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Selenium (Se) has been mobilised by leaching from coal and associated waste rock exposed by mining activities in Western Canada, with deleterious impact on aquatic wildlife. Waste rock characterisation indicates that up to 7% of the Se, as Se(IV), may be associated with organic matter, with ≈9%, as Se(0), associated with euhedral pyrite. Small 1−2 µm mineral particles with average Se concentration of 1.0 ± 0.4 wt% account for the remaining Se with the largest components likely to be associated with Fe oxide/hydroxide/carbonate as Se(0) and framboidal pyrite as Se(IV) and Se(0). No evidence was found for the presence of Se(−I), Se(−II) or Se(VI). In the first 8 weeks of leaching Se release was not correlated to the addition of aqueous silicate, added to aid pyrite passivation, but was reduced by approximately one third when the waste was treated with manure. This suggests the primary initial source of leached Se was not pyrite. Added organic C results in increased microbial numbers, particularly aerobic microbes, and promotes the formation of extensive coating of extracellular polymeric substances resulting in depletion of O2 at particle surfaces, reducing oxidation of Se(IV) and therefore reducing the leach rate of Se. Subsequent to 8 weeks of leaching the rates of release of Se from the treated wastes were similar regardless of treatment strategy but were reduced as compared to the untreated waste rock, suggestive of partial framboidal pyrite geochemical and microbial passivation. Se leaching was not correlated to S leaching, but the source(s) of the leached S was not known as approximately half of the S within the waste rock was non-sulfidic. These results indicate that utilisation of local organic carbon-containing wastes for coverage of coal waste rock may be a cost-effective strategy to reduce Se leaching to acceptable rates of release regardless of whether the Se is associated with framboidal pyrite or organics Refereed/Peer-reviewed

ZusammenfassungIn den letzten Jahren haben sich die Diagnose und die medizinische Behandlung von Lungenkarzinompatienten erheblich gewandelt. Auch wenn die Mehrzahl der Patienten weiterhin nicht von der Erkrankung geheilt wird, so können durch verschiedene, klug abgestimmte Therapieansätze eine deutlich längere Krankheitskontrolle und stark verlängerte Überlebenszeiten als noch vor wenigen Jahren erreicht werden. Diese Entwicklung ist nicht nur durch medizinische, sondern auch zahlreiche politische und organisatorische Aspekte charakterisiert. Diese verschiedenen Ebenen, die klinischen Konsequenzen und die resultierenden Herausforderungen werden im Folgenden kurz skizziert.

Background Vitamin D deficiency occurs frequently in patients with Crohn’s disease (CD) and ulcerative colitis (UC). While recent cohort studies support an association of vitamin D with important clinical parameters and outcomes in IBD, the complex interplay of inflammation with vitamin D metabolism in IBD poses a viscious circle. We sought to further illucidate the relation between inflammation and different vitamin D parameters. To the best our knowledge, this was the first study to focus on the relationship between vitamin D binding protein (VDBP), circulating total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D), and inflammation, in adult IBD patients. Methods This was a comparative, single-centred, cross-sectional study in patients with IBD aged 18–65 years. Full blood count, transferrin, albumin and hsCRP were determined by standard methods. The presence/absence of inflammation was assessed based on serum hsCRP levels (cutoff Results In total, 129 subjects with IBD (70 male/59 female; 82 CD/47 UC; mean age 41.7 ± 12.6 years) were enrolled. Of these, 38/129 had inflammation (19 m/19 f; 26 CD/12 UC; 39.6 ± 12.9 years) while 91/129 had no inflammation (40 m/51 f; 56 CD/35 UC; 42.5 ± 12.5 years). Subjects with disease activity had significantly higher leukocyte, erythrocyte sedimentation rate (ESR) and hsCRP, but lower transferrin, transferrin saturation (TSAT) and albumin levels than those without inflammation (p < 0.05). Average serum levels of 25(OH)D (24.6[6.8–54.8] vs. 26.4[5.0–74.4]ng/ml), free 25(OH)D (5.9[1.3–13.3] vs. 1.0[1.0–21.4]ng/ml) and bioavailable 25(OH)D(2.3 [0.1–4.7] vs. 2.4[0.5–19.5]ng/ml) were similar in patients with vs. without inflammation (p > 0.05). However, VDBP levels were significantly higher in inflammatory conditions (359.6[252.2–530.6] mg/l vs. 327.4[183.5–560.3]mg/l; p < 0.05) and showed a positive correlation with CRP levels (0.293, p < 0.001). Ratio of free/total 25(OH)D correlated negatively with CRP levels (−0.282, p = 0.002). Conclusion High levels of circulating VDBP were associated with inflammatory activity. Moreover, free/total 25(OH)D ratio was inversely associated with inflammation. Other vitamin D parameters including total, free and bioavailable 25(OH)D showed no association with inflammation. These findings suggest that VDBP may play a bigger role than thought as a modulator of vitamin D and inflammation, and that simultaneous detection and investigation of plasma VDBP may provide additional insights into this complex interaction.

A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.

The acid base account (ABA), commonly used in assessment of mine waste materials, relies in part on calculation of potential acidity from total sulfur measurements. However, potential acidity is overestimated where organic sulfur, sulfate sulfur and some sulfide compounds make up a substantial portion of the sulfur content. The chromium reducible sulfur (CRS) method has been widely applied to assess reduced inorganic sulfur forms in sediments and acid sulfate soils, but not in ABA assessment of mine wastes. This paper reports the application of the CRS method to measuring forms of sulfur commonly found in mine waste materials. A number of individual sulfur containing minerals and real waste materials were analyzed using both CRS and total S and the potential acidity estimates were compared with actual acidity measured from net acid generation tests and column leach tests. The results of the CRS analysis made on individual minerals demonstrate good assessment of sulfur from a range of sulfides. No sulfur was measured using the CRS method in a number of sulfate salts, including jarosite and melanterite typically found in weathered waste rocks, or from dibenzothiophene characteristic of organic sulfur compounds common to coal wastes. Comparison of ABA values for a number of coal waste samples demonstrated much better agreement of acidity predicted from CRS analysis than total S analysis with actual acidity. It also resulted in reclassification of most samples tested from PAF to NAF. Similar comparisons on base metal sulfide wastes generally resulted in overestimation of the acid potential by total S and underestimation of the acid potential by CRS in comparison to acidity measured during NAG tests, but did not generally result in reclassification. In all the cases examined, the best estimate of potential acidity included acidity calculated from both CRS and jarositic S. Refereed/Peer-reviewed

Objectives: We aimed to identify clinical characteristics and to assess effectiveness of different initial antibiotic regimens in adult patients with community-acquired pneumonia (CAP) caused by Haemophilus influenzae. Methods: Characteristics were compared between patients with H. influenzae monoinfection versus CAP of other and unknown aetiology enrolled by the German prospective cohort study CAPNETZ. Impact of initial antibiotic treatment on "early clinical response" according to FDA criteria and overall clinical cure were analysed. Results: H. influenzae was found in 176 out of 2790 patients with pathogen detection (6.3%). Characteristics significantly associated with a H. influenzae CAP (p

ObjectiveTo compare the effects of two treatment modalities of testosterone on sexual functioning and mood.DesignForty men were randomized to receive either parenteral testosterone enanthate (TE) or long-acting parenteral testosterone undecanoate (TU) over a period of 30 weeks. Thereafter, 20 men who had received TU and 16 men who had received TE continued with TU and completed another 65 weeks to study longer-term effects of TU.MethodsThe following variables of sexual functioning were studied: sexual thoughts and fantasy, sexual interest and desire, satisfaction with sex life, number of erections and ejaculations per week, and number of spontaneous morning erections per week. Also variables related to mood were analyzed.ResultsImprovements in these variables were significant and were of a similar magnitude in the group treated with TU and TE for 30 weeks. Improvements were maintained at the same levels over a period of another 65 weeks when all men received TU. Effects on mood were recorded for 30 weeks, but were more difficult to establish in the study population. There were significant differences in baseline values between the two groups and scores showed wide s.d.ConclusionsBoth TE and TU were effective in improving sexual functions in hypogonadal men. An advantage of TU over TE is its lower frequency of administration and its better tolerability and safety profile.

INTRODUCTION Several institutions are currently evaluating whether it is possible to gather valid, risk-adjusted quality indicators from routine billing data according to section 21 of the German Hospital Reimbursement Law (Krankenhaus-Entgeltgesetz, KHEntG). It is hoped that this method will enable hospitals to obtain quality assurance data in an easy and timely fashion. MATERIALS AND METHODS For analysis, section 21 data according to KHEntG, quality assurance forms, and patients' medical records of the University Medical Center Ulm were evaluated in comparison to state and federal benchmark data from 2006. RESULTS With regard to the quality indicator "Lethality in community-acquired pneumonia", it is possible to identify those cases that need to be included in quality assurance analysis by using predefined diagnosis lists. Risk adjustment can likewise be done according to the requirements set forth by the Federal Quality Assurance Office (Bundesgeschaftsstelle Qualitatssicherung, BQS), using only those data routinely collected for billing purposes. The results obtained are comparable to state and federal benchmark data. In addition, the analysis shows that the S3 recommendation to measure breathing rate as part of pneumonia risk assessment is not sufficiently being practiced at the moment. CONCLUSIONS Risk-adjusted quality indicators can be generated from routine billing data according to section 21 KHEntG. Taking the patients' medical records as a reference, these indicators can even be shown to be more valid than those generated from BQS quality assurance data at the University Medical Center Ulm.

PURPOSE: To assess interobserver agreement (IOA) in the diagnosis of pulmonary infiltrates on chest X-rays for patients with community-acquired pneumonia (CAP). MATERIALS AND METHODS: From 7/2002 to 12/2005, 806 adults with CAP were included in the multicenter study “CAPNETZ” (7 hospitals). Inclusion criteria were clinical signs of pneumonia and pulmonary opacification on chest X-rays. Each X-ray was reevaluated by two radiologists from the university hospital in consensus reading against the interpreter at the referring hospital in regard to: presence of infiltrate (yes/no/equivocal), transparency (≤/> 50 %), localization, and pattern of infiltrates (alveolar/interstitial). The following parameters were documented: digital or film radiography, hospitalization, fever, findings of auscultation, microbiological findings. RESULTS: The overall IOA concerning the detection of infiltrates was 77.7 % (n = 626; CI 0.75 - 0.81), the infiltrates were not verified in 16.4 % (n = 132) by the referring radiologist with equivocal findings in 5.9 % (n = 48). The IOA of the different clinical centers varied between 63.2 % (n = 38, CI 0.48 - 0.78) and 92.3 % (n = 65, CI 0.86 - 0.99). The IOA for the diagnosis of infiltrates was significantly higher for inpatients with 82.6 % (n = 546; CI 0.80 - 0.85) than for outpatients with 55.2 % (n = 80; CI 0.47 - 0.63), p 50 % was 95.1 % (n = 215; CI 0.92 - 0.98) versus 80.4 % (n = 403; CI 0.77 - 0.84) for infiltrates with a transparency > 50 % (p < 0.0001). In patients with positive auscultation, the IOA was higher (p = 0,034). Chest X-rays of patients with antibiotic therapy or an alveolar infiltrate showed more equivocal findings compared to patients without these features. CONCLUSION: There is considerable interobserver variability in the diagnosis of pulmonary infiltrates on chest radiographs. The IOA is higher in more opaque infiltrates, positive auscultation and inpatients.

The autoimmune polyglandular syndrome (APS) is characterized by a variable coexistence of several autoimmune diseases, affecting predominantly endocrine glands. In general two types of APS are distinguished. Type 1 APS is an autosomal recessive disorder often leading to insufficiency of the adrenal cortex, the parathyroid glands, and/or the gonads. This type of APS often affects the skin in form of chronic mucocutaneous candidiasis and ectodermal dystrophies (vitiligo, alopecia, keratopathy, dystrophy of dental enamel and nails). The second form of APS is a polygenic disease which usually involves the adrenal gland, the thyroid and the pancreatic beta-cells. In rare cases APS type 2 is associated with myasthenia gravis, autoimmune thrombocytopenic purpura, Sjogren's syndrome or rheumatoid arthritis. Here we describe a case of APS with the unusual combination of type 1 diabetes, secondary adrenocortical insufficiency, growth hormone deficiency, and primary hypothyroidism associated with lethal idiopathic giant cell myocarditis. The combination of APS and idiopathic giant cell myocarditis which is a rare, frequently fatal autoimmune disorder of myocardium affecting most commonly young individuals has not been reported so far.

Background. Smoking is highly prevalent in young women and little is known about early multilevel independent risk or protective factors that are predictive of daily smoking in young women. Methods. Multiple logistic regression was conducted on data from NGHS, a 10-year cohort study of Black (1,213) and White (1,166) girls recruited from three clinical centers in the United States, ages 9-10 years on entry to ages 18-19. Results. Compared with never smokers, White girls were at higher risk than Black girls of being daily smokers at ages 18-19. Early predictors of daily smoking at ages 18-19 years included lower parental education, one parent in the household, drinking alcohol at ages 11-12, higher drive for thinness at ages 11-12, lower behavioral conduct at ages 11-12, and lower stress at ages 10-11 and higher stress at ages 12-13. For both Black and White girls weight-related variables were significant. Stress, behavioral conduct, and one-parent household were also important predictors for White girls. Conclusions. There is evidence that childhood and adolescent factors are related to young adult smoking behavior. Body weight concerns as well as family, social environment, and behavioral factors are important issues in determining which girls will become daily smokers. (C) 2002 American Health Foundation and Elsevier Science (USA).

The expression of adrenomedullin (AM) and atrial natriuretic factor (ANF) were investigated in the myocardium of a rat model of chronic ischemic heart failure (CHF) compared with sham-operated controls. In addition, human myocardium of patients with end-stage heart failure due to idiopathic dilated cardiomyopathy compared with myocardium of normal subjects (NF) was studied. In CHF, similar AM levels but increased ANF expression were observed in left ventricular myocardium, as assessed by semiquantitative PCR. Functional experiments with freshly excised papillary muscles showed no influence of AM on myocardial contractility. In NF human myocardium, the expression of AM mRNA was threefold higher in atrial compared with ventricular tissue. In analogy, ANF mRNA was increased by ∼15-fold in atrial tissue. In dilated cardiomyopathy, the expression of AM was significantly increased in right and left ventricles compared with NF. In parallel, ventricular ANF expression was enhanced.

OBJECTIVE To examine the use of electronic medical records (EMRs) among US occupational medicine physicians (OMPs). METHODS An electronic- and paper-based survey was conducted among OMPs using an anonymous self-administered questionnaire. RESULTS The OMPs reported using an EMR for billing purposes only (14.6%), clinical purposes only (27.8%), or both (39.3%) with the total EMR use of 81.7%. About 60% were satisfied with their EMRs, and 64% to 66% believed that EMRs improve safety and quality of medical care. Among OMPs not using EMR, 17% reported that they were likely to adopt an EMR in the year after the survey, whereas 47% were very unlikely to do so. CONCLUSIONS Occupational physicians' use of EMRs was relatively high. They also seemed to be satisfied with their EMRs and believed that EMRs improve both safety and quality of clinical care.

This prospective, non-interventional study involving general practitioners and internists in Germany investigated the administration of tapentadol prolonged release (Palexia retard) for the treatment of severe chronic pain in routineclinical practice over a 3-month observation period.Collected data included tapentadol PR dosage, previous and concomitant analgesic treatment, pain intensity, sleep and quality of life parameters, and tolerability of tapentadol PR. Effectiveness was analyzed for 3134 patients; additionally, a subgroup analysis was performed in 1331 patients with WHO III pretreatment.A total of 97.8% of all patients received analgesic long-term pretreatment, 42.5% of those strong opioids. Switching to tapentadol PR resulted in a mean pain reduction of 3.9 points from 7.0 +/- 1.5 at baseline to 3.1 +/- 1.8 at end of observation (NRS-11, 11-point pain scale; descriptive p valueor = 0.001); 72.1% of patients experienced a clinically relevant pain relief ofor = 50% at end of observation. A total of 89.4% of the patients attained either their intended pain reduction and/or an additional individual treatment goal at end of observation; both were established at start of tapentadol PR treatment. This was accompanied by a significant decrease in pain-related impairments of daily activities and an improvement in quality of life (descriptive p valueor = 0.001) with an overall good tolerability of tapentadol PR. In particular, good effectiveness of tapentadol PR treatment was reported for various pain indications in patients who had already previously been treated with strong opioids. A clinically relevant pain reductionor = 50% was achieved in 67.2% of these patients.Tapentadol PR can be considered an alternative therapy to classical opioids for the treatment of severe chronic pain. Particularly for severe chronic pain requiring long-term medication, a reduction of common opioid side-effects with tapentadol PR therapy could contribute to better patient compliance.

BackgroundAdjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement.Patients and methodsPatients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy.ResultsOne hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P

We report here our results in a multi-sensor setup reproducing the conditions of an automated focused ultrasound surgery environment. The aim is to continuously predict the position of an internal organ (here the liver) under guided and non-guided free breathing, with the accuracy required by surgery. We have performed experiments with 16 healthy human subjects, two of those taking part in full-scale experiments involving a 3 Tesla MRI machine recording a volume containing the liver. For the other 14 subjects we have used the optical tracker as a surrogate target. All subjects where volunteers who agreed to participate in the experiments after being thoroughly informed about it. For the MRI sessions we have analyzed semi-automatically offline the images in order to obtain the ground truth, the true position of the selected feature of the liver. The results we have obtained with continuously updated random forest models are very promising, we have obtained good prediction-target correlation coefficients for the surrogate targets (0.71 ± 0.1) and excellent for the real targets in the MRI experiments (over 0.91), despite being limited to a lower model update frequency, once every 6.16 seconds.

7531 Background: Mutations in KRAS are present in ~25% of patients with advanced NSCLC. Preclinical data support the role of mammalian target of rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an inhibitor of mTOR which has been shown to have efficacy in advanced endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR inhibitor was previously evaluated in unselected patients with advanced NSCLC and found to have a response rate 30% tumor shrinkage remained on ridaforolimus and patients with >20% tumor growth discontinued treatment. Patients with stable disease were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of the study was progression-free survival (PFS) after randomization. Results: 79 patients were enrolled (40 women, median age 58 [range 28-85]). The overall response rate (CR+PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%). 28 patients with stable disease at 8 weeks were randomized to ridaforolimus or placebo. Median PFS based on investigator assessment from randomization was significantly longer with ridaforolimus (4 months) than placebo (2 months, p=0.013, HR 0.36). Median OS from randomization was 18 months in the ridaforolimus treated arm and 5 months in the placebo treated group, (HR 0.46, p=0.09). The most common grade ≥3 adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia (10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). Conclusions: In patients with KRAS mutant NSCLC who had stable disease after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged progression-free survival. Further evaluation of ridaforolimus in this patient population is warranted.

Objective: To (1) describe anthropometric and body-size measurements in the National Heart, Lung, and Blood Institute Growth and Health Study (NGHS) population at baseline and (2) examine potential secular trends in the prevalence of obesity in young black and white girls by comparing NGHS baseline data with those of the two National Health and Nutrition Examination Surveys (NHANES I and II) (measured before the NGHS). Design: Cross-sectional analysis of cohort baseline data. Setting: Recruitment in selected schools (Cincinnati and Berkeley) and among the membership of a group health association (Westat). Patients: Enrolled 2379 girls, 9 and 10 years of age, including 1213 black and 1166 white. Measurements: Anthropometric measures, including height, weight, and triceps and subscapular skin folds. Body mass index was used as a measure of body size. Nine- and ten-year-old black girls were taller, heavier, and had larger skin folds than white girls. Compared with age-similar girls in the 1970s, girls in the present study are taller and heavier and have thicker skin folds. The differences in body size were most notable among black girls. Conclusions: Black girls have a greater body mass than white girls even as young as 9 and 10 years of age. The prevalence of obesity appears to be increasing among young girls, especially in black girls. This progression, if not altered, could lead to increased disease in the future for adult women, particularly black women. (J P EDIATR 1994;124:675-80)

7002 Background: Adjuvant chemotherapy is beneficial in early stage NSCLC, but toxicity and dose delivery are an issue in many patients. Therapy with CPx showed clear activity and good tolerability...

Background: Although up to 15% of patients with whiplash injury develop chronic headache, the basis and mechanisms of this posttraumatic headache are not well understood. Methods: Thirty-two patients with posttraumatic headache following whiplash injury were investigated within 14 days after the accident and again after 3 months using magnetic resonance–based voxel-based morphometry. Twelve patients developed chronic headache lasting longer than 3 months and were studied a third time after 1 year. Results: Patients who developed chronic headache revealed decreases in gray matter in the anterior cingulate and dorsolateral prefrontal cortex after 3 months. These changes resolved after 1 year, in parallel to the cessation of headache. The same patients who developed chronic headache showed an increase of gray matter in antinociceptive brainstem centers, thalamus, and cerebellum 1 year after the accident. Conclusion: We demonstrate adaptive gray matter changes of pain processing structures in patients with chronic posttraumatic headache in regard to neuronal plasticity, thus providing a biologically plausible basis for this common, disabling problem.

The effects of testosterone have been extensively characterized, but little attention has been given to the timetable of occurrence of the various effects of testosterone.The timetables of effects on sexual and psychological variables in 40 hypogonadal men receiving treatment with either parenteral testosterone enanthate (TE) or undecanoate (TU).Sexual thoughts/fantasies and sexual interest/desire/spontaneous morning erections emerged quickly and plateaued after 3 weeks. Total erections rose to a maximum over 9 weeks and then plateaued. Ejaculations per week/satisfaction with sex life rose over the first 3 weeks, increasing steadily to a plateau at 12 weeks. Depression scores decreased to reach a plateau after 6 weeks. Aggressiveness did not change. Scores of concentration improved and reached a plateau after 3 weeks in the group treated with TE and after 9 weeks in the group treated with TU. Good mood improved after 6-9 weeks. Positive effects on self-confidence appeared between 3-6 weeks and on fatigue after 9-12 weeks.Insight into the emergence of effects may be useful information for the patient and for the attending physician in monitoring clinical effects of testosterone treatment of hypogonadal men.

Objective: To assess the efficacy and safety of a novel long-acting im testosterone undecanoate (TU) formulation in comparison with testosterone enanthate (TE). Subjects and methods: An open-label, randomized, prospective clinical trial in 40 hypogonadal men (baseline serum testosterone levels

This is a four-year follow-up of 25 men who received parenteral testosterone undecanoate (TU), 1000 mg every 12 weeks for at least four years. This study was a continuation of a 30-week study wherein the effects of TU had been compared to those of parenteral testosterone enanthate.Plasma testosterone (T) trough values of the injection interval of 12 weeks): median 11.9 - 15.9 nmol/L (N 10.0-30.0). E2 and SHBG were stable. Body weight, BMI, waist-to-hip ratio remained stable. Total cholesterol, and triglycerides were unchanged but plasma LDL declined while HDL, after an initial reduction over the first 30 weeks, had increased significantly after three years. Leptin levels, bone mineral density, blood pressure, liver function tests, haemoglobin and haematocrit levels remained stable without values above the upper limit of normal. Over the first 12 months of the study there was an increase in prostate volume from 19.7 +/- 8.8 mL to 22.0 +/- 8.4 mL (p0.05) but thereafter volumes remained stable, paralleled by an increase in PSA from 0.67 +/- 0.38 microg/dL to 0.75 +/- 0.35 microg/dL (p0.05) without any further changes after 12 months.TU appears to be a stable and safe treatment modality of hypogonadal men.

Background. Integrated positron emission tomography (PET)/computed tomography (CT) scanners have been recently introduced in the diagnostic work-up of suspected pulmonary malignancy and demonstrate encouraging results in the staging of nonsmall-cell lung cancer. Objective. To evaluate the usefulness of integrated FDG PET/CT in pulmonary carcinoid tumours. Setting. University hospital. Methods. We studied 13 patients (mean age ± 1 SD, 57 ± 11 years) with pulmonary carcinoid tumours. All patients demonstrated a single pulmonary lesion. Integrated PET/CT scan and surgical resection were performed in all patients. Results. The pulmonary lesion size ranged from 1.1 to 5.0 cm. Final histological diagnosis confirmed 12 typical and one atypical pulmonary carcinoid. Mean proliferation rate of the typical carcinoids was 1.7 ± 1.4%. None of the patients had recurrent carcinoid disease or died during follow-up (864 ± 218 days). Mean standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) in typical carcinoids was 3.0 ± 1.5 (range 1.2 – 6.6); SUV in the atypical carcinoid was remarkably high with a value of 8.5. The SUV was lower than 2.5 in 6 of 12 patients (50%). Mediastinal lymph node metastases or extrathoracic metastases were not detected in any patient. Conclusions. 18F-fluorodeoxyglucose PET/CT imaging improves accurate localization of metabolic activity and thus the interpretation of pulmonary lesions on CT. FDG uptake in pulmonary carcinoid tumours is often lower than expected for malignant tumours. Therefore, surgical resection or biopsy of lesions suspected to be carcinoids should be mandatory, even if they show no hypermetabolism on FDG PET images.

Aim: EGFR is detectable in most pts with sq-NSCLC tumors. Efficacy and safety of necitumumab (N), a human IgG1 anti-EGFR monoclonal antibody that inhibits ligand-binding and receptor activation, were evaluated in pts with advanced sq-NSCLC tumors. Methods: Pts with stage IV sq-NSCLC were randomized 1:1 to GC (G = 1250 mg/m2 iv, days 1 and 8; C = 75 mg/m2 iv, day 1) plus N (800 mg iv, days 1 and 8) (GC + N arm), or GC alone (GC arm) every 21 days for up to 6 cycles. GC + N pts with no progression continued on N alone until progressive disease or intolerable toxicity. The primary endpoint was overall survival (OS). Progression-free survival and safety were secondary endpoints. Subgroup analyses, evaluating efficacy by age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), gender, and race, were also performed. Planned sample size was 1080 pts, with 90% power and a 2-sided alpha level of 0.05. ClinicalTrials.gov identifier: NCT00981058. Results: 1093 pts were randomized. Baseline characteristics, exposure to chemotherapy, and post-progression anticancer therapy were similar between GC + N and GC arms. The table shows key OS results. The addition of N to GC statistically significantly improved OS (HR = 0.84, p = 0.012), and the safety profile of GC + N was acceptable across subgroups. OS Results N mOS, GC + N* N mOS, GC* HR† ITT population 545 11.5 548 9.9 0.84 Subgroups Age, y 520 11.5 529 9.9 0.84 ≥75 25 10.3 19 7.4 0.98 ECOG PS 0 164 13.8 180 12.9 0.82 1 332 10.7 320 9.2 0.85 2 49 9.5 47 6.9 0.78 Gender Female 95 13.0 90 11.4 0.88 Male 450 11.1 458 9.7 0.84 Race Caucasian 457 11.4 456 9.7 0.86 Non-Caucasian 88 12.6 92 11.8 0.78 mOS = median overall survival. *Data = median (months) estimated by the Kaplan-Meier method. †HR Conclusions: This study met its primary endpoint. GC + N demonstrated improved OS, with an acceptable safety profile, across all subgroups. Disclosure: M.A. Socinski: Steering Committee; L. Paz-Ares: I have provided scientific advice asn received honararium from Lilly; M. Reck: Member of advisory boards (compensated): Lilly, Hoffmann-La Roche, BMS, AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis; K. Park: Advisory Board; Eli Lilly; F.R. Hirsch: Research funding (through University of Colorado) from ImClone - Lilly. Participated in steering committee for the study and advisory borad for Lilly – ImClone; H. Depenbrock: Lilly Employee S. Nanda: I am a lilly employee and I have stock ownership; N. Chouaki: I am a Lilly Employee, I have stock ownership; N. Thatcher: Honoraria :Advsiory Board and Speaker Bureau Member Lilly Imclone. All other authors have declared no conflicts of interest.

Aim: Characterize QoL, tolerability, and supportive care of patients (pts) receiving necitumumab (N) + gemcitabine-cisplatin (GC) in the SQUIRE study. Methods: Pts with ECOG performance status (PS) 0-2, stage IV squamous NSCLC were randomized 1:1 to GC (G = 1250 mg/m2 IV days 1, 8; C = 75 mg/m2 IV day 1) + N (800 mg absolute dose IV), or GC alone (every 21 days up to 6 cycles). Pts treated with GC + N with no disease progression (PD) continued on N monotherapy until PD. Pt reported symptoms were measured by the Lung Cancer Symptom Scale (LCSS) prior to the start of each cycle (1-6) and every 6 weeks thereafter until PD. Physician reported PS was measured before every cycle. Tolerability was measured by number of cycles received, treatment discontinuation for adverse events (AEs), rates of serious AEs (SAEs), % of pts receiving N monotherapy post-induction. AEs (Safety Common Terminology Criteria [v3.0]) and supportive care data were collected while pts were on study. Results: 1093 pts were randomized (545 GC + N Arm, 548 GC Arm); 7 pts in each arm were not treated. 88.3% (GC + N) and 88.0% (GC) pts had a baseline and ≥ 1 post-baseline LCSS assessment. 95% CIs for the hazard ratios (HRs) for time to deterioration (TTD) of all 12 variables contained 1. The HR for TTD of PS by ≥1 point (cycles 1-6) was 0.861 (95% CI: 0.692-1.071). GC + N pts received a median of 6 cycles (interquartile [IQ] range 3-6) of GC, and a median of 6 cycles (IQ range 3-10) of N. GC pts received a median of 5 cycles (IQ range 3-6). Treatment discontinuation rates due to AEs were 13.6% (GC + N) and 14.6% (GC). SAEs were 47.8% (GC + N) and 37.5% (GC). The most common grade ≥3 AE was neutropenia, 24.3% (GC + N) and 27.5% (GC). 51% of GC + N pts continued on N monotherapy (median: 4 additional cycles). Select supportive care for treated patients is summarized in Table below. GC + N (538 pts) (%) GC (541 pts) (%) Concomitant medications 100 100 Transfusions 21.9 20.5 Hospitalizations 41.1 34.0 Colony stimulating factors 13.4 16.8 Erythropoietin 0.2 1.5 Conclusions: Long-term use of N was well tolerated. There were no major differences in AE rates, no detrimental effect overall of adding N to GC in terms of patients' QoL (symptoms and PS). Supportive care and associated resource use were modest. Disclosure: M. Reck: Member of Advisory Board: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer – Ingelheim Honoraria for lectures: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer-Ingelheim; M. Dediu: Consultant and Advisory Role (C) - Eli Lilly, Amgen, Boehringer-Ingleheim, Novartis. Speaker fee - TEVA, Boehringer-Ingelheim, MSD, GlaxoSmithkline, Amgen, Astra-Zeneca, Roche, Janssen, Eli Lilly, Pfizer; O. Molinier: Dr Olivier MOLINIER declares -consultant and advisory role for Eli Lilly and Roche -Speaker for Boehringer-Ingleheim; C. Schumann: Consultant and Advisory Role: -Eli Lilly, Pfizer, Roche, Boehringer-Ingelheim Speaker fee: -Eli Lilly, Novartis, Pfizer, Roche, Astra-Zeneca, Amgen, Boehringer-Ingelheim; J. Brown: I am an employee of Eli Lilly and Company and hold stock options and equity with Eli Lilly and Company; V. Soldatenkova: Employment: Lilly Deutschland GmbH, stock ownership. N. Chouaki: Employee of Eli Lilly and Company, I have stock ownership; N. Thatcher: Honoraria for advisory boards and speaker bureaus Eli Lilly and other companies. All other authors have declared no conflicts of interest.

8045 Background: P is a fully human anti-HER3 antibody that inhibits HER3 binding with its ligand heregulin (HRG). Preclinically, P enhances anti-tumor activity with EGFR inhibitors, prevents HER3 ...

Contributions of gluconeogenesis to glucose production were determined between 14 to 22 hours into a fast in type 2 diabetics (n = 9) and age-weight-matched controls (n = 7); ages, 60.4 +/- 2.3 versus 55.6 +/- 1.2 years and body mass indices (BMI) 28.6 +/- 2.3 versus 26.6 +/- 0.8 kg/m2. Production was measured using a primed-continuous [6,6-2H2]glucose infusion and gluconeogenesis from 2H enrichment at carbons 2 and 5 of blood glucose on 2H2O ingestion. Plasma glucose concentration declined from 9.6 +/- 0.6 at 14 hours to 7.3 +/- 0.6 at 22 hours in the diabetics (P = .001) and from 5.4 +/- 0.1 to 5.0 +/- 0.1 in the controls (P < .05). Production from the 17th to 22nd hour declined 27.1% +/- 0.6% in the diabetics versus 18.5% +/- 0.8% in the controls (P = .001); from 10.4 +/- 0.3 to 7.6 +/- 0.2 versus 10.0 +/- 0.4 to 8.2 +/- 0.4 micromol/kg/min. Percent contributions of gluconeogenesis to production measured at 1 1/2 to 2-hour intervals beginning the 15th hour were 6.8% +/- 1.0% more in the diabetics than controls. The quantity of glucose contributed by gluconeogenesis declined 19.8% +/- 3.8% (P < .001) in the diabetics and 6.9% +/- 2.3% in the controls (P = .05); 7.21 +/- 0.32 to 5.74 +/- 0.26 versus 6.20 +/- 0.28 to 5.75 +/- 0.24 micromol/kg/min. The contribution of glycogenolysis to production, estimated from the difference between production and gluconeogenesis, declined to the same extent in diabetic and control subjects, 40.7% +/- 6.6% and 37.7% +/- 4.1%; from 3.23 +/- 0.35 to 1.86 +/- 0.26 versus 3.81 +/- 0.22 to 2.42 +/- 0.28 micromol/kg/min. Thus, gluconeogenesis contributed more to glucose production in the diabetic than control subjects. Production and the contribution of gluconeogenesis declined more in the diabetic subjects during the fast. The factors regulating these changes remain uncertain.

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using [6,6-2H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.

Corticotropin-releasing hormone (CRH) and proenkephalin (PENK) are hypothalamic peptides involved in the stress response and hypothalamic-pituitary axis regulation. Previous research has implicated these peptides in the pathogenesis of affective disorders. In this study we investigated two polymorphisms located in the genes that code for CRH and PENK by means of association and linkage analyses. A total of 138 bipolar patients and 108 controls were included in the association study. In addition, 24 families were available for linkage analysis, including six families of probands with documented periodic positivity of dexamethasone suppression tests (DST) during remission. We found no association of bipolar disorder with either gene. Similarly, we did not find any evidence of linkage (P = 0.56 for CRH and 0.52 for PENK) in the entire sample or in the subsample of families of DST positive probands. In conclusion, our study does not support the hypothesis that genes coding for CRH or PENK contribute to the genetic susceptibility to bipolar disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:178-181, 2000.

Impaired glucose effectiveness (i.e., a diminished ability of glucose per se to facilitate its own metabolism), increased gluconeogenesis, and endogenous glucose release are, together with insulin resistance and beta-cell abnormalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in a group of healthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the 2H2O technique and 2) glucose effectiveness. The FDR group was insulin resistant when compared with an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 mg x kg(-1) lean body weight (lbw) x min(-1); P = 0.02). Fasting rates of gluconeogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg x kg(-1) lbw x min(-1); FDR vs. control subjects, P = 0.18) did not differ in the two groups and accounted for 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effectiveness was examined using a combined somatostatin and insulin infusion (0.17 vs. 0.14 mU x kg(-1) x min(-1), FDR vs. control subjects), the latter replacing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After glucose infusion, the integrated plasma glucose response above baseline (1,817 +/- 94 vs. 1,789 +/- 141 mmol/l per 6 h), the ability of glucose to simulate its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml x kg(-1) lbw x min(-1)), and the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast to overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near-basal insulinemia and normal fasting rates of gluconeogenesis.

A number of association studies have investigated the role of the monoamine oxidase A (MAOA) gene in the susceptibility to bipolar disorder. Although some studies have reported positive findings, there remains some controversy, because results from different studies have not been consistent. A common explanation for inconsistencies between studies is genetic heterogeneity. We have focused on lithium responsive bipolar disorder as a way to reduce heterogeneity. In this study, we investigated the role of MAOA in lithium responsive bipolar patients using association and linkage study designs. The investigation used 138 patients and 108 normal controls. In addition, 25 families were also studied. Our results were not supportive of a major role of MAOA in the predisposition to bipolar disorder.

We report a case of a 64-year-old woman with increasing shortness of breath due to massive pericardial effusion. Cardiac magnetic resonance imaging (CMRI) identified typical findings for pericarditis. Pericardectomy was needed due to suspicion of pericardial abscess formation. Histological examination of the resected tissue revealed an undifferentiated primary pericardial synovial sarcoma. The present case illustrates that pericardial tumours could be an important differential diagnosis to pericarditis, even if typical findings of pericarditis were present in CMRI.

TPS7109 Background: This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing -1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36). Methods: In all registered patients, before randomization, expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein. It is assumed that the 5-year survival in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of patients is 700. The final statistical analysis will group together all control arms and all tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, patients in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS) 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis. Currently, 312 patients have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 13 patients/month).

e18010 Background: CTX has been registered for head and neck and colorectal cancer. Our randomized phase II/III trial is to assess the efficacy and safety of CTX in combination with two different chemotherapy (CT) regimens. Methods: Chemonaive pts with histologically confirmed stage IIIB or IV NSCLC and PS 0–2 received CTX 400 mg/m2 (loading dose) and then 250 mg/m2 weekly either combined with G 1,000 mg/m2 days 1 + 8 for 2 cycles (3qw) followed by D 75 mg/m2 day 1 for 2 cycles (q3w) (arm A) or CP AUC5 day 1 and G 1,200 mg/m2 days 1 + 8 for 4 cycles (q3w) (arm B). If pts did not progress single agent CTX was continued (“maintenance”) until tumor progression or unacceptable toxicity. Results: 340 pts received 2,826 infusions of CTX combined with CT and 2,015 infusions without CT. Toxicities requiring clinical intervention are shown below (Table). 142 pts on single-agent CTX received up to 33 cycles without significant toxicity (arm A: 64 pts, range 1-33 cycles, median 3, mean 5.6, and 11 pts ≥10 cycles; ar...