Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia is an aggressive myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Seventy-five percent of patients harbor mutations in the NF1, NRAS, KRAS, or PTPN11 genes, which encode components of Ras signaling networks. Using single nucleotide polymorphism arrays, we identified a region of 11q isodisomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations in 27 of 159 JMML samples. Thirteen of these mutations alter codon Y371. In this report, we also demonstrate that CBL and RAS/PTPN11 mutations were mutually exclusive in these patients. Moreover, the exclusivity of CBL mutations with respect to other Ras pathway-associated mutations indicates that CBL may have a role in deregulating this key pathway in JMML.

Promoting Shared Decision-Making Behaviors During Inpatient Rounds: A Multimodal Educational Intervention.

PURPOSE: To estimate the effectiveness of a multimodal educational intervention to increase use of shared decision-making (SDM) behaviors by inpatient pediatric and internal medicine hospitalists and trainees at teaching hospitals at Stanford University and the University of California, San Francisco. METHOD: The 8-week Patient Engagement Project Study intervention, delivered at four services between November 2014 and January 2015, included workshops, campaign messaging, report cards, and coaching. For 12-week pre- and postintervention periods, clinician peers used the nine-point Rochester Participatory Decision-Making Scale (RPAD) to evaluate rounding teams' SDM behaviors with patients during ward rounds. Eligible teams included a hospitalist and at least one trainee (resident, intern, medical student), in addition to nonphysicians. Random-effects models were used to estimate intervention effects based on RPAD scores that sum points on nine SDM behaviors per patient encounter. RESULTS: In total, 527 patient encounters were scored during 175 rounds led by 49 hospitalists. Patient and team characteristics were similar across pre- and postintervention periods. Improvement was observed on all nine SDM behaviors. Adjusted for the hierarchical study design and covariates, the mean RPAD score improvement was 1.68 points (95% CI, 1.33-2.03; P < .001; Cohen d = 0.82), with intervention effects ranging from 0.7 to 2.5 points per service. Improvements were associated with longer patient encounters and a higher percentage of trainees per team. CONCLUSIONS: The intervention increased behaviors supporting SDM during ward rounds on four independent services. The findings recommend use of clinician-focused interventions to promote SDM adoption in the inpatient setting.

Shared Decision-Making During Inpatient Rounds: Opportunities for Improvement in Patient Engagement and Communication.

BACKGROUND: Shared decision-making (SDM) improves patient engagement and may improve outpatient health outcomes. Little is known about inpatient SDM. OBJECTIVE: To assess overall quality, provider behaviors, and contextual predictors of SDM during inpatient rounds on medicine and pediatrics hospitalist services. DESIGN: A 12-week, cross-sectional, single-blinded observational study of team SDM behaviors during rounds, followed by semistructured patient interviews. SETTING: Two large quaternary care academic medical centers. PARTICIPANTS: Thirty-five inpatient teams (18 medicine, 17 pediatrics) and 254 unique patient encounters (117 medicine, 137 pediatrics). INTERVENTION: Observational study. MEASUREMENTS: We used a 9-item Rochester Participatory Decision-Making Scale (RPAD) measured team-level SDM behaviors. Same-day interviews using a modified RPAD assessed patient perceptions of SDM. RESULTS: Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient's hospital stay, and amount of time rounding per patient (P < .05). The most frequently observed behaviors across all services included explaining the clinical issue and matching medical language to the patient's level of understanding. The least frequently observed behaviors included checking understanding of the patient's point of view, examining barriers to follow-through, and asking if the patient has any questions. Patients and guardians had substantially higher ratings for SDM quality compared to peer observers (7.2 vs 4.4 out of 9). CONCLUSIONS: Important opportunities exist to improve inpatient SDM. Team size, number of learners, patient census, and type of decision being made did not affect SDM, suggesting that even large, busy services can perform SDM if properly trained.

The SDM 3 Circle Model: A Literature Synthesis and Adaptation for Shared Decision Making in the Hospital.

Patient engagement through shared decision-making (SDM) is increasingly seen as a key component for patient safety, patient satisfaction, and quality of care. Current SDM models do not adequately account for medical and environmental contexts, which may influence medical decisions in the hospital. We identified leading SDM models and reviews to inductively construct a novel SDM model appropriate for the inpatient setting. A team of medicine and pediatric hospitalists reviewed the literature to integrate core SDM concepts and processes and iteratively constructed a synthesized draft model. We then solicited broad SDM expert feedback on the draft model for validation and further refinement. The SDM 3 Circle Model identifies 3 core categories of variables that dynamically interact within an "environmental frame." The resulting Venn diagram includes overlapping circles for (1) patient/family, (2) provider/team, and (3) medical context. The environmental frame includes all external, contextual factors that may influence any of the 3 circles. Existing multistep SDM process models were then rearticulated and contextualized to illustrate how a shared decision might be made. The SDM 3 Circle Model accounts for important environmental and contextual characteristics that vary across settings. The visual emphasis generated by each "circle" and by the environmental frame direct attention to often overlooked interactive forces and has the potential to more precisely define, promote, and improve SDM. This model provides a framework to develop interventions to improve quality and patient safety through SDM and patient engagement for hospitalists.

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates.

Progress in understanding the molecular pathogenesis of human myeloproliferative disorders (MPDs) has led to guidelines incorporating genetic assays with histopathology during diagnosis. Advances in flow cytometry have made it possible to simultaneously measure cell type and signaling abnormalities arising as a consequence of genetic pathologies. Using flow cytometry, we observed a specific evoked STAT5 signaling signature in a subset of samples from patients suspected of having juvenile myelomonocytic leukemia (JMML), an aggressive MPD with a challenging clinical presentation during active disease. This signature was a specific feature involving JAK-STAT signaling, suggesting a critical role of this pathway in the biological mechanism of this disorder and indicating potential targets for future therapies.