Citations

Abstract During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families.

A single monoclonal protein typically characterizes monoclonal gammopathies, but a small proportion may have more than one M protein identifiable. In the setting of symptomatic multiple myeloma (MM), the development of a new monoclonal protein following therapy is associated with better outcomes. As for the precursor conditions, monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM), there is limited information on the impact of a second monoclonal protein on the disease course, including progression and response to treatment. The outcomes of patients with MGUS and SMM with more than one monoclonal protein, after identifying 539 patients with biclonal proteins on electrophoresis and/or immunofixation, were reported. About 22 of 393 patients with MGUS/biclonal gammopathy of undetermined significance (BGUS) progressed to SMM (6), MM (11), AL (3), or WM (2), and 5 of 16 patients with biclonal SMM progressed to MM. The rate of progression for BGUS was approximately 1% per year, which is similar to MGUS with one monoclonal protein. The median estimated time of progression of biclonal SMM was 2.6 years; similar to monoclonal SMM. For patients with biclonal MM, both M spikes responded to treatment and, upon relapse, the original dominant M protein remained dominant as the disease progressed. In conclusion, the presence of a second monoclonal protein does not appear to affect the progression of precursor states and suggests multiple monoclonal proteins do not clinically impact one another in the course of the disease. Am. J. Hematol. 91:473–475, 2016. © 2016 Wiley Periodicals, Inc.

Objectives: Pulmonary complications are common following hematopoietic stem cell transplantation. Numerous idiopathic post-transplantation pulmonary syndromes have been described. Patients at the severe end of this spectrum may present with hypoxemic respiratory failure and pulmonary infiltrates, meeting criteria for acute respiratory distress syndrome. The incidence and outcomes of acute respiratory distress syndrome in this setting are poorly characterized. Design: Retrospective cohort study. Setting: Mayo Clinic, Rochester, MN. Patients: Patients undergoing autologous and allogeneic hematopoietic stem cell transplantation between January 1, 2005, and December 31, 2012. Interventions: None. Measurements and Main Results: Patients were screened for acute respiratory distress syndrome development within 1 year of hematopoietic stem cell transplantation. Acute respiratory distress syndrome adjudication was performed in accordance with the 2012 Berlin criteria. In total, 133 cases of acute respiratory distress syndrome developed in 2,635 patients undergoing hematopoietic stem cell transplantation (5.0%). Acute respiratory distress syndrome developed in 75 patients (15.6%) undergoing allogeneic hematopoietic stem cell transplantation and 58 patients (2.7%) undergoing autologous hematopoietic stem cell transplantation. Median time to acute respiratory distress syndrome development was 55.4 days (interquartile range, 15.1–139 d) in allogeneic hematopoietic stem cell transplantation and 14.2 days (interquartile range, 10.5–124 d) in autologous hematopoietic stem cell transplantation. Twenty-eight-day mortality was 46.6%. At 12 months following hematopoietic stem cell transplantation, 89 patients (66.9%) who developed acute respiratory distress syndrome had died. Only 7 of 133 acute respiratory distress syndrome cases met criteria for engraftment syndrome and 15 for diffuse alveolar hemorrhage. Conclusions: Acute respiratory distress syndrome is a frequent complication following hematopoietic stem cell transplantation, dramatically influencing patient-important outcomes. Most cases of acute respiratory distress syndrome following hematopoietic stem cell transplantation do not meet criteria for a more specific post-transplantation pulmonary syndrome. These findings highlight the need to better understand the risk factors underlying acute respiratory distress syndrome in this population, thereby facilitating the development of effective prevention strategies.

Background— Cardiac sarcoidosis is associated with an increased risk of heart failure and sudden death, but its risk in patients with preserved left ventricular ejection fraction is unknown. Using cardiovascular magnetic resonance in patients with extracardiac sarcoidosis and preserved left ventricular ejection fraction, we sought to (1) determine the prevalence of cardiac sarcoidosis or associated myocardial damage, defined by the presence of late gadolinium enhancement (LGE), (2) quantify their risk of death/ventricular tachycardia (VT), and (3) identify imaging-based covariates that predict who is at greatest risk of death/VT. Methods and Results— Parameters of left and right ventricular function and LGE burden were measured in 205 patients with left ventricular ejection fraction >50% and extracardiac sarcoidosis who underwent cardiovascular magnetic resonance for LGE evaluation. The association between covariates and death/VT in the entire group and within the LGE+ group was determined using Cox proportional hazard models and time-dependent receiver–operator curves analysis. Forty-one of 205 patients (20%) had LGE; 12 of 205 (6%) died or had VT during follow-up; of these, 10 (83%) were in the LGE+ group. In the LGE+ group (1) the rate of death/VT per year was >20× higher than LGE− (4.9 versus 0.2%, P <0.01); (2) death/VT were associated with a greater burden of LGE (14±11 versus 5±5%, P <0.01) and right ventricular dysfunction (right ventricular EF 45±12 versus 53±28%, P =0.04). LGE burden was the best predictor of death/VT (area under the receiver-operating characteristics curve, 0.80); for every 1% increase of LGE burden, the hazard of death/VT increased by 8%. Conclusions— Sarcoidosis patients with LGE are at significant risk for death/VT, even with preserved left ventricular ejection fraction. Increased LGE burden and right ventricular dysfunction can identify LGE+ patients at highest risk of death/VT.

Hyperviscosity syndrome is clinically manifested by oronasal bleeding, retinal hemorrhages, and variable neurological symptoms. It occurs when resistance to flow of blood increases sharply, resulting in impaired transit through the microcirculatory system. The most common cause of hyperviscosity is increased concentrations of gamma globulins, either monoclonal in malignant disease or polyclonal, usually seen with rheumatic disorders. Increased numbers of red blood cells, as in polycythemia vera, can result in viscous blood. Extreme increases in concentrations of mature and immature white blood cells can also produce hyperviscosity. Treatment with plasma exchange is required when the clinical syndrome is symptomatic. Although plasma exchange is not a completely benign procedure, it represents the most effective method of controlling hyperviscosity.

Abstract Objective The objective of the Strategic Health IT Advanced Research Project area four (SHARPn) was to develop open-source tools that could be used for the normalization of electronic health record (EHR) data for secondary use—specifically, for high throughput phenotyping. We describe the role of Intermountain Healthcare’s Clinical Element Models ([CEMs] Intermountain Healthcare Health Services, Inc, Salt Lake City, Utah) as normalization “targets” within the project. Materials and Methods Intermountain’s CEMs were either repurposed or created for the SHARPn project. A CEM describes “valid” structure and semantics for a particular kind of clinical data. CEMs are expressed in a computable syntax that can be compiled into implementation artifacts. The modeling team and SHARPn colleagues agilely gathered requirements and developed and refined models. Results Twenty-eight “statement” models (analogous to “classes”) and numerous “component” CEMs and their associated terminology were repurposed or developed to satisfy SHARPn high throughput phenotyping requirements. Model (structural) mappings and terminology (semantic) mappings were also created. Source data instances were normalized to CEM-conformant data and stored in CEM instance databases. A model browser and request site were built to facilitate the development. Discussion The modeling efforts demonstrated the need to address context differences and granularity choices and highlighted the inevitability of iso-semantic models. The need for content expertise and “intelligent” content tooling was also underscored. We discuss scalability and sustainability expectations for a CEM-based approach and describe the place of CEMs relative to other current efforts. Conclusions The SHARPn effort demonstrated the normalization and secondary use of EHR data. CEMs proved capable of capturing data originating from a variety of sources within the normalization pipeline and serving as suitable normalization targets.

Abstract Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case–control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10−9) and Hispanic children (OR, 2.77; P = 3.78 × 10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors. Cancer Res; 75(22); 4884–94. ©2015 AACR.