Adaptive Designs for Two Candidate Primary Time-to-Event Endpoints

In clinical trials, the choice of an adequate primary endpoint is often difficult. Besides its clinical relevance, the endpoint must be measurable within reasonable time and must allow differentiating between the treatments. Often, the most relevant endpoint is ‘’time-to-death,” but if the overall survival prognosis is good, only a few deaths are observed during the study duration. A possible solution is to use surrogate endpoints instead. However, various examples from the literature demonstrate that surrogates do not always perform as intended. Sometimes, the surrogate effect is smaller than for the original endpoint, or the latter shows a higher effect than anticipated so using the surrogate is not reasonable. In this work, different adaptive design strategies for two candidate endpoints are proposed to solve these problems. The idea is to base the efficacy proof on the significance of at least one endpoint. At an interim analysis, both candidates are evaluated. If it is not possible to stop the study early, the sample size is recalculated based on the more promising endpoint. The new methods are illustrated by a clinical study example and compared in terms of power and sample size using Monte Carlo simulations. The software code is provided as supplementary material.     

Corneal confocal microscopy reveals small nerve fibre loss correlating with motor function in adult spinal muscular atrophy

Background

5q Spinal muscular atrophy (SMA) is a progressive, inherited, and severely disabling – yet treatable – motor neuron disease. Although treatment options have evolved in recent years, biomarkers for treatment monitoring and prognosis prediction remain elusive. Here, we investigated the utility of corneal confocal microscopy (CCM), a non-invasive imaging technique to quantify small corneal nerve fibres in vivo, as a diagnostic tool in adult SMA.

Methods

In this cross-sectional study, 19 patients with SMA type 3 and 19 healthy controls underwent CCM to measure corneal nerve fibre density (CNFD), corneal nerve fibre length (CNFL), and corneal nerve branch density (CNBD), as well as corneal immune cell infiltration. Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores and a 6-Minute Walk Test (6MWT) were conducted to explore any correlation between CCM findings and motor function.

Results

Corneal nerve fibre parameters were decreased in SMA patients versus healthy controls (CNFD: p = 0.030; CNFL: p = 0.013; CNBD: p = 0.020) in the absence of relevant immune cell infiltration. CNFD and CNFL correlated with HFMSE scores (CNFD: r = 0.492, p = 0.038; CNFL: r = 0.484, p = 0.042) and distance covered in the 6MWT (CNFD: r = 0.502, p = 0.042; CNFL: r = 0.553, p = 0.023).

Conclusions

Corneal confocal microscopy CCM reveals sensory neurodegeneration in SMA, thereby supporting a multisystem view of the disorder. Subclinical small nerve fibre damage correlated with motor function. Thus, CCM may be ideally suited for treatment monitoring and prognosis.     

Across-study and within-subject functional connectivity of a right temporo-parietal junction subregion involved in stimulus-context integration

Bidirectional integration between sensory stimuli and contextual framing is fundamental to action control. Stimuli may entail context-dependent actions, while temporal or spatial characteristics of a stimulus train may establish a contextual framework for upcoming stimuli. Here we aimed at identifying core areas for stimulus-context integration and delineated their functional connectivity (FC) using meta-analytic connectivity modeling (MACM) and analysis of resting-state networks. In a multi-study conjunction, consistently increased activity under higher demands on stimulus-context integration was predominantly found in the right temporo-parietal junction (TPJ), which represented the largest cluster of overlap and was thus used as the seed for the FC analyses. The conjunction between task-dependent (MACM) and task-free (resting state) FC of the right TPJ revealed a shared network comprising bilaterally inferior parietal and frontal cortices, anterior insula, premotor cortex, putamen and cerebellum, i.e., a 'ventral' action/attention network. Stronger task-dependent (vs. task-free) connectivity was observed with the pre-SMA, dorsal premotor cortex, intraparietal sulcus, basal ganglia and primary sensori motor cortex, while stronger resting-state (vs. task-dependent) connectivity was found with the dorsolateral prefrontal and medial parietal cortex. Our data provide strong evidence that the right TPJ may represent a key region for the integration of sensory stimuli and contextual frames in action control. Task-dependent associations with regions related to stimulus processing and motor responses indicate that the right TPJ may integrate 'collaterals' of sensory processing and apply (ensuing) contextual frames, most likely via modulation of preparatory loops. Given the pattern of resting-state connectivity, internal states and goal representations may provide the substrates for the contextual integration within the TPJ in the absence of a specific task.     

Fourteen new microsatellite markers for the Visayan tarictic hornbill (Penelopides panini) and their cross-species applicability among other endangered Philippine hornbills

Fourteen microsatellite markers were isolated and characterized for the endangered Visayan tarictic hornbill (Penelopides panini, Aves: Bucerotidae). In an analysis of 76 individuals, the number of alleles per locus varied from one to 12. Expected and observed heterozygosity ranged from 0.00 to 0.87 and from 0.00 to 0.89, respectively. All primers also amplify microsatellite loci in Luzon tarictic hornbill (Penelopides manillae), Mindanao tarictic hornbill (Penelopides affinis), the critically endangered Walden??s hornbill (Aceros waldeni) and the near-threatened writhed hornbill (Aceros leucocephalus). Two loci which are monomorphic in P. panini were found polymorphic in at least one of the other species. These 14 new microsatellite markers specifically developed for two genera of Philippine hornbills, in combination with those already available for the hornbill genera Buceros and Bucorvus, comprise a reasonable number of loci to genetically analyse wild and captive populations of these and probably other related, often endangered hornbills.     

Incidental head and neck <Superscript>18</Superscript>F-FDG uptake on PET/CT without corresponding morphological lesion: early predictor of cancer development?

Purpose  To retrospectively determine whether increased/asymmetric FDG uptake on PET without a correlating morphological lesion on fully diagnostic CT indicates the development of a head and neck malignancy. Methods  In 590 patients (mean age 55.4 ± 13.3 years) without a head and neck malignancy/inflammation FDG uptake was measured at (a) Waldeyer’s ring, (b) the oral floor, (c) the larynx, and (d) the thyroid gland, and rated as absent (group A), present (group B), symmetric (group B1) or asymmetric (group B2). Differences between groups A and B and between B1 and B2 were tested for significance with the U-test (p < 0.05). An average follow-up of about 2.5 years (mean 29.5 ± 13.9 months) served as the reference period to determine whether patients developed a head and neck malignancy. Results  Of the 590 patients, 235 (40%) showed no evidence of enhanced FDG uptake in any investigated site, and 355 (60%) showed qualitatively elevated FDG uptake in at least one site. FDG uptake values (SUV_max, mean±SD) for Waldeyer’s ring were 3.0 ± 0.89 in group A (n = 326), 4.5 ± 2.18 in group B (n = 264; p < 0.01), 5.4 ± 3.35 in group B1 (n = 177), and 4.1 ± 1.7 in group B2 (n = 87; p < 0.01). Values for the oral floor were 2.8 ± 0.74 in group A (n = 362), 4.7 ± 2.55 in group B (n = 228; p < 0.01), 4.4 ± 3.39 in group B1 (n = 130), and 5.1 ± 2.69 in group B2 (n = 98, p = 0.01). Values for the larynx were 2.8 ± 0.76 in group A (n = 353), 4.2 ± 2.05 in group B (n = 237; p < 0.01), 4.0 ± 2.02 in group B1 (n = 165), and 4.6 ± 2.8 in group B2 (n = 72; p = 0.027). Values for the thyroid were 2.4 ± 0.63 in group A (n = 404), 3.0 ± 1.01 in group B (n = 186; p < 0.01), 2.6 ± 0.39 in group B1 (n = 130), and 4.0 ± 1.24 in group B2 (n = 56; p < 0.01). One patient developed a palatine tonsil carcinoma (group B1, SUV_max 3.2), and one patient developed an oral floor carcinoma (group B1, SUV_max 3.7). Conclusion  Elevated/asymmetric head and neck FDG accumulation without a correlating morphological lesion can frequently be found and does not predict cancer development. In populations in which goitre is endemic, FDG uptake by the thyroid is common and not associated with thyroid cancer.     

Convergence of human brain mapping tools: neuronavigated TMS parameters and fMRI activity in the hand motor area

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system.     

Low concordance between surgical and radiological assessment of degree of resection and treatment-related hypothalamic damage: results of KRANIOPHARYNGEOM 2007

Background

Assessment of presurgical hypothalamic involvement (psHI) and treatment-related hypothalamic damage (trHD) is relevant for the decision on risk-adapted treatment and rehabilitation strategies in craniopharyngioma.

Patients and methods

129 surgical reports of childhood-onset craniopharyngioma patients recruited 2007–2014 in KRANIOPHARYNGEOM 2007 were analyzed. Data on psHI were available based on surgeon’s (63%), reference neuroradiologist’s (95%), and local radiologist’s (23%) assessment. The surgical degree of resection (DoR) was assessed by neurosurgeon (95%), reference neuroradiologist (73%), and local radiologist (61%). TrHD was assessed by neurosurgeon (33%), by reference neuroradiologist (95%), and by local radiologist (2%). Neurosurgical center size was categorized based on patient load.

Results

Surgical assessments on psHI (n?=?78), DoR (n?=?89) and trHD (n?=?42) as documented in surgical reports could be compared with the assessment of respective parameters by reference neuroradiologist. Differences with regard to DoR (p?=?0.0001) and trHD (p?<?0.0001) were detectable between surgeon’s and reference neuroradiologist’s assessment, whereas psHI was assessed similarly. Concordance for DoR and trHD was observed in 48 and 62%, respectively. Surgeons estimated a higher rate of complete resections and a lower rate of trHD. Neuroradiological reference assessment of trHD had higher predictive value for hypothalamic sequelae then surgical assessment. Observed differences were not related to neurosurgical center size.

Conclusions

Observed differences between surgical and neuroradiological estimation of risk factors in craniopharyngioma support the necessity of neuroradiological reference review to assure standards of quality. This could be established by central internet-based neuroradiological review in KRANIOPHARYNGEOM 2007. Standardization of surgical reports including specific assessment of tumor/damage location is recommended.

     

Prognostic role of the Donor Risk Index,the Eurotransplant Donor Risk Index,and the Balance of Risk score on graft loss after liver transplantation

This study aimed to identify cutoff values for donor risk index (DRI), Eurotransplant (ET)-DRI, and balance of risk (BAR) scores that predict the risk of liver graft loss. MEDLINE and Web of Science databases were searched systematically and unrestrictedly. Graft loss odds ratios and 95% confidence intervals were assessed by meta-analyses using Mantel–Haenszel tests with a random-effects model. Cutoff values for predicting graft loss at 3 months, 1 year, and 3 years were analyzed for each of the scores. Measures of calibration and discrimination used in studies validating the DRI and the ET-DRI were summarized. DRI ≥ 1.4 (six studies, n = 35 580 patients) and ET-DRI ≥ 1.4 (four studies, n = 11 666 patients) were associated with the highest risk of graft loss at all time points. BAR > 18 was associated with the highest risk of 3-month and 1-year graft loss (n = 6499 patients). A DRI cutoff of 1.8 and an ET-DRI cutoff of 1.7 were estimated using a summary receiver operator characteristic curve, but the sensitivity and specificity of these cutoff values were low. A DRI and ET-DRI score ≥ 1.4 and a BAR score > 18 have a negative influence on graft survival, but these cutoff values are not well suited for predicting graft loss.     

Enhancing medication therapy in Parkinson's disease by establishing an interprofessional network including pharmacists

International Journal of Clinical Pharmacy - Background Optimizing therapy regimens through collaboration and combination of available resources is a promising approach to improve quality of life...     

Proteogenomic systems analysis identifies targeted therapy resistance mechanisms in EGFR-mutated lung cancer

Cancer precision medicine largely relies on knowledge about genetic aberrations in tumors and next-generation-sequencing studies have shown a high mutational complexity in many cancers. Although a large number of the observed mutations is believed to be not causally linked with cancer, the functional effects of many rare mutations but also of combinations of driver mutations are often unknown. Here, we perform a systems analysis of a model of EGFR-mutated nonsmall cell lung cancer resistant to targeted therapy that integrates whole exome sequencing, global time-course discovery phosphoproteomics and computational modeling to identify functionally relevant molecular alterations. Our approach allows for a complexity reduction from over 2,000 genetic events potentially involved in mediating resistance to only 44 phosphoproteins and 35 topologically close genetic alterations. We perform single- and combination-drug testing against the predicted phosphoproteins and discovered that targeting of HSPB1, DBNL and AKT1 showed potent antiproliferative effects overcoming resistance against EGFR-inhibitory therapy. Our approach may therefore be used to complement mutational profiling to identify functionally relevant molecular aberrations and propose combination therapies across cancers.