Welby, John P.

OBJECTIVES: To compare three fluoroscopic methods for determining femoral rotation. METHODS: Native femoral version was measured by computed tomography in 20 intact femurs from 10 cadaveric specimens. Two Steinmann pins were placed into each left femur above and below a planned transverse osteotomy which was completed through the diaphysis. Four surgeons utilized the true lateral (TL), neck-horizontal angle (NH), and lesser trochanter profile (LTP) techniques to correct the injured femur's rotation using the intact right femur as reference, yielding 120 measurements. Accuracy was assessed by comparing the angle subtended by the two Steinmann pins before and after manipulation and comparing against version measurements of the right femur. RESULTS: Absolute mean rotational error in the fractured femur compared to its uninjured state was 6.0° (95% CI, 4.6-7.5), 6.6° (95% CI, 5.0-8.2), and 8.5° (95% CI, 6.5-10.6) for the TL, NH, and LTP techniques, respectively, without significant difference between techniques (p = 0.100). Compared to the right femur, absolute mean rotational error was 6.6° (95% CI, 1.0-12.2), 6.4° (95% CI, 0.1-12.6), and 8.9° (95% CI, 0.8-17.0) for the TL, NH, and LTP techniques, respectively, without significant difference (p = 0.180). Significantly more femurs were malrotated by >15° using the LTP method compared to the TL and NH methods (20.0% vs 2.5% and 5.0%, p = 0.030). Absolute mean error in estimating femoral rotation of the intact femur using the TL and NH methods compared to CT was 6.6° (95% confidence interval [CI], 5.1-8.2) and 4.4° (95% CI, 3.4-5.4), respectively, with significant difference between the two methods (p = 0.020). CONCLUSIONS: The true lateral (TL), neck-horizontal angle (NH), and the lesser trochanter profile (LTP) techniques performed similarly in correcting rotation of the fractured femur, but significantly more femurs were malrotated by >15° using the LTP technique. This supports preferential use of the TL or NH methods for determining femoral version intraoperatively.

Abstract Background H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. Methods We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. Results Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. Conclusions STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

Focus on residents' role in teaching and learning has become a topic of increasing interest underscored by the responsibility that physicians in training are given as facilitators of medical student rotations, supervisors of peers and patient educators. Studies demonstrate that more developed teaching skills are predictive of increased knowledge base and improved clinical skill. As a coveted competency, development of teaching skill has become an established milestone in residency programs and a requirement by regulatory agencies (ACGME, LCME) that training institutions provide more opportunities for formal Resident‐as‐Teacher programs (RAT). In keeping with the authentic learning curriculum, the Student‐as‐Teacher (SAT) program in the Department of Anatomy, Mayo Clinic offers a structured and formal near‐peer teaching opportunity to third year medical students for advancing teaching skills. The program selects an average of 5–6 applicants to participate in teaching a 7‐week Anatomy block for first year medical students in an apprenticeship‐based model that emphasizes (1) Teamwork, (2) Leadership, (3) Lifelong learning, (4) Communication, (5) Core Knowledge, and (6) Teaching Skills/Professional development through individualized mentoring, structured debriefing, and reflective diaries. The purpose of this study is to assess the effectiveness of the apprenticeship model by measuring changes in the targeted competencies in the context of teaching practice. Teaching assistants (TAs) were asked to reflect and evaluate their pre‐ and post‐teaching experience in SAT program on a visual analog scale (VAS). All 5 TAs voluntarily responded to the survey. De‐identified VAS ratings were converted into numerical data from 1 to 100. Most reported increase in perception was in the area of non‐technical skills development: providing feedback (59.7; P = 0.0009); understanding expectations and teaching skills required in medical education (39.7; P = 0.002); and understanding teamwork in teaching role (33.1; P = 0.025). Additionally, TAs appreciated increased acquisition of technical skills: knowledge in anatomy, embryology and radiology (31.4; P = 007). Thematic analysis of responses generated a list of themes which included “appreciation for learning of non‐technical skills” and “skills in providing feedback”. The role of basic science educators is extended through facilitation of future physician required competencies in early medical education. While improvement of anatomical knowledge is an obvious benefit to medical students, improvement of non‐technical skills is reinforced by opportunity of the near‐peer teaching experience. In a teaching role, non‐technical skills supported through the art of “learning by doing” provides senior medical students with an authentic experience and ability to turn the intangible into the tangible. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Abstract Background Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression. Methods A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions. Results Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%). Conclusions Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with dismal prognosis despite initial radiation therapy (RT). The clinical consequences of attempting reirradiation (reRT) in these patients to alleviate both symptomatology and improve prognosis are currently unclear. Thus, the aim of this systematic review and meta-analysis was to clarify the efficacy and safety of reRT in DIPG. METHODS Searches of 7 electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against pre-specified criteria. The incidence and duration of clinical outcomes were then extracted and pooled by means of meta-analysis from the included studies. RESULTS A total of 7 studies satisfied all criteria, describing 90 cases of DIPG in which reRT was attempted 11.8–14 months after initial RT. Based on a random-effects model, the incidences of clinical improvement and radiologic response following reRT were 87% (95% CI, 78–95%) and 69% (95% CI, 52–84%) respectively. The incidence of acute serious toxicity was 0% (95% CI, 0–4%). Pooled overall survivals from initial diagnosis, and time of reRT, were 18.0 months (95% CI, 14.2–21.7) and 6.2 months (95% CI, 5.5–7.0) respectively. CONCLUSIONS Based on these results, the clinical consequences of reRT for DIPG when administered appropriately and safely at first progression appear acceptable, and potentially favorable, based on the limited evidence in the current literature. Concerns regarding acute serious toxicity were not realized. It is likely a sub-cohort of all DIPG diagnoses will be most amenable to improved prognosis with reRT, and greater investigation is required to identify their characteristics.

Abstract BACKGROUND Although rare, the propensity for pediatric low-grade glioma (pLGG) to recur despite upfront intervention presents a management conundrum for clinicians. One novel salvage option is anti-angiogenic bevacizumab, however, its safety and efficacy in this specific demographic is poorly defined. Correspondingly, our aim was to pool systematically-identified metadata in the literature to substantiate the clinical relevance of bevacizumab in treating recurrent pLGG. METHODS Searches of 7 electronic databases from inception to June 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of loss was then pooled by random-effects meta-analysis of proportions. RESULTS Six pertinent studies described the outcomes of 110 recurrent pLGG patients managed with bevacizumab. While on-treatment, the rate of clinical response was 58% (95% CI, 43–72%), and the rate of radiographic response was 80% (95% CI, 58–96%). Additionally, the rate of serious adverse events (Grade 3 and above) was 11% (95% CI, 5–18%), with proteinuria the most common of those events. By the time patients were off-treatment, the rate of progression was estimated to be 51% (95% CI, 28–74%). Certainty of these results ranged from very low to low. CONCLUSIONS The use of bevacizumab as therapy for recurrent pLGG appears to confer appreciable clinical and radiographic response with relatively low serious adverse events risk while on-treatment. However, the long-term off-treatment benefits of this therapy have yet to be consolidated. Traditional clinical heterogeneity concerns preclude the formalization of any recommendations until larger, more standardized investigations can be performed.

AbstractFibrosing mediastinitis is a rare, often debilitating and potentially lethal disease characterized by an exuberant fibroinflammatory response within the mediastinum. Patients typically present with insidious symptoms related to compression of adjacent structures including the esophagus, heart, airways, and cardiac vessels. Fibrosing mediastinitis is most often triggered by Histoplasmosis infection; however, antifungal and anti‐inflammatory therapies are largely ineffective. While structural interventions aimed at alleviating obstruction can provide significant palliation, surgical interventions are challenging with high mortality and clinical experience with percutaneous interventions is limited. Here, we will review the presentation, natural history, and treatment of fibrosing mediastinitis, placing particular emphasis on catheter‐based therapies.