Bortezomib in antibody-mediated autoimmune diseases (TAVAB): study protocol for a unicentric, non-randomised, non-placebo controlled trial

Introduction: The clinical characteristics of autoantibodymediated autoimmune diseases are diverse. Yet, medical treatment and the associated complications are similar, that is, the occurrence of long-term side effects and the problem that a significant proportion of patients are non-responders. Therefore, new therapeutic options are needed. Bortezomib, a proteasome inhibitor, is effective in the treatment of multiple myeloma and data from experimental models and case reports suggest an effect in the treatment of autoantibody-mediated autoimmunity. In our study, we will determine the effect of bortezomib treatment on a shared surrogate parameter for clinical efficacy, namely change in autoantibody levels, which we chose as primary parameter. Methods and analysis: We designed a phase IIa trial with altogether n=18 treatment-refractory patients suffering from myasthenia gravis, systemic lupus erythematosus and rheumatoid arthritis that will be treated with bortezomib add-on to pre-existing therapy. Primary endpoint is the change in autoantibody levels 6 months after therapy. Secondary endpoints include concomitant medication, disease-specific clinical scores and measures of quality of life and activities of daily living. Ethics and dissemination: Safety parameters include neurophysiological and clinical signs of peripheral neuropathy as well as potential central nervous system side effects determined by olfactory and neuropsychological testing. The study has been approved by the local ethical committee and first participants have already been enrolled. This proof of concept study will contribute to improve our understanding of plasma cellspecific treatment approaches by assessing its safety and efficacy in reducing serum levels of antibodies known to mediate autoimmune disorders. We plan to publish the final results of our study in a peer reviewed journal and to present our findings at international conferences. Trial registration number: NCT02102594

Temsirolimus Is Highly Effective as Third-Line Treatment in Chromophobe Renal Cell Cancer

We report unexpectedly high efficacy of temsirolimus as third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. After failure of two sequentially administered tyrosine kinase inhibitors, treatment with temsirolimus resulted in a prolonged partial remission of 14 months, and the response is still continuing. Up to now, no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third-line treatment after failure of tyrosine kinase inhibitors. The case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma

The course of pain intensity in patients undergoing herniated disc surgery: a 5-year longitudinal observational study

Objectives: The aims of this study are to answer the following questions (1) How does the pain intensity of lumbar and cervical disc surgery patients change within a postoperative time frame of 5 years? (2) Which sociodemographic, medical, work-related, and psychological factors are associated with postoperative pain in lumbar and cervical disc surgery patients? Methods: The baseline survey (T0; n = 534) was conducted 3.6 days (SD 2.48) post-surgery in the form of face-to-face interviews. The follow-up interviews were conducted 3 months (T1; n = 486 patients), 9 months (T2; n = 457), 15 months (T3; n = 438), and 5 years (T4; n = 404) post-surgery. Pain intensity was measured on a numeric rating-scale (NRS 0–100). Estimated changes to and influences on postoperative pain by random effects were accounted by regression models. Results: Average pain decreased continuously over time in patients with lumbar herniated disc (Wald Chi² = 25.97, p<0.001). In patients with cervical herniated disc a reduction of pain was observed, albeit not significant (Chi² = 7.02, p = 0.135). Two predictors were associated with postoperative pain in lumbar and cervical disc surgery patients: the subjective prognosis of gainful employment (p<0.001) and depression (p<0.001). Conclusion: In the majority of disc surgery patients, a long-term reduction of pain was observed. Cervical surgery patients seemed to benefit less from surgery than the lumbar surgery patients. A negative subjective prognosis of gainful employment and stronger depressive symptoms were associated with postoperative pain. The findings may promote multimodal rehabilitation concepts including psychological and work-related support

Physical Fitness Training in Patients with Subacute Stroke (PHYS-STROKE): multicentre, randomised controlled, endpoint blinded trial

OBJECTIVE: To determine the safety and efficacy of aerobic exercise on activities of daily living in the subacute phase after stroke. DESIGN: Multicentre, randomised controlled, endpoint blinded trial. SETTING: Seven inpatient rehabilitation sites in Germany (2013-17). PARTICIPANTS: 200 adults with subacute stroke (days 5-45 after stroke) with a median National Institutes of Health stroke scale (NIHSS, range 0-42 points, higher values indicating more severe strokes) score of 8 (interquartile range 5-12) were randomly assigned (1:1) to aerobic physical fitness training (n=105) or relaxation sessions (n=95, control group) in addition to standard care. INTERVENTION: Participants received either aerobic, bodyweight supported, treadmill based physical fitness training or relaxation sessions, each for 25 minutes, five times weekly for four weeks, in addition to standard rehabilitation therapy. Investigators and endpoint assessors were masked to treatment assignment. MAIN OUTCOME MEASURES: The primary outcomes were change in maximal walking speed (m/s) in the 10 m walking test and change in Barthel index scores (range 0-100 points, higher scores indicating less disability) three months after stroke compared with baseline. Safety outcomes were recurrent cardiovascular events, including stroke, hospital readmissions, and death within three months after stroke. Efficacy was tested with analysis of covariance for each primary outcome in the full analysis set. Multiple imputation was used to account for missing values. RESULTS: Compared with relaxation, aerobic physical fitness training did not result in a significantly higher mean change in maximal walking speed (adjusted treatment effect 0.1 m/s (95% confidence interval 0.0 to 0.2 m/s), P=0.23) or mean change in Barthel index score (0 (-5 to 5), P=0.99) at three months after stroke. A higher rate of serious adverse events was observed in the aerobic group compared with relaxation group (incidence rate ratio 1.81, 95% confidence interval 0.97 to 3.36). CONCLUSIONS: Among moderately to severely affected adults with subacute stroke, aerobic bodyweight supported, treadmill based physical fitness training was not superior to relaxation sessions for maximal walking speed and Barthel index score but did suggest higher rates of adverse events. These results do not appear to support the use of aerobic bodyweight supported fitness training in people with subacute stroke to improve activities of daily living or maximal walking speed and should be considered in future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01953549

Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP

Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[18F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15%) patients received statins throughout therapy. Five-year EFS was 67.3% in patients without statins compared with 79% in patients receiving statins during R-CHOP (HR, 0.47; 95% CI, 0.15-1.54, p = 0.2). Five-year OS was 81.4% for patients without statins compared with 93.3% for patients taking statins (HR, 0.58; 95% CI 0.07-4.55, p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75% in the non-statin group versus 86% in the statin group, p = 0.45). A trend toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84% versus 92%, p = 0.068). Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBC

a pilot study

Muscular weakness in myasthenia gravis (MG) is commonly assessed using Quantitative Myasthenia Gravis Score (QMG). More objective and quantitative measures may complement the use of clinical scales and might detect subclinical affection of muscles. We hypothesized that muscular weakness in patients with MG can be quantified with the non-invasive Quantitative Motor (Q-Motor) test for Grip Force Assessment (QGFA) and Involuntary Movement Assessment (QIMA) and that pathological findings correlate with disease severity as measured by QMG. Methods This was a cross-sectional pilot study investigating patients with confirmed diagnosis of MG. Data was compared to healthy controls (HC). Subjects were asked to lift a device (250 and 500 g) equipped with electromagnetic sensors that measured grip force (GF) and three- dimensional changes in position and orientation. These were used to calculate the position index (PI) and orientation index (OI) as measures for involuntary movements due to muscular weakness. Results Overall, 40 MG patients and 23 HC were included. PI and OI were significantly higher in MG patients for both weights in the dominant and non-dominant hand. Subgroup analysis revealed that patients with clinically ocular myasthenia gravis (OMG) also showed significantly higher values for PI and OI in both hands and for both weights. Disease severity correlates with QIMA performance in the non-dominant hand. Conclusion Q-Motor tests and particularly QIMA may be useful objective tools for measuring motor impairment in MG and seem to detect subclinical generalized motor signs in patients with OMG. Q-Motor parameters might serve as sensitive endpoints for clinical trials in MG

Double Blind, Randomised Controlled Trial

Purpose Surgical patients are at high risk for developing infectious complications and postoperative delirium. Prolonged infections and delirium result in worse outcome. Granulocyte-macrophage colony-stimulating factor (GM- CSF) and influenza vaccination are known to increase HLA-DR on monocytes and improve immune reactivity. This study aimed to investigate whether GM-CSF or vaccination reverses monocyte deactivation. Secondary aims were whether it decreases infection and delirium days after esophageal or pancreatic resection over time. Methods In this prospective, randomized, placebo-controlled, double-blind, double dummy trial setting on an interdisciplinary ICU of a university hospital 61 patients with immunosuppression (monocytic HLA-DR [mHLA-DR] <10,000 monoclonal antibodies [mAb] per cell) on the first day after esophageal or pancreatic resection were treated with either GM-CSF (250 μg/m2/d), influenza vaccination (Mutagrip 0.5 ml/d) or placebo for a maximum of 3 consecutive days if mHLA-DR remained below 10,000 mAb per cell. HLA-DR on monocytes was measured daily until day 5 after surgery. Infections and delirium were followed up for 9 days after surgery. Primary outcome was HLA-DR on monocytes, and secondary outcomes were duration of infection and delirium. Results mHLA-DR was significantly increased compared to placebo (p < 0.001) and influenza vaccination (p < 0.001) on the second postoperative day. Compared with placebo, GM-CSF-treated patients revealed shorter duration of infection (p < 0.001); the duration of delirium was increased after vaccination (p = 0.003). Conclusion Treatment with GM-CSF in patients with postoperative immune suppression was safe and effective in restoring monocytic immune competence. Furthermore, therapy with GM-CSF reduced duration of infection in immune compromised patients. However, influenza vaccination increased duration of delirium after major surgery

Universal Power Law in the Noise from a Crumpled Elastic Sheet

Using high-resolution digital recordings, we study the crackling sound emitted from crumpled sheets of mylar as they are strained. These sheets possess many of the qualitative features of traditional disordered systems including frustration and discrete memory. The sound can be resolved into discrete clicks, emitted during rapid changes in the rough conformation of the sheet. Observed click energies range over six orders of magnitude. The measured energy autocorrelation function for the sound is consistent with a stretched exponential C(t) ~ exp(-(t/T)^{b}) with b = .35. The probability distribution of click energies has a power law regime p(E) ~ E^{-a} where a = 1. We find the same power law for a variety of sheet sizes and materials, suggesting that this p(E) is universal.Comment: 5 pages (revtex), 10 uuencoded postscript figures appended, html version at http://rainbow.uchicago.edu/~krame