While the bone marrow in most patients with myelodysplastic syndromes (MDS) has normal or increased cellularity (hyper-MDS), approximately 10%-15% of MDS patients will present with a hypocellular bone marrow (hypo-MDS).1 Since the diagnosis of MDS relies mainly on the presence of dyplastic morphology of myeloid precursors and/or the presence of recurrent chromosomal abnormalities, low cellularity aspirates in patients with hypo-MDS may compromise morphologic evaluation and karyotypic analyses, and ultimately contribute to difficulties in distinguishing hypo-MDS from other bone marrow failure syndromes. Further, approximately 50% of MDS patients, including those with hypo-MDS, have normal karyotype by metaphase cytogenetics (MC), which makes the distinction even more difficult. 2We previously reported that single nucleotide polymorphism (SNP) array karyotyping can improve the detection of chromosomal lesions that can distinguish hypo-MDS patients from those with aplastic anemia (AA).3 This finding suggests that clonal abnormalities can be detected in haematologica 2015; 100:e434 LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o nhypo-MDS and AA by using higher sensitivity methods other than MC. Recently, next generation sequencing (NGS) technologies of the human genome identified several genes that are frequently affected by somatic mutations and play an important role in both the prognosis and the pathogenesis of MDS.4-6 Some of these mutations have a significant impact on disease phenotype, the progression of MDS to acute myeloid leukemia (AML), and on overall survival (OS).4-6 Somatic mutations in genes such as ASXL1, TET2, and DNMT3A are present in healthy individuals, and their incidence increases with age.7 More importantly, the presence of these mutations predisposes these individuals to develop hematologic malignancies.7 Furthermore, somatic mutations in genes such as ASXL1, TET2, DNMT3A and BCOR, were found in 19% of patients with AA, and their presence was associated with an increased risk of transformation to MDS and AML. 8These findings suggest that somatic mutations in certain genes have the potential to contribute to both disease initiation and progression.Using NGS technologies, we hypothesized that identification of somatic mutations and their combinations may help to define the clonal architecture that can lead to the development of hypo-MDS, and that these somatic mutations can possibly be used to aid in establishing the diagnosis.Bone marrow and peripheral blood samples were collected from 237 patients diagnosed with MDS (according to the 2008 WHO criteria) 9 at our institution between January 2000 and December 2013. Informed consent for sample collection was obtained according to protocols approved by the institutional review boards of Cleveland Clinic and in accordance with the Declaration of Helsinki. Hypo-MDS was defined using a standard definition of bone marrow cellularity

Background Historical controls continue to be used in early-phase brain tumor trials. We aim to show that historical changes in survival trends for glioblastoma (GBM) call into question the use of noncontemporary controls. Methods We analyzed data from 46 106 primary GBM cases from the SEER database (1998-2016). We performed trend analysis on survival outcomes (2-year survival probability, median survival, and hazard ratios) and patient characteristics (age, sex, resection extent, and treatment type). Results In 2005-2016 (ie, the post–Stupp protocol era), fitting a parameter independently to each year, there was a demonstrable increase in median survival (R2 = 0.81, P < .001) and 2-year survival probability (R2 = 0.55, P = .006) for GBM. Trend analysis of the hazard ratio showed a significant time-dependent downward trend (R2 = 0.62, P = .002). When controlling, via multivariable Cox regression modeling, for age, sex, resection extent, and treatment type, there was a persistent downward trend in hazard ratios with increases in calendar time, especially in the most recent data. Conclusion Contemporary GBM patients face a different overall hazard profile from their historical counterparts, which is evident in changes in measures of patient survival and parametric hazard modeling. Though there was a plateau in these measures before 2005 (pre–Stupp protocol), there is no evidence of a new plateau in recent years even when controlling for known prognostic factors (age, sex, resection extent, and treatment type), suggesting that it may be insufficient to match contemporary patients and noncontemporary controls on the basis of these factors.

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