Citations

Abstract BACKGROUND: Patients with pleomorphic xanthoastrocytoma (PXA) routinely undergo multiple procedures to ensure recurrence-free survival and are resultantly at increased risk of experiencing perioperative complications (regional, medical, and/or neurological), a combination of which has not been recorded in previous studies. OBJECTIVE: To determine perioperative outcomes in a cohort of patients (adult and pediatric) with intracranial PXA. METHODS: We retrospectively identified 39 patients who underwent surgery at our institution for intracranial PXA between 1994 and 2011. Demographic factors were recorded along with Karnofsky Performance Status (KPS), complications, and mortality. RESULTS: Mean patient age was 31 years at the most recent surgery. A majority of patients (24; 62%) had multiple surgeries with a mean of 2 operations per patient. Eleven PXAs (28%) were malignant (grade III or IV). Perioperative complications included permanent neurological worsening in 4 patients (10%), regional complications in 4 (10%), and medical complications in 3 (8%). Preoperative KPS was ≥70 in 34 of 38 patients (89%). Long-term postoperative KPS was ≥70 in 36 of 37 patients (97%), suggesting good functional outcomes. There was no perioperative mortality, but 7 patients (18%) died of tumor progression. Patients with malignant PXAs trended toward higher risk of regional complications (3 of 11 patients [27%]; P = .06), received adjuvant therapy more often (10 of 11 patients [91%]; P < .001), had higher mortality from tumor progression (7 of 11 patients [64%]; P < .001), and were significantly larger (mean, 6.05 ± 0.73 cm standard error of the mean; n = 7; P < .01). CONCLUSION: Both pediatric and adult PXAs may be resected with good functional outcomes. Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality. Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy.

Abstract Obesity is a major risk factor for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Expansion of the adipose mass requires adipocyte precursor cells that originate from multipotent adipose-derived stromal cells (ASCs), which in turn also participate in repair activities. ASC function might decline in a disease milieu, but it remains unclear whether ASC function varies during the development of obesity. We tested the hypothesis that microenvironmental inflammatory changes during development of metabolic disorders in obesity affect ASC function. Domestic pigs were fed with an atherogenic (n = 7) or normal (n = 7) diet for 16 weeks. Abdominal adipose tissue biopsies were collected after 8, 12, and 16 weeks of diet for ASC isolation and immunohistochemistry of in situ ASCs and tumor necrosis factor-α (TNF-α). Longitudinal changes in proliferation, differentiation, and anti-inflammatory functions of ASCs were assessed. At 16 weeks, upregulated TNF-α expression in adipose tissue from obese pigs was accompanied by increased numbers of adipocyte progenitors (CD24+/CD34+) in adipose tissue and enlarged adipocyte size. In vitro, ASCs from obese pigs showed enhanced adipogenic and osteogenic propensity, which was abolished by anti-TNF-α treatment, whereas lean ASCs treated with TNF-α showed enhanced adipogenesis. Furthermore, obese ASCs showed increased senescence compared with lean ASCs, whereas their immunomodulatory capacity was preserved. Adipose tissue inflammation promotes an increase in resident adipocyte progenitors and upregulated TNF-α enhances ASC adipogenesis. Thus, adipose tissue anti-inflammatory strategies might be a novel target to attenuate obesity and its complications. Significance Adipose-derived stromal cell (ASC) function might decline in a disease milieu, but it remains unclear whether ASC function varies during the development of obesity. This study tested the hypothesis that microenvironmental inflammatory changes during development of metabolic disorders in obesity affect ASC function. It was found that ASCs show increased propensity for differentiation into adipocytes, which is partly mediated by upregulated tumor necrosis factor-α (TNF-α), likely in their adipose tissue microenvironment. Furthermore, TNF-α magnified obese ASC senescence, although it did not regulate their anti-inflammatory properties. Thus, adipose tissue inflammation might be a novel therapeutic target to avert ASC maldifferentiation and senescence.

Abstract Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti–programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti–PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS &lt;90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS &lt; 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02–1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569–73. ©2016 AACR.

Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep venous thrombosis (DVT), is a major cause of morbidity and mortality of particular relevance for intensivists and hospitalists. Acute VTE is usually managed with parenteral unfractionated heparin or low-molecular-weight heparin, followed by an oral vitamin K antagonist. Data are lacking for optimal treatment of less common occurrences, such as upper extremity DVT, and for approaches such as thrombolysis for PE associated with early signs of hemodynamic compromise or inferior vena cava filters when anticoagulation is contraindicated. Direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are now added to the armamentarium of agents available for acute management of VTE and/or reducing the risk of recurrence. This review outlines an algorithmic approach to acute VTE treatment: from aggressive therapies when anticoagulation may be inadequate, to alternative choices when anticoagulation is contraindicated, to anticoagulant options in the majority of patients in whom anticoagulation is appropriate. Evidence-based guidelines and the most recent DOAC clinical trial data are discussed in the context of the standard of care. Situations and treatment approaches for which data are unavailable or insufficient are identified. VTE therapy in care transitions is discussed, as are choices for secondary prevention.

Background Ischemic stroke is a time-sensitive disease, with improved outcomes associated with decreased time from onset to treatment. It was hypothesised that ambulance-based assessment of the National Institutes of Health Stroke Scale (NIHSS) using a Health Insurance Portability and Accountability Act (HIPAA)–compliant mobile platform immediately prior to arrival is feasible. Methods This is a proof-of-concept feasibility pilot study in two phases. The first phase consisted of an ambulance-equipped HIPAA-compliant video platform for remote NIHSS assessment of a simulated stroke patient. The second phase consisted of remote NIHSS assessment by a hospital-based neurologist of acute stroke patients en route to our facility. Five ambulances were equipped with a 4G/LTE-enabled tablet preloaded with a secure HIPAA-compliant telemedicine application. Secondary outcomes assessed satisfaction of staff with the remote platform. Results Phase one was successful in the assessment of three out of three simulated patients. Phase two was successful in the assessment of 10 out of 11 (91%) cases. One video attempt was unsuccessful because local LTE was turned off on the device. The video signal was dropped transiently due to weather, which delayed NIHSS assessment in one case. Average NIHSS assessment time was 7.6 minutes (range 3–9.8 minutes). Neurologists rated 83% of encounters as ‘satisfied’ to ‘very satisfied’, and the emergency medical service (EMS) rated 90% of encounters as ‘satisfied’ to ‘very satisfied’. The one failed video attempt was associated with ‘poor’ EMS satisfaction. Conclusion This proof-of-concept pilot demonstrates that remote ambulance-based NIHSS assessment is feasible. This model could reduce door-to-needle times by conducting prehospital data collection.

ABSTRACT Injury to the joint provokes a number of local pathophysiological changes, including synthesis of inflammatory cytokines, death of chondrocytes, breakdown of the extra‐cellular matrix of cartilage, and reduced synthesis of matrix macromolecules. These processes combine to engender the subsequent development of post‐traumatic osteoarthritis (PTOA). To prevent this from happening, it is necessary to inhibit these disparate responses to injury; given their heterogeneity, this is challenging. However, dexamethasone has the necessary pleiotropic properties required of a drug for this purpose. Using in vitro models, we have shown that low doses of dexamethasone sustain the synthesis of cartilage proteoglycans while inhibiting their breakdown after injurious compression in the presence or absence of inflammatory cytokines. Under these conditions, dexamethasone is non‐toxic and maintains the viability of chondrocytes exposed chronically to such cytokines as interleukin (IL) ‐1, IL‐6, and tumor necrosis factor‐α. Moreover, the anti‐inflammatory properties of dexamethasone have been appreciated for decades. In view of this information, we have initiated a pilot clinical study to determine whether a single, intra‐articular injection of dexamethasone into the wrist shows promise in preventing PTOA after intra‐articular fracture of the distal radius. CLINICAL SIGNIFICANCE: Suppressing the various etiopathophysiological responses to injury in the joint is an attractive strategy for lowering the clinical burden of PTOA. The intra‐articular administration of dexamethasone soon after injury offers a simple and inexpensive means of accomplishing this. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:406–411, 2017.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.

Ebstein anomaly of the tricuspid valve (EA) can be associated with left ventricular non‐compaction (LVNC), a rare congenital cardiomyopathy. We report a 2 year‐old female with EA and severe tricuspid regurgitation, LVNC, pulmonary hypertension, and chronic biventricular systolic heart failure, who died during evaluation for cardiac transplantation. Gene panel testing revealed a heterozygous de novo missense mutation in TPM1, which encodes the cardiac sarcomeric thin filament protein α‐tropomyosin. The c.475G>A variant results in a p.Asp159Asn substitution, altering a highly conserved residue predicted to be damaging to protein structure and function. TPM1 is the second gene linked to EA with LVNC in humans, implicating overlap in the molecular basis of structural and myopathic heart disease. © 2016 Wiley Periodicals, Inc.

Both vitamin D deficiency and cognitive impairment are common in patients with chronic kidney disease (CKD). Vitamin D exerts neuroprotective and regulatory roles in the central nervous system. Hypovitaminosis D has been associated with muscle weakness and bone loss, cardiovascular diseases (hypertension, diabetes and hyperlipidemia), inflammation, oxidative stress, immune suppression and neurocognitive impairment. The combination of hypovitaminosis D and CKD can be even more debilitating, as cognitive impairment can develop and progress through vitamin D-associated and CKD-dependent/independent processes, leading to significant morbidity and mortality. Although an increasingly recognized comorbidity in CKD, cognitive impairment remains underdiagnosed and often undermanaged. Given the association of cognitive decline and hypovitaminosis D and their deleterious effects in CKD patients, determination of vitamin D status and when appropriate, supplementation, in conjunction with neuropsychological screening, should be considered integral to the clinical care of the CKD population.