Amyloidosis is a severe disease caused by protein misfolding and deposition in tissues and organs. Thirty-eight different proteins are known to be amyloidogenic. Amyloidosis is categorized into inherited or acquired, and systemic or localized. Light-chain (AL)- and transthyretin (ATTR) amyloidosis are the two most common subtypes. Awareness, early diagnosis, accurate subtyping and relevant treatment are crucial for the management. Novel therapies of systemic AL and ATTR amyloidosis have considerably improved outcome and survival. The aim of this review is to increase awareness and knowledge on diagnosing amyloidosis.
Solitary plasmacytoma is an infrequent form of plasma cell dyscrasia that presents as a single mass of monoclonal plasma cells, located either extramedullary or intraosseous. In some patients, a bone marrow aspiration can detect a low monoclonal plasma cell infiltration which indicates a high risk of early progression to an overt myeloma disease. Before treatment initiation, whole body positron emission tomography–computed tomography or magnetic resonance imaging should be performed to exclude the presence of additional malignant lesions. For decades, treatment has been based on high-dose radiation, but studies exploring the potential benefit of systemic therapies for high-risk patients are urgently needed. In this review, a panel of expert European hematologists updates the recommendations on the diagnosis and management of patients with solitary plasmacytoma.
Background: Several authors have highlighted the importance of a deep response to chemotherapy in multiple myeloma (MM), especially in first line. Aims: The objective was to assess which patient/treatment/disease characteristics are prognostic for a deep response. Also, to assess whether the deep response is prognostic for overall survival (OS) independent of treatment, treatment line and patient/disease characteristics. Methods: A retrospective analysis was performed on 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics such as age, gender, ISS stage, albumin, creatine, and MM type, which were recorded at start of first line therapy. The following outcomes were considered; response, time to next line of treatment (TTNT) and OS. The following categories of response were differentiated: progressive disease (PD), no response (NR), partial response (PR), very good PR (VGPR) and equal or better than near complete response (>=nCR). To identify prognostic factors for response, univariate and multivariate multinomial regression were conducted with response as dependent and patient baseline characteristics and type of treatment as independent variables. To assess whether response is an independent predictor of OS, multivariate cox-proportional hazard models were run for the first four lines of treatment. Results: Patients in the dataset were on average 67 years old, 48% were male, 28%, 41% and 31% in ISS stages I, II and III, respectively. Multinomial regression showed that type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. In second line, first line response, type of treatment and age were significant prognostic factors for response in second line. Multivariate cox-regression showed that in first line patients with NR, PR, VGPR and >=nCR had significant lower hazard ratio's (HRs) 0.61 (0.43-0.85), 0.56 (0.41-0.78), 0.34 (0.22-0.51) and 0.36 (0.24-0.54) respectively compared to PD. Age, Albumin, Calcium and Beta-2-microglobulin levels were also significant prognostic factors for OS with HRs of 1.03 (1.01- 1.04), 0.98 (0.96-0.99), 1.41 (1.11-1.79) and 1.02 (1.01-1.03) respectively. The following categorical variables also were significant prognostic factors for first line OS; type of treatment, ISS-stage and MM type. For second line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.58 (0.46-0.73), 0.42 (0.3-0.58), 0.4 (0.27-0.6) compared to PD respectively. Age also had a significant HR of 1.02 (1.01-1.03). For third line OS multivariate cox-regression showed that patients with NR, PR, VGPR and >=nCR had significant lower HR's 0.67 (0.5-0.89), 0.37 (0.27-0.51), 0.32 (0.21-0.5), 0.18 (0.1-0.34) compared to PD respectively. Age also had a significant HR of 1.01 (1.00-1.02). For fourth line OS multivariate cox-regression showed that patients with PR, VGPR and >=nCR had significant lower HR's 0.45 (0.31-0.64), 0.31 (0.19-0.52) and 0.39 (0.21-0.73) compared to PD respectively. Age was also identified as a significant prognostic factor. Summary and Conclusions: Type of treatment, age, ISS type and MM type were significant prognostic factors for response in first line. For second line response, the significant prognostic factors were response in first line, type of treatment and age. Moreover, multivariate cox-regressions shows that in the first four lines of treatment, response is an independent prognostic factor for OS. Future research should include genetic prognostic factors, which were not collected in our dataset and could therefore not be assessed.
Background: Chromosomal instability, leading to full or partial aneuploidy, is a common feature of solid tumors and hematological malignancies, with several recurrent aberrations recognized as important diagnostic or prognostic molecular markers. While genome‐wide genotyping and genomic hybridization microarray analyses have been performed in clinical laboratories for several years the usage of next generation sequencing for detection of acquired copy number alterations (CNA) has not yet reached full clinical integration. Algorithmic strategies based on whole exome sequencing (WES) have been proposed, primarily focusing on read depth alterations affected by copy gain or loss. Aims: We aimed to identify copy‐neutral loss of heterozygosity (CN‐LoH), which is not detectable by sequencing read depth correlation or the analogous microarray CGH, by means of simple statistical analyses for increased transparency and direct clinical implementation. Methods: 23 paired samples from different hematological disorders were selected from 14 individuals with MCL, CLL, CML, AML, T‐ALL and monoclonal B cell lymphocytosis. Detection of CN‐LoH by means of significant allele frequency (AF) shift using Fisher's exact test and χ2 was performed in combination with paired gene‐wise read depth ratios correlations in order to resolve both copy altering and neutral chromosomal aberrations. Alignment (GRCh37) and variant calling was performed using BWA (Li and Durbin 2009) and GATK (McKenna et al. 2010) (v. 3.6/3.8). Variants and reads located outside targeted regions were excluded, and a base quality threshold of 25 and minimum allele read depth of 20 was applied. Gene‐wise read depths were retrieved with BEDTools (Quinlan and Hall 2010) from RefSeq coordinates (UCSC, Karolchik et al. 2004). Statistics and plotting were performed in Mathematica and software developed for demonstration purposes ( http://doi.org/10.7910/DVN/KFMGNY , Harvard Dataverse). Results: Sequencing yield spanned 48.5–188.6 million (median 84.3x10 6 ) paired‐end reads. The 23 paired variant call sets comprised a median of 19,101 coding variants, matching the expected number (Frebourg 2014; Ng et al. 2009), with a median read depth of 96 and lower and upper quartiles at 71 and 136, respectively. The combination of significant AF shifts identified 69 altered chromosomes and offered mutual confirmation. Six evident CN‐LoHs (>1% AF shifts, p < 0.01) were found in MCL, CML, AML and T‐ALL with one additional suspected low frequency deletion (estimated 10–15% burden) in a case of CLL. Robust test of equal variances (Brown and Forsythe 1974) between the paired diagnosis and remission sample was needed to detect this low burden aberration (p < 10 –10 in contrast to the other paired autosomes (p median = 0.019)). This also clearly indicates that low burden CN‐LoH pose a challenge – as with other methods. Another patient (MCL) harbored both a balanced tetrasomy (not evident by AF alone, see figure) and a CN‐LoH on chromosome 22 (not evident by DP‐ratios alone). Summary/Conclusion: The samples from 6 of the 14 patients with hematological malignancies/disorders were found to harbor 7 copy neutral deletions in total – all escaping previous clinical cytogenetic analyses. One was detected in a diagnostic sample from a patient otherwise diagnosed as cytogenically normal AML, which emphasize the importance of such methods. We conclude that this low‐complexity method, juxtaposing DP and AF, is directly applicable for the detection of copy neutral chromosomal loss of single genes from WES with intermediate coverage and medium to high burden chromosomal aberrations. image
