The Infarct-Limiting Effect of Remote Ischemic Conditioning in Rats Is Not Affected by Aspirin.

PURPOSE: Remote ischemic conditioning (RIC) has been shown to be a powerful cardioprotective therapy in animal models. However, a protective effect in patients presenting with acute myocardial infarction has failed to be confirmed. A recent pre-clinical study reported that aspirin which is routinely given to patients undergoing reperfusion therapy blocked the infarct-limiting effect of ischemic postconditioning. The present study was designed to test whether aspirin could also be blocking the infarct-limiting effect of RIC. METHODS: This was investigated in vivo using male Sprague Dawley rats (n = 5 to 6 per group) subjected to either 30 min of regional myocardial ischemia, followed by 120-min reperfusion, or additionally to a RIC protocol initiated after 20-min myocardial ischemia. The RIC protocol included four cycles of 5-min hind limb ischemia interspersed with 5-min reperfusion. Intravenous aspirin (30 mg/kg) or vehicle (saline) was administered after 15-min myocardial ischemia. RESULTS: RIC significantly reduced infarct size (IS) normalized to the area at risk, by 47%. Aspirin administration did not affect IS nor did it attenuate the infarct-limiting effect of RIC. CONCLUSION: Aspirin administration in the setting of myocardial infarction is not likely to interfere with the cardioprotective effect of RIC.

Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Workshop.

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

The impact of cultural stress and gender norms on alcohol use severity among Latino immigrant men.

Alcohol misuse affects 15 million people in the United States. Compared to White men, Latino men have disproportionately higher rates of both alcohol misuse and negative alcohol-related consequences (e.g. drunk driving, liver disease, alcohol dependence, HIV/AIDS). This cross sectional study examined how cultural stressors [immigration stress and negative context of reception (NCR)] coupled with traditional Latino male gender norms (machismo and caballerismo) influences alcohol use severity (AUS) among adult Latino immigrant men. Data for the present study was collected between 2017 and 2018 from 279 Cuban, Central American, and South American adult Latino men who immigrated to the US approximately 10 years prior. Results from hierarchical multiple regression analysis revealed higher levels of perceived NCR (ß = 0.15, p = .01), and machismo (ß = 0.16, p = .02) were associated with greater AUS. Significant interaction effects were found between both cultural stressors and machismo [immigration stress x machismo (ß = 0.22, p < .001); NCR x machismo (ß = 0.22, p < .001)] whereby higher levels of machismo strengthened the association between cultural stress and AUS. Findings from the present study can inform culturally appropriate interventions aimed at mitigating alcohol use among Latino immigrant men.

Targeting myocardial ischaemic injury in the absence of reperfusion.

Sudden myocardial ischaemia causes an acute coronary syndrome. In the case of ST-elevation myocardial infarction (STEMI), this is usually caused by the acute rupture of atherosclerotic plaque and obstruction of a coronary artery. Timely restoration of blood flow can reduce infarct size, but ischaemic regions of myocardium remain in up to two-thirds of patients due to microvascular obstruction (MVO). Experimentally, cardioprotective strategies can limit infarct size, but these are primarily intended to target reperfusion injury. Here, we address the question of whether it is possible to specifically prevent ischaemic injury, for example in models of chronic coronary artery occlusion. Two main types of intervention are identified: those that preserve ATP levels by reducing myocardial oxygen consumption, (e.g. hypothermia; cardiac unloading; a reduction in heart rate or contractility; or ischaemic preconditioning), and those that increase myocardial oxygen/blood supply (e.g. collateral vessel dilation). An important consideration in these studies is the method used to assess infarct size, which is not straightforward in the absence of reperfusion. After several hours, most of the ischaemic area is likely to become infarcted, unless it is supplied by pre-formed collateral vessels. Therefore, therapies that stimulate the formation of new collaterals can potentially limit injury during subsequent exposure to ischaemia. After a prolonged period of ischaemia, the heart undergoes a remodelling process. Interventions, such as those targeting inflammation, may prevent adverse remodelling. Finally, harnessing of the endogenous process of myocardial regeneration has the potential to restore cardiomyocytes lost during infarction.

The risk of developing major depression among individuals with subthreshold depression: a systematic review and meta-analysis of longitudinal cohort studies.

BACKGROUND: Studies have consistently shown that subthreshold depression is associated with an increased risk of developing major depression. However, no study has yet calculated a pooled estimate that quantifies the magnitude of this risk across multiple studies. METHODS: We conducted a systematic review to identify longitudinal cohort studies containing data on the association between subthreshold depression and future major depression. A baseline meta-analysis was conducted using the inverse variance heterogeneity method to calculate the incidence rate ratio (IRR) of major depression among people with subthreshold depression relative to non-depressed controls. Subgroup analyses were conducted to investigate whether IRR estimates differed between studies categorised by age group or sample type. Sensitivity analyses were also conducted to test the robustness of baseline results to several sources of study heterogeneity, such as the case definition for subthreshold depression. RESULTS: Data from 16 studies (n = 67 318) revealed that people with subthreshold depression had an increased risk of developing major depression (IRR = 1.95, 95% confidence interval 1.28-2.97). Subgroup analyses estimated similar IRRs for different age groups (youth, adults and the elderly) and sample types (community-based and primary care). Sensitivity analyses demonstrated that baseline results were robust to different sources of study heterogeneity. CONCLUSION: The results of this study support the scaling up of effective indicated prevention interventions for people with subthreshold depression, regardless of age group or setting.

Centralized Clinical Trial Imaging Data Management: Practical Guidance from a Comprehensive Cancer Center's Experience.

Medical imaging is an integral part of clinical trial research and it must be managed properly to provide accurate data to the sponsor in a timely manner (Clune in Cancer Inform 4:33-56, 2007; Wang et al. in Proc SPIE Int Soc Opt Eng 7967, 2011). Standardized workflows for site qualification, protocol preparation, data storage, retrieval, de-identification, submission, and query resolution are paramount to achieve quality clinical trial data management such as reducing the number of imaging protocol deviations and avoiding delays in data transfer. Centralization of data management and implementation of relational databases and electronic workflows can help maintain consistency and accuracy of imaging data. This technical note aims at sharing the practical implementation of our centralized clinical trial imaging data management processes to avoid the fragmentation of tasks among various disease centers and research staff, and enable us to provide quality, accurate, and timely imaging data to clinical trial sponsors.

Unusually high illness severity and short incubation periods in two foodborne outbreaks of Salmonella Heidelberg infections with potential coincident Staphylococcus aureus intoxication.

We describe the investigation of two temporally coincident illness clusters involving salmonella and Staphylococcus aureus in two states. Cases were defined as gastrointestinal illness following two meal events. Investigators interviewed ill persons. Stool, food and environmental samples underwent pathogen testing. Alabama: Eighty cases were identified. Median time from meal to illness was 5·8 h. Salmonella Heidelberg was identified from 27 of 28 stool specimens tested, and coagulase-positive S. aureus was isolated from three of 16 ill persons. Environmental investigation indicated that food handling deficiencies occurred. Colorado: Seven cases were identified. Median time from meal to illness was 4·5 h. Five persons were hospitalised, four of whom were admitted to the intensive care unit. Salmonella Heidelberg was identified in six of seven stool specimens and coagulase-positive S. aureus in three of six tested. No single food item was implicated in either outbreak. These two outbreaks were linked to infection with Salmonella Heidelberg, but additional factors, such as dual aetiology that included S. aureus or the dose of salmonella ingested may have contributed to the short incubation periods and high illness severity. The outbreaks underscore the importance of measures to prevent foodborne illness through appropriate washing, handling, preparation and storage of food.

Comparison of Insulin Dose Adjustments by Primary Care Physicians and Endocrinologists.

IN BRIEF Insulin dose adjustment decisions in 20 simulated patients by nine primary care physicians (PCPs) and nine endocrinologists were compared to the algorithms used in a diabetes program in a large safety-net clinic. The number of dose changes was similar in the PCP and endocrinologist groups; however, the amounts of the dose changes in the PCP group were significantly closer to the diabetes program algorithms than the amounts in the endocrinologist group. Time constraints, rather than lack of ability, seem to be the major barrier to PCPs treating patients with insulin.

Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning.

This study aimed to investigate the role of the intrinsic cardiac nervous system in the mechanism of classical myocardial ischaemic preconditioning (IPC). Isolated perfused rat hearts were subjected to 35-min regional ischaemia and 60-min reperfusion. IPC was induced as three cycles of 5-min global ischaemia-reperfusion, and provided significant reduction in infarct size (IS/AAR = 14 ± 2% vs control IS/AAR = 48 ± 3%, p < 0.05). Treatment with the ganglionic antagonist, hexamethonium (50 µM), blocked IPC protection (IS/AAR = 37 ± 7%, p < 0.05 vs IPC). Moreover, the muscarinic antagonist, atropine (100 nM), also abrogated IPC-mediated protection (IS/AAR = 40 ± 3%, p < 0.05 vs IPC). This indicates that intrinsic cardiac ganglia remain intact in the Langendorff preparation and are important in the mechanism of IPC. In a second group of experiments, coronary effluent collected following IPC, from ex vivo perfused rat hearts, provided significant cardioprotection when perfused through a naïve isolated rat heart prior to induction of regional ischaemia-reperfusion injury (IRI) (IS/ARR = 19 ± 2, p < 0.05 vs control effluent). This protection was also abrogated by treating the naïve heart with hexamethonium, indicating the humoral trigger of IPC induces protection via an intrinsic neuronal mechanism (IS/AAR = 46 ± 5%, p < 0.05 vs IPC effluent). In addition, a large release in ACh was observed in coronary effluent was observed following IPC (IPCeff = 0.36 ± 0.03 µM vs C eff = 0.04 ± 0.04 µM, n = 4, p < 0.001). Interestingly, however, IPC effluent was not able to significantly protect isolated cardiomyocytes from simulated ischaemia-reperfusion injury (cell death = 45 ± 6%, p = 0.09 vs control effluent). In conclusion, IPC involves activation of the intrinsic cardiac nervous system, leading to release of ACh in the ventricles and induction of protection via activation of muscarinic receptors.

9th Hatter Biannual Meeting: position document on ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection.

In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.

Analysis of the effects of depression associated polymorphisms on the activity of the BICC1 promoter in amygdala neurones.

The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62.

Effect of supplementing pasteurized milk balancer products to heat-treated whole milk on the growth and health of dairy calves.

Two experiments were conducted to determine the growth and health effects of supplementing heat-treated whole milk with pasteurized milk balancer products in calf-feeding programs. All calves were removed from their dams at birth (d 0), fed 3.8L of heat-treated colostrum, and received assigned treatments from d 1 until weaning at d 56. Calves were weighed and skeletal measurements taken every 7 d from d 0 until 56. Average daily gain (ADG) and feed efficiency (FE) were calculated. In experiment 1, 80 Holstein heifer calves were used to investigate the effects of supplementing 2 levels of heat-treated whole milk with or without a pasteurized all-milk balancer. Four dietary treatments (n=20) were used. Calves receiving milk (M) and milk plus balancer (M+B) were fed 3.8L of milk divided into 2 equal feedings daily. Calves fed increased milk (IM) and increased milk plus balancer (IM+B) received 3.8L of milk divided into 2 equal feedings from d 1 to 14, 5.7L from d 15 to 42, and 2.85L fed once daily from d 43 to 56. Treatments M+B and IM+B included pasteurized all-milk balancer fed at a rate of 0.23kg per 3.8L of milk. In experiment 2, 72 Holstein heifer calves were used to investigate the effects of supplementing either a pasteurized all-milk balancer or a pasteurized protein-blend milk balancer. Three dietary treatments (n=24) were used. Calves were fed 3.8L of milk divided into 2 equal feedings from d 1 to 14 and 5.7L from d 15 to 56. Treatment IM did not include any supplements. Balancer was added to IM+B and increased milk plus protein-blend balancer (IM+PB). Balancer was supplemented at a rate of 0.23kg per 3.8L of milk. In experiment 1, calves fed IM+B had greater average body weight (BW) and average daily gain compared with calves given other treatments. Calves fed 5.7L of milk had greater FE than those fed 3.8L regardless of balancer added. In experiment 2, calves fed IM+B and IM+PB had greater BW when compared with calves given M. Calves fed IM+PB had comparable BW and FE to calves given IM+B. The enhanced calf-feeding programs evaluated in this study were successful in increasing growth in preweaned calves when supplementing milk balancer product to heat-treated whole milk. Health scores of fecal, respiratory, and attitude determined illness. Feces were looser for calves receiving IM+B and IM+PB, but attitude scores did not confirm an illness and so overall health was not different between treatments.

Insufficiency fractures in patients treated with pelvic radiotherapy and chemotherapy for uterine and cervical cancer.

Insufficiency fractures are recognised consequences of radiotherapy in gynaecological malignancy with reported incidences between 2.7% and 89%. We aimed to determine the incidence and risk factors for insufficiency fractures in patients receiving radical pelvic radiotherapy for uterine and cervical cancer. A case-note review was undertaken of patients treated between January 2007 and December 2008. Insufficiency fractures were identified from radiographs, computed tomography and magnetic resonance images. Chi-squared and Mann-Whitney tests were performed to determine associations between insufficiency fractures and chemotherapy, steroids and age. A total of 285 patients received pelvic radiotherapy, 137 with uterine and 148 with cervical cancer. Mean age was 59 years. A total of 144 patients received chemotherapy, 101 concurrently and 35 adjuvantly. Bone abnormalities affected 67 patients, 33 had pelvic insufficiency fractures, 12 had multiple fractures and 3 patients developed femoral head avascular necrosis. Use of chemotherapy was not associated with development of fractures (P = 0.949). However, cervical cancer patients had a significantly higher incidence of insufficiency fractures (P = 0.018) and bone pain (P = 0.03) compared with uterine cancer patients. This suggests concurrent chemotherapy may be a significant factor in increasing insufficiency fractures and bone morbidity in these patients and highlights a need for further research to identify, prevent and reduce these long-term complications.

Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib.

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

Management of raised glucose, a clinical decision tool to reduce length of stay of patients with hyperglycaemia.

OBJECTIVE: To assess whether the introduction of a management of raised glucose clinical decision tool could improve assessment of patients with hyperglycaemia by non-specialist physicians, leading to early discharge and improved quality of inpatient care. METHODS: Participants were adults aged 18 years or over presenting to the Medical Assessment Unit with a capillary blood glucose level > 11.1 mmol/l. Phase 1 of the study (phase 1) evaluated current clinical practice and potential impact of the clinical decision tool. Phase 2 evaluated the effectiveness of the management of raised glucose tool in clinical practice. Primary outcome measures were inpatient length of stay and same-calendar-day discharges. Secondary outcome measures were diabetes specialist input, patient assessment, intravenous insulin infusion use and patient satisfaction. RESULTS: Implementation of the management of raised glucose clinical decision tool allowed safe, same-calendar-day discharges of 40% of patients with hyperglycaemia as their primary reason for attendance. Median length of stay was lower in the phase 1 than in phase 2 (1.0 vs. 3.5 days, P < 0.01). Early discharge did not result in an increase in readmissions. There was improvement in hyperglycaemia assessment for all patients (P < 0.01), a reduction in the use of intravenous insulin infusions (P < 0.01) and high level of patient satisfaction. CONCLUSION: The management of raised glucose clinical decision tool resulted in a significant increase in the number of same-calendar-day discharges and reduction in hospital length of stay without adverse impact on readmission rates. Additionally, the tool was associated with improvements in inpatient diabetes care and patient satisfaction.

Effect of experimental feed additives on aflatoxin in milk of dairy cows fed aflatoxin-contaminated diets.

Three studies were conducted to determine the potential of experimental feed additives (EFAs), clays or non-digestible yeast oligosaccharides, to reduce milk aflatoxin (AFM1) concentrations in lactating Holstein cows consuming aflatoxin-contaminated diets. All studies included a pre-treatment period and a 2-week experimental period in a randomized block design. During the pre-treatment period, cows received a total mixed ration (TMR) with no aflatoxin contamination. During both experimental weeks, all cows were fed a TMR containing aflatoxin-contaminated corn. During experimental week 1, cows received no EFA's in the TMR, but EFA's were included in the TMR for the second experimental week. In studies 1 and 2, the experimental period consisted of 2 weeks each lasting 7 days with 12 cows per treatment. Aflatoxin M1 concentrations were analysed by HPLC for milk samples collected on days 5-7 and days 11-14. In various experiments, treatments included control (no EFA), 100 g/cow daily of experimental Lallemand(®) product, 10 g/cow daily of MTB-100(®) -2004, (Alltech, Inc.), 10 g/cow daily of MTB-100(®) -2006, (Alltech, Inc.), 10 g/cow daily of experimental Alltech(®) product (Alltech, Inc.) and 227 g/cow daily of Astra-Ben 20(®) (AB-20(®) ; Prince Agri Products, Inc.). In study 3, the experimental period of 2 weeks each lasting 8 days and milk samples were collected from day 4 to 8 and day 11 to 16. Milk samples from study 3 were analysed for AFM1 concentrations by ELISA. For all experiments, changes in AFM1 concentrations because of the addition of EFA's were calculated. Four of the five EFAs tested in this study had no significant effect on AFM1 concentrations. However, the addition of AB-20(®) resulted in a significant decrease in AFM1 concentrations (60.4%). In summary, the addition of AB-20(®) to the diet of cattle appears to be effective for significantly reducing AFM1 concentrations in the milk of cows fed an aflatoxin-contaminated diet.

Vaccine hesitancy educational tools for healthcare providers and trainees: A scoping review.

In the era of vaccine hesitancy, highlighted by the current SARS-CoV2 pandemic, there is an acute need to develop an approach to reduce and address apprehension towards vaccinations. We sought to map and present an overview of existing educational interventions for healthcare providers (HCPs) on strategies to engage in effective vaccine discussion. We applied the Joanna Briggs Institute methodology framework in this scoping review. We searched five relevant databases (MEDLINE, CINAHL, EMBASE, PsycInfo, and SCOPUS) and grey literature through the Google search engine using keywords and subject headings that were systematically identified. We identified 3384 citations in peer-reviewed literature and 41 citations in grey literature. After screening for our inclusion criteria, we included 28 citations from peer reviewed literature and 16 citations from grey literature for analysis. We identified a total of 41 unique education interventions. Interventions were available from multiple disciplines, training levels, clinical settings, and diseases/vaccines. Interventions predominantly centered around two foci: knowledge sharing and communication training. Most interventions identified from peer-reviewed literature were facilitated and were applied with multiple modes of delivery. Interventions from grey literature were more topical and generally self-directed. We identified several gaps in knowledge. Firstly, accessibility and generalizability of interventions was limited. Secondly, distribution of interventions did not adequately address nursing and pharmacy disciplines, and did not cover the breadth of medical specialties for whom vaccine discussions apply. Thirdly, no interventions addressed self monitoring and the clinicians' recognition and management of emotions during difficult conversations. There is a need to address this gap and provide available, credible and comprehensive educational interventions that will support our healthcare providers in effective communication with vaccine hesitant patients.

Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients.

Head and neck squamous cell carcinoma (HNSCC) patients treated with high-dose cisplatin concurrently with radiotherapy (hdCis-RT) commonly suffer kidney injury leading to acute and chronic kidney disease (AKD and CKD, respectively). We conducted a retrospective analysis of renal function and kidney injury-related plasma biomarkers in a subset of HNSCC subjects receiving hdCis-RT in a double-blinded, placebo-controlled clinical trial (NCT02508389) evaluating the superoxide dismutase mimetic, avasopasem manganese (AVA), an investigational new drug. We found that 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo. Moreover, AVA treatment may have allowed renal repair in the first 22 days following cisplatin treatment as evidenced by an increase in epithelial growth factor (EGF), known to aid in renal recovery. An upward trend was also observed in plasma iron homeostasis proteins including total iron (Fe-blood) and iron saturation (Fe-saturation) in the 90 mg AVA group versus placebo. These data support the hypothesis that treatment with 90 mg AVA mitigates cisplatin-induced CKD by inhibiting hdCis-induced renal changes and promoting renal recovery.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.

BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.