Sequential appetite suppression by oral and visceral feedback to the brainstem.

The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge is to understand how these circuits transform the sensory signals generated during feeding into dynamic control of behaviour. The caudal nucleus of the solitary tract (cNTS) is the first site in the brain where many meal-related signals are sensed and integrated1-4, but how the cNTS processes ingestive feedback during behaviour is unknown. Here we describe how prolactin-releasing hormone (PRLH) and GCG neurons, two principal cNTS cell types that promote non-aversive satiety, are regulated during ingestion. PRLH neurons showed sustained activation by visceral feedback when nutrients were infused into the stomach, but these sustained responses were substantially reduced during oral consumption. Instead, PRLH neurons shifted to a phasic activity pattern that was time-locked to ingestion and linked to the taste of food. Optogenetic manipulations revealed that PRLH neurons control the duration of seconds-timescale feeding bursts, revealing a mechanism by which orosensory signals feed back to restrain the pace of ingestion. By contrast, GCG neurons were activated by mechanical feedback from the gut, tracked the amount of food consumed and promoted satiety that lasted for tens of minutes. These findings reveal that sequential negative feedback signals from the mouth and gut engage distinct circuits in the caudal brainstem, which in turn control elements of feeding behaviour operating on short and long timescales.

Increasing Health Risks During Outdoor Sports Due To Climate Change in Texas: Projections Versus Attitudes.

Extreme heat is a recognized threat to human health. This study examines projected future trends of multiple measures of extreme heat across Texas throughout the next century, and evaluates the expected climate changes alongside Texas athletic staff (coach and athletic trainer) attitudes toward heat and climate change. Numerical climate simulations from the recently published Community Earth System Model version 2 and the Climate Model Intercomparison Project were used to predict changes in summer temperatures, heat indices, and wet bulb temperatures across Texas and also within specific metropolitan areas. A survey examining attitudes toward the effects of climate change on athletic programs and student athlete health was also distributed to high-school and university athletic staff. Heat indices are projected to increase beyond what is considered healthy/safe limits for outdoor sports activity by the mid-to-late 21st century. Survey results reveal a general understanding and acceptance of climate change and a need for adjustments in accordance with more dangerous heat-related events. However, a portion of athletic staff still do not acknowledge the changing climate and its implications for student athlete health and their athletic programs. Enhancing climate change and health communication across the state may initiate important changes to athletic programs (e.g., timing, duration, intensity, and location of practices), which should be made in accordance with increasingly dangerous temperatures and weather conditions. This work employs a novel interdisciplinary approach to evaluate future heat projections alongside attitudes from athletic communities toward climate change.

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study.

BACKGROUND: Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE: To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS: An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS: A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION: AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.

Clinical and radiographic adverse events after Gamma Knife radiosurgery for brainstem lesions: A dosimetric analysis.

OBJECTIVES: To analyze the association between dosvolume relationships and adverse events in brainstem lesions treated with Gamma Knife radiosurgery (GKRS). METHODS: Treatment plans were generated on BrainLab Elements and GammaPlan software. Dosimetric data were analyzed as continuous variables for patients who received GKRS to brain metastases or arteriovenous malformations (AVM) within or abutting the brainstem. Adverse events were classified as clinical and/or radiographic. Logistic and cox regression were used to assess the relationship between dosimetric variables and adverse events. RESULTS: Sixty-one patients who underwent single fraction GKRS for brain metastases or AVM were retrospectively analyzed. Median age was 62 years (range: 12-92 years) and the median prescription dose was 18 Gy (range: 13-25 Gy). Median follow-up was 6months. Clinical and radiographic complications were seen in ten (16.4%) and 17 (27.9%) patients, respectively. On logistic regression, increasing D05% was found to be associated with an increased probability of developing a clinical complication post-GKRS (OR: 1.18; 95% CI: 1.01-1.39; p = 0.04). Furthermore, mean brainstem dose (HR: 1.43; 95% CI: 1.05-1.94; p < 0.02), D05% (HR: 1.09; 95% CI: 1.01-1.18; p = 0.03), and D95% (HR: 2.37; 95% CI: 0.99-5.67; p = 0.05) were associated with an increased hazard of experiencing post-GKRS complications over time. CONCLUSIONS: Increasing D05% to the brainstem is associated with an increased risk of developing clinical complications. Clinicians may consider this parameter in addition to fractionated stereotactic radiation therapy when well-established dose constraints are not met in this patient population. Additional data are needed to further validate these findings.

The impact of preradiosurgery embolization on intracranial arteriovenous malformations: a matched cohort analysis based on de novo lesion volume.

OBJECTIVE: The benefits and risks of pre-stereotactic radiosurgery (SRS) embolization have been reported in different studies. The goal of this study was to compare the long-term outcome of arteriovenous malformations (AVMs) treated with and without pre-SRS embolization. METHODS: A database including 1159 patients with AVMs who underwent SRS was reviewed. The embolized group was selected by including AVMs with pre-SRS embolization, maximal diameter > 30 mm, and estimated volume > 8 ml. The nonembolized group was defined as AVMs treated by SRS alone with matched de novo nidus volume. Outcomes including incidences of favorable clinical outcome (obliteration without hemorrhage, cyst formation, worsening, or new seizures), obliteration, adverse effects, and angioarchitectural complexity were evaluated. RESULTS: The study cohort comprised 17 patients in the embolized group (median AVM volume 17.0 ml) and 35 patients in the nonembolized group (median AVM volume 13.1 ml). The rates of obliteration (embolized cohort: 33%, 44%, and 56%; nonembolized cohort: 32%, 47%, and 47% at 4, 6, and 10 years, respectively) and favorable outcome were comparable between the 2 groups. However, the embolized group had a significantly higher incidence of repeat SRS (41% vs 23%, p = 0.012) and total procedures (median number of procedures 4 vs 1, p < 0.001), even with a significantly higher margin dose delivered at the first SRS (23 Gy vs 17 Gy, p < 0.001). The median angioarchitectural complexity score was reduced from 7 to 5 after embolization. Collateral flow and neovascularization were more frequently observed in the embolized nonobliterated AVMs. CONCLUSIONS: Both embolization plus SRS and SRS alone were effective therapies for moderately large (8-39 ml) AVMs. Even with a significantly higher prescription dose at the time of initial SRS, the embolized group still required more procedures to reach final obliteration. The presence of collateral flow and neovascularization could be risk factors for a failure to obliterate following treatment.

Gamma Knife radiosurgery for the treatment of Nelson's syndrome: a multicenter, international study.

OBJECTIVE: Nelson's syndrome is a rare and challenging neuroendocrine disorder, and it is associated with elevated adrenocorticotrophic hormone (ACTH) level, skin hyperpigmentation, and pituitary adenoma growth. Management options including resection and medical therapy are traditional approaches. Ionizing radiation in the form of Gamma Knife radiosurgery (GKRS) is also being utilized to treat Nelson's syndrome. In the current study the authors sought to better define the therapeutic role of stereotactic radiosurgery (SRS) in Nelson's syndrome. METHODS: Study patients with Nelson's syndrome were treated with single-fraction GKRS (median margin dose of 25 Gy) at 6 different centers as part of an International Radiosurgery Research Foundation (IRRF) investigation. Data including neurological function, endocrine response, and radiological tumor response were collected and sent to the study-coordinating center for review. Fifty-one patients with median endocrine and radiological follow-ups of 91 and 80.5 months from GKRS, respectively, were analyzed for endocrine remission, tumor control, and neurological outcome. Statistical methods were used to identify prognostic factors for these endpoints. RESULTS: At last follow-up, radiological tumor control was achieved in 92.15% of patients. Endocrine remission off medical management and reduction in pre-SRS ACTH level were achieved in 29.4% and 62.7% of patients, respectively. Improved remission rates were associated with a shorter time interval between resection and GKRS (p = 0.039). Hypopituitarism was seen in 21.6% and new visual deficits were demonstrated in 15.7% of patients. CONCLUSIONS: GKRS affords a high rate of pituitary adenoma control and improvement in ACTH level for the majority of Nelson's syndrome patients. Hypopituitarism is the most common adverse effect from GKRS in Nelson's syndrome patients and warrants longitudinal follow-up for detection and endocrine replacement.

Impact of Integral Dose on the Maintenance of Pain Relief in Patients with Idiopathic Trigeminal Neuralgia Treated with Upfront Gamma Knife Radiosurgery.

BACKGROUND: Integral dose (ID) defined as the product of mean dose and target volume, is a measure of the absorbed radiation energy. OBJECTIVE: To evaluate the effect of ID on the duration of pain relief after primary Gamma knife stereotactic radiosurgery (GKSRS) in trigeminal neuralgia. PATIENTS AND METHODS: A total of 78 patients who achieved initial pain response of I-III on the Barrow Neurological Institute Pain Scale (BNI-PS) following primary GKSRS for idiopathic trigeminal neuralgia were included in this study. A Cox regression model was used to compute the prognostic factor with respect to the ID within the 50% isodose line. Facial pain relief maintenance interval was defined as time interval between the day of improved BNI-PS grade and pain level back to the BNI-PS IV or V. The median duration of follow-up was 42 months (range 6-108 months). RESULTS: After the initial GKSRS, patients achieved pain relief at a median of 0.5 months (range, 7 days to 6 months); 28 patients developed recurrence of pain. There was a positive correlation between the pain relief maintenance and increasing ID within 50% isodose line (hazard ratio 1.85, P = 0.04) on multivariable Cox-regression analysis. Using logistic regression analysis, we found that ID was not predictive of developing post-stereotactic radiosurgery hypoesthesia (P = 0.64, hazard ratio 1.057). CONCLUSIONS: Stereotactic radiosurgery can be individualized based on trigeminal nerve morphology to achieve durable pain relief in patients with trigeminal neuralgia. ID calculation aids in planning an optimal radiation dose based on the nerve morphology to provide durable pain relief of idiopathic trigeminal neuralgia.

Treatment of Asymptomatic Meningioma With Gamma Knife Radiosurgery: Long-Term Follow-up With Volumetric Assessment and Clinical Outcome.

BACKGROUND: Some patients are diagnosed with asymptomatic meningioma(s) after undergoing a screening CT and MRI for minor ailments or postresection. OBJECTIVE: To help clinicians in decision making for treatment of asymptomatic meningiomas. METHODS: A single center retrospective cohort study of 117 patients with 122 tumors treated with Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden). Patients were followed with longitudinal imaging and clinical evaluations. Tumor volumetry and developments of new signs or symptoms after GKRS were the end points in the study. RESULTS: Median patient age at GKRS was 60 yr (range 21-86 yr) with a median clinical follow-up of 53 mo (range 20-252 mo). The median pre-GKRS tumor volume was 3.6 ± 3.8 cc (±standard deviation). Tumors were treated with a median margin dose of 14 ± 2 Gy. At last follow-up, median tumor volume was 2.5 ± 3.6 cc. Radiological progression-free survival (PFS) rates were 97% and 94.4% at 5 yr and 10 yr, respectively. Clinical PFS rates were 86% and 70% at 5 yr and 10 yr, respectively. Development of neurological complications was seen in 21 (18%) patients, and 11 (52%) of them had undergone surgical resection prior to GKRS. CONCLUSION: GKRS is a reasonable treatment strategy for asymptomatic meningiomas and compares favorably to natural history studies in terms of tumor control and neurological preservation. It results in relatively low morbidity in previously untreated meningiomas and serves as an appealing alternative treatment modality for recurrent meningiomas in asymptomatic patients.

Gamma Knife radiosurgery for brain metastases from small-cell lung cancer: Institutional experience over more than a decade and review of the literature.

INTRODUCTION: In the present study, we reviewed the efficacy of stereotactic radiosurgery (SRS) alone or in combination with WBRT, for the treatment of patients with BM secondary to SCLC. We further identified patient and treatment specific factors that correlated with improved survival. METHODS: Forty-one patients treated with GKRS for BM secondary to SCLC from 2004 to 2017 at the University of Virginia were identified with histopathologically proven SCLC and included in the study. RESULTS: Following the first GKRS treatment, the median survival was 6 months (1-41 months). There was no statistical difference in overall survival and tumor control between the patients who had PCI, WBRT or upfront GKRS. The only factor associated with decreased OS after the diagnosis of BM from SCLC was active extracranial disease (P=0.045, HR=2.354). CONCLUSION: Stereotactic radiosurgery is a reasonable treatment option for patients with brain metastases of SCLC who had PCI or WBRT failure.

Aspirin Suppresses PGE2 and Activates AMP Kinase to Inhibit Melanoma Cell Motility, Pigmentation, and Selective Tumor Growth In Vivo.

There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E2 (PGE2) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) in vitro at concentrations of 1 mmol/L and 20 µmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE2 or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE2 levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE2 in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE2 and activation of AMPK and reduces growth of some melanoma tumors in vivo This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans. Cancer Prev Res; 11(10); 629-42. ©2018 AACR.

Loss of p16INK4A stimulates aberrant mitochondrial biogenesis through a CDK4/Rb-independent pathway.

The tumor suppressor p16INK4A (p16) inhibits cell cycle progression through the CDK4/Rb pathway. We have previously shown that p16 regulates cellular oxidative stress, independent of its role in cell cycle control. We investigated whether loss of p16 had a direct impact on the mitochondria. We found that p16-null primary mouse fibroblasts (PMFs) displayed increased mitochondrial mass and expression of mitochondrial respiratory subunit proteins compared to wild-type (WT) PMFs. These findings in p16-null PMFs were associated with increased expression of the mitochondrial biogenesis transcription factors PRC and TFAM. On the other hand, p16-deficient PMFs demonstrated reduced mitochondrial respiration capacity consistent with electron microscopy findings showing that mitochondria in p16-deficient PMFs have abnormal morphology. Consistent with increased mitochondrial mass and reduced respiratory capacity, p16-deficient PMFs generated increased mitochondrial superoxide. One biological consequence of elevated ROS in p16-deficient PMFs was enhanced migration, which was reduced by the ROS scavenger N-acetylcysteine. Finally, p16-deficient PMFs displayed increased mitochondrial membrane potential, which was also required for their enhanced migration. The mitochondrial and migration phenotype was restored in p16-deficient PMFs by forced expression of p16. Similarly, over-expression of p16 in human melanocytes and A375 melanoma cells led to decreased expression of some mitochondrial respiratory proteins, enhanced respiration, and decreased migration. Inhibition of Rb phosphorylation in melanocytes and melanoma cells, either by addition of chemical CDK4 inhibitors or RNAi-mediated knockdown of CDK4, did not mimic the effects of p16 loss. These results suggest that p16 regulates mitochondrial biogenesis and function, which is independent of the canonical CDK4/Rb pathway.

Feasibility of metal recovery from soil using DTPA and its biostability.

Removal of heavy metals from contaminated soil by chelation can be a valid remediation method. Important properties of the chelating agent used are: strength of the chelation bonding, reusability, and biostability during the remediation operation. This work tested the extraction, recovery, and biostability of diethylenetriaminepentaacetate (DTPA) as a remediation agent for soils contaminated with metals. Reported here are effects of parameters such as DTPA concentration, precipitant type and concentration, and pH relative to extraction and recovery efficiencies of the chelator, as well as workable recovery conditions. The assessment of biostability was determined at different DTPA concentrations, in aqueous and soil slurry systems, and in presence of lead using acclimated and unacclimated activated sludge cultures. The results showed that DTPA was capable of extracting lead from the tested contaminated soils and could be recovered by the use of cationic and anionic precipitants in alkaline pH conditions. It was biostable to some extent especially with unacclimated cultures. Thus, DTPA proved to be a strong and reusable chelating agent for some metals in soils, and it was relatively biostable, which makes it a valid remediation agent for soil metal extraction.