Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most

Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progressionfree survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies

Background and Objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. // Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). // Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91–0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = −0.52, CI −0.74 to −0.30, p < 0.001) and participants with AD (β = −0.30, CI −0.58 to −0.02, p = 0.04). // Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. // Classification of Evidence: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline. // Glossary: Aβ=β-amyloid; AD=Alzheimer disease; CU=cognitively unimpaired; DLB=dementia with Lewy bodies; US FDA=US Food and Drug Administration; GMM=Gaussian mixture model; LMM=linear mixed model; MCI=mild cognitive impairment; MMSE=Mini-Mental State Examination; OR=odds ratio; ROI=region of interest; SCD=subjective cognitive decline; SUVr=standardized uptake value ratio

Digital remote assessment of speech acoustics in cognitively unimpaired adults:feasibility, reliability and associations with amyloid pathology

Background: Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. Methods: Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2–3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. Results: The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. Conclusion: Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD.</p

Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology

BACKGROUND: Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer's disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) pathology of speech acoustics measured over multiple assessments in a remote setting. METHODS: Fifty cognitively unimpaired adults (Age 68 ± 6.2 years, 58% female, 46% Aβ-positive) completed remote, tablet-based speech assessments (i.e., picture description, journal-prompt storytelling, verbal fluency tasks) for five days. The testing paradigm was repeated after 2-3 weeks. Acoustic speech features were automatically extracted from the voice recordings, and mean scores were calculated over the 5-day period. We assessed feasibility by adherence rates and usability ratings on the System Usability Scale (SUS) questionnaire. Test-retest reliability was examined with intraclass correlation coefficients (ICCs). We investigated the associations between acoustic features and Aβ-pathology, using linear regression models, adjusted for age, sex and education. RESULTS: The speech assessment was feasible, indicated by 91.6% adherence and usability scores of 86.0 ± 9.9. High reliability (ICC ≥ 0.75) was found across averaged speech samples. Aβ-positive individuals displayed a higher pause-to-word ratio in picture description (B = -0.05, p = 0.040) and journal-prompt storytelling (B = -0.07, p = 0.032) than Aβ-negative individuals, although this effect lost significance after correction for multiple testing. CONCLUSION: Our findings support the feasibility and reliability of multi-day remote assessment of speech acoustics in cognitively unimpaired individuals with and without Aβ-pathology, which lays the foundation for the use of speech biomarkers in the context of early AD

Survival advantage of partial over radical nephrectomy in patients presenting with localized renal cell carcinoma

Background Partial nephrectomy (PN) preserves renal function and has become the standard approach for T1a renal cell carcinoma (RCC). However, there is still an ongoing debate as to which patients will actually derive greater benefit from partial than from radical nephrectomy (RN). The aim of this study was to retrospectively evaluate the impact of the type of surgery on overall survival (OS) in patients with localized RCC. Methods Renal surgery was performed in 4326 patients with localized RCC (pT ≤ 3a N/M0) at six German tertiary care centers from 1980 to 2010: RN in 2955 cases (68.3%), elective (ePN) in 1108 (25.6%), and imperative partial nephrectomy (iPN) in 263 (6.1%) cases. The median follow-up for all patients was 63 months. Kaplan-Meier and Cox regression analyses were carried out to identify prognosticators for OS. Results PN was performed significantly more often than RN in patients presenting with lower tumor stages, higher RCC differentiation, and non-clear cell histology. Accordingly, the calculated 5 (10)-year OS rates were 90.0 (74.6)% for ePN, 83.9 (57.5)% for iPN, and 81.2 (64.7)% for RN (p < 0.001). However, multivariate analysis including age, sex, tumor diameter and differentiation, histological subtype, and the year of surgery showed that ePN compared to RN still qualified as an independent factor for improved OS (HR 0.79, 95% CI 0.66-0.94, p = 0.008). Conclusion Even allowing for the weaknesses of this retrospective analysis, our multicenter study indicates that in patients with localized RCC, PN appears to be associated with better OS than RN irrespective of age or tumor size

Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal

An evaluation of classification systems for stillbirth

<p>Abstract</p> <p>Background</p> <p>Audit and classification of stillbirths is an essential part of clinical practice and a crucial step towards stillbirth prevention. Due to the limitations of the ICD system and lack of an international approach to an acceptable solution, numerous disparate classification systems have emerged. We assessed the performance of six contemporary systems to inform the development of an internationally accepted approach.</p> <p>Methods</p> <p>We evaluated the following systems: Amended Aberdeen, Extended Wigglesworth; PSANZ-PDC, ReCoDe, Tulip and CODAC. Nine teams from 7 countries applied the classification systems to cohorts of stillbirths from their regions using 857 stillbirth cases. The main outcome measures were: the ability to retain the important information about the death using the <it>InfoKeep </it>rating; the ease of use according to the <it>Ease </it>rating (both measures used a five-point scale with a score <2 considered unsatisfactory); inter-observer agreement and the proportion of unexplained stillbirths. A randomly selected subset of 100 stillbirths was used to assess inter-observer agreement.</p> <p>Results</p> <p><it>InfoKeep </it>scores were significantly different across the classifications (<it>p </it>≤ 0.01) due to low scores for Wigglesworth and Aberdeen. CODAC received the highest mean (SD) score of 3.40 (0.73) followed by PSANZ-PDC, ReCoDe and Tulip [2.77 (1.00), 2.36 (1.21), 1.92 (1.24) respectively]. Wigglesworth and Aberdeen resulted in a high proportion of unexplained stillbirths and CODAC and Tulip the lowest. While <it>Ease </it>scores were different (<it>p </it>≤ 0.01), all systems received satisfactory scores; CODAC received the highest score. Aberdeen and Wigglesworth showed poor agreement with kappas of 0.35 and 0.25 respectively. Tulip performed best with a kappa of 0.74. The remainder had good to fair agreement.</p> <p>Conclusion</p> <p>The Extended Wigglesworth and Amended Aberdeen systems cannot be recommended for classification of stillbirths. Overall, CODAC performed best with PSANZ-PDC and ReCoDe performing well. Tulip was shown to have the best agreement and a low proportion of unexplained stillbirths. The virtues of these systems need to be considered in the development of an international solution to classification of stillbirths. Further studies are required on the performance of classification systems in the context of developing countries. Suboptimal agreement highlights the importance of instituting measures to ensure consistency for any classification system.</p

Expression of nectin-4 in papillary renal cell carcinoma

Background Nectin-4 contributes to tumor proliferation, lymphangiogenesis and angiogenesis in malignant tumors and is an emerging target in tumor therapy. In renal cell carcinoma (RCC) VEGF-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. Enfortumab vedotin-ejf (EV) is an antibody drug conjugate that targets Nectin-4. The aim of our study was to investigate the expression of Nectin-4 in a large cohort of papillary RCC specimens. Patients and methods Specimens were derived from the PANZAR consortium (Erlangen, Heidelberg, Herne, Homburg, Mainz, Mannheim, Marburg, Muenster, LMU Munich, TU Munich, and Regensburg). Clinical data and tissue samples from n = 190 and n = 107 patients with type 1 and 2 pRCC, respectively, were available. Expression of Nectin-4 was determined by immunohistochemistry (IHC). Results In total, Nectin-4 staining was moderately or strongly positive in of 92 (48.4%) of type 1 and 39 (36.4%) type 2 of pRCC cases. No associations between Nectin-4 expression and age at diagnosis, gender, grading, and TNM stage was found. 5 year overall survival rate was not statistically different in patients with Nectin-4 negative versus Nectin-4 positive tumors for the overall cohort and the pRCC type 2 subgroup, but higher in patient with Nectin-4 positive pRCC type 1 tumors compared to Nectin-4 negative tumors (81.3% vs. 67.8%, p = 0.042). Conclusion Nectin-4 could not be confirmed as a prognostic marker in pRCC in general. Due to its high abundance on pRCC specimens Nectin-4 is an interesting target for therapeutical approaches e.g. with EV. Clinical trials are warranted to elucidate its role in the pRCC treatment landscape.Open Access funding enabled and organized by Projekt DEAL.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Deutsche Gesellschaft für Urologie http://dx.doi.org/10.13039/501100006186Medizinische Hochschule Hannover (MHH) (3118