Real-time monitoring of live mycobacteria with a microfluidic acoustic-Raman platform

Funding: UK Engineering and Physical Sciences Research Council for funding through grant EP/P030017/1 and fellowship EP/L025035/1. This work was also supported by the PreDiCT-TB consortium [IMI Joint undertaking grant agreement number 115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution (www.imi.europa.eu)] and the PanACEA consortium [funded by the European & Developing Countries Clinical Trials Partnership (EDCTP); grant agreement: TRIA-2015-1102]Tuberculosis (TB) remains a leading cause of death worldwide. Lipid rich, phenotypically antibiotic tolerant, bacteria are more resistant to antibiotics and may be responsible for relapse and the need for long-term TB treatment. We present a microfluidic system that acoustically traps live mycobacteria, M. smegmatis, a model organism for M. tuberculosis. We then perform optical analysis in the form of wavelength modulated Raman spectroscopy (WMRS) on the trapped M. smegmatis for up to eight hours, and also in the presence of isoniazid (INH). The Raman fingerprints of M. smegmatis exposed to INH change substantially in comparison to the unstressed condition. Our work provides a real-time assessment of the impact of INH on the increase of lipids in these mycobacteria, which could render the cells more tolerant to antibiotics. This microfluidic platform may be used to study any microorganism and to dynamically monitor its response to different conditions and stimuli.Publisher PDFPeer reviewe

Randomised, open-label, phase II study of Gemcitabine with and without IMM-101 for advanced pancreatic cancer

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

Selecting a TNT Schedule in Locally Advanced Rectal Cancer: Can We Predict Who Actually Benefits?

Many consider the standard of care for locally advanced rectal cancer (LARC) to be preoperative chemoradiotherapy, radical surgery involving a total mesorectal excision, and post-operative adjuvant chemotherapy based on the pathology of the specimen. The poor impact on distant control is a major limitation of this strategy, with metastasis rates remaining in the 25–35% range and recovery after radical surgery leading to reluctance with prescription and inconsistent patient compliance with adjuvant chemotherapy. A second limitation is the low rate of pathologic complete response (pCR) (around 10–15%) despite multiple efforts to potentiate preoperative chemoradiation regimens, which in turn means it is less effective at achieving non-operative management (NOM). Total neoadjuvant treatment (TNT) is a pragmatic approach to solving these problems by introducing systemic chemotherapy at an early timepoint. Enthusiasm for delivering TNT for patients with LARC is increasing in light of the results of published randomized phase III trials, which show a doubling of the pCR rate and a significant reduction in the risk of subsequent metastases. However, there has been no demonstrated improvement in quality of life or overall survival. A plethora of potential chemotherapy schedules are available around the radiotherapy component, which include preoperative induction or consolidation with a range of options (FOLFOXIRI, FOLFOX, or CAPEOX,) and a varying duration of 6–18 weeks, prior to long course chemoradiation (LCCRT) or consolidation NACT following short-course preoperative radiation therapy (SCPRT) using 5 × 5 Gy or LCCRT using 45–60 Gy, respectively. The need to maintain optimal local control is a further important factor, and preliminary data appear to indicate that the RT schedule remains a crucial issue, especially in more advanced tumors, i.e., mesorectal fascia (MRF) invasion. Thus, there is no consensus as to the optimum combination, sequence, or duration of TNT. The selection of patients most likely to benefit is challenging, as clear-cut criteria to individuate patients benefiting from TNT are lacking. In this narrative review, we examine if there are any necessary or sufficient criteria for the use of TNT. We explore potential selection for the individual and their concerns with a generalized use of this strategy