Novel delivery methods bypassing the blood-brain and blood-tumor barriers.

Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood-cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.

Efficacy of postoperative seizure prophylaxis in intra-axial brain tumor resections.

The effectiveness of seizure prophylaxis in controlling postoperative seizures following craniotomy for tumor resection is unclear. Most patients are seizure-free before surgery. To prevent seizures, it is common to treat tumor craniotomy patients postoperatively with an antiepileptic drug (AED). The authors retrospectively analyzed seizure occurrence with and without postoperative prophylactic AEDs. Between 2005 and 2011 at the authors' institution, 588 patients underwent craniotomy for brain tumors and were screened. Data on seizures, AED use, histopathology, comorbidities, complications, and follow-up were collected. Exclusion criteria included lack of follow-up data, previous operation, preoperative seizures, or preoperative AED prophylaxis. The incidence of postoperative seizures in patients with and without prophylactic AEDs was compared using logistic regression analysis. A total of 202 patients (50.5% female) were included. The most common tumor diagnosis was metastasis (42.6%). Of the 202 patients, 66.3% were prescribed prophylactic AED after surgery. Forty-six of 202 (22.8%) suffered a postoperative seizure. The odds of seizure for patients on prophylactic AED was 1.62 times higher than those not on AED (p = 0.2867). No difference was found in seizure occurrence between patients with glioblastoma multiforme compared with other tumor types (odds ratio 1.75, p = 0.1468). No difference was found in time-to-seizure between the two groups (hazard ratio 1.38, p = 0.3776). These data show no statistically significant benefit to prophylactic postoperative AED and a nonsignificant trend for increased seizure risk with AEDs. A randomized, placebo-controlled trial is needed to clarify the benefit of postoperative AED use for brain tumor resection.

A Guide to Expanding the Use of Buprenorphine Beyond Standard Initiations for Opioid Use Disorder.

Buprenorphine has become an important medication in the context of the ongoing opioid epidemic. However, complex pharmacologic properties and varying government regulations create barriers to its use. This narrative review is intended to facilitate buprenorphine use-including non-traditional initiation methods-by providers ranging from primary care providers to addiction specialists. This article briefly discusses the opioid epidemic and the diagnosis and treatment of opioid use disorder (OUD). We then describe the basic and complex pharmacologic properties of buprenorphine, linking these properties to their clinical implications. We guide readers through the process of initiating buprenorphine in patients using full agonist opioids. As there is no single recommended approach for buprenorphine initiation, we discuss the details, advantages, and disadvantages of the standard, low-dose, bridging-strategy, and naloxone-facilitated initiation techniques. We consider the pharmacology of, and evidence base for, buprenorphine in the treatment of pain, in both OUD and non-OUD patients. Throughout, we address the use of buprenorphine in children and adolescent patients, and we finish with considerations related to the settings of pregnancy and breastfeeding.

Literature review of management of brain metastases from germ cell tumors.

OBJECTIVE: In this review article, we discuss the role of chemotherapy, surgery, and radiation therapy in the treatment of brain metastases from germ cell tumors (GCT). BACKGROUND: GCT rarely metastasize to the brain and there is limited data to guide management. Most instances of brain metastases occur in patients with non-seminomatous germ cell tumors (NSGCT). METHODS: We searched PubMed using the terms 'central nervous system (CNS) metastases' or 'brain metastases' and 'germ cell' from 2011 through August 2021. Review articles and prospective trials related to the treatment of brain metastases in GCT were included in addition to articles obtained by hand search of the references and clinical practice guidelines. CONCLUSIONS: We highlight the importance of using chemotherapy as first-line therapy in most situations. We discuss the very minimal data regarding surgery and its primary role when there is significant mass effect or brain shift. We also compare whole brain radiation therapy (WBRT) with the use of radiosurgery. We then provide overall recommendations based on the reviewed data and our experience as a referral center for GCT.

Fatigue countermeasures in aviation.

Pilot fatigue is a significant problem in modern aviation operations, largely because of the unpredictable work hours, long duty periods, circadian disruptions, and insufficient sleep that are commonplace in both civilian and military flight operations. The full impact of fatigue is often underappreciated, but many of its deleterious effects have long been known. Compared to people who are well-rested, people who are sleep deprived think and move more slowly, make more mistakes, and have memory difficulties. These negative effects may and do lead to aviation errors and accidents. In the 1930s, flight time limitations, suggested layover durations, and aircrew sleep recommendations were developed in an attempt to mitigate aircrew fatigue. Unfortunately, there have been few changes to aircrew scheduling provisions and flight time limitations since the time they were first introduced, despite evidence that updates are needed. Although the scientific understanding of fatigue, sleep, shift work, and circadian physiology has advanced significantly over the past several decades, current regulations and industry practices have in large part failed to adequately incorporate the new knowledge. Thus, the problem of pilot fatigue has steadily increased along with fatigue-related concerns over air safety. Accident statistics, reports from pilots themselves, and operational flight studies all show that fatigue is a growing concern within aviation operations. This position paper reviews the relevant scientific literature, summarizes applicable U.S. civilian and military flight regulations, evaluates various in-flight and pre-/postflight fatigue countermeasures, and describes emerging technologies for detecting and countering fatigue. Following the discussion of each major issue, position statements address ways to deal with fatigue in specific contexts with the goal of using current scientific knowledge to update policy and provide tools and techniques for improving air safety.

Blunted Nocturnal Salivary Melatonin Secretion Profiles in Military-Related Posttraumatic Stress Disorder.

Background: Sleep disturbances are a hallmark of posttraumatic stress disorder (PTSD), yet few studies have evaluated the role of dysregulated endogenous melatonin secretion in this condition. Methods: This study compared the sleep quality and nocturnal salivary melatonin profiles of Canadian Armed Forces (CAF) personnel diagnosed with PTSD, using the Clinician Administered PTSD Scale (CAPS score ≥50), with two healthy CAF control groups; comprising, a "light control" (LC) group with standardized evening light exposure and "normal control" (NC) group without light restriction. Participants were monitored for 1-week using wrist actigraphy to assess sleep quality, and 24-h salivary melatonin levels were measured (every 2h) by immunoassay on the penultimate day in a dim-light (< 5 lux) laboratory environment. Results: A repeated measures design showed that mean nocturnal melatonin concentrations for LC were higher than both NC (p = .03) and PTSD (p = .003) with no difference between PTSD and NC. Relative to PTSD, NC had significantly higher melatonin levels over a 4-h period (01 to 05 h), whereas the LC group had higher melatonin levels over an 8-h period (23 to 07 h). Actigraphic sleep quality parameters were not different between healthy controls and PTSD patients, likely due to the use of prescription sleep medications in the PTSD group. Conclusions: These results indicate that PTSD is associated with blunted nocturnal melatonin secretion, which is consistent with previous findings showing lower melatonin after exposure to trauma and suggestive of severe chronodisruption. Future studies targeting the melatonergic system for therapeutic intervention may be beneficial for treatment-resistant PTSD.

Brainstem metastases treated with Gamma Knife stereotactic radiosurgery: the Indiana University Health experience.

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01-2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14-22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8-45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14-22 Gy) to brainstem metastases.

Toxicity of Radiosurgery for Brainstem Metastases.

BACKGROUND: Although stereotactic radiosurgery (SRS) is an effective modality in the treatment of brainstem metastases (BSM), radiation-induced toxicity remains a critical concern. To better understand how severe or life-threatening toxicity is affected by the location of lesions treated in the brainstem, a review of all available studies reporting SRS treatment for BSM was performed. METHODS: Twenty-nine retrospective studies investigating SRS for BSM were reviewed. RESULTS: The rates of grade 3 or greater toxicity, based on the Common Terminology Criteria for Adverse Events, varied from 0 to 9.5% (mean 3.4 ± 2.9%). Overall, the median time to toxicity after SRS was 3 months, with 90% of toxicities occurring before 9 months. A total of 1243 cases had toxicity and location data available. Toxicity rates for lesions located in the medulla were 0.8% (1/131), compared with midbrain and pons, respectively, 2.8% (8/288) and 3.0% (24/811). CONCLUSIONS: Current data suggest that brainstem substructure location does not predict for toxicity and lesion volume within this cohort with median tumor volumes 0.04-2.8 cc does not predict for toxicity.

Circadian phase delay induced by phototherapeutic devices.

INTRODUCTION: The Canadian Forces has initiated a multiple study project to optimize circadian phase changes using appropriately timed phototherapy and/or ingestion of melatonin for those personnel on long-range deployments and shift workers. The work reported here compared four phototherapeutic devices for efficacy in effecting circadian phase delays. METHODS: In a partially counterbalanced treatment order, 14 subjects (7 men and 7 women), ages 18-51 yr, participated in 5 weekly experimental sessions of phototherapy with 4 different phototherapy devices (light tower, light visor, Litebook, LED spectacles) and a no-phototherapy control. Phototherapy was applied from 24:00 to 02:00 on night. (1) Dim light melatonin onset (DLMO) was assessed on night 1 and night. (2) Subjects were tested for psychomotor performance (serial reaction time, logical reasoning, and serial subtraction tasks) and completed the Stanford Sleepiness Scale on night 1 at 19:00, 23:00, 01:00, 02:00, and 03:00. After phototherapy, subjects completed a phototherapy side-effects questionnaire. RESULTS: All phototherapy devices produced melatonin suppression and significant phase delays. Sleepiness was significantly decreased with the light tower, the light visor, and the Litebook. Task performance was only slightly improved with phototherapy. The LED spectacles and light visor caused greater subjective performance impairment, more difficulty viewing the computer monitor and reading printed text than the light tower or the Litebook. The light visor, the Litebook, and the LED spectacles caused more eye discomfort than the light tower. CONCLUSIONS: The light tower was the best device, producing melatonin suppression and circadian phase change while relatively free of side effects.

Residence at moderate altitude improves ventilatory response to high altitude.

BACKGROUND: This study compared the distribution of arterial oxygen saturation (SaO2) and susceptibility to Acute Mountain Sickness (AMS) in moderate altitude residents (MAR) and low altitude residents (LAR) following rapid ascent to 4056 m. METHODS: Resting PETCO2 and SaO2 were measured in 38 subjects residing for > 3 mo near Colorado Springs, CO (MAR group), at 1940 m (USAF Academy), and after approximately 1 h at 4056 m on the summit of Pikes Peak, CO, following ascent by car. SaO2 was also measured at 610-m elevation intervals during the ascent. Of the LAR (50 m) group, 39 subjects were exposed to a similar ascent profile in a hypobaric chamber. RESULTS: At 1940 m the MAR SaO2 and PETCO2 were 94 +/- 1% (X +/- SD) and 33.6 +/- 2.8 mmHg, respectively. At 3048 m and higher, MAR SaO2 decreased, reaching 86 +/- 2% (p < 0.001) at 4056 m, and PETCO2 (32.1 +/- 4.5 mmHg) decreased (p < 0.05). At 50 m the LAR SaO2 and PETCO2 were 98 +/- 1% and 38.7 +/- 2.7 mmHg, respectively. At 1940 m and higher, LAR SaO2 decreased (p < 0.001), reaching 82 +/- 5% at 4056 m, and PETCO2 (36.4 +/- 3.5 mmHg) decreased (p < 0.05). Above 2438 m, the MAR SaO2 was higher (p < 0.001) than the LAR. Only one MAR subject, but nine LAR subjects reported AMS symptoms. CONCLUSIONS: Ventilatory acclimatization developed during moderate altitude residence substantially enhances arterial oxygenation during rapid ascents to higher altitudes. Compared with prior studies, the level of ventilatory acclimatization achieved at moderate altitude is similar to residing at 4056 m for approximately 5-9 d.

Fatigue models for applied research in warfighting.

The U.S. Department of Defense (DOD) has long pursued applied research concerning fatigue in sustained and continuous military operations. In 1996, Hursh developed a simple homeostatic fatigue model and programmed the model into an actigraph to give a continuous indication of performance. Based on this initial work, the Army conducted a study of 1 wk of restricted sleep in 66 subjects with multiple measures of performance, termed the Sleep Dose-Response Study (SDR). This study provided numerical estimation of parameters for the Walter Reed Army Institute of Research Sleep Performance Model (SPM) and elucidated the relationships among several sleep-related performance measures. Concurrently, Hursh extended the original actigraph modeling structure and software expressions for use in other practical applications. The model became known as the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) Model, and Hursh has applied it in the construction of a Fatigue Avoidance Scheduling Tool. This software is designed to help optimize the operational management of aviation ground and flight crews, but is not limited to that application. This paper describes the working fatigue model as it is being developed by the DOD laboratories, using the conceptual framework, vernacular, and notation of the SAFTE Model. At specific points where the SPM may differ from SAFTE, this is discussed. Extensions of the SAFTE Model to incorporate dynamic phase adjustment for both transmeridian relocation and shift work are described. The unexpected persistence of performance effects following chronic sleep restriction found in the SDR study necessitated some revisions of the SAFTE Model that are also described. The paper concludes with a discussion of several important modeling issues that remain to be addressed.

Phase advance with separate and combined melatonin and light treatment.

INTRODUCTION: Melatonin and light treatment are recommended for hastening adaptation to time zone change. We evaluated an afternoon regimen of 3 mg sustained release (SR) melatonin with and without next morning green light treatment for circadian phase advance. Effects of melatonin and light were tested separately and then combined to determine if the total phase change is additive or synergistic. MATERIAL AND METHODS: For each condition (melatonin, placebo, light, melatonin plus light), 11 subjects spent from Tuesday evening until Friday afternoon in the laboratory. For all four conditions, the following sleep schedule was maintained: night 1, 2345 to 0630 hours, night 2, 1600 to 0530 hours, and night 3, 2345 to 0700 hours. For the light-only condition, light treatment was administered between 0700 and 0800 hours on Thursday. For melatonin-only or placebo conditions, capsules were administered at 1600 hours on Wednesday. For the combined condition, melatonin was administered at 1600 hours on Wednesday with light treatment between 0600 and 0700 hours on Thursday. Circadian phase was assessed by calculating dim light melatonin onset (DLMO) from salivary melatonin, using a mean baseline +2 standard deviations (BL+2 SD) threshold. For all four conditions, pre-treatment and post-treatment DLMO assessments were on Tuesday and Thursday evenings, respectively. RESULTS: Phase advances were: melatonin at 1600 hours, 0.72 h p<0.005, light treatment from 0700 to 0800 hours, 0.31 h, non-significant, and the combined treatment, 1.04 h p<0.0002. CONCLUSION: The phase advance from the combination of afternoon melatonin with next morning light is additive.

Melatonin treatment for eastward and westward travel preparation.

INTRODUCTION: Melatonin is recommended for hastening adaptation to phase shift, but there is little information on appropriate formulations. MATERIALS AND METHODS: We evaluated the efficacy of three melatonin formulations for circadian phase advance and delay: (a) 3 mg regular release (RR), (b) 3 mg sustained release (SR), and (c) 3 mg surge-sustained release (SSR; consisting of 1 mg RR and 2 mg SR). Circadian phase was assessed by salivary melatonin dim light melatonin onset (DLMO) or offset (MelOff) using thresholds of (1) 1.0 pg/ml and (2) mean baseline + 2 standard deviations (BL + 2SD). Subjects spent from Tuesday evenings until Thursday in the laboratory. Melatonin (or placebo) was administered at 1600 hours (phase advance) Wednesday, with DLMO assessment on Tuesday and Thursday and at 0600 hours (phase delay) Wednesday, with DLMO assessment Tuesday, Wednesday, and MelOff Thursday morning. Phase advances using the 1.0 pg/ml DLMO were as follows: placebo, 0.73 h; RR, 1.23 h (p < 0.003); SR, 1.44 h (p < 0.0002); SSR, 1.16 h (p < 0.012), with no difference between formulations. RESULTS AND DISCUSSION: Similar but smaller phase advances were found with BL + 2SD. Using MelOff, posttreatment phase position for the RR formulation was delayed compared to placebo by 1.12 h (p < 0.012), 1.0 pg/ml, and 0.75 h (p < 0.036), BL+2SD. Phase shifts for the SR and SSR conditions could not be determined due to persistent high melatonin levels during sampling times. Similar phase advances were induced by all formulations, and slow clearance of slow release preparations impeded the determination of phase delays. CONCLUSION: Appropriately timed 0.5 mg melatonin doses may avoid these problems.