Evaluation of Intraoperative Fluoroscopic Techniques to Estimate Femoral Rotation: A Cadaveric Study.

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.

Noncompliance with Guidelines on the Use of Ultrasound and Pentoxifylline in the Treatment of Venous Ulcers in a Rural Health Care System.

Guidelines based on randomized controlled data recommend patients with newly diagnosed venous leg ulcers (VLUs) to undergo venous reflux duplex ultrasound (US) and be considered for treatment with pentoxifylline to accelerate ulcer healing. A retrospective review was conducted of 2,061 patients with VLU diagnosed between 2011 and 2020 in a rural health care system to identify factors associated with increased or decreased likelihood of being prescribed venous reflux duplex US and pentoxifylline. Venous reflux duplex US (16%) and pentoxifylline (0.7%) were prescribed infrequently. Evaluation by a vascular specialist was associated with a significantly increased frequency of undergoing venous reflux duplex US (5%-38%). Seeing a wound care specialist was associated with an increased frequency of being prescribed pentoxifylline (0.7%-1.4%). Increased referral to specialists and/or referring clinician education on guideline-based care may be of benefit to patients with VLUs. Pentoxifylline seems underused, even by specialists. Further study is needed to confirm these findings and determine whether they are generalizable.

Dorsoventral splitting of the infundibulum in a child with pituitary hypoplasia.

Pituitary development arises from ectodermal tissue creating Rathke's pouch and ultimately the adenohypophysis anteriorly whereas neuroectodermal tissue arising from the diencephalon creates the neurohypophysis posteriorly. Alterations in pituitary development can lead to hormonal dysregulation and dysfunction. Following clinical suspicion of pituitary endocrinopathy, MRI plays a vital role in identifying and characterizing underlying structural abnormalities of the pituitary gland, as well as any associated extrapituitary findings. Here we report a case of an 18-month-old female presenting with short stature and growth hormone deficiency. MRI was notable for a shallow sella turcica, a hypoplastic adenohypophysis, thin pituitary stalk, and ectopic neurohypophysis. Interestingly, the pituitary stalk was noted to split dorsoventrally with a split pituitary bright spot and T1 hypointense lobe hypothesized to represent separation of the posterior pituitary lobes.

STAT3 is a biologically relevant therapeutic target in H3K27M-mutant diffuse midline glioma.

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.

Prospective multicenter assessment of patient preferences for properties of gadolinium-based contrast media and their potential socioeconomic impact in a screening breast MRI setting.

OBJECTIVE: It is unknown how patients prioritize gadolinium-based contrast media (GBCM) benefits (detection sensitivity) and risks (reactions, gadolinium retention, cost). The purpose of this study is to measure preferences for properties of GBCM in women at intermediate or high risk of breast cancer undergoing annual screening MRI. METHODS: An institutional reviewed board-approved prospective discrete choice conjoint survey was administered to patients at intermediate or high risk for breast cancer undergoing screening MRI at 4 institutions (July 2018-March 2020). Participants were given 15 tasks and asked to choose which of two hypothetical GBCM they would prefer. GBCMs varied by the following attributes: sensitivity for cancer detection (80-95%), intracranial gadolinium retention (1-100 molecules per 100 million administered), severe allergic-like reaction rate (1-19 per 100,000 administrations), mild allergic-like reaction rate (10-1000 per 100,000 administrations), out-of-pocket cost ($25-$100). Attribute levels were based on published values of existing GBCMs. Hierarchical Bayesian analysis was used to derive attribute "importance." Preference shares were determined by simulation. RESULTS: Response (87% [247/284]) and completion (96% [236/247]) rates were excellent. Sensitivity (importance = 44.3%, 95% confidence interval = 42.0-46.7%) was valued more than GBCM-related risks (mild allergic-like reaction risk (19.5%, 17.9-21.1%), severe allergic-like reaction risk (17.0%, 15.8-18.1%), intracranial gadolinium retention (11.6%, 10.5-12.7%), out-of-pocket expense (7.5%, 6.8-8.3%)). Lower income participants placed more importance on cost and less on sensitivity (p < 0.01). A simulator is provided that models GBCM preference shares by GBCM attributes and competition. CONCLUSIONS: Patients at intermediate or high risk for breast cancer undergoing MRI screening prioritize cancer detection over GBCM-related risks, and prioritize reaction risks over gadolinium retention. KEY POINTS: • Among women undergoing annual breast MRI screening, cancer detection sensitivity (attribute "importance," 44.3%) was valued more than GBCM-related risks (mild allergic reaction risk 19.5%, severe allergic reaction risk 17.0%, intracranial gadolinium retention 11.6%, out-of-pocket expense 7.5%). • Prospective four-center patient preference data have been incorporated into a GBCM choice simulator that allows users to input GBCM properties and calculate patient preference shares for competitor GBCMs. • Lower-income women placed more importance on out-of-pocket cost and less importance on cancer detection (p < 0.01) when prioritizing GBCM properties.

Evaluation of Outcomes Following Pulmonary Artery Stenting in Fibrosing Mediastinitis.

PURPOSE: Fibrosing mediastinitis is a rare disease characterized by fibrosis of mediastinal structures with subsequent constriction of the bronchi and pulmonary vessels leading to potential respiratory compromise and death. Presently, there is no effective curative treatment with available treatments focused on reducing symptomology, including placement of pulmonary artery stents. Limited studies examine the use of stents in fibrosing mediastinitis. Given this knowledge gap, we assessed stent patency, hemodynamics, complications, and secondary outcomes of clinical improvement of pulmonary artery stenting for fibrosing mediastinitis. MATERIALS AND METHODS: Nine patients with fibrosing mediastinitis and pulmonary artery stents were retrospectively identified for inclusion (six females, three males; mean age 44.17 years, range 13-68; total 13 primary stents) from 2005 to 2018. Eight patients had history of PH. All patients had dyspnea on presentation. Seven patients had ventilation/perfusion studies demonstrating impairment. Results from computed tomography and echocardiography studies were collected to assess patency and physiologic response. RESULTS: All patients received initial angioplasty and stenting of the right pulmonary artery (10 stents). Two patients underwent additional left-sided intervention (3 stents). Stenting significantly increased lesion luminal patency (54-79%; P < 0.005) and reduced systolic pressure gradients across stenoses (mean -9.38 mmHg; P < 0.005). Primary patency at one year was 90%. Two stents received reintervention at 276 and 497 days. 89% reported improvement in dyspnea in the initial post-stenting period. There were no mortalities or major complications. CONCLUSION: Pulmonary artery stenting improves vascular patency and provides symptomatic relief in patients with fibrosing mediastinitis.

Efficacy and safety of bevacizumab in progressive pediatric low-grade glioma: a systematic review and meta-analysis of outcome rates.

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.

Pseudoprogression after radiation therapies for low grade glioma in children and adults: A systematic review and meta-analysis.

BACKGROUND: Pseudoprogression (PsP) following radiation therapy (RT) for low grade glioma (LGG, WHO grade I and II), including both photon-based intensity-modulated RT (IMRT) and proton beam therapy (PBT), has been described. However, its incidence has yet to be consolidated. The aim of this systematic review and meta-analysis was to pool the current literature and establish the incidence of PsP in these groups to better inform surveillance protocols in the future. METHODS: Searches of 4 electronic databases from inception to April 2019 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. The incidence of outcomes was then extracted and pooled by random-effects meta-analysis of proportions. RESULTS: A total of 5 pediatric and 4 adult cohort studies describing 517 and 424 LGG subjects respectively satisfied all selection criteria. The estimated incidences of PsP in pediatric subjects following IMRT and PBT were 33% (95% CI, 20-47%) and 34% (95% CI, 23-45%) respectively, with no difference between modalities. The estimated incidences of PsP in adult subjects following IMRT and PBT were 18% (95% CI, 12-25%) and 30% (95% CI, 21-39%) respectively, with PsP significantly less common following IMRT than PBT (P-heterogeneity = 0.04). Median time from radiation initiation to first detection of PsP ranged from 6 to 12 months across all modalities and age groups. CONCLUSIONS: The incidence of PsP following both IMRT and PBT in the management of pediatric and adult LGG is not negligible, and should therefore be recognized as a pertinent sequala within the first year at least following treatment. However, a lack of accountability in the current literature for the differences in PsP interpretation, radiation modality, radiobiology and molecular biology of LGGs precludes any firm surveillance recommendations at this time.

Current Murine Models and New Developments in H3K27M Diffuse Midline Gliomas.

Diffuse Midline Gliomas with Histone 3-Lysine-27-Methionine (H3K27M) mutation constitute the majority of Diffuse Intrinsic Pontine Glioma (DIPG), which is the most aggressive form of pediatric glioma with a dire prognosis. DIPG are lethal tumors found in younger children with a median survival <1 year from diagnosis. Discovery of the characteristic H3K27M mutations offers opportunity and hope for development of targeted therapies for this deadly disease. The H3K27M mutation, likely through epigenetic alterations in specific H3 lysine trimethylation levels and subsequent gene expression, plays a significant role in pathogenesis of DIPG. Animal models accurately depicting molecular characteristics of H3K27M DIPG are important to elucidate underlying pathologic events and for preclinical drug evaluation. Here we review the past and present DIPG models and describe our efforts developing patient derived cell lines and xenografts from pretreated surgical specimens. Pre-treated surgical samples retain the characteristic genomic and phenotypic hallmarks of DIPG and establish orthotopic tumors in the mouse brainstem that recapitulate radiographic and morphological features of the original human DIPG tumor. These models that contain the H3K27M mutation constitute a valuable tool to further study this devastating disease and ultimately may uncover novel therapeutic vulnerabilities.

Reirradiation for diffuse intrinsic pontine glioma: a systematic review and meta-analysis.

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 seven electronic databases from inception to January 2019 were conducted following the appropriate guidelines. Articles were screened against prespecified 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 that a subcohort of all DIPG diagnoses will be most amenable to improve prognosis with reRT, and greater investigation is required to identify their characteristics.

Catheter based treatments for fibrosing mediastinitis.

Fibrosing 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.

The progeroid gene BubR1 regulates axon myelination and motor function.

Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.

Gadd45b Mediates Electroconvulsive Shock Induced Proliferation of Hippocampal Neural Stem Cells.

BACKGROUND: Electroconvulsive shock (ECS), also known as an electroconvulsive therapy (ECT), is an effective and safe treatment for neuropsychiatric disorders including pharmacoresistant major depressive disorder. Previous research in animal models suggests ECS efficacy is achieved by Gadd45b-mediated increases in adult hippocampal neurogenesis. OBJECTIVE/HYPOTHESIS: The present study aims to delineate the role of Gadd45b in mediating proliferation of neural stem cell types including quiescent radial glia-like (RGL) and amplifying non-radial glia-like (non-RGL) neural precursors following ECS. METHODS: RGL and non-RGL neural stem cell populations defined by co-localization of MCM2+ and nestin+ cells and morphologically by the presence of radial processes were stereologically analyzed. RESULTS: ECS increased hippocampal density of both quiescent RGLs and amplifying non-RGLs. CONCLUSIONS: Gadd45b mediates the action of ECS-induced proliferation through activation of quiescent neural stem cells.