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Background Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment. Methods A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated. Results A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full-time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12-month follow-up (78%). Work-related productivity loss due to health was high during treatment. Conclusions This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at-risk patients.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Summary Background Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course. Methods In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician's global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony. Finding Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitis-related JIA and lower socioeconomic status, compared with those in other groups. Interpretation Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician's global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA. Funding Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and National Institute for Health Research.

Exercise is recognized as a frontline therapy for the prevention and treatment of type 2 diabetes (T2D) but the optimal type of exercise is not yet determined. We compared the effects of high-intensity interval training (HIIT) with moderate-intensity continuous training (MICT) for improvement of continuous glucose monitoring (CGM)-derived markers of glycaemic variability, and biomarkers of endothelial cell damage (CD31+ and CD62+ endothelial microparticles (EMPs)) within a population at elevated risk of developing T2D. Fifteen inactive overweight or obese women were randomized to 2 weeks (10-sessions) of progressive HIIT (

Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia).

BACKGROUND. T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR–T cell products were prepared from unselected T cells. METHODS. We conducted a clinical trial to evaluate CD19 CAR–T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS. The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR–T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR–T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell–mediated anti-CAR transgene product immune responses developed after CAR–T cell infusion in some patients, limited CAR–T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR–T cell persistence and disease-free survival. CONCLUSION. Immunotherapy with a CAR–T cell product of defined composition enabled identification of factors that correlated with CAR–T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR–T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01865617","term_id":"NCT01865617"}}NCT01865617. FUNDING. R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.

Cancer survival has improved in Scotland from an age-standardised relative survival at five years of 39.6 % in 1987–1991 to 59.3 % in 2007–2011 in men and women aged 15–74 years. However, long-term cancer survival is associated with increased incidence of diet-related diseases including coronary artery disease, osteoporosis, and diabetes. This study aimed to assess diet and attitudes towards diet in cancer survivors in Scotland. Eligible participants were men and women aged ≥ 18 years who had received a diagnosis of cancer and used CLAN Cancer Support in Aberdeen. CLAN Cancer Support is a charity that supports individuals of any age who are, or have been, affected by cancer across North-East Scotland, Moray, Orkney and Shetland.

Quality of Life (QoL) is the preferred outcome in non-pharmacological trials, but there is little UK population evidence of QoL in epilepsy. In advance of evaluating an epilepsy self-management course we aimed to describe, among UK participants’, what clinical and psycho-social characteristics are associated with QoL? We recruited 404 adults attending specialist clinics, with at least two seizures in the prior year and measured their self-reported seizure frequency, co-morbidity, psychological distress, social characteristics, including self-mastery and stigma, and epilepsy-specific QoL (QOLIE-31-P). Mean age was 42 years, 54% were female, and 75% white. Median time since diagnosis was 18 years, and 69% experienced ≥10 seizures in the prior year. Nearly half (46%) reported additional medical or psychiatric conditions, 54% reported current anxiety and 28% reported current depression symptoms at borderline or case-level, with 63% reporting felt-stigma. While a maximum QOLIE-31-P score is 100, participants’ mean score was 66, with a wide range (25-99). In order of large to small magnitude: depression, low self-mastery, anxiety, felt stigma, a history of medical and psychiatric comorbidity, low self-reported medication adherence, and greater seizure frequency were associated with low QOLIE-31-P scores. Despite specialist care, UK people with epilepsy and persistent seizures experience low QoL. If QoL is the main outcome in epilepsy trials, developing and evaluating ways to reduce psychological and social disadvantage are likely to be of primary importance. Educational courses may not change QoL, but be one component supporting self-management for people with long-term conditions, like epilepsy.

CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that impact toxicity and efficacy have been difficult to define because of differences in lymphodepletion regimens and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4+:CD8+ ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had markedly increased CAR-T cell expansion and persistence, and higher response rates (50% CR, 72% ORR, n=20) than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR, n=12). The complete response (CR) rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR, n=11). Cy/Flu minimized the effects of an immune response to the murine scFv component of the CAR, which limited CAR-T cell expansion, persistence, and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥ 3 neurotoxicity were observed in 13% and 28% of all patients, respectively. Serum biomarkers one day after CAR-T cell infusion correlated with subsequent development of sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4+:CD8+ ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of a lymphodepletion regimen that improved disease response and overall and progression-free survival.

Food consumption and preferences may be shaped by exposure to stressful environments during sensitive periods in development, and even small changes in consumption can have important effects on long term health. Adolescence is increasingly recognized as a sensitive period, in which adverse experiences can alter development, but the specific programming effects that may occur during adolescence remain incompletely understood. The current study seeks to explore the effects of stress during late adolescence on consumption of a palatable, high-fat, high-sugar food in adulthood—under basal conditions, as well following acute stress. Male Long-Evans rats were exposed to a regimen of variable stress for seven days in late adolescence (PND 45–51). During the stress regimen, stressed animals gained significantly less weight than control animals, but weight in adulthood was unaffected by adolescent stress. Palatable food consumption differed between experimental groups, and the direction of effect depended on context; stressed rats ate significantly more palatable food than controls upon first exposure, but ate less following an acute stressor. Leptin levels and exploratory behaviors did not differ between stressed and non-stressed groups, suggesting that other factors regulate preference for a palatable food. Altered food consumption following adolescent stress suggests that rats remain sensitive to stress during late adolescence, and that adult feeding behavior may be affected by previous adverse experiences. Such programming effects highlight adolescence as a period of plasticity, with the potential to shape long term food consumption patterns and preferences.

Exercise can have anti-inflammatory effects in obesity, but the optimal type and intensity of exercise are not clear. This study compared short-term high-intensity interval training (HIIT) with moderate-intensity continuous training (MICT) in terms of improvement in cardiorespiratory fitness, markers of inflammation, and glucose control in previously inactive adults at elevated risk of developing type 2 diabetes. Thirty-nine inactive, overweight/obese adults (32 women) were randomly assigned to 10 sessions over 2 wk of progressive HIIT ( n = 20, four to ten 1-min sessions at ∼90% peak heart rate, 1-min rest periods) or MICT ( n = 19, 20-50 min at ∼65% peak heart rate). Before and 3 days after training, participants performed a peak O2 uptake test, and fasting blood samples were obtained. Both HIIT (1.8 ± 0.4 vs. 1.9 ± 0.4 l/min, pre vs. post) and MICT (1.8 ± 0.5 vs. 1.9 ± 0.5 l/min, pre vs. post) improved peak O2 uptake ( P < 0.001) and lowered plasma fructosamine ( P < 0.05). Toll-like receptor (TLR) 4 (TLR4) expression was reduced on lymphocytes and monocytes after both HIIT and MICT ( P < 0.05) and on neutrophils after MICT ( P < 0.01). TLR2 on lymphocytes was reduced after HIIT and MICT ( P < 0.05). Plasma inflammatory cytokines were unchanged after training in both groups, but MICT led to a reduction in fasting plasma glucose ( P < 0.05, 5.9 ± 1.0 vs. 5.6 ± 1.0 mmol/l, pre vs. post). Ten days of either HIIT or MICT can improve cardiorespiratory fitness and glucose control and lead to reductions in TLR2 and TLR4 expression. MICT, which involved a longer duration of exercise, may be superior for reducing fasting glucose.

We observed the relief of hot flashes in breast cancer survivors taking tamoxifen and treated with sertraline for depression. Our objective was to assess the effect of sertraline on the frequency and severity of hot flashes, mood status, and health-related quality of life. We used a randomized, double-blind, placebo-controlled, crossover study using 6 weeks of sertraline (50 mg each morning) versus placebo. Study participants were 62 breast cancer survivors from an oncology clinic in a tertiary care center on adjuvant tamoxifen reporting bothersome hot flashes. Patients were asked to keep a daily hot flash diary to record hot flash frequency and severity, from which hot flash scores (frequency × severity) were calculated. The Center for Epidemiologic Studies depression scale and Functional Assessment of Cancer Therapy—Breast (FACT-B) (at baseline, 6 weeks, and 12 weeks) were used to assess mood and quality of life. Sixty-two women were accrued. Forty-seven women (median age 53.9 years, range 36.6–77.1 years; 89% postmenopausal; 85.5% Caucasian) completed the first 6 weeks and 39 completed 12 weeks. The baseline daily hot flash frequency and score were 5.8 (standard deviation 4.1) and 11.5 (14.0), respectively. At the end of the first 6 weeks, hot flash frequency decreased by 50% in 36% of those taking sertraline compared to 27% taking placebo. In the crossover analysis, sertraline was significantly more effective than placebo: women crossing from placebo to sertraline had a decrease (−0.9 and −1.7) in hot flash frequency and score, whereas those crossing from sertraline to placebo had an increase (1.5 and 3.4) in hot flash frequency and score (p = 0.03 and 0.03). Forty-eight percent preferred the sertraline period, 11% preferred the placebo period, and 41% had no preference (p = 0.006). Measures of depression and quality of life were within normal range and did not change significantly within treatment groups. Sertraline decreases hot flashes in breast cancer survivors taking tamoxifen and women prefer sertraline to placebo. Further study of sertraline for the management of hot flashes is warranted.

Background An acute bout of exercise can improve endothelial function and insulin sensitivity when measured on the day following exercise. Our aim was to compare acute high-intensity continuous exercise (HICE) to high-intensity interval exercise (HIIE) on circulating endothelial microparticles (EMPs) and insulin sensitivity in overweight/obese men and women. Methods Inactive males (BMI = 30 ± 3, 25 ± 6 yr, n = 6) and females (BMI = 28 ± 2, 21 ± 3 yr, n = 7) participated in three experimental trials in a randomized counterbalanced crossover design: 1) No exercise control (Control); 2) HICE (20 min cycling @ just above ventilatory threshold); 3) HIIE (10 X 1-min @ ∼90% peak aerobic power). Exercise conditions were matched for external work and diet was controlled post-exercise. Fasting blood samples were obtained ∼18 hr after each condition. CD62E+ and CD31+/CD42b- EMPs were assessed by flow cytometry and insulin resistance (IR) was estimated by homeostasis model assessment (HOMA-IR). Results There was a significant sex X exercise interaction for CD62E+ EMPs, CD31+/CD42b- EMPs, and HOMA-IR (all P

Aims. High-intensity interval training (HIIT) leads to improvements in various markers of cardiometabolic health but adherence to HIIT following a supervised laboratory intervention has yet to be tested. We compared self-report and objective measures of physical activity after one month of independent exercise in individuals with prediabetes who were randomized to HIIT (n=15) or traditional moderate-intensity continuous training (MICT,n=17).Method. After completing 10 sessions of supervised training participants were asked to perform HIIT or MICT three times per week for four weeks.Results. Individuals in HIIT (89 ± 11%) adhered to their prescribed protocol to a greater extent than individuals in MICT (71 ± 31%) as determined by training logs completed over one-month follow-up (P = 0.05, Cohen’sd = 0.75). Minutes spent in vigorous physical activity per week measured by accelerometer were higher in HIIT (24 ± 18) as compared to MICT (11 ± 10) at one-month follow-up (P = 0.049, Cohen’sd = 0.92). Cardiorespiratory fitness and systolic blood pressure assessed at one-month follow-up were equally improved (P’s Conclusions. This study provides preliminary evidence that individuals with prediabetes can adhere to HIIT over the short-term and do so at a level that is greater than MICT.

Peripheral blood mononuclear cells (PBMCs) are known to respond to systematic changes in nutrient availability. The impact of a short-term high fat diet (HFD), with and without acute glucose ingestion, on the energy-sensing enzyme 5' AMP-activated protein kinase (AMPK) as well as mitochondrial oxidative phosphorylation (OXPHOS) proteins in PBMCs is currently unknown.Nine healthy, lean young males participated in a 7 day HFD intervention, designed to induce transient glucose intolerance. The phosphorylation status and total protein content of AMPK and inflammatory mitogen-activated protein kinases (MAPKs), and total OXPHOS protein in PBMCs, along with circulating cytokines, were assessed in the fasted state and following an oral glucose tolerance test (OGTT) before and after the HFD.One week of HFD resulted in relative glucose intolerance. The HFD resulted in a reduction of AMPK phosphorylation under fasting basal conditions and following the OGTT (both P0.05), while there were no differences in OXPHOS protein expression. Although the short-term HFD had no effect on basal phosphorylation of p38, JNK or ERK1/2, the activation of MAPKs signalling in response to glucose ingestion was attenuated post-HFD as compared to pre-HFD (P0.05 for all). Circulating cytokines were not significantly affected by the HFD.We conclude that impaired glucose tolerance in response to 7 day HFD resulted in decreased AMPK activity and impaired glucose-stimulated MAPK activation following glucose ingestion in vivo in PBMCs from young, lean subjects. Further studies are warranted to explore how dietary manipulations impact interplay between AMPK and inflammatory signalling, along with immune function, in PBMCs.

18 Background: Impaired work performance that when significant leads to decreased productivity (work limitations) contribute to the “financial toxicity” of cancer treatment. Factors influencing work limitations and employment outcomes are poorly understood for cancer pts. We prospectively examined the proportion of cancer pts with significant increases in work limitations during curative treatment (co-primary endpoint). Methods: Eligible pts were ≥ 18 years, employed, intended to work during or after end of treatment (EOT), and had received ≤ 1 CT cycle. The Work Limitations Questionnaire (WLQ) survey was administered (baseline [BL], EOT, 3 and 6-months post EOT) to determine change in work limitations (WLQ index scale: 0 = no limitations to 28.6 = limited all of the time). “Significantly affected” pts had > 5-point increase in WLQ - an increase associated with decreased work productivity. Descriptive statistics (estimates with 95% confidence intervals [CI]; means with standard deviations [SD]) were calculated. A two-factor ANOVA (pt, timepoint) was used for analysis of WLQ changes over time. Results: 120 pts enrolled 5/2013 - 10/2015 at 8 sites (85 breast, 16 colon, 19 other). 110 took 1+ surveys: median age 50 (range 24-69), 92 (84%) female, 105 (96%) White; 93 (85%) had surgery, 110 (100%) CT, 57 (52%) RT. The mean increase in WLQ index from BL to EOT was +4.4 (95% CI [+2.1,+6.8], p < 0.001). A total of 44% were “significantly affected” by treatment (37/85, 95% CI [33%,55%]). WLQ index decreased at 3 and 6-mos (as compared to BL or EOT, see table). Conclusions: Among largely White pts getting CT, 44% experienced a significant increase in work limitations from BL to EOT. An improvement in group WLQ scores was noted after EOT. Analysis of factors (e.g., job type, education, symptoms) most associated with work limitations is underway to assist in prospectively identifying at-risk pts. [Table: see text]

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2250 mg/m2 PO every 8 hours × 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.

Summary Subarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra) reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1) was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC). Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs) in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP) driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.

Background Mass drug administration (MDA) of antibiotics is a key component of the so-called “SAFE” strategy for trachoma control, while MDA of anthelminthics provides the cornerstone for control of a number of other neglected tropical diseases (NTDs). Simultaneous delivery of two or more of these drugs, renowned as “integrated NTD control,” is being promoted to reduce costs and expand intervention coverage. A cost analysis was conducted alongside an MDA campaign in a remote trachoma endemic area, to inform budgeting for NTD control in South Sudan. Methods and Findings A first round of antibiotic MDA was conducted in the highly trachoma endemic county of Mayom, Unity state, from June to August 2010. A core team of seven staff delivered the intervention, including recruitment and training of 44 supervisors and 542 community drug distributors. Using an ingredients approach, financial and economic costs were captured from the provider perspective in a detailed costing database. Overall, 123,760 individuals were treated for trachoma, resulting in an estimated treatment coverage of 94%. The economic cost per person treated was USD 1.53, excluding the cost of the antibiotic azithromycin. Ninety four per cent of the delivery costs were recurrent costs, with personnel and travel/transport costs taking up the largest share. Conclusions In a remote setting and for the initial round, MDA of antibiotics was considerably more expensive than USD 0.5 per person treated, an estimate frequently quoted to advocate for integrated NTD control. Drug delivery costs in South Sudan are unlikely to decrease substantially during subsequent MDA rounds, as the major cost drivers were recurrent costs. MDA campaigns for delivery of one or more drugs in South Sudan should thus be budgeted at around USD 1.5 per person treated, at least until further costing data for delivery of other NTD drugs, singly or in combination, are available., Author Summary Trachoma is one of a group of so-called “neglected tropical diseases” (NTDs) for which safe and effective treatments are available. The International Trachoma Initiative oversees donation of the antibiotic azithromycin to endemic countries. Delivery of this drug to communities affected by trachoma is the responsibility of national programmes and their implementing partners, and should be conducted as part of a comprehensive control strategy termed “SAFE,” which includes trichiasis surgery, health education and water/sanitation interventions. There are little data on how much the different components of a trachoma control programme cost and none from South Sudan. To inform budgeting to scale up control of trachoma, and of other NTDs whose control relies on large-scale mass drug administration (MDA), the present study set out to determine the cost per person treated when antibiotics were delivered through a vertical campaign that covered 94% of the target population in a remote trachoma endemic area of South Sudan. The average economic cost per person treated was USD 1.53, which included all inputs not paid for in cash except for the cost of the donated azithromycin and the opportunity cost of community members attending treatment.

Background Increasing emphasis on integrated control of neglected tropical diseases (NTDs) requires identification of co-endemic areas. Integrated surveys for lymphatic filariasis (LF), schistosomiasis and soil-transmitted helminth (STH) infection have been recommended for this purpose. Integrated survey designs inevitably involve balancing the costs of surveys against accuracy of classifying areas for treatment, so-called implementation units (IUs). This requires an understanding of the main cost drivers and of how operating procedures may affect both cost and accuracy of surveys. Here we report a detailed cost analysis of the first round of integrated NTD surveys in Southern Sudan. Methods and Findings Financial and economic costs were estimated from financial expenditure records and interviews with survey staff using an ingredients approach. The main outcome was cost per IU surveyed. Uncertain variables were subjected to univariate sensitivity analysis and the effects of modifying standard operating procedures were explored. The average economic cost per IU surveyed was USD 40,206 or USD 9,573, depending on the size of the IU. The major cost drivers were two key categories of recurrent costs: i) survey consumables, and ii) personnel. Conclusion The cost of integrated surveys in Southern Sudan could be reduced by surveying larger administrative areas for LF. If this approach was taken, the estimated economic cost of completing LF, schistosomiasis and STH mapping in Southern Sudan would amount to USD 1.6 million. The methodological detail and costing template provided here could be used to generate cost estimates in other settings and readily compare these to the present study, and may help budget for integrated and single NTDs surveys elsewhere., Author Summary Control of neglected tropical diseases (NTDs) is suggested to be more cost-effective when drugs are co-administered through a single integrated delivery system rather than separate systems. An essential prerequisite for such efficiency gains is sufficient geographical overlap of the targeted diseases – lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminth infection and trachoma. Lack of data on geographical NTD distribution currently hampers the implementation of integrated control in many African countries. To generate the required data quickly and efficiently, integrated surveys of several NTDs simultaneously have been recommended. However, experience with integrated surveys is limited and requires additional research on cost and effectiveness to inform improvements in methodology and to guide scale-up. Here we analyse costs of the first integrated NTD survey round in Southern Sudan, generating average costs per implementation unit surveyed. Cost estimates are presented for use of the existing survey method and for modified versions. Key cost drivers were survey consumables and personnel, both of which are recurrent costs. These inputs could be reduced or put to more efficient use by modifying sampling for LF. To generate comparable cost estimates and identify key cost drivers in other settings we provide detailed cost data and guidance on how to replicate this work.

Background Trachoma is thought to be endemic over large parts of Southern Sudan, but empirical evidence is limited. While some areas east of the Nile have been identified as highly endemic, few trachoma surveys have been conducted in the remainder of the country. This study aimed to determine whether trachoma constitutes a problem to public health in Northern Bahr-el-Ghazal and Unity State, both located west of the Nile. Methods and Principal Findings Trachoma rapid assessments (TRA) were conducted between July and September 2009. Seven villages in Northern Bahr-el-Ghazal State and 13 villages in Unity State were surveyed; an average of 50 children (age 1–9 years) and 44 women (age 15 years and above) were examined per village. Samples for analysis using the APTIMA Combo-2 nucleic acid amplification test (NAAT) were collected from participants with active trachoma in eight villages in Unity State. In Northern Bahr-el-Ghazal State, only three children with active trachoma (trachomatous inflammation follicular (TF) and/or trachomatous inflammation intense (TI)) and two women with trichiasis (TT) were found, in two of the seven villages surveyed. In Unity State, trachoma was endemic in all thirteen villages surveyed; the proportion of children with active trachoma ranged from 33% to 75% between villages, while TF in children ranged from 16% to 44%. Between 4% to 51% of examined women showed signs of TT. Samples from active trachoma cases tested using the NAAT were positive for Chlamydia trachomatis infection for 46.6% of children and 19.0% of women. Conclusions Trachoma presents a major problem to public health Unity State, while the disease is of low priority in Northern-Bahr-el-Ghazal State. Implementation of a population-based prevalence survey is now required in Unity State to generate baseline prevalence data so that trachoma interventions can be initiated and monitored over time.

Objective— To report inguinal herniation of the ascending colon in a Standardbred colt. Study Design— Case report. Animals— A 6-month-old Standardbred colt. Methods— The colt underwent surgical exploration of the hernia with large colon resection and anastomosis. Results— A successful large colon resection and anastomosis was completed, however, the colt was euthanatized at the end of surgery upon owner request. Conclusions and Clinical Relevance— Although uncommon, indirect inguinal herniation of the ascending colon can occur in young horses.

Background There are few detailed data on the geographic distribution of most neglected tropical diseases (NTDs) in post-conflict Southern Sudan. To guide intervention by the recently established national programme for integrated NTD control, we conducted an integrated prevalence survey for schistosomiasis, soil-transmitted helminth (STH) infection, lymphatic filariasis (LF), and loiasis in Northern Bahr-el-Ghazal State. Our aim was to establish which communities require mass drug administration (MDA) with preventive chemotherapy (PCT), rather than to provide precise estimates of infection prevalence. Methods and Findings The integrated survey design used anecdotal reports of LF and proximity to water bodies (for schistosomiasis) to guide selection of survey sites. In total, 86 communities were surveyed for schistosomiasis and STH; 43 of these were also surveyed for LF and loiasis. From these, 4834 urine samples were tested for blood in urine using Hemastix reagent strips, 4438 stool samples were analyzed using the Kato-Katz technique, and 5254 blood samples were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests (ICT). 4461 individuals were interviewed regarding a history of ‘eye worm’ (a proxy measure for loiasis) and 31 village chiefs were interviewed regarding the presence of clinical manifestations of LF in their community. At the village level, prevalence of Schistosoma haematobium and S. mansoni ranged from 0 to 65.6% and from 0 to 9.3%, respectively. The main STH species was hookworm, ranging from 0 to 70% by village. Infection with LF and loiasis was extremely rare, with only four individuals testing positive or reporting symptoms, respectively. Questionnaire data on clinical signs of LF did not provide a reliable indication of endemicity. MDA intervention thresholds recommended by the World Health Organization were only exceeded for urinary schistosomiasis and hookworm in a few, yet distinct, communities. Conclusion This was the first attempt to use an integrated survey design for this group of infections and to generate detailed results to guide their control over a large area of Southern Sudan. The approach proved practical, but could be further simplified to reduce field work and costs. The results show that only a few areas need to be targeted with MDA of PCT, thus confirming the importance of detailed mapping for cost-effective control., Author Summary Integrated control of neglected tropical diseases (NTDs) is being scaled up in a number of developing countries, because it is thought to be more cost-effective than stand-alone control programmes. Under this approach, treatments for onchocerciasis, lymphatic filariasis (LF), schistosomiasis, soil-transmitted helminth (STH) infection, and trachoma are administered through the same delivery structure and at about the same time. A pre-requisite for implementation of integrated NTD control is information on where the targeted diseases are endemic and to what extent they overlap. This information is generated through surveys that can be labour-intensive and expensive. In Southern Sudan, all of the above diseases except onchocerciasis require further mapping before a comprehensive integrated NTD control programme can be implemented. To determine where treatment for which disease is required, integrated surveys were conducted for schistosomiasis, STH infection, LF, and loiasis, throughout one of ten states of the country. Our results show that treatment is only required for urinary schistosomiasis and STH in a few, yet separate, geographical area. This illustrates the importance of investing in disease mapping to minimize overall programme costs by being able to target interventions. Integration of survey methodologies for the above disease was practical and efficient, and minimized the effort required to collect these data.

Background Trachoma is thought to be common over large parts of Southern Sudan. However, many areas of the country, particularly west of the Nile, have not yet been surveyed. The aim of this study was to confirm whether trachoma extends into Western Equatoria State from neighboring Central Equatoria, where trachoma is highly prevalent, and whether intervention with the SAFE strategy is required. Methods and Findings Population-based cross-sectional surveys were conducted using a two-stage cluster random sampling method to select the study population. Subjects were examined for trachoma by experienced graders using the World Health Organization (WHO) simplified grading scheme. Two counties thought to be most likely to have trachoma were surveyed, Maridi and Mundri. In Maridi, prevalence of one of the signs of active trachoma (trachomatous inflammation-follicular (TF)) in children aged 1–9 years was 0.4% (95% confidence interval (CI), 0.0%–0.8%), while no children showing the other possible sign, trachomatous inflammation-intense (TI), were identified. No trachomatous trichiasis (TT) was found in those aged under 15, and prevalence was 0.1% (95% CI, 0.0%–0.4%) in those aged 15 years and above. In Mundri, active trachoma was also limited to signs of TF, with a prevalence of 4.1% (95% CI, 1.4%–6.9%) in children aged 1–9 years. Again, no TT was found in those aged under 15, and prevalence in those aged 15 years and above was 0.3% (95% CI, 0.0%–0.8%). Conclusion Trachoma prevalence in the east of Western Equatoria State is below the WHO recommended intervention threshold for mass drug administration of antibiotic treatment in all villages. However, the prevalence of TF and TT in some villages, particularly in Mundri County, is sufficiently high to warrant targeted interventions at the community level. These results demonstrate that trachoma is not a major public health problem throughout Southern Sudan. Further studies will be required to determine trachoma prevalence in other areas, particularly west of the Nile, but there are presently no resources to survey each county. Studies should thus be targeted to areas where collection of new data would be most informative., Author Summary Baseline data on trachoma prevalence is a prerequisite for intervention. Prior to the present study, all surveys in Southern Sudan reported trachoma prevalences that exceeded the threshold for large-scale intervention. This gave rise to the notion that the disease may be endemic throughout the country. The present study was conducted under the auspices of the National Program for Integrated Control of Neglected Tropical Diseases, to verify whether prevalences in two counties west of the Nile exceeded the WHO recommended intervention threshold for mass drug administration (MDA) of antibiotic treatment. The results show that trachoma prevalence at county level was below this threshold. However, prevalences in some communities within the county were above the threshold, meaning that they should be targeted with MDA of antibiotics, as well as with other interventions such as trichiasis surgery, health promotion and improved water and sanitation. This finding reminds us of the need for geographical targeting of resources, both for surveys and subsequent intervention. Current resources are insufficient to conduct population-based prevalence surveys for trachoma throughout Southern Sudan. Further surveys should thus be conducted in areas where collection of additional information will be most informative. We propose that a combination of risk-mapping and rapid assessments is used to identify such areas.

BACKGROUND: Chemotherapy followed by autologous T cells that are genetically modified to express a CD19-specific chimeric antigen receptor (CAR) has shown promise as a novel therapy for patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL); however, the risk of severe cytokine release syndrome (sCRS) and neurotoxicity has tempered enthusiasm for widespread application of this approach. The functional heterogeneity that is inherent in CAR-T cell products that are manufactured from undefined T cell subsets has hindered definition of dose-response relationships and identification of factors that may impact efficacy and toxicity. METHODS: We are conducting the first clinical trial that administers CD19 CAR-T cells manufactured from a defined composition of T cell subsets to adults with relapsed or refractory B-ALL. CD8+ and CD4+ T cells were enriched from each patient, transduced with a CD19 CAR lentivirus and separately expanded in vitro before formulation for infusion in a 1:1 ratio of CD8+:CD4+ CAR+ T cells at 2x105, 2x106 or 2x107 CAR-T cells/kg. Prior to CAR-T cell infusion, patients underwent lymphodepletion with a high-dose cyclophosphamide (Cy)-based regimen with or without fludarabine (Flu). RESULTS: Twenty-nine adults with B-ALL (median age 40, range 22 - 73 years; median 17% marrow blasts, range 0 - 97%), including 10 patients who had relapsed after allogeneic transplantation, received at least one CAR-T cell infusion. Twenty-four of 26 restaged patients (92%) achieved bone marrow (BM) complete remission (CR) by flow cytometry. CD4+ and CD8+ CAR-T cells expanded in vivo after infusion and their number in blood correlated with the infused CAR-T cell dose. Thirteen patients received lymphodepletion with Cy-based regimens without Flu. Ten of 12 restaged patients (83%) achieved BM CR by flow cytometry; however, 7 of these (70%) relapsed a median of 66 days after CAR-T cell infusion. Disease relapse correlated with a loss of CAR-T cell persistence in blood. We observed a CD8 cytotoxic T cell response to the murine scFv component of the CAR transgene that contributed to CAR-T cell rejection, and resulted in lack of CAR-T cell expansion after a second CAR-T cell infusion in 5 patients treated for persistent or relapsed disease. To minimize immune-mediated CAR-T cell rejection 14 patients were treated with Cy followed by Flu lymphodepletion (Cy/Flu, Cy 60 mg/kg x 1 and Flu 25 mg/m2 x 3-5) before CAR-T cell infusion. All patients (100%) who received Cy/Flu lymphodepletion achieved BM CR after CAR-T cell infusion. CAR-T cell expansion and persistence in blood was higher in Cy/Flu-lymphodepleted patients compared to their counterparts who received Cy alone (Day 28 after 2x106 CAR-T cells/kg: CD8+ CAR-T cells, mean 55.8/μL vs 0.10/μL, p CAR-T cell infusion was associated with sCRS, characterized by fever and hypotension requiring intensive care in 7 of 27 patients (26%) and neurotoxicity (≥ grade 3 CTCAE v4.03) in 13 of 27 patients (48%). Two patients died following complications of sCRS. Patients with sCRS or neurotoxicity had higher peak serum levels of IL-6, IFN-γ, ferritin and C-reactive protein compared to those without serious toxicity. Importantly IL-6, IFN-γ and TNF-α levels in serum collected on day 1 after CAR-T cell infusion from those who subsequently developed neurotoxicity were higher than those collected from their counterparts who did not develop neurotoxicity (IL-6, p CONCLUSION: Risk-stratified dosing of CD19 CAR-T cells of defined subset composition is feasible and safe in a majority of patients with refractory B-ALL, and results in a CR rate of 92%. Addition of Flu to Cy-based lymphodepletion improves CAR-T cell expansion, persistence and DFS. Disclosures Turtle: Juno Therapeutics: Patents & Royalties, Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Jensen:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Riddell:Adaptive Biotechnologies: Consultancy; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Membership on an entity's Board of Directors or advisory committees. Maloney:Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding.

BACKGROUND: Autologous T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) have demonstrated activity in patients with relapsed or refractory B cell NHL and CLL. The functional heterogeneity that is inherent in CAR-T cell products that are manufactured from undefined T cell subsets has hindered definition of dose-response relationships and identification of factors that may impact efficacy and toxicity, such as the lymphodepletion regimen and infused cell dose. We manufactured anti-CD19 CAR-T cells from a defined composition of CD4+ and CD8+ T cell subsets to treat adults with relapsed or refractory B cell NHL or CLL. T cell subsets were enriched from each patient, transduced with a CD19 CAR lentivirus and separately expanded in vitro before formulation for infusion in a 1:1 ratio of CD8+:CD4+ CAR+ T cells at one of three dose levels (2x105, 2x106 or 2x107 CAR-T cells/kg). CAR-T cells were administered 48-96 hours after lymphodepletion with either cyclophosphamide (Cy, 60 mg/kg)+/- etoposide or Cy (60 mg/kg) and fludarabine (25 mg/m2 daily for 3-5 days (Cy/Flu). RESULTS: Adult patients with relapsed/refractory CD19 expressing B cell NHL (n=28, median age 59 years, range 36-70) or CLL (n=6, median age 60 years, range 54-64) were treated with at least one CAR-T cell infusion. NHL histologies include diffuse large B cell or transformed NHL (DLBCL, n=18), follicular NHL (FL, n= 6) or mantle cell lymphoma (MCL, n=4). 15 patients had failed prior autologous (n=13) or allogeneic (n=3) transplants. Twelve of the 28 NHL patients received lymphodepletion with Cy-based regimens without fludarabine. Expansion of CAR-T cells and clinical responses were observed in 50% (CR=1 (DLBCL), PR=5 (2 FL, 2 DLBCL, 1 MCL), no response=6). Patients were treated at all three dose levels without dose limiting toxicity or severe cytokine release syndrome (sCRS). With this regimen, we observed short CAR-T cell persistence in most patients and demonstrated a CD8-mediated immune response to the murine scFv component of the CAR transgene that correlated with loss of CAR-T cells. Retreatment with CAR-T cells with or without chemotherapy in 5 patients led to no significant T cell expansion or clinical responses. To minimize transgene rejection fludarabine was added to the lymphodepletion regimen administered to the subsequent 16 NHL patients. Clinical responses were evaluated in 12 of 16 patients (2 not yet evaluable, 2 early deaths). Addition of Flu to the lymphodepletion regimen increased the CR rate to 42%, compared to 8% with Cy alone. Clinical responses were identified in 6 of 8 patients with DLBCL (3 CR, 3 PR) and 2 of 3 patients with FL (2 CR). The overall response rate was 67%. We noted higher peak CAR-T cell levels in blood in the Cy/Flu group (n=13) compared with the Cy only group (n=11) (CD8+ CAR-T cells, median 31.9 cells/ml vs 0.55 cells/ml, p = 0.009; CD4+ CAR-T cells, median 16.5 cells/ml vs 0.31 cells/ml, p= 0.007), and CAR-T cell persistence was longer in Flu-treated patients (see Figure 1 for patients treated at 2 x 107/kg). Surprisingly, 2 of 7 patients who received 2 x 107 CAR-T cells/kg experienced dose-limiting toxicity necessitating dose de-escalation. Markedly elevated IL-6 levels were observed within the first day after CAR-T cell infusion in patients who subsequently developed severe toxicity, which may provide an opportunity to test early interventional approaches to minimize toxicity. Six patients with relapsed and refractory CLL received CAR-T cells. Five of 6 restaged patients had complete clearance of blood and/or marrow disease by high-resolution flow cytometry 4 weeks following treatment. Overall clinical responses included 3 CR, 1 PR and 2 no response. One patient with a PR died from refractory pulmonary aspergillus infection. Patients with CR remain in remission at 1-10 months after therapy. CONCLUSION: Immunotherapy with CD19 CAR-T cells of defined subset composition is feasible in patients with NHL and CLL and has potent anti-tumor activity. Toxicity is related to cell dose. The addition of Flu to a Cy-based lymphodepletion regimen results in greater CAR-T cell expansion and persistence, and improves the CR rate after CD19 CAR-T cell therapy. Disclosures Turtle: Juno Therapeutics: Patents & Royalties, Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Jensen:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Maloney:Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria.

The aim of this study was to gain greater insight into the experience of being diagnosed with type 1 diabetes during adolescence, and the factors that influence how a young person makes sense of the condition over time. Interpretative phenomenological analysis (IPA) was employed in an attempt to convey an understanding of what it feels like to be diagnosed with diabetes during adolescence and to highlight implications for health care professionals. The perspectives of eight adults, aged 28 ‐36 years who were diagnosed with diabetes during adolescence, were gathered using an unstructured interview and were analysed using IPA. The results showed that chronic illness impacts on the sense of self and can be especially devastating for an adolescent trying to cope with the conflicting nature of adolescence and the demanding, restrictive nature of diabetes. In some young people this can lead to risky self-care behaviours. However, through active encouragement and support from significant others, young people are able to develop an integrated sense of self, which is more suited to living with a chronic condition. These findings suggest that the relationships between illness beliefs and psychological adjustment lie in the family and social context. It was concluded that health care professionals need to support the young person by having a better understanding of the impact of diabetes on adolescent development and by tailoring their approach to these young people. Psychology teams can be approached to provide consultation and training for diabetes teams to assist in the setting up of developmentally appropriate transition services for young people. A list of training and educational resources for health care professionals and young people is provided. Copyright © 2015 John Wiley & Sons. Practical Diabetes 2015; 32(9): 339 ‐344

Objective. We conducted a phase II multicenter trial of perillyl alcohol in patients with advanced hormone refractory prostate cancer (HRPC). The primary endpoint was to evaluate the 6-month progression-free survival given the potential cytostatic nature of the drug. Secondary objectives included assessing acute and chronic toxicities, as well as measuring objective response rates. Methods. Patients with metastatic androgen-independent prostate cancer that failed at least one prior chemotherapeutic or experimental regimen were eligible. Perillyl alcohol was administered orally at 1200 mg/m2/dose four times daily and continued until disease progression or development of unacceptable toxicity. Results. Fifteen patients were eligible. Six patients received less than one cycle (4 weeks) of drug, four of which stopped because of drug intolerance. Only six patients received more than two cycles of therapy and were considered evaluable for response. Main toxicity included grade 1–2 gastrointestinal intolerance (nausea/vomiting in 60% of the patients) and fatigue (47%). One patient developed a grade 4 hypokalemia that was felt likely attributable to the drug. No objective responses were seen. All patients either progressed or withdrew from the study secondary to drug intolerance before the 6-month time period. Conclusion. Perillyl alcohol administered at this dose and formulation did not have any objective clinical activity in this patient population.

Tamoxifen is a synthetic antiestrogen with both agonist and antagonist properties. It is believed to act primarily through binding to estrogen receptors in breast cancer cells, acting as a competitive inhibitor of estrogen. Tamoxifen has a wide range of systemic effects, possibly acting on every estrogen target tissue in the body. Tamoxifen therapy is associated with a significant reduction in the risk of recurrence and death in postmenopausal women with early stage breast cancer. In addition, it has been shown to effectively suppress preclinical breast cancer, as evidenced by the decrease in second primary breast cancers in adjuvant trials. Tamoxifen is also the most widely used endocrine therapy for women with metastatic breast cancer. Tamoxifen, acting predominantly as an estrogen agonist in the liver, has generally favourable effects on serum lipids in postmenopausal women. In addition, tamoxifen has been shown to preserve bone mineral density and may even decrease the risk of osteoporosis in these women. Most patients treated with tamoxifen have minimal adverse effects. Vasomotor symptoms are the most commonly reported events. Less frequently, vaginal discharge or dryness, nausea and depression have been reported. A slight increase in thromboembolic events in postmenopausal women taking tamoxifen has been suggested in some adjuvant trials. Rarely, ocular toxicity and hepatotoxicity are found. The adverse effect of primary importance is the increased incidence of endometrial carcinoma. Several studies indicate that almost all of the tumours are of low histological grade and stage, similar to those seen with exogenous estrogen use. The relative risk of endometrial cancer in women taking tamoxifen is about 2 to 4 times higher than for postmenopausal women not taking tamoxifen. The benefits of tamoxifen outweigh the risks in almost all postmenopausal women with estrogen receptor-positive early stage breast cancer and in all women with metastatic breast cancer. Should tamoxifen prove to be an effective chemopreventive agent for breast cancer, the risks and benefits of treatment will have to be more carefully assessed for this setting.

7567 Background: Third-line treatment option for advanced NSCLC patients is very limited with a lack of effective drugs and specific trials targeting this patient population. V+B combination was pr...