Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab

We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks x2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33+/CD11b+ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4+CD25hi+Foxp3+) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8+ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69+) CD3+/CD4+ and CD3 +/CD8+ T cells with evidence of induction/potentiation of memory T cells (CD45RO+). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33+/CD11b+ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy. © 2014 Tarhini et al

The zoogeomorphology of case‐building caddisfly: Quantifying sediment use

Caddisfly (Trichoptera) larvae are an abundant and widespread aquatic insect group characterised by the construction of silk structures, including nets and cases. Case‐building caddisfly have the potential to modify the sorting and mobility of sand and fine gravel via; 1) case construction, resulting in altered sediment properties; 2) transporting sediment incorporated into cases over the river bed and; 3) changing the structure of river‐beds via burrowing. To investigate these mechanisms, it is necessary to understand the mass, size distribution and spatial variability of sediment use by case‐building caddisfly larvae.We quantified the mineral sediment used by individuals and communities of case‐building caddisfly in 27 samples, from three sites on a gravel‐bed stream. The mass and size distribution of sediment in individual cases varied between taxa (mass = 0.001 – 0.83 g, D50 = 0.17 – 4 mm). The mean mass of sediment used by the caddisfly community was 38 g m‐2 and varied locally. Sediment use was predominantly coarse sand (D50 = 1 mm). 64% of sediment use was attributable to Agapetus fuscipes (Glossosomatidae).Due to within‐species variability in case mass, the abundance of most taxa, including A. fuscipes, was only weakly associated with the mass of sediment used at the river scale. Whilst the caddisfly community used a small percentage of the total sediment available (average 2.99% of the 1‐1.4 mm size fraction), A. fuscipes used more fine sediment in their cases at sites where it was more available. Despite variability in local habitat, all sites supported diverse case‐building caddisfly communities utilising mineral sediment. Consequently, geomorphological effects of case‐building caddisfly are potentially widespread. The results provide novel insights into the specific grain sizes and quantities of fine sediment particles (g m‐2) used by caddisfly larvae, which represents an important step towards understanding their zoogeomorphic activities

Study protocol: Cost-effectiveness of transmural nutritional support in malnourished elderly patients in comparison with usual care

BACKGROUND: Malnutrition is a common consequence of disease in older patients. Both in hospital setting and in community setting oral nutritional support has proven to be effective. However, cost-effectiveness studies are scarce. Therefore, the aim of our study is to investigate the effectiveness and cost-effectiveness of transmural nutritional support in malnourished elderly patients, starting at hospital admission until three months after discharge. METHODS: This study is a randomized controlled trial. Patients are included at hospital admission and followed until three months after discharge. Patients are eligible to be included when they are > or = 60 years old and malnourished according to the following objective standards: Body Mass Index (BMI in kg/m2) < 20 and/or > or = 5% unintentional weight loss in the previous month and/or > or = 10% unintentional weight loss in the previous six months. We will compare usual nutritional care with transmural nutritional support (energy and protein enriched diet, two additional servings of an oral nutritional supplement, vitamin D and calcium supplementation, and consultations by a dietitian). Each study arm will consist of 100 patients. The primary outcome parameters will be changes in activities of daily living (determined as functional limitations and physical activity) between intervention and control group. Secondary outcomes will be changes in body weight, body composition, quality of life, and muscle strength. An economic evaluation from a societal perspective will be conducted alongside the randomised trial to evaluate the cost-effectiveness of the intervention in comparison with usual care. CONCLUSION: In this randomized controlled trial we will evaluate the effect of transmural nutritional support in malnourished elderly patients after hospital discharge, compared to usual care. Primary endpoints of the study are changes in activities of daily living, body weight, body composition, quality of life, and muscle strength. An economic evaluation will be performed to evaluate the cost-effectiveness of the intervention in comparison with usual care. TRIAL REGISTRATION: Netherlands Trial Register (ISRCTN29617677, registered 14-Sep-2005)

Nutritional supplementation of very old people at hospital discharge increases muscle strength:a randomised controlled trial

BACKGROUND: Undernutrition is common in older people admitted to hospital, but little is known about how nutritional state changes after discharge.OBJECTIVE: This randomised controlled trial was designed to examine the effect of oral nutritional supplementation of undernourished very old people prepared to take supplements after hospital discharge following acute illness.METHODS: Participants aged&gt;or=75 years with a BMI&lt;or=24 kg/m2 and triceps skin fold thickness or mid-arm muscle circumference below the 10th centile and/or weight loss&gt;or=5% during an acute hospital stay were allocated at random to either oral nutritional supplementation for 8 weeks from hospital discharge or to usual care. Primary outcome was change in weight, secondary outcomes were handgrip strength and anthropometry.RESULTS: Of 198 patients eligible to participate, 136 patients (mean age 85 years) were randomised and 76/136 (56%) completed the study. Twenty percent (13/66) of the intervention group withdrew after only 2 weeks, citing intolerance of the supplements. Using intention-to-treat analysis, body weight increased by a mean of 1.6 and 2.2% in the control and intervention groups, respectively, but this between-group difference was not significant (p = 0.188). However, handgrip strength increased more (p=0.055) in the intervention group (13.9%) than in the control group (7.2%).CONCLUSIONS: Oral nutritional supplementation was associated with a greater increase in handgrip strength than in non-supplemented controls and this observation merits further study.</p