Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role of TET2 in PAH is unknown. Methods: To test for a role of TET2, we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic Tet2-knockout mice. Results: We observed an increased burden of rare, predicted deleterious, germline variants in TET2 in PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years, p<0.0001) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH. Conclusions: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP), defined as the presence of a somatic mutation in the peripheral blood at a variant allele frequency (VAF) ≥2%, affects at least 10% of individuals older than 65, but low-VAF clones can be detected in 95% of individuals older than 50. CHIP associates with a wide range of comorbidities from atherosclerosis to pulmonary disease. A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities. Mutant leukocytes from animal models contribute to an inflammatory milieu that may confer a selective advantage to the clone, thus perpetuating a cycle of inflammation and expansion. Although it is unclear whether inflammation or expansion sets this cycle in motion, some evidence suggests that inflammation from infections or pre-existing comorbidities initiates this cycle. The pro-inflammatory phenotypes of macrophages from mutant clones and their contributions to disease are well characterized in murine models, but have not yet been confirmed in humans. Furthermore, the roles of other cell types that can carry mutations of CHIP are not fully understood. We propose a rationale for further investigation of neutrophils, other granulocytes and T, B, and NK cells as they may play a role in CHIP-associated comorbidities. As the understanding of CH has advanced, potential interventions, especially those targeting aberrant inflammation, have been proposed. We are hopeful that as studies continue to unravel the complex links between CHIP, inflammation, and leukocyte dysfunction, CHIP-related comorbidities may be more effectively managed.

Key Points CH may be associated with broader ill health (worse performance status, increased and potentially novel comorbidities). Serum interleukin-6 is elevated in people with CH and genetic subtypes, providing a view of the human systemic inflammatory landscape of CH.

Background Clonal hematopoiesis of indeterminate potential (CHIP) is an inflammatory premalignant disorder resulting from acquired genetic mutations in hematopoietic stem cells. This condition is common in aging populations and associated with cardiovascular morbidity and overall mortality, but its role in chronic kidney disease (CKD) is unknown. Methods We performed targeted sequencing to detect CHIP mutations in two independent cohorts of 87 and 85 adults with an eGFR<60 ml/min per 1.73m2. We also assessed kidney function, hematologic, and mineral bone disease parameters cross-sectionally at baseline, and collected creatinine measurements over the following 5-year period. Results At baseline, CHIP was detected in 18 of 87 (21%) and 25 of 85 (29%) cohort participants. Participants with CHIP had a lower eGFR and were at higher risk of kidney failure, as predicted by the Kidney Failure Risk Equation (KFRE) compared with those without CHIP. Individuals with CHIP manifested a 2.2-fold increased risk of a 50% decline in eGFR or endstage kidney disease (ESKD) over 5 years of follow-up (hazard ratio 2.2; 95% confidence interval, 1.2 to 3.8) in a Cox proportional hazard model adjusted for age, sex, and baseline eGFR. The addition of CHIP to 2-year and 5-year calibrated KFRE risk models improved ESKD predictions. Those with CHIP also had lower hemoglobin, higher ferritin, and higher red blood cell mean corpuscular volume versus those without CHIP. Conclusion In this exploratory analysis of individuals with preexisting CKD, CHIP was associated with higher baseline KFRE scores, greater progression of CKD, and anemia. Further research is needed to define the nature of the relationship between CHIP and kidney disease progression.

Normal tissue radiation toxicities are evaluated subjectively and cannot predict the development of severe side-effects. Using a hand-held diffuse reflectance optical spectroscopy probe, we measured optical parameters in mouse skin 1-4 days after irradiation. Using a radiation toxicity model and a therapeutic mitigator described previously [BMC Cancer 14, 614 (2014)], we found that hemoglobin (Hb) levels increased sharply 24 h after irradiation only in the irradiated group without the mitigator. This group also had the largest peak wound areas after 14 days. We conclude that increased Hb one day after skin irradiation predicts the severity of the subsequent irradiation-induced wound. 19216 (2016). 27. R. Noble-Adams, "Radiation-induced skin reactions. 3: Evaluating the RISRAS," Br.

Clinician scientists are physicians who are uniquely trained to bridge the gap between scientific discovery and clinical practice. However, the challenges of integrating research and medicine are often not directly addressed in the clinician scientist training programs. Furthermore, the demanding training path is financially and personally daunting. Previous studies have shown that MD/PhD trainees value the advice and expertise of senior mentors in navigating their academic career path. Despite this demand for mentors, there is a lack of formal mentorship initiatives at the institutional level across Canada. Recently, MD/PhD trainees have attempted to address this issue by implementing a nationwide mentorship match, with the aim of making mentorship more accessible to trainees across Canada.

The 2017 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national Annual General Meeting (AGM) held in Toronto, Ontario November 20–22, 2017, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for this year’s meeting was “Roll up your sleeves—How to manage your physician scientist career”, emphasizing lectures and workshops that were designed to provide tools for being proactive and successful in career planning. The keynote speakers were Dr. Rod McInnes (McGill University and Canadian Institutes of Health Research Acting President), who was the Distinguished Scientist Award recipient, Dr. David Goltzman (McGill University), who was the 2017 Henry Friesen Award recipient, Dr. Gillian Hawker (University of Toronto), Dr. Mike Sapieha (Université de Montréal), who was the 2017 Joe Doupe Award recipient, and Dr. Alex MacKenzie (Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa). The workshops, focusing on career development for clinician scientists, were hosted by Dr. Lisa Robinson, Dr. Nicola Jones, Kevin Vuong, Fran Brunelle, Dr. Jason Berman and Dr. Alan Underhill. Further to this, the Young Investigators’ Forum encompasses presentations from scientist-clinician trainees from across the country. All scientific abstracts are summarized in this review. There were over 100 abstracts showcased at this year’s meeting during the highlighted poster sessions, with six outstanding abstracts selected for oral presentations during the President’s Forum.