ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit

An unusual cause of gastrointestinal bleeding: duodenal lipoma.

‘The final, published version of this article is available at http://www.karger.com/ 10.1159/000327219Common causes of chronic upper gastrointestinal bleeding include oesophageal varices, gastroduodenal ulcers and malignancy, and patients mostly present with iron deficiency type anaemia. We present the case of a 60-year-old lady who presented with iron deficiency anaemia and on investigation was found to have a large duodenal polyp requiring surgical excision. On histological examination, the polyp was revealed to be a lipoma. We review the recent literature and formulate a management plan for this rare entity

EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis

Objective To develop evidence-based recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Methods A task force comprising 7 rheumatologists, 15 other healthcare professionals and 3 patients was established. Following a systematic literature review performed to inform the recommendations, statements were formulated, discussed during online meetings and graded based on risk of bias assessment, level of evidence (LoE) and strength of recommendation (SoR; scale A–D, A comprising consistent LoE 1 studies, D comprising LoE 4 or inconsistent studies), following the European Alliance of Associations for Rheumatology standard operating procedure. Level of agreement (LoA; scale 0–10, 0 denoting complete disagreement, 10 denoting complete agreement) was determined for each statement through online voting. Results Four overarching principles and 12 recommendations were developed. These concerned common and disease-specific aspects of non-pharmacological management. SoR ranged from A to D. The mean LoA with the overarching principles and recommendations ranged from 8.4 to 9.7. Briefly, non-pharmacological management of SLE and SSc should be tailored, person-centred and participatory. It is not intended to preclude but rather complement pharmacotherapy. Patients should be offered education and support for physical exercise, smoking cessation and avoidance of cold exposure. Photoprotection and psychosocial interventions are important for SLE patients, while mouth and hand exercises are important in SSc. Conclusions The recommendations will guide healthcare professionals and patients towards a holistic and personalised management of SLE and SSc. Research and educational agendas were developed to address needs towards a higher evidence level, enhancement of clinician–patient communication and improved outcomes

Projected WIMP sensitivity of the LUX-ZEPLIN dark matter experiment

LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4 × 10-48cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3 × 10−43 cm2 (7.1 × 10−42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020

Measurement of the gamma ray background in the Davis Cavern at the Sanford Underground Research Facility

Deep underground environments are ideal for low background searches due to the attenuation of cosmic rays by passage through the earth. However, they are affected by backgrounds from γ-rays emitted by 40K and the 238U and 232Th decay chains in the surrounding rock. The LUX-ZEPLIN (LZ) experiment will search for dark matter particle interactions with a liquid xenon TPC located within the Davis campus at the Sanford Underground Research Facility, Lead, South Dakota, at the 4,850-foot level. In order to characterise the cavern background, in-situ γ-ray measurements were taken with a sodium iodide detector in various locations and with lead shielding. The integral count rates (0--3300~keV) varied from 596~Hz to 1355~Hz for unshielded measurements, corresponding to a total flux in the cavern of 1.9±0.4~γ cm−2s−1. The resulting activity in the walls of the cavern can be characterised as 220±60~Bq/kg of 40K, 29±15~Bq/kg of 238U, and 13±3~Bq/kg of 232Th

Vascular Remodeling in Health and Disease

The term vascular remodeling is commonly used to define the structural changes in blood vessel geometry that occur in response to long-term physiologic alterations in blood flow or in response to vessel wall injury brought about by trauma or underlying cardiovascular diseases.1, 2, 3, 4 The process of remodeling, which begins as an adaptive response to long-term hemodynamic alterations such as elevated shear stress or increased intravascular pressure, may eventually become maladaptive, leading to impaired vascular function. The vascular endothelium, owing to its location lining the lumen of blood vessels, plays a pivotal role in regulation of all aspects of vascular function and homeostasis.5 Thus, not surprisingly, endothelial dysfunction has been recognized as the harbinger of all major cardiovascular diseases such as hypertension, atherosclerosis, and diabetes.6, 7, 8 The endothelium elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation.8, 9, 10 Among the primary biologic mediators emanating from the endothelium is nitric oxide (NO) and the arachidonic acid metabolite prostacyclin [prostaglandin I2 (PGI2)], which exert powerful vasodilatory, antiadhesive, and antiproliferative effects in the vessel wall

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Larger hepatic metastases are more frequent with N0 colorectal tumours and are associated with poor prognosis: Implications for surveillance

AbstractBackgroundSurgery is the treatment of choice for colorectal cancer liver metastases (CLM). The aim of our study was to analyze which clinical and pathological risk factors can predict recurrence after liver resection.MethodsConsecutive patients who underwent hepatic resection for CLM were studied retrospectively to identify risk factors influencing cancer recurrence, by univariate and multivariable analyses.Results97 patients (2004–2008) with a median age of 64.6 years (inter-quartile range 57.6–72.6) had a median disease free survival of 16.4 months. On univariate analysis the largest metastasis >5 cm (hazard ratio, HR 2.04, 95% CI 1.10–3.80, p = 0.03), presence of extra-hepatic disease (HR 2.39, 95% CI 1.14–5.02, p = 0.02) and a resection margin ≤5 mm (HR 1.91, 95% CI 1.06–3.47, p = 0.03) were significantly associated with a higher risk of recurrence after curative resection for CLM. These were confirmed as independent predictors for recurrence on multivariable analysis. There were significantly more patients with lymph node negative (N0) primary in the group with liver secondary > 5 cm (n = 18, 39%), than in the group with liver secondary £5 cm (n = 7, 14.6%) (p = 0.01).ConclusionWe demonstrated a positive correlation between N0 primary tumour and large liver metastases, which have a higher risk of disease recurrence. If validated in larger, independent studies, this study would suggest routine imaging surveillance follow up of even N0 colorectal tumours, until the biology of these tumours is fully understood