Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.

Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

Period-Prevalence and Risk Factors for Delirium in a Tertiary Referral ICU: A prospective cohort study.

BACKGROUND: Delirium is common in intensive care and leads to increases in morbidity, mortality, Intensive Care Unit (ICU) length of stay, and hospital length of stay. Certain risk factors predict the appearance of delirium. STUDY OBJECTIVES: To determine the rates of delirium, the rate of risk factors, and their relationship to the occurrence of delirium in an adult ICU. METHODS: Single-centre, prospective, observational study. Demographic and treatment data were collected. The Confusion Assessment Method for ICU (CAM-ICU) was performed twice daily to assess for delirium continuously during a 3-week period. Statistical analysis was used to determine the relationship between risk factors and the occurrence of delirium. RESULTS: 86 patients were screened, 44 patients were included, and 260 patient-days were analyzed. The incidence of delirium was 42.9%, the prevalence of delirium in ICU was 50%. Urinary catheters and use of opioids were the most common factors with a positive association for occurrence of delirium. Exposure to daylight and sleeping for more than 4 hours at night were the factors most commonly associated with a lack of delirium. CONCLUSION: The rates of delirium in ICU were high and risk factors occurred frequently. Addressing modifiable risk factors, including the promotion of adequate sleep, could improve outcomes.

The learning curve for endoscopic tympanoplasties: a single-institution experience, in Birmingham, UK.

OBJECTIVE: This study aimed to assess whether increasing operative experience results in better surgical outcomes in endoscopic middle-ear surgery. METHODS: A retrospective single-institution cohort study was performed. Patients underwent endoscopic tympanoplasty between May 2013 and April 2019 performed by the senior surgeon or a trainee surgeon under direct supervision from the senior surgeon. Following data collection, statistical analysis compared success rates between early (learning curve) surgical procedures and later (experienced) tympanoplasties. RESULTS: In total, 157 patients (86 male, 71 female), with a mean age of 41.6 years, were included. The patients were followed up for an average of 43.2 weeks. The overall primary closure rate was 90.0 per cent. CONCLUSION: This study demonstrates an early learning curve for endoscopic ear surgery that improves with surgical experience. Adoption of the endoscopic technique did not impair the success rates of tympanoplasty.

Weekly paclitaxel, carboplatin, cetuximab, and cetuximab, docetaxel, cisplatin, and fluorouracil, followed by local therapy in previously untreated, locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The survival advantage of induction chemotherapy (IC) followed by locoregional treatment is controversial in locally advanced head and neck squamous cell carcinoma (LAHNSCC). We previously showed feasibility and safety of cetuximab-based IC (paclitaxel/carboplatin/cetuximab-PCC, and docetaxel/cisplatin/5-fluorouracil/cetuximab-C-TPF) followed by local therapy in LAHNSCC. The primary end point of this phase II clinical trial with randomization to PCC and C-TPF followed by combined local therapy in patients with LAHNSCC stratified by human papillomavirus (HPV) status and T-stage was 2-year progression-free survival (PFS) compared with historical control. PATIENTS AND METHODS: Eligible patients were ≥18 years with squamous cell carcinoma of the oropharynx, oral cavity, nasopharynx, hypopharynx, or larynx with measurable stage IV (T0-4N2b-2c/3M0) and known HPV by p16 status. Stratification was by HPV and T-stage into one of the two risk groups: (i) low-risk: HPV-positive and T0-3 or HPV-negative and T0-2; (ii) intermediate/high-risk: HPV-positive and T4 or HPV-negative and T3-4. Patient reported outcomes were carried out. RESULTS: A total of 136 patients were randomized in the study, 68 to each arm. With a median follow up of 3.2 years, the 2-year PFS in the PCC arm was 89% in the overall, 96% in the low-risk and 67% in the intermediate/high-risk groups; in the C-TPF arm 2-year PFS was 88% in the overall, 88% in the low-risk and 89% in the intermediate/high-risk groups. CONCLUSION: The observed 2-year PFS of PCC in the low-risk group and of C-TPF in the intermediate/high-risk group showed a 20% improvement compared with the historical control derived from RTOG-0129, therefore reaching the primary end point of the trial.

The magnitude of Yo-Yo test improvements following an aerobic training intervention are associated with total genotype score.

Recent research has demonstrated that there is considerable inter-individual variation in the response to aerobic training, and that this variation is partially mediated by genetic factors. As such, we aimed to investigate if a genetic based algorithm successfully predicted the magnitude of improvements following eight-weeks of aerobic training in youth soccer players. A genetic test was utilised to examine five single nucleotide polymorphisms (VEGF rs2010963, ADRB2 rs1042713 and rs1042714, CRP rs1205 & PPARGC1A rs8192678), whose occurrence is believed to impact aerobic training adaptations. 42 male soccer players (17.0 ± 1y, 176 ± 6 cm, 69 ± 9 kg) were tested and stratified into three different Total Genotype Score groups; "low", "medium"and "high", based on the possession of favourable polymorphisms. Subjects underwent two Yo-Yo tests separated by eight-weeks of sports-specific aerobic training. Overall, there were no significant differences between the genotype groups in pre-training Yo-Yo performance, but evident between-group response differentials emerged in post-training Yo-Yo test performance. Subjects in the "high" group saw much larger improvements (58%) than those in the 'medium" (35%) and "low" (7%) groups. There were significant (p<0.05) differences between the groups in the magnitude of improvement, with athletes in the "high" and medium group having larger improvements than the "low" group (d = 2.59 "high" vs "low"; d = 1.32 "medium" vs "low"). In conclusion, the magnitude of improvements in aerobic fitness following a training intervention were associated with a genetic algorithm comprised of five single nucleotide polymorphisms. This information could lead to the development of more individualised aerobic training designs, targeting optimal fitness adaptations.

Using a model based fourth-corner analysis to explain vegetation change following an extraordinary fire disturbance.

In ecosystems where large-scale disturbances are infrequent, the mode of succession may be difficult to discern and floristic surveys alone cannot be used determine the underlying processes causing vegetation change. To determine the causes of vegetation change in response to a large-scale fire event, we combined traditional floristic survey data, plant functional traits and environmental variables in a model-based solution to the fourth-corner problem. This approach allowed us to describe the trait-environment relationship and provides an intuitive matrix of environment by trait interaction coefficients. We could then quantify the strength and direction of associations between plant traits, species life-forms and environmental factors in two alpine plant communities over nine years post-fire. Initially, the fire drastically reduced vegetation cover and species density to very low levels. The fourth-corner analysis interaction coefficients indicated that over the course of the nine-year study a high abundance of graminoids, a low abundance of shrubs, tall species and those with high leaf dry matter content had the strongest associations with the two plant communities. We also found evidence for functional homogenisation between these two communities using this novel technique. Analysing plant traits and species responses post-fire in this manner can be used to infer the ecological processes driving shifts in vegetation.

A genetic-based algorithm for personalized resistance training.

Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete's genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete's potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual's genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.

Hypersensitivity pneumonitis in workers exposed to metalworking fluids.

BACKGROUND: This study used data from a large UK outbreak investigation, to develop and validate a new case definition for hypersensitivity pneumonitis due to metalworking fluid exposure (MWF-HP). METHODS: The clinical data from all workers with suspected MWF-HP were reviewed by an experienced panel of clinicians. A new MWF-HP Score was then developed to match the "gold standard" clinical opinion as closely as possible, using standard diagnostic criteria that were relatively weighted by their positive predictive value. RESULTS: The new case definition was reproducible, and agreed with expert panel opinion in 30/37 cases. This level of agreement was greater than with any of the three previously utilized case definitions (agreement in 16-24 cases). Where it was possible to calculate, the MWF-HP Score also performed well when applied to 50 unrelated MWF-HP cases. CONCLUSIONS: The MWF-HP Score offers a new case definition for use in future outbreaks.

CT imaging correlates of genomic expression for oral cavity squamous cell carcinoma.

BACKGROUND AND PURPOSE: Imaging correlates of genetic expression have been found for prognostic and predictive biomarkers of some malignant diseases, including breast and brain tumors. This study tests the hypothesis that imaging findings correlate with relevant genomic biomarkers in oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Surplus frozen tissue from 27 untreated patients with oral cavity squamous cell carcinoma who underwent preoperative CT imaging was analyzed for gene expression. A team of neuroradiologists blinded to the genomic analysis results reviewed an extensive list of CT findings. The imaging correlated with genomic expression for cyclin D1, angiogenesis-related genes (vascular endothelial growth factor receptors and ligands), which relate to enhancement on the basis of other tumor types; and epidermal growth factor receptor, which may relate to proliferation and mass effect. RESULTS: Expression of vascular endothelial growth factor receptors 1 and 2 correlated with the enhancement of the primary tumor (P = .018 and P = .025, respectively), whereas the epidermal growth factor receptor correlated with mass effect (P = .03). Other exploratory correlations included epidermal growth factor receptor to perineural invasion (P = .05), and certain vascular endothelial growth factor receptors and ligands to mass effect (P = .03) and increased (P = .01) or decreased (P = .02) primary tumor size. CONCLUSIONS: We report that CT imaging correlates with gene expression in untreated oral cavity squamous cell carcinoma. Enhancement of the primary tumor and degree of mass effect correlate with relevant genomic biomarkers, which are also potential drug targets. Eventually, treatment decisions may be aided by combining imaging findings into meaningful phenotypes that relate directly to genomic biomarkers.

SU-E-T-261: Determination of Initial Exposure Rates and Clearance Constants in a Sequence of 165 Consecutive Thyroid Cancer Patients Undergoing NaI-131 Therapy.

PURPOSE: Following surgery, papillary and follicular thyroid cancers are usually treated with oral administration of NaI-131. In order to estimate subsequent staff, family, and public exposures, it is important to measure both exposure rates as well as the time of clearance of residual activity from these individuals. There is the additional possibility that patient whole-body absorbed dose estimates may be made using the data. METHODS: During the historical interval 2006 - 2010, a total of 165 consecutive thyroid cancer patients were assayed at the time of activity administration and over the following several days. Using a calibrated radiation detector, exposure rates at one meter from the navel were measured between 2 and 5 times before release. By using these measurements and assuming a single-exponential clearance, we were able to evaluate initial exposure rates as well as the biological rate constant [k(biol)] for clearance of I-131 from the body. RESULTS: Regression analyses were used to fit the initial exposure [X(0)] results as a function of administered activity. By least-squares, the slope was determined to be 0.15 mR/h/mCi over a clinically determined activity range of 25 to 250 mCi. At a given activity, there was wide variation of X(0) due to individual factors such as amount of residual thyroid mass and body habitus. For example, at 150 mCi, X(0) varied from 15 to 35 mR/h at one meter with the average being 25 mR/h. For the 165 patients, the mean biological clearance constant was 0.049/h. CONCLUSION: Average initial exposure rates at one meter from 165 NaI-131 patients have been determined. The biological clearance was seen to be much more rapid than the physical decay constant for I-131 (0.0036/h). At a given activity level, variation of exposure rates was approximately +/- 40% over the corresponding patient population.

Dopamine D1 receptor gene expression decreases in the nucleus accumbens upon long-term exposure to palatable food and differs depending on diet-induced obesity phenotype in rats.

The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants' hedonic value. NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals' obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether the NAcc dopamine response to palatable food depends on obesity susceptibility. We investigated the effect of unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D(1) and D(2) gene expression in OP and OR rats subjected to HFHS withdrawal (bland chow for 18 days). Effects of restricted access to HFHS by pair-feeding were also studied. Using reverse transcriptase PCR (RT-PCR), we found that NAcc D(1) mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect was also observed after 18 days of HFHS withdrawal. Furthermore, restricted HFHS led to downregulation of D(1) as well as of D(2) mRNA levels compared to chow-fed controls. A difference in the expression of mu opioid receptor in the NAcc was also detected between the OP and OR rats during access to palatable food but not after withdrawal. We conclude that exposure to HFHS diets has lasting consequences for the NAcc dopamine system, perhaps modifying the motivation to search for food reward. The fact that the NAcc D(1) expression changes in OP animals after long-term exposure to palatable food and that this effect extends well into the reward discontinuation phase, implicates the D(1) receptor in the propensity to overeat and, in effect, gain weight in obesity prone individuals.

Natural history and risk factors of early respiratory responses to exposure to cotton dust in newly exposed workers.

OBJECTIVE: A prospective study of newly exposed cotton workers was performed to investigate the natural history of respiratory symptoms and lung function changes. METHODS: A total of 157 workers naive to cotton dust exposure were investigated by questionnaire, spirometry, and skin tests. They were examined before employment (baseline) and at the end of the first week, and the first, third, sixth, and 12th month after starting work. Acute airway response was defined as either a cross-first-shift or a cross-week fall in forced expiratory volume in one second (FEV1). The longitudinal change of lung function over the year was also calculated. Five hundred seventy-two personal dust sampling and 191 endotoxin measurements were performed to assess the exposure. RESULTS: Forty percent of workers reported work-related symptoms in the first week of the study. Smoking, endotoxin, and dust concentrations were risk factors for all work-related symptoms. Acute airway responses were witnessed after immediate exposure. Female status was the only factor found to be predictive of acute airway response. The mean longitudinal fall in FEV1 at 1 year was 65.5 mL (standard error = 37.2). Age, early respiratory symptoms, and early fall in cross-week FEV1 were found to predict the 12-month fall in FEV1. Cross-first-shift and cross-week falls in FEV1 reduced in magnitude during the course of the study. CONCLUSIONS: This study of workers naive to cotton dust exposure has demonstrated that respiratory symptoms and acute airway responses develop early following first exposure, and a tolerance effect develops in those workers with the continued exposure. Current smoking and increasing exposure predicts the development of work-related lower respiratory tract symptoms, while early symptoms and acute airway changes across the working week predict the longitudinal loss of lung function at 1 year.

Diabetic Goto-Kakizaki rats display pronounced hyperglycemia and longer-lasting cognitive impairments following ischemia induced by cortical compression.

Hyperglycemia has been shown to worsen the outcome of brain ischemia in several animal models but few experimental studies have investigated impairments in cognition induced by ischemic brain lesions in hyperglycemic animals. The Goto-Kakizaki (GK) rat naturally develops type 2 diabetes characterized by mild hyperglycemia and insulin resistance. We hypothesized that GK rats would display more severe cerebral damage due to hyperglycemia-aggravated brain injury and, accordingly, more severe cognitive impairments. In this study, recovery of motor and cognitive functions of GK and healthy Wistar rats was examined following extradural compression (EC) of the sensorimotor cortex. For this purpose, tests of vestibulomotor function (beam-walking) and combined tests of motor function and learning (locomotor activity from day (D) 1 to D5, operant lever-pressing from D14 to D25) were used. EC consistently reduced cerebral blood flow in both strains. Anesthesia-challenge and EC resulted in pronounced hyperglycemia in GK but not in Wistar rats. Lower beam-walking scores, increased locomotor activity, impairments in long-term habituation and learning of operant lever-pressing were more pronounced and observed at later time-points in GK rats. Fluoro-Jade, a marker of irreversible neuronal degeneration, revealed consistent degeneration in the ipsilateral cortex, hippocampus and thalamus at 2, 7 and 14 days post-compression. The amount of degeneration in these structures was considerably higher in GK rats. Thus, GK rats exhibited marked hyperglycemia during EC, as well as longer-lasting behavioral deficits and increased neurodegeneration during recovery. The GK rat is thus an attractive model for neuropathologic and cognitive studies after ischemic brain injury in hyperglycemic rats.

Sensitivity and specificity of immunohistochemical antibodies used to distinguish between benign and malignant pleural disease: a systematic review of published reports.

AIMS: A systematic review of published reports that have evaluated the ability of immunohistochemistry and argyrophil nucleolar organizing region (AgNOR) staining to distinguish between benign and malignant pleural disease. METHODS: Nineteen relevant papers published during the period 1979-2005 were identified. Individual results of immunohistochemistry for five diagnostic antibodies were extracted to calculate diagnostic sensitivity and specificity. results from five of these studies that had evaluated proliferation markers or AgNOR staining techniques were also summarized. RESULTS: Most antibodies demonstrated poor to moderate diagnostic ability. Desmin and epithelial membrane antigen (EMA) were the most useful, with sensitivity and specificity both above 74%. The combination of EMA and AgNOR was reported as having 95% diagnostic sensitivity. A high MCM2 labelling index also differentiated between benign and malignant pleural disease. CONCLUSIONS: Immunohistochemistry is of limited value, but newer diagnostic methods may be useful additions in this area of pathology. The diagnostic importance of histological features seen on plain tissue sections is emphasized as vital for correctly differentiating between benign pleural disease and malignant pleural mesothelioma.

Randomized trial of two physiotherapy interventions for primary care neck and back pain patients: 'McKenzie' vs brief physiotherapy pain management.

OBJECTIVES: Interventions that take psychosocial factors into account are recommended for patients with persistent back or neck pain. We compared the effectiveness of a brief physiotherapy pain management approach using cognitive-behavioural principles (Solution-Finding Approach-SFA) with a commonly used method of physical therapy (McKenzie Approach-McK). METHODS: Eligible patients referred by GPs to physiotherapy departments with neck or back pain lasting at least 2 weeks were randomized to McK (n= 161) or to SFA (n= 154). They were further randomized to receive an educational booklet or not. The primary outcome was the Tampa Scale of Kinesiophobia (TSK) (Activity-Avoidance scale used as a proxy for coping) at 6 weeks, and 6 and 12 months. RESULTS: Of 649 patients assessed for eligibility, 315 were recruited (219 with back pain, 96 with neck pain). There were no statistically significant differences in outcomes between the groups, except that at any time point SFA patients supported by a booklet reported less reliance on health professionals (Multidimensional Health Locus of Control Powerful Others Scale), while at 6 months McK patients showed slightly more improvement on activity-avoidance (TSK). At 6 weeks, patient satisfaction was greater for McK (median 90% compared with 70% for SFA). Both interventions resulted in modest but clinically important improvements over time on the Roland Disability Questionnaire Scores and Northwick Park Neck Pain Scores. CONCLUSIONS: The McK approach resulted in higher patient satisfaction overall but the SFA could be more cost-effective, as fewer (three vs four) sessions were needed.

IPEADAM study: indoor endotoxin exposure, family status, and some housing characteristics in English children.

BACKGROUND: Many environmental factors have been investigated to determine their involvement in the asthma epidemic. OBJECTIVE: We sought to investigate the indoor environment of English children. METHOD: The Indoor Pollutants, Endotoxin, Allergens, Damp and Asthma in Manchester (IPEADAM) study recruited 200 asthmatic and age-, sex-, and sibship size-matched nonasthmatic children after a questionnaire-based community screening epidemiology survey. Their homes were sampled for several indoor air factors, and reservoir dust samples were obtained. Endotoxin, Der p 1, and dampness levels were assayed. Questionnaires were administered to record housing characteristics. Indoor pollutants, including environmental tobacco smoke, volatile organic compounds, nitrogen dioxide, formaldehyde, temperature, and relative humidity, were investigated. STATA univariate and multivariate analyses were used to compare the indoor environments of the children. RESULTS: The levels of endotoxin (adjusted odds ratio, 1.88; 95% CI, 1.11-3.18; P=.018), living in a single-parent family (adjusted odds ratio, 3.89; 95% CI, 1.25-12.1; P=.019), redecoration in the living room (adjusted odds ratio, 3.15; 95% CI, 1.36-7.33; P=.008), and self-reported absence of dampness (adjusted odds ratio, 0.36; 95% CI, 0.14-0.91; P=.030) were all independent predictive factors of asthma. There was no difference between asthmatic and healthy children in their exposure to Der p 1, objective measurements of dampness, guardian's smoking habits, pet ownership, house type or age, time in residence, central heating systems, insulation types, glazing systems, floor types, and age and measurements of several indoor pollutants. CONCLUSION: The IPEADAM study has shown that there were very few differences in the indoor environments of English asthmatic and nonasthmatic children. However, once asthma has been established, the presence of endotoxin is positively associated with an asthmatic child's living room carpet reservoir dust. CLINICAL IMPLICATIONS: There are no direct clinical implications of this research, although it needs interpreting with other clinical data on endotoxin exposure in epidemiologic settings.

Predictors of early leaving from the cotton spinning mill environment in newly hired workers.

OBJECTIVE: This longitudinal study aimed to identify the predictors of leaving during the first year of employment from the cotton spinning mill environment in newly hired workers. METHODS: One hundred and ninety eight consecutively appointed new employees were investigated by questionnaire, lung function test, and skin test. They were examined before employment and at the end of the 1st week, and the 1st, 3rd, 6th, and 12th month after starting work and when possible before leaving their job. 572 personal dust sampling and 191 endotoxin measurements were performed to assess the environmental exposure. For the univariate analysis chi2, Student t tests, ANOVA, and Kruskall Wallis tests were used. Cox proportional hazards analysis was used to identify factors associated with leaving the job. RESULTS: Fifty three per cent of workers left the mill environment during their first working year. Work related lower respiratory tract symptoms reported at the third month were associated with an increase rate of leaving the industry compared to those remaining in the industry (25% v 4.8%; p<0.005). Having respiratory symptoms at the first month of work predicted those leaving the industry at some point in the next 11 months. According to the Cox model, increasing age and having work related lower respiratory tract symptoms were found to be predictors for leaving job at the first working year. Atopic status, dust and endotoxin levels, and lung function changes were not consistently predictive of workers who left the industry in the follow up period. CONCLUSION: This study demonstrated that work related respiratory symptoms can predict workers likely to leave the cotton mill environment during the first year of employment, but atopy or acute lung function changes do not.

Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data.

AIMS: Immunohistochemistry is frequently employed to aid the distinction between mesothelioma and pulmonary adenocarcinoma metastatic to the pleura, but there is uncertainty as to which antibodies are most useful. We analysed published data in order to establish sensitivity and specificity of antibodies used to distinguish between these tumours with a view to defining the most appropriate immunohistochemical panel to use when faced with this diagnostic problem. METHODS AND RESULTS: A systematic analysis of the results of 88 published papers comparing immunohistochemical staining of a panel of antibodies in mesothelioma with epithelioid areas, and pulmonary adenocarcinoma metastatic to the pleura. Results for a total of 15 antibodies were analysed and expressed in terms of sensitivity and specificity. The most sensitive antibodies for identifying pulmonary adenocarcinoma were MOC-31 and BG8 (both 93%), whilst the most specific were monoclonal CEA (97%) and TTF-1 (100%). The most sensitive antibodies to identify epithelioid mesothelioma were CK5/6 (83%) and HBME-1 (85%). The most specific antibodies were CK5/6 (85%) and WT1 (96%). CONCLUSIONS: No single antibody is able to differentiate reliably between these two tumours. The use of a small panel of antibodies with a high combined sensitivity and specificity is recommended.