Automated Osteosclerosis Grading of Clinical Biopsies Using Infrared Spectroscopic Imaging.

Osteosclerosis and myefibrosis are complications of myeloproliferative neoplasms. These disorders result in excess growth of trabecular bone and collagen fibers that replace hematopoietic cells, resulting in abnormal bone marrow function. Treatments using imatinib and JAK2 pathway inhibitors can be effective on osteosclerosis and fibrosis; therefore, accurate grading is critical for tracking treatment effectiveness. Current grading standards use a four-class system based on analysis of biopsies stained with three histological stains: hematoxylin and eosin (H&E), Masson's trichrome, and reticulin. However, conventional grading can be subjective and imprecise, impacting the effectiveness of treatment. In this Article, we demonstrate that mid-infrared spectroscopic imaging may serve as a quantitative diagnostic tool for quantitatively tracking disease progression and response to treatment. The proposed approach is label-free and provides automated quantitative analysis of osteosclerosis and collagen fibrosis.

An exploratory clinical trial of bortezomib in patients with lower risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P = .025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-κB activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study.