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BACKGROUND Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. METHODS A total of 199 patients with melanoma and non-small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per-metastasis basis, using a sandwich estimator to account for intrapatient correlation. RESULTS The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P

Like in many tumor types, immunotherapy is currently under investigation to assess its potential efficacy in glioblastoma patients. Trials are under way to assess the efficacy of new immune checkpoint inhibitors including anti-PD-1 or CTLA4. We here investigate the expression and efficacy of a novel immune-checkpoint inhibitor, called LAG-3. We show that LAG-3 is expressed in human glioblastoma samples and in a mouse glioblastoma model we show that knock out or LAG-3 inhibition with a blocking antibody is efficacious against glioblastoma and can be used in combination with other immune checkpoint inhibitors toward complete eradication of the model glioblastoma tumors. From a mechanistic standpoint we show that LAG-3 expression is an early marker of T cell exhaustion and therefore early treatment with LAG-3 blocking antibody is more efficacious than later treatment. These data provide insight and support the design of trials that incorporate LAG-3 in the treatment of glioblastoma.

Aim The aim of this study was to test the feasibility and acceptability of a novel interdisciplinary intervention on weight loss. Methods A 3-month parallel, blinded, randomised controlled trial compared the effects of an interdisciplinary model of care (individualised interdisciplinary advice delivered through dietitians) with control (general advice on diet and physical activity delivered by primary care nurses). The primary outcome was assessing feasibility and acceptability of the protocol, with secondary outcomes including body weight, clinical, dietary, physical activity and psychological variables. Results Twenty-four participants were randomised and 21 included in the final analysis. The recruitment rate was 42% (24/57) and the eligibility rate 83% (24/29). The withdrawal rate was low (13% overall) compared with similar trials. Attendance at study visits was higher in the intervention arm compared with control (100 vs 83%), which may be an artefact of the greater individualised treatment provided in the integrated model. Conclusions This study confirmed the feasibility and acceptability of the novel interdisciplinary lifestyle intervention within the region.

Obesity may lead to depression or be one of its consequences. We reviewed population-based studies in order to, first, identify the most commonly used research methods, and, second, to evaluate the strength of evidence for prospective associations among obesity and depression. We examined 25 studies, of which 10 tested 'obesity-to-depression' pathways, and 15 tested 'depression-to-obesity' pathways. Descriptive statistics summarized the frequency with which various measurements, designs and data analytic strategies were used. We tallied the number of studies that reported any vs. no statistically significant associations, and report on effect sizes, identified moderating variables within reports, and sought common findings across studies. Results indicated considerable methodological heterogeneity in the literature. Depression was assessed by clinical interview in 44% of studies, weight and height were directly measured in 32%, and only 12% used both. In total, 80% of the studies reported significant obesity-to-depression associations, with odds ratios generally in the range of 1.0 to 2.0, while only 53% of the studies reported significant depression-to-obesity associations. Sex was a common moderating variable. Thus, there was good evidence that obesity is prospectively associated with increased depression, with less consistent evidence that depression leads to obesity. Recommendations for future research regarding study samples, measurement and data analysis are provided.

Background Neurocognitive deficits are common after childhood cancer and impact academic performance. Parents need to be knowledgeable of long-term complications impacting school and the resources necessary to support educational achievement. The oncology team plays an important role in preparing parents for the challenges of returning to school after treatment. Methods An online survey developed by parents and stakeholders was used to assess parent experiences and preferences associated with oncology team support around neurocognitive deficits and school transition. Recruitment included social media sites, foundation contacts, and clinic/event flyers. Topics included information content, timing, and frequency of information; and utility or perceived value of information. Inclusion criteria included respondent identifying as a parent (caregiver) of child treated for cancer who has returned to school. Results Surveys from 203 parents were completed representing diverse geographic locations. Nearly half (48%) did not recall receiving information about neurocognitive deficits. The most frequently reported time to receive this information was at diagnosis, but parents reported a need for conversations throughout the cancer trajectory, especially at transition to survivorship and school reentry. In addition, half of the parents (51%) felt inadequately prepared for the return to school. Information about neuropsychological testing, resources for learning difficulties, educational terms, and legal rights related to school services were the topics most inadequately provided. Conclusions Parents feel inadequately prepared by their oncology team for their child's return to school. Research is needed to identify effective oncology team approaches to fill the gaps in knowledge around school reentry after cancer treatment.

Objective: To evaluate whether MK-0557, a highly selective, orally administered neuropeptide Y Y5 receptor antagonist, could limit weight regain after very-low-calorie diet (VLCD)-induced weight loss. Research Methods and Procedures: We enrolled 502 patients 18 to 65 years of age with a BMI of 30 to 43 kg/m2. Patients were placed on a VLCD (800 kcal/d liquid diet) for 6 weeks. Patients who lost ≥6% of initial body weight (n = 359) were randomized to 52 weeks of 1 mg/d MK-0557 or placebo and maintained on a hypocaloric diet (300 kcal below weight maintenance requirements). Results: In randomized patients, the VLCD was associated with an average weight loss of 9.1 kg. After 12 weeks of double-blind treatment, weight began to gradually increase for both placebo- and MK-0557-treated patients. The mean weight change (95% confidence interval) from baseline at the end of the VLCD to Week 52 was +3.1 (2.1, 4.0) and +1.5 (0.5, 2.4) kg for patients treated with placebo and MK-0557, respectively. The difference of 1.6 kg between the two groups was significant (p = 0.014). Secondary endpoints, such as blood pressure, lipid profile, insulin, and leptin, as well as waist circumference and quality-of-life measurements, did not show significant differences between MK-0557 and placebo treatments. Discussion: Although the difference in weight regain between placebo- and MK-0557-treated patients was statistically significant, the magnitude of the effect was small and not clinically meaningful. Antagonism of the neuropeptide Y Y5 receptor is not an efficacious treatment strategy for reducing weight regain after VLCD.

Summary: The objective of the study was to measure energy metabolism and body composition during pregnancy and postpartum, compared to non-pregnant women, using non-invasive techniques. A longitudinal study of eight normotensive pregnant women was carried out at 19 ± 1 and 36 ± 1 weeks gestation, and postpartum. A cross-sectional study was also performed comparing postpartum to 12 nonpregnant women. Indirect calorimetry was performed while fasting to measure basal metabolic rate (BMR) and postprandially to measure diet-induced thermogenesis (DIT). Body composition consists of fat mass, lean body mass (LBM), and total body water (TBW) and was measured by bio-electrical impedance. Insulin resistance was indirectly assessed by glucose and insulin concentration and DIT. Weight gain in pregnancy was predominantly fat mass (p < 0.01), but LBM and TBW also increased (p < 0.01). Weight loss postpartum was comprised of fat mass, LBM and TBW (p < 0.01). BMR, glucose and insulin increased in pregnancy and decreased postpartum (p < 0.05), but DIT was unchanged. The BMR was not correlated with weight gain. Apart from fat mass, postpartum and non-pregnant women were similar. The insulin resistance increased insulin and glucose levels but not DIT. Fat mass was the major component of weight gain during pregnancy and there was an increase in BMR, glucose and insulin but no change in DIT. BMR decreased to normal but fat mass remained elevated 16 weeks post-partum.

Luteinizing thecoma with sclerosing peritonitis (LTSP) is a rare ovarian tumor of unclear etiology and pathogenesis. The diagnostic entity was proposed in 1994, but a number of earlier reports described possible cases, and some suggested an association with anti-epileptic drugs (AEDs). In presenting a new case we review the literature of previous cases to evaluate the possibility of such a link. When cases in reproductively immature patients are considered, evidence for an association between LTSP and AEDs is strongly suggested despite the rarity of the condition. Pediatr Blood Cancer 2010;54:470–472. © 2009 Wiley-Liss, Inc.

Forearm or calf venous plethysmography has been used in pregnant women to examine the effects of pregnancy on the vascular system and more recently to measure blood flow changes in response to intra-arterial infusion of vasoactive substances. To examine the assumption that venous capacitance and blood flow measurements are the same in the forearm and calf, venous plethysmography was conducted simultaneously on the forearm and calf in normal (NP) and hypertensive pregnant women (HTP) in their third trimester and in normal nonpregnant women (N). All studies were made on the right forearm and calf with subjects in the left lateral recumbent position. There was no significant difference between venous capacitance in the forearm (median: 124 x 10(3)mL/100mL/mmHg for both NP and HTP) and leg (134 [NP] and 106 [HTP] x 10(3)mL/100mL/mmHg) for both pregnant groups but venous capacitance in the nonpregnant group was greater in the leg than arm (174 versus 112 x 10(3)mL/100mL/mmHg, p < 0.001). Blood flow was similar in the leg and forearm (median 4.9 versus 3.9mL/100mL/min respectively) in nonpregnant women. Forearm blood flow was also similar to calf flow in NP women (6.2 versus 4.3mL/100mL/min respectively) but greater than calf blood flow in HTP (9.7 versus 5.3mL/100mL/min, p < 0.01). Using left lateral recumbency, forearm and calf vein capacitances are similar in pregnant women, in contrast to nonpregnant women. Blood flow is higher in the forearm than the calf only in hypertensive pregnant women. These observations should be borne in mind when interpreting studies of regional blood flow in pregnancy.

1. We tested the ability of ouabain to cause chronic hypertension by continuously infusing ouabain for 28 days (miniosmotic pump implantation; i.p.). The blood pressure and metabolic effects of sham (150 mmol/L NaCl; n = 12) or ouabain infusion (10 micrograms/kg per day; n = 14; 100 micrograms/kg per day; n = 14) were examined in conscious Sprague-Dawley rats. 2. Plasma ouabain concentrations measured after 28 days of ouabain infusion were as follows: sham, not detectable (n = 11); ouabain 10 micrograms/kg per day, 0.60 +/- 0.07 nmol/L (n = 14); and ouabain 100 micrograms/kg per day, 7.17 +/- 0.57 nmol/L (n = 14; P < 0.001). 3. Sham or ouabain infusion did not alter food intake, bodyweight, water intake or urine output in conscious rats. 4. Blood pressure was not altered by sham treatment. Ouabain at 10 micrograms/kg per day or 100 micrograms/kg per day did not produce consistent rises in blood pressure. Ouabain at 10 micrograms/kg per day increased blood pressure on treatment day 12 only (+6 mmHg; P < 0.05), while at 100 micrograms/kg per day blood pressure increased on treatment days 16 (+9 mmHg; P < 0.05) and day 18 (+8 mmHg; P < 0.05) only. There was no significant difference in blood pressure between sham and ouabain groups. 5. Renal blood flow was decreased in rats infused with ouabain at 10 micrograms/kg per day (2.0 +/- 0.3 mL/min per 100 g bodyweight; n = 5; P < 0.01) and 100 micrograms/kg per day (2.2 +/- 0.4 mL/min per 100 g bodyweight; n = 7; P < 0.05) compared with sham treatment (3.5 +/- 0.2 mL/min per 100 g bodyweight; n = 6). Renal vascular resistance was increased in rats treated with ouabain at 10 micrograms/kg per day (65.5 +/- 12.6 mmHg/mL per min per 100 g bodyweight; n = 5; P < 0.01) and 100 micrograms/kg per day (66.0 +/- 15.6 mmHg/mL per min per 100 g bodyweight; n = 7; P < 0.05) compared with sham treatment (32.6 +/- 2.5 mmHg/mL per min per 100 g bodyweight; n = 6). 6. High plasma concentrations of ouabain do not cause consistent increases in blood pressure in conscious Sprague-Dawley rats.

Summary: The effects of renal denervation were examined in cyclosporin A (CyA) treated Wistar rats 14 days prior to 1 day prior to and 10 days after CyA was administered. the rise in blood pressure was attenuated when the renal denervation was performed 1 day prior to and 10 days after administration, but not 14 days prior to CyA, presumably reflecting re-innervation of the kidney. Plasma renin activity (PRA) was increased by CyA 10 mg/kg per day and 20 mg/kg per day, but decreased by renal denervation 1 day prior to CyA. Plasma creatinine was increased by CyA at 10 mg/kg per day and decreased by renal denervation 1 day prior to CyA. These data support the notion that renal sympathetics play a role in CyA induced hypertension.

SUMMARY 1. We tested the hypothesis that dehydroepiandrosterone (DHEA), which prevents dexamethasone-induced hypertension in rats, may block adrenocorticotrophin (ACTH) hypertension, which has been presumed due to corticosterone excess. The blood pressure and metabolic effects of DHEA (18 mg/kg per day) were examined in sham and ACTH-treated (0.5 mg/kg per day) conscious Sprague-Dawley rats (n= 20). 2. ACTH but not sham injection increased blood pressure, water intake and urine output and decreased bodyweight. 3. DHEA administration for 10 days did not alter blood pressure or metabolic effects in either sham or ACTH-treated rats. 4. DHEA, which is known to block dexamethasone-induced hypertension, did not modify ACTH-induced hypertension in the rat. This suggests either that ACTH-induced hypertension is not simply a consequence of glucocorticoid activity or that the action of DHEA in dexamethasone hypertension is not through blocking the glucocorticoid receptor.

Objectives (1) to compare the magnitude of the white-coat effect in patients with mild and resistant hypertension and (2) to determine the prevalence of controlled BP in patients with ‘resistant’ hypertension. Methods Referring doctors' BP was compared with awake and 24 hour ambulatory BP monitor (ABPM) BP in 922 hypertensive patients referred for ABPM by their general practitioners (42%) or specialists (58%). 432 were taking no antihypertensives at the time of their ABPM study (Group 0), 336 were taking 1-2 antihypertensive drugs (Group 1) and 154 were taking ≥ 3 antihypertensive drugs (Group 2 - resistant hypertension). Controlled BP was defined as awake ABPM BP < 135/85mmHg. Results Patients with resistant hypertension were significantly older (60 ± 13 yrs) than group 0 (44 ± 15 yrs) and group 1 (55 ± 14 yrs) patients (p < 0.001) but were of similar weight, height and upper arm circumference. The difference between referral BP and awake ABPM BP, the white-coat effect (WCE), increased significantly across the groups (15/9 vs 26/14 vs 29/15 mmHg, p < 0.005). 34% of group 0 patients had normal ABPM BP, ie. white-coat hypertension, while 34% of group 1 and 26% of group 2 patients had controlled BP by ABPM criteria. Conclusion Approximately 1 in 3 of this selected cohort exhibited white coat hypertension and 1 in 4 of those with apparent resistant hypertension had well controlled BP when assessed by 24 hour ABPM. ABPM appears an appropriate initial step in the investigation of both mild hypertension and apparent drug resistant hypertension, thereby reducing unnecessary drug treatment and investigations for secondary causes of hypertension in these patients.