for a period exceeding 14 days might be used for identification of patients at risk of developing cardiotoxicity and requiring further cardiological follow up.

Endocrine late effects after hematopoietic stem cell transplantation.

The long-term quality of life of patients after hematopoietic stem cell transplantation (HSCT) represents a multidisciplinary problem. HSCT can induce damage of various organs and tissues-from minimal potentially progressive subclinical changes to life-threatening conditions. Endocrine complications are among the most common late effects observed in survivors after HSCT. The relative risk of these complications is likely to be influenced by the underlying disease, type of therapy, and age at HSCT. Understanding the pathogenetic mechanisms of late complications that can occur after HSCT provides a basis for optimal surveillance and early intervention. Further research is needed for improved risk stratification of patients who are at low and high risk of developing late toxicity. Through collaboration between pathophysiologists, clinicians, and patient associations we can enhance the implementation of prospective studies and set forth effective preventive programs for survivors after HSCT.