Polymerisation von fulvenen, 3. Strukturbeweis für kationische polyfulvene durch vergleich mit modellverbindungen

The structure of cationic poly(6,6-dimethylfulvene) ( 2a ) has been confirmed by synthesis of 4 model compounds 6, 7, 8, 9 and comparison of the spectral data with those of the polyfulvene. 5-Isoproylidenetricyclo[5.2.1.0^2.6]dec-3-ene ( 6 ) shows the same sensitivity towards oxygen as 2a . The reaction of 6 with oxygen yields a 1:1-copolymer, for which structure 10 has been proved by means of spectroscopic methods.     

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).     

Radiation exposures of cancer patients from medical X-rays: how relevant are they for individual patients and population exposure?

X-ray procedures have a substantial impact not only on patient care but also on man-made radiation exposure. Since a reliable risk-benefit analysis of medical X-rays can only be performed for diagnosis-related groups of patients, we determined specific exposure data for patients with the ten most common types of cancer. For all patients with the considered cancers undergoing medical X-ray procedures in a maximum-care hospital between 2000 and 2005, patient- and examination-specific data were retrieved from the hospital/radiology information system. From this data, the cumulative 5-year effective dose was estimated for each patient as well as the mean annual effective dose per patient and the mean patient observation time for each cancer site. In total, 151,439 radiographic, fluoroscopic, and CT procedures, carried out in 15,866 cancer patients (age, 62 ± 13 years), were evaluated. The mean 5-year cumulative dose varied between 8.6 mSv (prostate cancer) and 68.8 mSv (pancreas cancer). Due to an increasing use of CT scans, the mean annual effective dose per patient increased from 13.6 to 18.2 mSv during the 6-year period. Combining the results obtained in this study for a particular hospital with cancer incidence data for Germany, we estimated that cancer patients having X-ray studies constitute at least 1% of the population but receive more than 10% of the total effective dose related to all medical X-ray procedures performed nationwide per year. A large fraction of this dose is radiobiologically ineffective due to the reduced life expectancy of cancer patients.     

Clinical verification of the superiority of the current International Union Against Cancer staging criteria in an Australian population of patients with nasopharyngeal carcinoma

The purpose of this study is to assess the prognostic abilities of the fourth and fifth edition International Union Against Cancer (UICC) staging systems for nasopharyngeal carcinoma (NPC) in Australian patients. All patients planned for curative treatment at the Peter MacCallum Cancer Centre from April 1985 to December 1999 were included in this study. There were 181 patients eligible for this study. The median follow up was 7.6 years. Histological subgroups were World Health Organization (WHO) 1 (23), WHO 2 (12), and WHO 3 (146). Presentation with stage IV disease was 83% by UICC fourth edition staging and 34% by UICC fifth edition staging. The 5 years failure-free survival (FFS) rates for stage 1, 2, 3 and 4 disease by the fourth edition was 77, 100, 93, and 49% respectively,and by the fifth edition was 85, 76, 57 and 36%, respectively. The 5 years overall survival (OS) for stage 1, 2, 3, and 4 disease by the fourth edition was 77, 100, 100 and 61%; respectively, and by the fifth edition was 85, 82, 67 and 53%, respectively. Stage 4 patients by the fourth edition were reclassified as stages 2, 3 and 4 by the fifth edition with hazard ratios of 0.77, 1.01 and 1.79, respectively. In multifactor analysis, the fifth edition staging system was significantly related to FFS and OS after allowing for the fourth edition (FFS: P = 0.002; OS: P = 0.005), but the fourth edition was not significantly related to FFS or OS after allowing for the fifth edition (FFS: P = 0.96; OS: P = 0.96). This study confirms the prognostic superiority of the fifth edition UICC staging system over the fourth edition staging system in an Australian NPC population.     

Impact of 131I diagnostic activities on the biokinetics of thyroid remnants.

Recent publications described many discrepant findings about thyroid "stunning" after the administration of (131)I diagnostic activities to patients with differentiated thyroid carcinoma. Stunning may play a major role in reducing the therapeutic efficacy of high (131)I activities given for ablation therapy. METHODS: Participation in a multicenter study to investigate differences in iodine biokinetics in the hypothyroid state and after the application of recombinant human thyroid-stimulating hormone enabled us to study quantitative changes in thyroid iodine biokinetics after the administration of 74 MBq of (131)I twice within 6 wk and an ablation activity of 3-4 GBq 7-12 d after the second diagnostic administration of (131)I in 6 patients. RESULTS: The uptake and half-life of the first 74 MBq of (131)I were significantly reduced to a mean of 44% and a mean of 51%, respectively, after the second diagnostic administration and further reduced to a mean of 40% and a mean of 30%, respectively, during ablation therapy. The residence times were reduced to 25% in the second dosimetric assessment and to 10% during therapy compared with the value in the first assessment. For one patient, an estimated absorbed dose as high as 38 Gy was found in the first diagnostic study. The mean dose for all patients after the first assessment was 15 Gy; after each further assessment, the dose was reduced according to the decrease in residence time. CONCLUSION: This study shows a severe impact of 74 MBq of (131)I on the biokinetics of thyroid remnants during subsequent radioiodine therapy.     

Predictive value and reward in implicit classification learning

Learning efficacy depends on its emotional context. The contents learned and the feedback received during training tinges this context. The objective here was to investigate the influence of content and feedback on the efficacy of implicit learning and to explore using functional imaging how these factors are processed in the brain. Twenty-one participants completed 150 trials of a probabilistic classification task (predicting sun or rain based on combinations of playing cards). Smileys or frowneys were presented as feedback. In 10 of these subjects, the task was performed during functional magnetic resonance imaging. Card combinations predicting sun were remembered better than those predicting rain. Similarly, positive feedback fortified learning more than negative feedback. The presentation of smileys recruited bilateral nucleus accumbens, sensorimotor cortex, and posterior cingulum more than negative feedback did. The higher the predictive value of a card combination, the more activation was found in the lateral cerebellum. Both context and feedback influence implicit classification learning. Similar to motor skill acquisition, positive feedback during classification learning is processed in part within the sensorimotor cortex, potentially reflecting the activation of a dopaminergic projection to motor cortex (Hosp et al., 2011). Activation of the lateral cerebellum during learning of combinations with high predictive value may reflect the formation of an internal model.     

Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

Sympathetic activation triggers endogenous opioid release and analgesia within peripheral inflamed tissue

Stress induces analgesia by mechanisms within and outside the brain. Here we show that the sympathetic nervous system is an essential trigger of intrinsic opioid analgesia within peripheral injured tissue. Noradrenaline, injected directly into inflamed hind paws of male Wistar rats, produced dose-dependent antinociception, reversible by alpha(1)-, alpha(2)- and beta(2)-antagonists. alpha(1)-, alpha(2)- and beta(2)-adrenergic receptors were demonstrated on beta-endorphin-containing immune cells and noradrenaline induced adrenergic receptor-specific release of beta-endorphin from immune cell suspensions. This antinociceptive effect of noradrenaline was reversed by micro - and delta-opioid antagonists as well as by anti-beta-endorphin. Stress-induced peripheral analgesia was abolished by chemical sympathectomy and by adrenergic antagonists. These findings indicate that sympathetic neuron-derived noradrenaline stimulates adrenergic receptors on inflammatory cells to release beta-endorphin, which induces analgesia via activation of peripheral opioid receptors.