Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine.We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome.Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. MethodsIn this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Düsseldorf MDS registry (n=1185).Recruitment periods for these cohorts were between 1990 and 2016.The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort.The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts.Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R).This study is registered with ClinicalTrials.gov,NCT04889729.Findings The study included 7792 (58•7%) men and 5492 (41•3%) women.10 906 (82•1%) patients were White, and race was not reported for 2378 (17•9%) patients.Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p<0•0001 in both cohorts; DDX41 not available in the EuroMDS cohort vs p=0•0062 in the IWG-PM cohort; IDH2 p<0•0001 in EuroMDS vs p=0•042 in IWG-PM; TET2 p=0•031 vs p=0•035; U2AF1 p=0•033 vs p<0•0001) and mutations in two genes were enriched in women (DNMT3A p<0•0001 in EuroMDS vs p=0•011 in IWG-PM; TP53 p=0•030 vs p=0•037).Additionally, sex biases were observed in co-mutational pathways of founding genomic lesions (splicing-related genes, predominantly in men, p<0•0001 in both the EuroMDS and IWG-PM cohorts), in DNA methylation (predominantly in men, p=0•046 in EuroMDS vs p<0•0001 in IWG-PM), and TP53 mutational pathways (predominantly in women, p=0•0073 in EuroMDS vs p<0•0001 in IWG-PM).In the retrospective EuroMDS cohort, men had worse median overall survival (81•3 months, 95% CI 70•4-95•0 in men vs 123•5 months, 104•5-127•5 in women; hazard ratio [HR] 1•40, 95% CI 1•26-1•52; p<0•0001).This result was confirmed in the prospective validation cohorts (median overall survival was 54•7 months, 95% CI 52•4-59•1 in men vs 74•4 months, 69•3-81•2 in women; HR 1•30, 95% CI 1•23-1•35; p<0•0001 in the GEMSD MDS registry; 40•0 months, 95% CI 33•4-43•7 in men vs 54•2 months, 38•6-63•8 in women; HR 1•23, 95% CI 1•08-1•36; p<0•0001 in the Dusseldorf MDS registry).We developed new personalised prognostic tools that included sex information (the sex-informed prognostic scoring system and the sex-informed genomic scoring system).Sex maintained independent prognostic power in all prognostic systems; the highest performance was observed in the model that included both sex and genomic information.A five-to-five mapping between the IPSS-R and new score categories resulted in the re-stratification of 871 (43•0%) of 2025 patients from the EuroMDS cohort and 1003 (42•0%) of 2387 patients from the IWG-PM cohort by using the sex-informed prognostic scoring system, and of 1134 (56•0%) patients from the EuroMDS cohort and 1265 (53•0%) patients from the IWG-PM cohort by using the sex-informed genomic scoring system.We created a web portal that enables outcome predictions based on a sexinformed personalised approach.Interpretation Our results suggest that a sex-informed approach can improve the personalised decision making process in patients with myelodysplastic syndromes and should be considered in the design of clinical trials including low-risk patients.
Summary. The urokinase‐type plasminogen activator (uPA) system, which consists of a proteinase (uPA), a receptor (uPAR or CD87) and inhibitors, is involved in proteolysis, cell migration, tissue remodelling, angiogenesis and cell adhesion. Recent findings suggest that malignant plasma cells express uPA and uPAR. The expression of these factors could represent a process by which myeloma plasma cells interact with the bone marrow (BM) environment and influence important biological events such as bone matrix degradation, plasma cell invasion and homing and, possibly, clinical evolution. We evaluated uPAR (CD87) and its soluble form (suPAR) in 49 multiple myeloma (MM) patients and correlated their expression and levels with clinico‐biological characteristics of the disease. Flow cytometric analysis demonstrated that CD87 was expressed in all MM patients. High CD87 expression was associated with higher intensity of expression of CD56 ( P = 0·038), CD38 ( P = 0·058) and CD138 ( P = 0·054) and CD45 bright positivity ( P = 0·014). suPAR levels correlated positively with soluble serum CD138 ( P = 0·001), creatinine ( P = 0·001), beta 2 ‐microglobulin ( P < 0·001), disease stage ( P = 0·017) and extra‐BM involvement ( P = 0·002). In the 46 evaluable patients, multivariate analysis showed that high levels of suPAR ( P = 0·0214) and disease stage ( P = 0·0064) were predictive of extra‐BM involvement. In multivariate Cox analysis, 13q deletion ( P = 0·0278), high soluble serum CD138 ( P = 0·0201) and high suPAR ( P = 0·0229) were the only parameters that independently affected survival. We conclude that CD87 is expressed on myeloma plasma cells and that suPAR, which predicts extra‐BM involvement and poor prognosis, possibly represents a molecule with a relevant role in the biology of MM.
Structural fibrils constitute a physiological component of the bone marrow stromal microenvironment and contribute to providing a connective tissue structure and a support for hematopoietic progenitor cells.[1][1] The most common fibers in the bone marrow are reticulin and collagen type I/III. Bone
Summary The in vivo effect of recombinant human erythropoietin (rHuEpo) and granulocyte colony‐stimulating factor (G‐CSF) combined treatment on CD34 + cells was evaluated by fluorescence in situ hybridization (FISH) in 13 myelodysplastic syndrome (MDS) patients with known cytogenetic abnormalities. After treatment, responsive patients presented a significantly lower proportion of FISH abnormal CD34 + cells than before treatment ( P = 0·003), and in comparison with unresponsive cases ( P = 0·007). Response to treatment was associated with a reduced degree of apoptosis in CD34 + cells ( P = 0·021): however, no difference in telomere length was observed in responsive patients after growth factor administration. Although the number of patients analysed was relatively small, the present data suggest that, in MDS patients, response to rHuEpo and G‐CSF may be related to the proliferation of karyotypically normal but potentially defective CD34 + progenitor cells.
