Masayuki Umeda

Background: Bone marrow cells possess multipotentiality and have been used for several treatments. We hypothesized that bone marrow cells might differentiate into regenerated tendon and that several cytokines within bone marrow cells might accelerate tendon healing. Therefore, we treated Achilles tendon ruptures in a rat model with transplantation of whole bone marrow cells. Methods: Nine F344/Nslc (Fisher) rats were the source of bone marrow cells and mesenchymal stem cells as well as normal Achilles tendons. Eighty-seven Fisher rats were used for the experiments. The rats were divided into three groups: the BMC group (bone marrow cells injected around the tendon), the MSC group (mesenchymal stem cells injected around the tendon), and the non-treated control group (incision only). Outcome measures included mechanical testing, collagen immunohistochemistry, histological analysis, and reverse transcription-polymerase chain reaction to detect expression of transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF). Results: The ultimate failure load in the BMC group was significantly greater than that in the non-treated or the MSC group at seven days after incision (3.8 N vs. 0.9 N or 2.1 N, p < 0.016) and at fourteen days after incision (10.2 N vs. 6.1 N or 8.2 N, p < 0.016). The ultimate failure load in the BMC group at twenty-eight days after incision (33.8 N) was the same as that of normal tendon (34.8 N). The BMC group demonstrated stronger staining for type-III collagen at seven days after incision and stronger staining for type-I collagen at twenty-eight days than did the MSC group. Expression of TGF-β and VEGF in the BMC group was significantly increased compared with that in the other groups at four days after incision (TGF-β: 1.6 vs. 1.3 or 0.6, p < 0.01; VEGF: 1.7 vs. 1.1 or 0.9, p < 0.01). Conclusions: Transplantation of whole bone marrow cells may be a better and more readily available treatment for Achilles tendon rupture than cultured mesenchymal stem cells. Clinical Relevance: The present study provides evidence that transplantation of bone marrow cells may be a promising therapy for the treatment of Achilles tendon rupture.

Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

OBJECT: Surgical outcome and radiographic changes after microsurgical bilateral decompression via a unilateral approach (MBDU) for lumbar spinal canal stenosis during midterm follow-up periods (> 2 years) have not been reported. The authors retrospectively investigated surgical outcomes after MBDU in patients with lumbar degenerative spondylolisthesis with stenosis in comparison with patients with degenerative stenosis during a minimum follow-up period of 2 years. Radiographic changes at the affected intervertebral level were analyzed during that follow-up period. METHODS: Forty-eight patients (23 in the spondylolisthesis group, 25 in the degenerative stenosis group) were included in the study. The average follow-up period was 46 months (range 24-71 months). Surgical outcome was evaluated using the Neurogenic Claudication Outcome Score (NCOS) and the Oswestry Disability Index (ODI). Additionally, the back pain score within the NCOS was also compared. There were no statistically significant differences between the spondylolisthesis group and the degenerative stenosis group with regard to sex, age, follow-up period, operating time, blood loss, surgical sites, approach side, preoperative NCOS, preoperative back pain score, and preoperative ODI. Comparisons were also made between groups using 2 satisfaction measurements at the last follow-up visit. Radiographically, intervertebral angles of 80 sites and slip percentages of 24 sites were measured preoperatively and at the last follow-up. RESULTS: No patient in either group had additional surgery in the lumbar spine, including fusion procedures. The NCOS, back pain score, and ODI had significantly improved at the last follow-up in both groups. There were no significant differences between the 2 groups in these 3 parameters and the 2 satisfaction measurements at the last follow-up, although those for the spondylolisthesis group indicated a somewhat worse outcome. Intervertebral angles, dynamic intervertebral angles, and dynamic slip percentage did not significantly change after surgery, whereas only slip percentage significantly increased postoperatively (p = 0.0319). CONCLUSIONS: A satisfactory outcome of MBDU persisted for a period longer than 2 years for patients with degenerative spondylolisthesis with stenosis as well as for those with degenerative stenosis. Radiographically in both groups this less invasive procedure was not likely to result in postoperative dynamic instability at the affected level, although the slippage progressed in the spondylolisthesis group.

The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML. SIGNIFICANCE: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171.