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NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite the impact of homozygous CRIM1 on thiopurine toxicity, several patients with wild-type NUDT15, TPMT, and CRIM1 experience thiopurine toxicity, therapeutic failure, and relapse of acute lymphoblastic leukemia (ALL). Novel pharmacogenetic interactions associated with thiopurine intolerance from hematological toxicities were investigated using whole-exome sequencing for last-cycle 6-mercaptopurine dose intensity percentages (DIP) tolerated by pediatric ALL patients (N = 320). IL6 rs13306435 carriers (N = 19) exhibited significantly lower DIP (48.0 ± 27.3%) than non-carriers (N = 209, 69.9 ± 29.0%; p = 0.0016 and 0.0028 by t test and multiple linear regression, respectively). Among 19 carriers, 7 with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7 ± 8.9%) than those with IL6 (N = 12, 61.6 ± 25.1%) or CRIM1 (N = 94, 68.1 ± 28.4%) variants. IL6 and CRIM1 variants showed marked inter-ethnic variability. Four-gene-interplay models revealed the best odds ratio (8.06) and potential population impact [relative risk (5.73), population attributable fraction (58%), number needed to treat (3.67), and number needed to genotype (12.50)]. Interplay between IL6 rs13306435 and CRIM1 rs3821169 was suggested as an independent and/or additive genetic determinant of thiopurine intolerance beyond NUDT15 and TPMT in pediatric ALL.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Alveolar RMS (ARMS) is characterized by FOXO1-related chromosomal translocations that result in a poorer clinical outcome compared with embryonal RMS (ERMS). Because the chromosomal features of RMS have not been comprehensively defined, we analyzed the clinical and laboratory data of childhood RMS patients and determined the clinical significance of chromosomal abnormalities in the bone marrow., Methods: Fifty-one Korean patients with RMS <18 years of age treated between 2001 and 2015 were enrolled in this study. Clinical factors, bone marrow and cytogenetic results, and overall survival (OS) were analyzed., Results: In total, 36 patients (70.6%) had ERMS and 15 (29.4%) had ARMS; 80% of the ARMS patients had stage IV disease. The incidences of bone and bone marrow metastases were 21.6% and 19.6%, respectively, and these results were higher than previously reported results. Of the 40 patients who underwent bone marrow cytogenetic investigation, five patients had chromosomal abnormalities associated with the 13q14 rearrangement. Patients with a chromosomal abnormality (15 vs 61 months, P=0.037) and bone marrow involvement (17 vs 61 months, P=0.033) had a significantly shorter median OS than those without such characteristics. Two novel rearrangements associated with the 13q14 locus were detected. One patient with concomitant MYCN amplification and PAX3/FOXO1 fusion showed an aggressive clinical course., Conclusions: A comprehensive approach involving conventional cytogenetics and FOXO1 FISH of the bone marrow is needed to assess high-risk ARMS patients and identify novel cytogenetic findings., Competing Interests: No potential conflicts of interest relevant to this article were reported., (© The Korean Society for Laboratory Medicine)

Aims: Although bone marrow (BM) involvement in Langerhans cell histiocytosis (LCH) is a negative prognostic indicator, there are no widely accepted criteria to define BM involvement in LCH. We evaluated the BM of LCH patients at diagnosis by immunohistochemical (IHC) staining for S100, CD1a and Langerin, along with other features., Methods and Results: We retrospectively reviewed the records of 75 patients diagnosed as LCH at our center. IHC stains of Langerin, CD1a and S100 were done using paraffin-embedded tissue sections. Only three cases showed massive involvement of clustered Langerhans cells. There were linear associations between positive cell count and disease extent. Some discordant results between Langerin and CD1a IHC stains were noted. Among cases showing positive results for all three IHC stains, six patients (54.5%) were in the multisystem group, and three patients (27.3%) had cytopenias. The reactivation-free survival rates did not differ between the group positive for CD1a or Langerin, and the group negative for Langerin and CD1a., Conclusions: Langerin and CD1a seem to be useful markers of Langerhans cells, and S100 might be a nonspecific marker for these cells, in the BM. Both Langerin and CD1a IHC staining is needed to evaluate the BM involvement of LCH., (© 2014 John Wiley & Sons Ltd.)

Background: The prognostic impact of the presence of differentiating neuroblasts in bone marrow (BM) remains unclear in BM metastatic neuroblastoma (NB). We aimed to identify the prognostic impact of differentiating neuroblasts in BM at diagnosis and after chemotherapy., Methods: A total of 51 patients diagnosed with BM metastatic NB at Asan Medical Center between January 1990 and July 2005 were enrolled. BM histology and laboratory data along with overall survival (OS) were compared with regard to the differentiation status of neuroblasts in BM at diagnosis and after chemotherapy., Results: Among the 51 patients, 13 (25.5%) exhibited differentiating neuroblasts in BM at diagnosis and 17/51 (33.3%) exhibited them after chemotherapy. The only significant difference among patient groups was the improved OS in patients with differentiated neuroblasts in BM at diagnosis (P=0.021). In contrast, the differentiation status of neuroblasts in BM after chemotherapy did not affect OS (P=0.852)., Conclusions: Our study is the first report describing the presence of differentiating neuroblasts in BM. The presence of differentiating neuroblasts in BM at diagnosis may be a favorable prognostic factor for patients with BM metastatic NB; however, the same phenomenon after chemotherapy is irrelevant to prognosis.