Monoclonal gammopathies: Electronic subspecialty consultation.

IMPORTANCE: Electronic consultation (e-consult) is an important component of care for patients in the Veterans Health Administration who require subspecialty consultation but not urgent face-to-face evaluation. Monoclonal gammopathy of undetermined significance (MGUS) is a common reason for e-consult. While often benign, MGUS requires careful evaluation and persistent surveillance over time. OBJECTIVE: To identify areas to improve MGUS care delivery by e-consult. METHODS: We performed a retrospective review of our e-consult database and identified a cohort of 152 MGUS patients triaged for e-consult over a 5-year period (2010-2014). RESULTS: The median time to completion of an e-consult was 2 days. Ninety-six percent of MGUS e-consults had a hemoglobin >10 g/dL, and 90% had a creatinine <2 mg/dL. While the majority of e-consults were low risk, paraprotein surveillance varied over time and tracked with consult utilization. With a median follow-up of 44 months, there were 6 documented progression events, representing a mean rate of progression of 1% per year. CONCLUSIONS: E-consult is a helpful mechanism for the evaluation of MGUS, reducing the need for outpatient appointments. However, timely risk stratification and persistent surveillance over time are critical for e-consult to work well.

Preclinical Medical Student Hematology/Oncology Education Environment.

To better prepare medical students to care for patients in today's changing health-care environment as they transition to continuing their education as residents, many US medical schools have been reviewing and modifying their curricula and are considering integration of newer adult learning techniques, including team-based learning, flipped classrooms, and other active learning approaches (Assoc Am Med Coll. 2014). Directors of hematology/oncology (H/O) courses requested an assessment of today's H/O education environment to help them respond to the ongoing changes in the education content and environment that will be necessary to meet this goal. Several recommendations for the improvement of cancer education resulted from American Association for Cancer Education's (ACCE's) "Cancer Education Survey II" including a call for medical schools to evaluate the effectiveness of current teaching methods in achieving cancer education objectives (Chamberlain et al. J Cancer Educ 7(2):105-114.2014). To understand the current environment and resources used in medical student preclinical H/O courses, an Internet-based, Survey Monkey®-formatted, questionnaire focusing on nine topic areas was distributed to 130 United States Hematology/Oncology Course Directors (HOCDs). HOCDs represent a diverse group of individuals who work in variably supportive environments and who are variably satisfied with their position. Several aspects of these courses remain relatively unchanged from previous assessments, including a predominance of traditional lectures, small group sessions, and examinations that are either written or computer-based. Newer technology, including web-based reproduction of lectures, virtual microscopes, and availability of additional web-based content has been introduced into these courses. A variety of learner evaluation and course assessment approaches are used. The ultimate effectiveness and impact of these changes needs to be determined.

Acquired von Willebrand syndrome in a patient with monoclonal gammopathy of undetermined significance.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that typically presents as mucocutaneous bleeding in individuals with no personal or family history of bleeding disorder. Here we present a case in which a patient presented with profound epistaxis and was found to have AVWS in the setting of monoclonal gammopathy of undetermined significance (MGUS).

Teaching hematology to second year medical students: results of a national survey of hematology course directors.

Increasing clinical productivity expectations at academic medical centers and new faculty effort reporting requirements for NIH-supported investigators challenge the tradition of faculty volunteerism for medical student teaching. To better define the structure, content, and financial support of second year medical school hematology courses nationwide, we mailed a survey to the hematology course directors at 85 of the 125 accredited US medical schools. The 58 course directors who returned the survey represent all regions of the US and both public and private medical schools. Median class size was 150 students (range 40-200), and some courses included a substantial proportion (up to 33%) of other types of students. The median number of hours per course was 33 h (range 8 to 74). Approximately 50% of the total teaching time was devoted to lecture (range 5 to 100%). Web-based teaching was used by 62% of course directors. The median number of faculty responsible for teaching the second year hematology course was 12 (range 1-36). The hematology course directors identified a number of obstacles, including difficulty in recruiting teachers, the lack of well-defined content, and the very modest budget (less than $1,500 for most courses). Only three of the course directors indicated that they received salary support for this role. These findings suggest that a national effort to define learning objectives for the hematology courses and to share teaching materials among medical schools is warranted. Little financial support is provided for the hematology course, and these findings compel the identification of resources to pay faculty for teaching medical student required courses.

AMG531 stimulates megakaryopoiesis in vitro by binding to Mpl.

Thrombopoietin (TPO) plays a pivotal role in megakaryopoiesis. TPO initiates its biological effects by binding to its receptor Mpl. A recombinant protein consisting of a carrier Fc domain linked to multiple Mpl-binding domains was constructed, and is called AMG531. To define the biological activity of AMG531, we examined the ability of AMG531 to support CFU-Meg growth and to promote megakaryocyte maturation in vitro. AMG531 stimulates CFU-Meg growth in a dose-dependent manner, and acts in concert with erythropoietin, stem cell factor, interleukin-3, and interleukin-6 to enhance CFU-Meg growth, similar to parallel experiments with TPO. AMG531-stimulated serum-free liquid cultures support the development of mature polyploid megakaryocytes with a predominant DNA content of 32 N and 64 N, identical to that of parallel TPO-stimulated cultures. Competitive binding experiments show that AMG531 effectively competes with 125I-TPO for binding to BaF3-Mpl cells or normal platelets. Treatment of BaF3-Mpl cells with AMG531 or with TPO resulted in rapid tyrosine phosphorylation of Mpl, JAK2, and STAT5. These results indicate that AMG531 is a potent stimulant of megakarypoiesis in vitro, and provide support for its further characterization in vivo.

Internalization of the thrombopoietin receptor is regulated by 2 cytoplasmic motifs.

Receptor-mediated internalization appears to be the primary mean of regulating the plasma level of thrombopoietin (TPO). However, the processes that regulate Mpl internalization have not previously been described. Using the cytokine-dependent cell line BaF3, we have identified 2 distinct motifs within the cytoplasmic domain of Mpl that underlie ligand-dependent internalization. Removal of the fourth cytoplasmic tyrosine residue by deletion or truncation results in a significant decrease in maximal internalization. The remaining receptor internalization is abrogated by deletion of cytoplasmic residues 54-69, which include the core box2 region (L54L55E56I57L58) and the only dileucine motifs (L54L55 and I57L58) within the cytoplasmic domain of Mpl. Receptor internalization mediated by this latter subdomain does not require Jak2 activation. Furthermore, TPO-stimulated cellular proliferation appears to be directly correlated with receptor internalization, indicating that internalization of the TPO/Mpl complex may be essential for normal signal transduction. Finally, we have demonstrated that upon removal of TPO from the supernatant, Mpl promptly reappears on the cell surface, suggesting that a pool of intracellular Mpl can be rapidly recycled to the cell surface. These data help identify the receptor motifs involved in TPO-induced internalization of Mpl and suggest that Mpl translocation may be necessary for normal cellular proliferation.

Identification and characterization of an isoform of murine Mpl.

A new isoform of the full-length murine thrombopoietin (Tpo) receptor was isolated from a murine spleen cDNA library. This isoform, c-mpl-II, differs from full-length c-mpl (c-mpl-I) by virtue of deletion of 180 nucleotides that encode 60 amino acids located in the extracellular domain of Mpl. Normal murine megakaryocytes were found to express both c-mpl-I and c-mpl-II transcripts. BaF3 cells transfected with c-mpl-I expressed a 95 kDa protein that was displayed on the cell surface and bound 125I-Tpo. BaF3 cells transfected with c-mpl-II expressed a 70 kDa protein. However, these cells were not able to bind 125I-Tpo and surface display of Mpl-II could not be detected. In summary, c-mpl-II is an isoform of murine Mpl expressed by megakaryocytes that lacks a 60 amino acid region required for surface expression of the protein.