Dummy run and conformity indices in the ongoing EORTC low-grade glioma trial 22033-26033: First evaluation of quality of radiotherapy planning.

PURPOSE: Early assessment of radiotherapy (RT) quality in the ongoing EORTC trial comparing primary temozolomide versus RT in low-grade gliomas. MATERIALS AND METHODS: RT plans provided for dummy cases were evaluated and compared against expert plans. We analysed: (1) tumour and organs-at-risk delineation, (2) geometric and dosimetric characteristics, (3) planning parameters, compliance with dose prescription and Dmax for OAR (4) indices: RTOG conformity index (CI), coverage factor (CF), tissue protection factor (PF); conformity number (CN = PF x CF); dose homogeneity in PTV (U). RESULTS: Forty-one RT plans were evaluated. Only two (5%) centres were requested to repeat CTV-PTV delineations. Three (7%) plans had a significant under-dosage and dose homogeneity in one deviated > 10%. Dose distribution was good with mean values of 1.5, 1, 0.68, and 0.68 (ideal values = 1) for CI, CF, PF, and CN, respectively. CI and CN strongly correlated with PF and they correlated with PTV. Planning with more beams seems to increase PTV(Dmin), improving CF. U correlated with PTV(Dmax). CONCLUSION: Preliminary results of the dummy run procedure indicate that most centres conformed to protocol requirements. To quantify plan quality we recommend systematic calculation of U and either CI or CN, both of which measure the amount of irradiated normal brain tissue.

Swiss Interdisciplinary Management Programme for Heart Failure (SWIM-HF): a randomised controlled trial study of an outpatient inter-professional management programme for heart failure patients in Switzerland.

PRINCIPLES: International guidelines for heart failure (HF) care recommend the implementation of inter-professional disease management programmes. To date, no such programme has been tested in Switzerland. The aim of this randomised controlled trial (RCT) was to test the effect on hospitalisation, mortality and quality of life of an adult ambulatory disease management programme for patients with HF in Switzerland.METHODS: Consecutive patients admitted to internal medicine in a Swiss university hospital were screened for decompensated HF. A total of 42 eligible patients were randomised to an intervention (n = 22) or usual care group (n = 20). Medical treatment was optimised and lifestyle recommendations were given to all patients. Intervention patients additionally received a home visit by a HF-nurse, followed by 17 telephone calls of decreasing frequency over 12 months, focusing on self-care. Calls from the HF nurse to primary care physicians communicated health concerns and identified goals of care. Data were collected at baseline, 3, 6, 9 and 12 months. Mixed regression analysis (quality of life) was used. Outcome assessment was conducted by researchers blinded to group assignment.RESULTS: After 12 months, 22 (52%) patients had an all-cause re-admission or died. Only 3 patients were hospitalised with HF decompensation. No significant effect of the intervention was found on HF related to quality of life.CONCLUSIONS: An inter-professional disease management programme is possible in the Swiss healthcare setting but effects on outcomes need to be confirmed in larger studies.

Functional multidisciplinary rehabilitation versus outpatient physiotherapy for non specific low back pain: randomized controlled trial.

INTRODUCTION: In recent decades the treatment of non-specific low back pain has turned to active modalities, some of which were based on cognitive-behavioural principles. Non-randomised studies clearly favour functional multidisciplinary rehabilitation over outpatient physiotherapy. However, systematic reviews and meta-analysis provide contradictory evidence regarding the effects on return to work and functional status. The aim of the present randomised study was to compare long-term functional and work status after 3-week functional multidisciplinary rehabilitation or 18 supervised outpatient physiotherapy sessions. METHODS: 109 patients with non-specific low back pain were randomised to either a 3-week functional multidisciplinary rehabilitation programme, including physical and ergonomic training, psychological pain management, back school and information, or 18 sessions of active outpatient physiotherapy over 9 weeks. Primary outcomes were functional disability (Oswestry) and work status. Secondary outcomes were lifting capacity (Spinal Function Sort and PILE test), lumbar range-of-motion (modified-modified Schöber and fingertip-to-floor tests), trunk muscle endurance (Shirado and Biering-Sörensen tests) and aerobic capacity (modified Bruce test). RESULTS: Oswestry disability index was improved to a significantly greater extent after functional multidisciplinary rehabilitation compared to outpatient physiotherapy at follow-up of 9 weeks (P = 0.012), 9 months (P = 0.023) and 12 months (P = 0.011). Work status was significantly improved after functional multidisciplinary rehabilitation only (P = 0.012), resulting in a significant difference compared to outpatient physiotherapy at 12 months' follow-up (P = 0.012). Secondary outcome results were more contrasted. CONCLUSIONS: Functional multidisciplinary rehabilitation was better than outpatient physiotherapy in improving functional and work status. From an economic point of view, these results should be backed up by a cost-effectiveness study.

Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P<0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P<0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P<0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis.

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia: A Randomized Noninferiority Trial.

IMPORTANCE: The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE: To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS: Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS: Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES: Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS: After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE: We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818610.

RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422.

Specific vs general cognitive remediation for executive functioning in schizophrenia: A multicenter randomized trial.

BACKGROUND: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT). METHODS: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3). RESULTS: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms. CONCLUSIONS: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

Small bowel bacterial overgrowth is found in 71% of IBS patients and associated symptoms respond well to Rifaximin in a phase IV trial

Background a nd A ims: The prevalence of small intestinal bowel bacterial o vergrowth (SIBO) i n patients w ith irritable bowel syndrome (IBS) ranges from 43% to 78% as determined by t he lactulose hydrogen breath (LHBT) t est. Although rifaximine, a non-absorbable antibiotic, h as b een able to decrease I BS s ymptoms i n placebo-controlled r andomized trials, these results were not repeated in phase IV studies. We aimed to assess the prevalence of SIBO in an IBS cohort and to evaluate the response to rifaximin. Methods: I BS p atients f ulfilled Rome III criteria, had an absence of alarm symptoms, n ormal f ecal c alproectin, and normal e ndoscopic workup. They underwent lactulose hydrogen breath t esting (LHBT) for SIBO diagnosis. P atients with SIBO were t reated w ith rifaximine tablets f or 14 d ays. Symptoms were a ssessed by q uestionnaires before rifaximin treatment and at week 6. Results: Hundred-fifty IBS patients were enrolled (76% female, mean age 44 ± 16 years), of whom 106 (71%) were diagnosed with SIBO and consequently treated with rifaximine. Rifaximine treatment s ignificantly reduced the following symptoms as assessed by t he s ymptom q uestionnaire: bloating (5.5 ± 2.6 before vs. 3 .6 ± 2.7 after treatment, p <0.001), flatulence (5 ± 2.7 vs. 4 ± 2.7, p = 0.015), diarrhea (2.9 ± 2.4 vs. 2 ± 2.4, p = 0.005), abdominal pain (4.8 ± 2.7 vs. 3.3 ± 2.5, p <0.001) and resulted in improved overall well-being (3.9 ± 2.4 vs. 2.7 ± 2.3, p <0.001). The LHBT was repeated 2-4 weeks after rifaximine treatment in 6 5/93 (70%) patients. Eradication of SIBO was documented in 85% of all patients (55/65). Conclusions: The results o f our phase IV trial i ndicate that a high proportion of IBS p atients t ested positive f or SIBO. I BS symptoms w ere significantly diminished following a 2-week treatment with rifaximine.

Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.

BACKGROUND: The true benefit of iron supplementation for nonanemic menstruating women with fatigue is unknown. We studied the effect of oral iron therapy on fatigue and quality of life, as well as on hemoglobin, ferritin and soluble transferrin receptor levels, in nonanemic iron-deficient women with unexplained fatigue. METHODS: We performed a multicentre, parallel, randomized controlled, closed-label, observer-blinded trial. We recruited from the practices of 44 primary care physicians in France from March to July 2006. We randomly assigned 198 women aged 18-53 years who complained of fatigue and who had a ferritin level of less than 50 ug/L and hemoglobin greater than 12.0 g/dL to receive either oral ferrous sulfate (80 mg of elemental iron daily; n = 102) or placebo (n = 96) for 12 weeks. The primary outcome was fatigue as measured on the Current and Past Psychological Scale. Biological markers were measured at 6 and 12 weeks. RESULTS: The mean score on the Current and Past Psychological Scale for fatigue decreased by 47.7% in the iron group and by 28.8% in the placebo group (difference -18.9%, 95% CI -34.5 to -3.2; p = 0.02), but there were no significant effects on quality of life (p = 0.2), depression (p = 0.97) or anxiety (p = 0.5). Compared with placebo, iron supplementation increased hemoglobin (0.32 g/dL; p = 0.002) and ferritin (11.4 μg/L; p < 0.001) and decreased soluble transferrin receptor (-0.54 mg/L; p < 0.001) at 12 weeks. INTERPRETATION: Iron supplementation should be considered for women with unexplained fatigue who have ferritin levels below 50 μg/L. We suggest assessing the efficiency using blood markers after six weeks of treatment. Trial registration no. EudraCT 2006-000478-56.

Decoding decisions in healthy subjects and auditory discrimination in comatose patients through single-trial topographic EEG analyses

Neuroimaging studies analyzing neurophysiological signals are typically based on comparing averages of peri-stimulus epochs across experimental conditions. This approach can however be problematic in the case of high-level cognitive tasks, where response variability across trials is expected to be high and in cases where subjects cannot be considered part of a group. The main goal of this thesis has been to address this issue by developing a novel approach for analyzing electroencephalography (EEG) responses at the single-trial level. This approach takes advantage of the spatial distribution of the electric field on the scalp (topography) and exploits repetitions across trials for quantifying the degree of discrimination between experimental conditions through a classification scheme. In the first part of this thesis, I developed and validated this new method (Tzovara et al., 2012a,b). Its general applicability was demonstrated with three separate datasets, two in the visual modality and one in the auditory. This development allowed then to target two new lines of research, one in basic and one in clinical neuroscience, which represent the second and third part of this thesis respectively. For the second part of this thesis (Tzovara et al., 2012c), I employed the developed method for assessing the timing of exploratory decision-making. Using single-trial topographic EEG activity during presentation of a choice's payoff, I could predict the subjects' subsequent decisions. This prediction was due to a topographic difference which appeared on average at ~516ms after the presentation of payoff and was subject-specific. These results exploit for the first time the temporal correlates of individual subjects' decisions and additionally show that the underlying neural generators start differentiating their responses already ~880ms before the button press. Finally, in the third part of this project, I focused on a clinical study with the goal of assessing the degree of intact neural functions in comatose patients. Auditory EEG responses were assessed through a classical mismatch negativity paradigm, during the very early phase of coma, which is currently under-investigated. By taking advantage of the decoding method developed in the first part of the thesis, I could quantify the degree of auditory discrimination at the single patient level (Tzovara et al., in press). Our results showed for the first time that even patients who do not survive the coma can discriminate sounds at the neural level, during the first hours after coma onset. Importantly, an improvement in auditory discrimination during the first 48hours of coma was predictive of awakening and survival, with 100% positive predictive value. - L'analyse des signaux électrophysiologiques en neuroimagerie se base typiquement sur la comparaison des réponses neurophysiologiques à différentes conditions expérimentales qui sont moyennées après plusieurs répétitions d'une tâche. Pourtant, cette approche peut être problématique dans le cas des fonctions cognitives de haut niveau, où la variabilité des réponses entre les essais peut être très élevéeou dans le cas où des sujets individuels ne peuvent pas être considérés comme partie d'un groupe. Le but principal de cette thèse est d'investiguer cette problématique en développant une nouvelle approche pour l'analyse des réponses d'électroencephalographie (EEG) au niveau de chaque essai. Cette approche se base sur la modélisation de la distribution du champ électrique sur le crâne (topographie) et profite des répétitions parmi les essais afin de quantifier, à l'aide d'un schéma de classification, le degré de discrimination entre des conditions expérimentales. Dans la première partie de cette thèse, j'ai développé et validé cette nouvelle méthode (Tzovara et al., 2012a,b). Son applicabilité générale a été démontrée avec trois ensembles de données, deux dans le domaine visuel et un dans l'auditif. Ce développement a permis de cibler deux nouvelles lignes de recherche, la première dans le domaine des neurosciences cognitives et l'autre dans le domaine des neurosciences cliniques, représentant respectivement la deuxième et troisième partie de ce projet. En particulier, pour la partie cognitive, j'ai appliqué cette méthode pour évaluer l'information temporelle de la prise des décisions (Tzovara et al., 2012c). En se basant sur l'activité topographique de l'EEG au niveau de chaque essai pendant la présentation de la récompense liée à un choix, on a pu prédire les décisions suivantes des sujets (en termes d'exploration/exploitation). Cette prédiction s'appuie sur une différence topographique qui apparaît en moyenne ~516ms après la présentation de la récompense. Ces résultats exploitent pour la première fois, les corrélés temporels des décisions au niveau de chaque sujet séparément et montrent que les générateurs neuronaux de ces décisions commencent à différentier leurs réponses déjà depuis ~880ms avant que les sujets appuient sur le bouton. Finalement, pour la dernière partie de ce projet, je me suis focalisée sur une étude Clinique afin d'évaluer le degré des fonctions neuronales intactes chez les patients comateux. Des réponses EEG auditives ont été examinées avec un paradigme classique de mismatch negativity, pendant la phase précoce du coma qui est actuellement sous-investiguée. En utilisant la méthode de décodage développée dans la première partie de la thèse, j'ai pu quantifier le degré de discrimination auditive au niveau de chaque patient (Tzovara et al., in press). Nos résultats montrent pour la première fois que même des patients comateux qui ne vont pas survivre peuvent discriminer des sons au niveau neuronal, lors de la phase aigue du coma. De plus, une amélioration dans la discrimination auditive pendant les premières 48heures du coma a été observée seulement chez des patients qui se sont réveillés par la suite (100% de valeur prédictive pour un réveil).

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial.

OBJECTIVE. The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC).SUBJECTS AND METHODS. Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography.RESULTS. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018).CONCLUSION. PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.