Prediction of Malingant Plasma Cell Biology Related Survival in AL-Amyloidosis

Background. Survival in AL-amyloidosis is thought to be primarily determined by signs and symptoms caused by deposition of amyloid light chains, most prominently in the heart. In contrast, molecular characteristics of the underlying malignant plasma cell disease have been described, but are mostly considered less important. Aim of our study is to predict malignant plasma cell biology related survival in AL-amyloidosis by establishing the first gene expression based risk stratification (HDAL) and assessing its independence from clinical serum parameter assessing risk. Methods. CD138+-purified plasma cell samples of 919 patients with malignant plasma cell diseases, i.e. 195 AL-amyloidosis and 724 symptomatic myeloma patients were investigated by gene expression profiling, 124 AL-amyloidosis patients by RNA-sequencing. Gene expression profiling data of AL-amyloidosis patients were spitted in a training (TG, n=99) and a validation group (VG, n=96). A two-step model according to Rème et al. was applied on the training group, including a running log rank test for gene selection and a multi-cut-off running log-rank algorithm for optimal cut-off-selection, leading to a selection of 15 genes associated with good and 44 genes with adverse prognosis. The resulting HDAL-score was validated on the independent VG and our myeloma patient cohort using survival estimates for censored data. Differences between curves were assessed using the Log-rank test. The continuous RNA-Seq HDAL-score (R-HDAL) was subsequently derived to validate the survival association of the selected genes. HDAL was tested for independence with serum parameter assessing clinical staging systems by multivariate Cox regression. Results. Categorical split of the HDAL-score delineates three significantly predictive groups of 48%, 29% and 23% of AL-amyloidosis patients with a median survival of 105, 53 and 3 months in the training, and 72, 33 and 6 months in the validation group, respectively. In symptomatic myeloma patients, HDAL significantly stratifies two groups with a median survival of 128 and 78 months. Thus, HDAL is a malignant plasma biology related derived risk stratification. HDAL and R-HDAL are significantly predictive for survival as continuous parameters. Categorial and continuous HDAL are individually independent predictive from clinical staging systems, i.e. Mayo 2004, 2012 and Euro score, and the assessed serum parameters, i.e. NT-ProBNP, cTNT and dFLC. In conclusion, malignant plasma cell biology related and amyloid deposition mediated survivals in AL-amyloidosis are independent. Prognosis driven by the first component can significantly be assessed by transcriptome profiling (HDAL or R-HDAL). We thank U. Hegenbart and S. Schönland for clinical collaboration in this work. Disclosures Moreaux: Diag2Tec: Other: Co-founder of Diag2Tec company.

Markers of bone metabolism during short-term administration of thyroxine in healthy volunteers

Frevert EU, Biester A, Müller MJ, Schmidt-Gayk H, von zur Mühlen A, Brabant G. Markers of bone metabolism during short-term administration of thyroxine in healthy volunteers. Eur J Endocrinol 1994;131:145–9. ISSN 0804–4643. We investigated the influence of L-thyroxine (L-T4) treatment over 3 weeks on biochemical markers of bone turnover in 12 healthy young men (age 25.6 ± 1.4 years, BMI: 22.6 ± 2.5 kg/m2). Serum parameters indicating bone formation [bone Gla protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and bone-specific alkaline phosphatase (BAP)] and bone resorption [cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and the urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (D-Pyr)] were measured before and after three weeks of treatment with 300 μg L-T4/d. T3 and T4 significantly increased and TSH decreased to almost undetectable levels even when measured with a third generation TSH assay. Markers of bone formation showed variable responses with a small but significant increase in BGP but not in PICP or BAP. In contrast, all parameters of bone resorption increased significantly with a good correlation between D-Pyr excretion and the serum parameter ICTP (r = 0.78, p < 0.0001). These changes in bone-turnover markers were not necessarily paralleled by comparable increments of other markers of tissue thyrotoxicosis (SHBG, pulse rate, VO2), suggesting a variability in tissue sensitivity. These rapid responding parameters, especially in the easily obtainable serum parameter ICTP, might be valuable tools in the evaluation of several states of thyroxine excess. G Brabant, Dept. Klinische Endokrinologie, Medizinische Hochschule Hannover, D-30 623 Hannover, Germany