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BACKGROUND: EUS response assessment in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation therapy (CRT) is limited by disintegration of the involved anatomic structures. OBJECTIVE: Predictive and prognostic values of a prospectively defined maximum tumor thickness (MTT). DESIGN: Prospective open-label phase ll study (SAKK 75/02). SETTING: Multicenter, nationwide. PATIENTS: Of 66 patients with primary CRT, 56 underwent en bloc esophagectomy. INTERVENTIONS: EUS-measured MTT before and 2-5 weeks after CRT (yMTT). MAIN OUTCOME MEASUREMENTS: Cutoffs: (1) absolute thickness (yMTT) after CRT

Objectives: To describe the long-term effectiveness and safety of certolizumab pegol in patients with moderate-to-severe rheumatoid arthritis (RA) in a real-world setting in France., Methods: ECLAIR was a 3-year longitudinal, prospective, observational, multicentre study. The primary objective was to describe the EULAR response after 1 year of certolizumab pegol treatment. Other endpoints included DAS28, clinical disease activity index, health assessment questionnaire disability index, fatigue assessment scale, patient's assessment of arthritis pain, patient and physician global assessments of disease activity, patient quality of life, and long-term safety., Results: A total of 792 patients were enrolled, of whom 776 comprised the safety set, and 733 the full analysis set. In the full analysis set, 559, 469 and 430 patients had a 12-, 24- and 36-month visit, respectively. This included 378, 296 and 246 patients still receiving certolizumab pegol at these visits. The percentage of EULAR responders was 75.3% (305/405 patients with an available EULAR response) at 12, 76.5% (261/341) at 24, and 79.6% (226/284) at 36 months. Among those still receiving certolizumab pegol, the percentage of EULAR responders was 81.7% (237/290) at 12, 81.1% (185/228) at 24, and 87.3% (158/181) at 36 months. Sustained improvements were observed in other effectiveness outcomes. Overall, 45.1% (350/776) of patients experienced 776 adverse drug reactions. No new safety signals were identified., Conclusions: This is the first prospective, observational study of an anti-TNF treatment in France. The results confirm the effectiveness and safety profile of certolizumab pegol treatment in patients with RA in a real-world setting.

Background: Sodium oxybate (Xyrem ® ), approved by the European Medicines Agency (EMA) for narcolepsy with cataplexy, is only available through risk mitigation programs due to potential adverse effects including respiratory and central nervous system depression, neuropsychiatric events, and misuse., Objective: We report findings from a survey evaluating effectiveness of the European Union Xyrem ® Risk Management Plan (RMP)., Patients and Methods: A cross-sectional, online, multiple-choice survey was distributed to randomly selected healthcare professionals (HCPs) from six European countries (April 2016-May 2018). Eligibility criteria: current/potential Xyrem ® prescriber and/or sleep disorder specialist; contact information available; on the Xyrem ® RMP educational materials mailing list., Primary Outcome: proportion of respondents answering each question correctly (< 50% responses correct = unsatisfactory comprehension, 50% to < 70% = satisfactory, ≥ 70% = excellent), with precision assessed using 95% confidence intervals (CIs)., Results: Of the 709 HCPs contacted, 601 did not agree to take part, 108 were screened with 35/108 eligible for inclusion; 31 HCPs completed the survey. Of the 31 respondents, 29 (93.5%; 95% CI 84.4-100.0) reported receiving Xyrem ® safety information, commonly from a sales representative, EMA Summary of Product Characteristics (SmPC), or educational meeting; only 9/31 (31.0%; 14.3-50.0) recalled receiving mailed educational materials. The number of HCPs answering dosing-related questions correctly ranged from 24/31 to 31/31. All Xyrem ® contraindications were correctly identified by 26/31 (83.9%; 70.0-96.7) respondents. All respondents 'always' or 'sometimes' completed SmPC recommended activities upon treatment initiation. The majority indicated signs of abuses/misuse/diversion (23/31; 74.2%; 58.6-88.0) and criminal use (23/31; 74.2%; 59.4-89.3) should be monitored at follow-up., Conclusions: These data demonstrate the importance of providing a range of educational materials. However, the low sample size limits interpretation; increased HCP engagement would improve understanding of how best to develop educational materials., European Post-Authorization Study (pas) Register Number: EUPAS15024.

Background: PD0013 was a 6-month noninterventional study in clinical practice comparing effectiveness/tolerability of rotigotine+levodopa in younger (<70 years) vs. older (≥70 years) Parkinson's disease (PD) patients., Methods: Patients previously received levodopa for ≥6 months as monotherapy/in combination with another dopamine-agonist (DA). Primary variable: Unified PD Rating Scale (UPDRS) Part-II change from baseline to end-of-observation-period (EOP)., Results: 91 younger/99 older patients started rotigotine; 68 younger/62 older patients completed the study. Most switched from levodopa+another DA. Addition of rotigotine as first DA was more common in older patients (20.2% vs.15.4%). Mean ± SD rotigotine-exposure: 6.1 ± 3.4 mg/24h younger vs. 4.9 ± 2.4 mg/24h older. Eleven patients changed levodopa dose. At EOP, improvement in mean UPDRS-II was greater in younger patients (p = 0.0289). UPDRS-II responder-rate (≥20% decrease in UPDRS-II score) was higher in younger patients (42.3% vs. 25.9%). Improvement across age groups was similar on PD Sleep Scale-2 and Clinical Global Impressions-Improvement Scale. Adverse drug reactions (ADRs), and discontinuations because of ADRs, were more common among older patients. There were no new safety signals., Conclusions: Despite low rotigotine doses, when added to levodopa/switched from levodopa+another DA, rotigotine led to greater improvement in UPDRS-II in younger patients (<70 years). Individual patient data revealed clinically meaningful improvements in UPDRS-II in both groups.

This phase II trial investigated rituximab and cladribine in chronic lymphocytic leukemia. Four induction cycles, comprising cladribine (0.1 mg/kg/day days 1-5, cycles 1-4) and rituximab (375 mg/m(2) day 1, cycles 2-4), were given every 28 days. Stem cell mobilization (rituximab 375 mg/m(2) days 1 and 8; cyclophosphamide 4 g/m(2) day 2; and granulocyte colony-stimulating factor 10 microg/kg/day, from day 4) was performed in responders. Of 42 patients, nine achieved complete remission (CR), 15 very good partial remission, and two nodular partial remission (overall response rate 62%). Stem cell mobilization and harvesting (> or = 2 x 10(6) stem cells/kg body weight) were successful in 12 of 20 patients. Rituximab infusion-related adverse events were moderate. The main grade 3/4 adverse events during induction were neutropenia and lymphocytopenia. Rituximab plus cladribine was effective; however, the CR rate was modest and stem cell harvest was impaired in a large number of responding patients.

Aim: To investigate feasibility, morbidity and surgical mortality of a docetaxel-based chemotherapy regimen randomly administered before or after gastrectomy in patients suffering from locally-advanced resectable gastric cancer., Methods: Patients suffering from locally-advanced (T3-4 any N M0 or any T N1-3 M0) gastric carcinoma, staged with endoscopic ultrasound, bone scan, computed tomography, and laparoscopy, were assigned to receive four 21 d/cycles of TCF (docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2) per day for days 1-14), either before (Arm A) or after (Arm B) gastrectomy. Operative morbidity, overall mortality, and severe adverse events were compared by intention-to-treat analysis., Results: From November 1999 to November 2005, 70 patients were treated. After preoperative TCF (Arm A), thirty-two (94%) resections were performed, 85% of which were R0. Pathological response was complete in 4 patients (11.7%), and partial in 18 (55%). No surgical mortality and 28.5% morbidity rate were observed, similar to those of immediate surgery arm (P = 0.86). Serious chemotherapy adverse events tended to be more frequent in arm B (23% vs 11%, P = 0.07), with a single death per arm., Conclusion: Surgery following docetaxel-based chemotherapy was safe and with similar morbidity to immediate surgery in patients with locally-advanced resectable gastric carcinoma.

Background: There is no standard treatment for patients with locally advanced esophageal carcinoma without systemic metastasis in whom surgery is no longer considered a reasonable option., Patients and Methods: Patients with cervical esophageal tumors, locally very advanced stage (T4 and/or M1a) or locally advanced (T3 and/or N+) with comorbidities were included., Therapy: 2 cycles of induction chemotherapy (cisplatin and docetaxel, both 75 mg/m(2) 3-weekly) followed by chemoradiation therapy (CRT) comprising a total radiation dose of 59.4 Gy together with docetaxel 15 mg/m(2) and cisplatin 25 mg/m(2) (5 weekly doses). Primary endpoint: Histologically proven freedom from local failure 6 months after CRT completion., Results: 21 patients were included: 12 had locally very advanced tumors, 3 had cervical esophagus tumors, and 6 were medically unfit for surgery. 18 patients completed therapy per protocol. Grade 3/4 toxicities during CRT were thrombopenia (10%) and dysphagia (15%). 1 patient died due to herpes simplex infection. The primary endpoint was achieved by 4 patients, 6 were alive after median follow-up of 34 months, and median survival was 16 months. Most patients experienced lasting improvement of dysphagia following induction chemotherapy., Conclusions: This regimen is feasible, showed clinically meaningful, long-lasting improvements in quality of life and resulted in long-term survival in 29% of the patients., (Copyright 2010 S. Karger AG, Basel.)

Background: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery., Patients and Methods: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT., Results: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%)., Conclusions: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery., (Copyright 2009 S. Karger AG, Basel.)

Purpose: To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas., Methods and Materials: Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0., Results: Mean follow-up period was 38 months (range, 14-92 months). Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%., Conclusions: Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.

Background: This multicenter phase II study investigated the efficacy and feasibility of preoperative induction chemotherapy followed by chemoradiation and surgery in patients with esophageal carcinoma., Patients and Methods: Patients with locally advanced resectable squamous cell carcinoma or adenocarcinoma of the esophagus received induction chemotherapy with cisplatin 75 mg/m(2) and docetaxel (Taxotere) 75 mg/m(2) on days 1 and 22, followed by radiotherapy of 45 Gy (25 x 1.8 Gy) and concurrent chemotherapy comprising cisplatin 25 mg/m(2) and docetaxel 20 mg/m(2) weekly for 5 weeks, followed by surgery., Results: Sixty-six patients were enrolled at eleven centers and 57 underwent surgery. R0 resection was achieved in 52 patients. Fifteen patients showed complete, 16 patients nearly complete and 26 patients poor pathological remission. Median overall survival was 36.5 months and median event-free survival was 22.8 months. Squamous cell carcinoma and good pathologically documented response were associated with longer survival. Eighty-two percent of all included patients completed neoadjuvant therapy and survived for 30 days after surgery. Dysphagia and mucositis grade 3/4 were infrequent (<9%) during chemoradiation. Five patients (9%) died due to surgical complications., Conclusions: This neoadjuvant, taxane-containing regimen was efficacious and feasible in patients with locally advanced esophageal cancer in a multicenter, community-based setting and represents a suitable backbone for further investigation.

Goals of Work: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy., Materials and Methods: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful., Main Results: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection., Conclusions: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

We developed a novel diagram to depict patient flow and outcomes in clinical trials. In contrast to flow diagrams such as the CONSORT chart, our diagram enables individual patient histories to be traced and depicts important patterns of treatment administration and outcomes, such as response and adverse events. Also, it is particularly useful for multimodal treatments or a sequence of different therapies where the CONSORT flow chart is less informative and can be confusing.

Background: In patients with malignant pleural mesothelioma undergoing a multimodality therapy, treatment toxicity may outweigh the benefit of progression-free survival. The subjective experience across different treatment phases is an important clinical outcome. This study compares a standard with an individual quality of life (QoL) measure used in a multi-center phase II trial., Patients and Methods: Sixty-one patients with stage I-III technically operable pleural mesothelioma were treated with preoperative chemotherapy, followed by pleuropneumonectomy and subsequent radiotherapy. QoL was assessed at baseline, at day 1 of cycle 3, and 1, 3 and 6 months post-surgery by using the Rotterdam Symptom Checklist (RSCL) and the Schedule for the Evaluation of Quality of Life-Direct Weighting (SEIQoL-DW), a measure that is based on five individually nominated and weighted QoL-domains., Results: Completion rates were 98% (RSCL) and 92% (SEIQoL) at baseline and 98%/89% at cycle 3, respectively. Of the operated patients (N=45) RSCL and SEIQoL were available from 86%/72%, 93%/74%, and 94%/76% at months 1, 3, and 6 post-surgery. Average assessment time for the SEIQoL was 24min compared to 8min needed for the RSCL. Median changes from baseline indicate that both RSCL QoL overall score and SEIQoL index remained stable during chemotherapy with a clinically significant deterioration (change>or=8 points) 1 month after surgery (median change of -66 and -14 for RSCL and SEIQoL, respectively). RSCL QoL overall scores improved thereafter, but remained beneath baseline level until 6 months after surgery. SEIQoL scores improved to baseline-level at month 3 after surgery, but worsened again at month 6. RSCL QoL overall score and SEIQoL index were moderately correlated at baseline (r=.30; p

Background: We evaluated previously established regimens of capecitabine plus vinorelbine in older patients with advanced breast cancer stratified for presence versus absence of bone metastases., Patients and Methods: Patients > or =65 years who had received no prior chemotherapy for advanced breast cancer received up to six 21-day cycles of vinorelbine 20 mg/m(2) i.v. on days 1 + 8 with oral capecitabine on days 1-14 (1,000 vs. 1,250 mg/m(2) daily in patients with vs. without bone involvement)., Results: Median age was 72 years in patients with bone metastases (n = 47) and 75 years in patients without bone metastases (n = 23). Response rates were 43% (95% confidence interval, CI, 28.3-58.8) and 57% (95% CI = 34.5-76.8), respectively. Median time to progression was 4.3 (95% CI = 3.5-6.0 months) and 7.0 months (CI = 4.1-8.3), respectively. Neutropenia was the most common toxicity, with grade 3/4 occurring in 43 and 39%, respectively. Pulmonary embolism was seen in 5 and grade 3 thrombosis in 3 patients. Other toxicities were mild to moderate., Conclusions: These regimens of capecitabine and vinorelbine are active and well tolerated in patients with advanced breast cancer > or =65 years. Response rates were comparable to published results. The lower capecitabine doses appeared appropriate given the advanced age, bone involvement and prior radiotherapy., ((c) 2008 S. Karger AG, Basel)

Objective: To provide a method for correcting muscle artefacts in fast band power at EEG derivations., Methods: We define an indicator of surface EMG as power in the band 51.0-69.0 Hz ('muscle power'). This indicator is used to approximately eliminate the contribution of muscle activity on fast band power via a regression model., Results: (1) Patients show a larger proportion of muscle activity in fast band power. (2) There is a clear topographic pattern, frontal-temporal derivations being most susceptible to EMG artefacts. (3) The contribution of surface EMG can be drastically reduced by the proposed correction method. (4) Without correction, results for fast bands can be biased when e.g. comparing control and patient groups and the proposed correction method by and large eliminates this bias., Conclusions: It is advisable to correct the quantitative EEG reflecting fast activity for the extent of EMG artefacts., Significance: To render the quantitative EEG more valid as an indicator of cerebral activity.