MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer. METHODS: Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422. FINDINGS: Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12-2·77, p=0·0045). The most common grade 3-4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0·07). INTERPRETATION: The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer. FUNDING: XBiotech

Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells

Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome and patient survival. In this study, resistance to treatment and metastasis has been attributed to expansion of stem-like tumor-initiating cells (TICs). Molecular analysis of the tumor stroma in neoadjuvant chemotherapy–treated human desmoplastic cancers and orthotopic tumor xenografts revealed that traditional maximum-tolerated dose chemotherapy, regardless of the agents used, induces persistent STAT-1 and NF-κB activity in carcinoma-associated fibroblasts. This induction results in the expression and secretion of ELR motif–positive (ELR(+)) chemokines, which signal through CXCR-2 on carcinoma cells to trigger their phenotypic conversion into TICs and promote their invasive behaviors, leading to paradoxical tumor aggression after therapy. In contrast, the same overall dose administered as a low-dose metronomic chemotherapy regimen largely prevented therapy-induced stromal ELR(+) chemokine paracrine signaling, thus enhancing treatment response and extending survival of mice carrying desmoplastic cancers. These experiments illustrate the importance of stroma in cancer therapy and how its impact on treatment resistance could be tempered by altering the dosing schedule of systemic chemotherapy

Exercise, not to exercise, or how to exercise in patients with chronic pain? Applying science to practice

Background: Exercise is an effective treatment strategy in various chronic musculoskeletal pain disorders, including chronic neck pain, osteoarthritis, headache, fibromyalgia and chronic low back pain. Although exercise can benefit those with chronic pain (CP), some patients (eg, those with fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome and chronic whiplash associated disorders) encounter exercise as a pain inducing stimulus and report symptom flares due to exercise

The Diamond Nano-Balance

Detecting nano-gram quantities of analyte in the liquid or gas phase is crucial for pathogen detection, antigen/DNA detection, water monitoring, electrochemical analysis, and many other bio-electrochemical applications. The quartz crystal microbalance (QCM) has become a significant sensor for both liquid and gas phase graviometry due to its high sensitivity, robustness, ease of use and simultaneous electrochemistry capabilities. One key factor plaguing the QCM in most sensor applications is the stability of the surface functionalisation. Diamond offers the most stable surface for functionalisation, the widest electrochemical window and the lowest noise floor. Unfortunately the growth of diamond on QCMs is problematic due to the low curie point of quartz, resulting in the loss of the piezoelectric properties of the QCM. In this work the replacement of the quartz with a high temperature stable piezoelectric material is proposed, and a nanocrystalline diamond coated sensor demonstrated

The Sensitivity of an Electro-Thermal Photovoltaic DC-DC Converter Model to the Temperature Dependence of the Electrical Variables for Reliability Analyses

status: publishe

Practical considerations for designing reliable DC/DC converters, applied to a BIPV case

State-of-the-art reliability assessment typically starts from a given circuit topology, for which the most suitable components are selected using a Physics of Failure analysis. This paper, however, addresses the topology selection stage, which is the foundation in designing reliable converters. Based on an overview of the reliability performance of different components, a methodology is presented as a guideline for comparing topologies to one another. The focus is directed at practical consequences associated with certain designs. Furthermore, an overview is provided on the latest developments in component technology reliability improvements. The developed methodology is mainly intended for demanding applications, where long lifetimes are required or elevated ambient temperatures are present. After the topology selection, an overview of possibilities is given that allows further increasing converter availability. Finally, the methodology is applied to the design of module level converters for building integrated photovoltaics, which is a high temperature application with a high desired lifetime. A prototype and experimental results are presented

Boron doped nanocrystalline diamond temperature regulator for sensing applications

status: publishe