Alcohol intake, tobacco smoking, and esophageal adenocarcinoma survival: a molecular pathology epidemiology cohort study.

PURPOSE: To investigate the association between cigarette smoking, alcohol consumption, and esophageal adenocarcinoma survival, including stratified analysis by selected prognostic biomarkers. METHODS: A population-representative sample of 130 esophageal adenocarcinoma patients (n = 130) treated at the Northern Ireland Cancer Centre between 2004 and 2012. Cox proportional hazards models were applied to evaluate associations between smoking status, alcohol intake, and survival. Secondary analyses investigated these associations across categories of p53, HER2, CD8, and GLUT-1 biomarker expression. RESULTS: In esophageal adenocarcinoma patients, there was a significantly increased risk of cancer-specific mortality in ever, compared to never, alcohol drinkers in unadjusted (HR 1.96 95% CI 1.13-3.38) but not adjusted (HR 1.70 95% CI 0.95-3.04) analysis. This increased risk of death observed for alcohol consumers was more evident in patients with normal p53 expression, GLUT-1 positive or CD-8 positive tumors. There were no significant associations between survival and smoking status in esophageal adenocarcinoma patients. CONCLUSIONS: In esophageal adenocarcinoma patients, cigarette smoking or alcohol consumption was not associated with a significant difference in survival in comparison with never smokers and never drinkers in fully adjusted analysis. However, in some biomarker-selected subgroups, ever-alcohol consumption was associated with a worsened survival in comparison with never drinkers. Larger studies are needed to investigate these findings, as these lifestyle habits may not only be linked to cancer risk but also cancer survival.

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.

Biological testing during acute psychological stress: A hindrance or an opportunity?

All humans deal with acute psychological stress periodically. Some individuals are affected by needle phobia in which a heightened sense of arousal is precipitated by venepuncture. Acute psychological stress invokes a range of physiological changes including activation of the sympathetic-adrenal-medullary and hypothalamic-pituitary-adrenal axes. In this review article, we first examine the human response to acute stress. We then provide an overview of how psychological stress in a subject is likely to be a source of pre-analytical variability for certain measurands, and the major biochemical markers that have been studied in research aiming to quantify stress. As such, we highlight how stress can be a hindrance to the accurate interpretation of certain laboratory results (particularly cortisol, prolactin, metanephrines and growth hormone), and point out the role that biochemical analysis might play in future studies looking at the effects of stress on human behaviour.

Association between statin therapy dose intensity and radiation cardiotoxicity in non-small cell lung cancer: Results from the NI-HEART study.

INTRODUCTION: Radiation cardiotoxicity is a dose-limiting toxicity and major survivorship issue for patients with non-small cell lung cancer (NSCLC) completing curative-intent radiotherapy, however patients' cardiovascular baseline is not routinely optimised prior to treatment. In this study we examined the impact of statin therapy on overall survival and post-radiotherapy cardiac events. METHODS: Patients treated between 2015-2020 at a regional center were identified. Clinical notes were interrogated for baseline patient, tumor and cardiac details, and both follow-up cancer control and cardiac events. Three cardiologists verified cardiac events. Radiotherapy planning scans were retrieved for application of validated deep learning-based autosegmentation. Pre-specified Cox regression analyses were generated with varying degrees of adjustment for overall survival. Fine and Gray regression for the risk of cardiac events, accounting for the competing risk of death and cardiac covariables was undertaken. RESULTS: Statin therapy was prescribed to 59% of the 478 included patients. The majority (88%) of patients not prescribed a statin had at least one indication for statin therapy according to cardiovascular guidelines. In total, 340 patients (71%) died and 79 patients (17%) experienced a cardiac event. High-intensity (HR 0.68, 95%CI 0.50-0.91, p = 0.012) and medium-intensity (HR 0.70, 95%CI 0.51-0.97, p = 0.033) statin therapy were associated with improved overall survival after adjustment for patient, cancer, treatment, response and cardiovascular clinical factors. There were no consistent differences in the rate or grade of cardiac events according to statin intensity. CONCLUSIONS: Statin therapy is associated with improved overall survival in patients receiving curative-intent radiotherapy for NSCLC, and there is evidence of a dose-response relationship. This study highlights the importance of a pre-treatment cardiovascular risk assessment in this cohort. Further studies are needed to examine if statin therapy is cardioprotective in patients undergoing treatment for NSCLC with considerable incidental cardiac radiation dose and a low baseline cardiac risk.

Investigating the effects of endogenous lipaemia on the measurement of sodium by indirect ion specific electrode potentiometry.

BACKGROUND: The widely automated method using indirect ion specific electrodes (ISE) potentiometry for determination of sodium concentration is prone to interference from lipaemia. Manufacturer-specified lipaemic (L)-index cut offs may underestimate the effects of endogenous lipaemia. METHODS: We assessed the interference on sodium concentration caused by endogenous lipaemia in 32 residual samples (from 13 patients) using indirect ISE (Cobas® 8000 modular analyser with c702 module, Roche diagnostics) and direct ISE (GEM 4000 premier, Werfen) potentiometric methods. Regression analysis (linear and non-linear) was used to determine a reliable (L)-index cut off for reporting sodium concentration. RESULTS: There was a poor correlation observed between triglyceride concentration and (L)-index. There was significant negative interference caused by endogenous lipaemia within analysed samples. Non-linear regression demonstrated a negative interference of approximately 5% at an (L)-index of 250. CONCLUSION: At present, the manufacturer advises not to report sodium concentration by indirect ISE on the Cobas® 8000 modular analyser if the (L)-index is >2000. However, this has been determined by the addition of exogenous lipids (Intralipid®) and it is clear that this is not comparable to endogenous lipaemia. To ensure patient safety, clinical laboratories should consider lowering the cut off for (L)-index that they use for reporting sodium concentration.

Images of the month 2: Electrocardiographic QRS alternans caused by gastric volvulus.

QRS electrical alternans is characterised by alternating amplitude of the QRS complexes, and is well-documented in cardiac conditions such as pericardial effusion. We describe a case of QRS alternans in a patient with gastric volvulus.

Improving the uptake: Barriers and facilitators to pulmonary rehabilitation.

BACKGROUND: Pulmonary rehabilitation (PR) is a well-established therapeutic management programme for patients with chronic lung disease. Despite good clinical evidence, patient engagement can be poor. AIM: The aim of the study was to determine the number of patients who are referred to PR at a District General Hospital, explore barriers and facilitators to attending and completing and identify strategies for improvement. METHODS: All patients invited to attend PR in the calendar year 2016 were included in an analysis (N = 281). A structured questionnaire composed of barriers and facilitators was administered to patients that did not attend (non-attenders, N = 20) and those that attended but did not complete the programme (non-completers/"drop-outs," N = 13). Improvement strategies were identified and implemented followed by analysis of patients invited to attend in 2017 and 2018. RESULTS: Age, sex and smoking status are factors that affect both attendance and completion rates of patients attending PR. In our analysis, we were able to demonstrate that lack of awareness and low perceived benefits were important barriers for non-attendance. In addition, overall uptake rate was improved but at the expense of completion rate. CONCLUSION: Our local non-attendance rate in 2016 was 42%, with strategies aimed at improving patient and physician information, this was reduced to 11% (2018), below the national United Kingdom average. Unexpectedly, there was a worsening of completion rates and this raises questions about both appropriateness of referrals and whether completion rate rather than non-attendance rate should be used as a performance indicator and standard.

Exploring the translational disconnect between the murine and human inflammatory response: analysis of LPS dose-response relationship in murine versus human cell lines and implications for translation into murine models of sepsis.

BACKGROUND: Inflammation forms an important part of the human innate immune system and is largely dependent on the activation of the "classical" NF-κB pathway through Toll-like receptors (TLRs). Understanding this has allowed researchers to explore roles of therapeutic targets in managing conditions such as sepsis. Recapitulating an inflammatory response using lipopolysaccharide (LPS), a "sterile" technique, can provide information that is dissimilar to the clinical condition. By examining NF-κB activation (through immunoblotting of the p65 subunit) in two separate cell lines (murine and human) and analyzing two murine models of sepsis (intraperitoneal [IP] LPS and IP stool inoculation), an evaluation of the translational disconnect between experimental and clinical sepsis can be made. METHODS: THP-1 (human) cells and RAW 264.7 (murine) cells were dosed with concentrations of LPS (human, 1 pg/mL to 100 ng/mL; murine, 30 pg/mL to 1,000 ng/mL) and nuclear actin and p65 were immunoblotted to measure changes in nuclear density. In vivo, C57BL/6 mice received either IP injection of stool suspension (5 µL/g) or LPS (25 mg/kg) or saline (1 mL/kg). Animals were culled at 6 hours and tissues were analyzed. RESULTS: An increase in basal p65:actin density in THP-1 cells (mean 0.214, standard error of the mean 0.024) was seen at doses as small as 0.1 ng/mL (0.519±0.064). In contrast to RAW 264.7 cells, basal increases (0.170±0.025) were only seen when a dose of 3 ng/mL (0.387±0.078) was used. Dose-response analysis of p65:actin ratio showed that THP-1 cells respond to lower doses of LPS than RAW 264.7 cells and lower doses produce a greater fold increase in the nuclear p65 density. Both in vivo models showed evidence of neutrophil (NL) recruitment into tissues (which was more intense after LPS treatment). IP stool inoculation resulted in an acute suppurative peritonitis and more substantial evidence of NL recruitment into adipose tissue and skeletal muscle. CONCLUSION: Our results support previous observations that translation of murine models into the human clinical setting suffers from considerable limitations including species-associated differences in LPS response seen at a molecular level. Furthermore, the histopathological changes during clinical sepsis cannot be adequately reproduced by injection of LPS. Therefore, the so-called translational disconnect that exists between murine LPS models and human sepsis involves NF-κB activation at a molecular level and is further augmented by the use of LPS as a stimulus for infectious responses in vivo.