Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma

Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy)

MOESM6 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 6. Alignment of the repetitive elements at the beginning of the 6-kb candidate segment according to bosTaurus6 and bosTaurus8. The pairwise alignment of the reference sequence of the SINE element ART2A (bosTau6) and the LINE element BovB (bosTau8) at the beginning of the 6-kb candidate segment shows that ART2A is part of BovB

MOESM3 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 3. TLA results. The genomic region chr3:118,590,000–118,632,000 (bosTau8) is displayed. The arrows indicate the position of the primer sets used for TLA. For the belted animal (GLW54-2), an increased copy number (3 to 4.5 times) was detected in the region indicated by the red rectangle. The y-axis is limited to max. 1000X

MOESM2 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 2. Alignment of CH240-104M22 and the reference sequence. Pairwise alignment of the BAC-clone CH240-104M22 with the bosTaurus6 reference sequence of the 6-kb candidate region showing almost complete identity

MOESM1 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 1. Inner candidate haplotypes detected by manual analysis of the extended confidence interval. This file shows the 60-SNP haplotypes of the extended candidate interval for all 110 animals that were used for remapping of the belt locus. SNPs that were excluded from the mapping procedure (MAF < 0.025) are marked with grey color in the first line. The black box indicates the 336-kb interval identified by Drögemüller et al. [13]. The first five haplotypes represent the most common and extended haplotypes for Belted Galloway (BGAhap1 and BGAhap2, shown in bright and dark blue), Dutch Belted (DBEhap, shown in beige) and Gurtenvieh (GUVhap1 and GUVhap2, shown in dark and bright green). Red boxes indicate common parts of these five haplotypes and represent the four inner candidate haplotypes (IC-Hap1-4, Table 3). The haplotypes of the animals that were used for remapping are shown below in the following order: (i) Belted Galloway, (ii) Dutch Belted, (iii) Gurtenvieh, (iv) a belted cross between Gurtenvieh and Pinzgauer cattle and (v) non-belted control animals

MOESM5 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 5. Nanopore sequencing results. (a) Nanopore reads mapped (minimap2) to the belted candidate region are shown. The shaded parts of the reads highlight unmapped portions of the read that were mapped as a secondary alignment in a separate read. These secondary alignments are highlighted by blue borders. (b) Split-alignment of breakpoint-spanning read visualized by Ribbon [52]. The highlighted read (bold blue line) is shown as a zoom in the lower panel, showing that the beginning of the read is found at the end of the repeated region and the end is found at the beginning, thus illustrating the concatenation of the repeat units found in belted cattle. (c) Exact breakpoints were identified by inspection of the partially mapped reads. The right breakpoint at 118,614,132 bp shows that the unmapped portion of the split-aligned reads starts with a sequence that is located at 118,608,362 bp, which thus defines the left breakpoint

MOESM8 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 8. Haplotypes of the Russian Yakutian animals checked by qPCR. This file shows 42-SNP haplotypes of the 10 Russian Yakutian animals that were checked by qPCR. As in Additional file 1, SNPs that were excluded from the mapping procedure (MAF < 0.025) are marked in grey color in the first line, and the first five haplotypes represent the most common and extended haplotypes of the European breeds Belted Galloway (BGAhap1 and BGAhap2), Dutch Belted (DBEhap) and Gurtenvieh (GUVhap1 and GUVhap2). Red boxes again indicate common parts of these five haplotypes and represent the four inner candidate haplotypes (IC-Hap1-4, Table 3). Below these common haplotypes, the haplotypes of the 10 Siberian Russian Yakutian animals are grouped as follows: the first seven animals were belted according to phenotype and qPCR, the next animal was belted according to phenotype but non-belted in the qPCR, and the last two animals were non-belted according to phenotype and qPCR. Interestingly, the belted Russian Yakutian (RUY) animals do not share a common haplotype within IC-Hap4, which carries the candidate mutation BeltMulti6kb

Sampling_sites_coordinates

Excel file with Ovis niviola sampling sites coordinates

MOESM7 of Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation

Additional file 7. Gene interaction network. This figure illustrates the interactions between KIT (causal for the belt in pigs), ADAMTS20 (causal for the belt in mice) and TWIST2 (most likely causal for the belt in cattle) in mice. Interaction line colors are as follows: orange: predicted functional relationship, red: physical interactions, purple: co-expression; grey: phenotype (based on mouse genome informatics) and blue: participation in the same reaction within a pathway

Dotsev_et_al_Ovis_nivicola_SNPs_2018_map

PLINK .map file for Ovis nivicola SNP Genotype