Background Two recent randomized, placebo-controlled phase II/III trials (clinicaltrials.gov: NCT01110720, NCT01049399) of davunetide and tideglusib in progressive supranuclear palsy (PSP) generated prospective, 1-year longitudinal datasets of high-resolution T1-weighted 3D MRI. Objectives Develop a quantitative MRI disease progression measurement for clinical trials. Methods We performed a fully automated quantitative MRI analysis employing atlas-based volumetry and provide sample size calculations based on data collected in N=99 PSP patients, assigned to placebo in these trials. Based on individual volumes of N=44 brain compartments and structures at baseline and 52 weeks follow-up, means and standard deviations of annualized percentage volume changes were used to estimate standardized effect sizes and the required sample sizes per group for future two-armed, placebo-controlled therapeutic trials. Results The highest standardized effect sizes were found for midbrain, frontal lobes, and third ventricle. Using the annualized percentage volume change of these structures to detect a 50% change in the 1-year progression (80% power, significance level 5%) required lower numbers of patients per group [third ventricle, N=32; midbrain, N=37; frontal lobe, N= 43] than the best clinical scale (PSP rating scale total score, N=58). A combination of volume changes in these three structures reduced the number of required patients to only N=20 and correlated best with the progression in the clinical scales. Conclusions We propose the 1-year change in the volumes of third ventricle, midbrain, and frontal lobe as combined imaging read-out for clinical trials in PSP, requiring the least number of patients for detecting efficacy to reduce brain atrophy.

Repair of the bicuspid aortic valve combined with root remodeling leads to excellent 10- and 15-year results. Cusp calcification and the need for partial cusp replacement are associated with valve failure.

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BackgroundRadical treatment for oligometastatic non-small-cell lung cancer (NSCLC) has a curative potential for selected patients. The present retrospective study was designed to examine the relevance of synchronous vs. metachronous manifestations as a potential prognostic factor when ablative treatments are performed in oligometastatic disease.MethodsSeventy-five patients with radically treated oligometastatic NSCLC were identified, of whom 39 presented with synchronous and 36 with metachronous metastatic manifestations. For patients with synchronous metastases, an additional therapy of the thoracic locoregional disease with a curative intent (either surgery or radiochemotherapy) was required. All patients with metachronous metastases had a documented remission of the primary tumor. Ablative treatment of the complete extent of oligometastatic disease consisted (as a minimum requirement) of either complete surgical resection or definitive ablative stereotactic radiotherapy. A comparative survival analysis of two groups of patients with oligometastatic NSCLC (synchronous vs. metachronous) and a complementary analysis of prognostic factors for the whole group of patients (by means of Cox regression analysis) was performed. Endpoints were median overall and progression-free survival (OS, PFS, respectively).ResultsOf the 75 patients, 57 presented with a solitary metastasis, in only 7 patients metastastatic lesions were present in ≥2 organs and 66 patients had a Karnofsky performance score (KPS) of 80 % or 90 %. The median follow-up was 54.0 months (95 % CI 28–81), the median OS 21.8 months (16.1–27.6) and the median PFS 13.7 months (9.7–17.6). In univariable Cox regression analysis, no single clinical factor was significantly associated with OS. For PFS both ‘metastatic involvement of ≥2 organs vs. 1 organ’ (hazard ratio (HR) 0.43, 0.23–0.83, p = 0.012) and a ‘KPS of 90 % vs. 70–80 %’ (HR 4.32, 1.73–10.89, p = 0.02) were significant prognostic factors as calculated by multivariable analysis. Comparing the cohorts with synchronous (n = 39) vs. metachronous oligometastases (n = 36), no differences in median OS and PFS were found. Both cohorts were well-balanced except for the KPS, which was significantly superior in patients with synchronous oligometastases.ConclusionsRadical treatment of oligometastatic NSCLC was associated with acceptable long-term survival rates in patients with good KPS and it was equally effective for synchronous and metachronous manifestations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2379-x) contains supplementary material, which is available to authorized users.

IMPORTANCE Bicuspid aortic valve (BAV) repair has been used in limited cohorts, but its long-term results in a large population are unknown.OBJECTIVES To analyze the long-term stability of BAV repair for survival and the factors associated with repair failure and to evaluate whether a differentiated anatomic repair approach may improve repair stability. DESIGN, SETTING, AND PARTICIPANTSIn this case series, 1024 patients underwent BAV repair for aortic regurgitation or aneurysm between October 1995 and June 2018, with a mean (SD) follow-up time of 56 (49) months and maximum follow-up of 271 months. Systematic modifications in technique based on anatomic principles were introduced in 2009 and applied for the last 727 patients. Data were acquired prospectively and analyzed retrospectively.EXPOSURES Repair of BAV with or without concomitant aortic replacement, as well as postoperative clinical and echocardiographic follow-up.MAIN OUTCOMES AND MEASURES Survival and incidence of reoperation or recurrent aortic regurgitation, as well as factors associated with valve repair failure. RESULTS Among the 1024 patients in the study (920 male [89.8%]; mean [SD] age, 47 [13] years [range, 15-86 years]), the survival rate at 15 years was 82.1%. The cumulative incidence of reoperation was 30.7% (95% CI, 22.7%-38.7%) at 15 years. Cusp calcification (subdistribution hazard ratio, 1.78; 95% CI, 1.14-2.77; P = .01), asymmetric commissural orientation (subdistribution hazard ratio, 1.95; 95% CI, 1.02-3.72; P = .04), and use of a pericardial patch for cusp repair (subdistribution hazard ratio, 5.25; 95% CI, 3.52-7.82; P < .001) were associated with time to reoperation. At 10 years, the incidence of reoperation was significantly reduced among patients who received the anatomic repair concept compared with those who had undergone surgery in the earlier period (8.8% vs 24.6%; P < .001). CONCLUSIONS AND RELEVANCEThis study suggests that survival after BAV repair is excellent and that a large proportion of BAV repairs will remain stable. Repair stability can be markedly improved by an anatomic repair concept. Cusp calcification and the need for cusp repair using a patch remain the factors most strongly associated with valve failure. In those instances, valve replacement should be preferred.

Background Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. Methods We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. Results The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. Conclusions We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome.

PBMT using a compactly designed treatment regime in combination with a cluster laser device did not significantly improve quality of life, pain scores, grip strength and limb volume over the time course.

Background Physicians' adherence to guideline‐recommended therapy is associated with short‐term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer‐term outcomes is poorly documented. Here, we present results from the 18‐month follow‐up of the QUALIFY registry. Methods and results Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF‐related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF‐related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all‐cause, CV or HF hospitalizations were not (all‐cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion These results suggest that physicians' adherence to guideline‐recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines.