Development and multicenter validation of a multiparametric imaging model to predict treatment response in rectal cancer

Funding Information: This study has received funding from the Dutch Cancer Society (project number 10138). Publisher Copyright: © 2023, The Author(s).Objectives: To develop and validate a multiparametric model to predict neoadjuvant treatment response in rectal cancer at baseline using a heterogeneous multicenter MRI dataset. Methods: Baseline staging MRIs (T2W (T2-weighted)-MRI, diffusion-weighted imaging (DWI) / apparent diffusion coefficient (ADC)) of 509 patients (9 centres) treated with neoadjuvant chemoradiotherapy (CRT) were collected. Response was defined as (1) complete versus incomplete response, or (2) good (Mandard tumor regression grade (TRG) 1–2) versus poor response (TRG3-5). Prediction models were developed using combinations of the following variable groups: (1) Non-imaging: age/sex/tumor-location/tumor-morphology/CRT-surgery interval (2) Basic staging: cT-stage/cN-stage/mesorectal fascia involvement, derived from (2a) original staging reports, or (2b) expert re-evaluation (3) Advanced staging: variables from 2b combined with cTN-substaging/invasion depth/extramural vascular invasion/tumor length (4) Quantitative imaging: tumour volume + first-order histogram features (from T2W-MRI and DWI/ADC) Models were developed with data from 6 centers (n = 412) using logistic regression with the Least Absolute Shrinkage and Selector Operator (LASSO) feature selection, internally validated using repeated (n = 100) random hold-out validation, and externally validated using data from 3 centers (n = 97). Results: After external validation, the best model (including non-imaging and advanced staging variables) achieved an area under the curve of 0.60 (95%CI=0.48–0.72) to predict complete response and 0.65 (95%CI=0.53–0.76) to predict a good response. Quantitative variables did not improve model performance. Basic staging variables consistently achieved lower performance compared to advanced staging variables. Conclusions: Overall model performance was moderate. Best results were obtained using advanced staging variables, highlighting the importance of good-quality staging according to current guidelines. Quantitative imaging features had no added value (in this heterogeneous dataset). Clinical relevance statement: Predicting tumour response at baseline could aid in tailoring neoadjuvant therapies for rectal cancer. This study shows that image-based prediction models are promising, though are negatively affected by variations in staging quality and MRI acquisition, urging the need for harmonization. Key Points: This multicenter study combining clinical information and features derived from MRI rendered disappointing performance to predict response to neoadjuvant treatment in rectal cancer. Best results were obtained with the combination of clinical baseline information and state-of-the-art image-based staging variables, highlighting the importance of good quality staging according to current guidelines and staging templates. No added value was found for quantitative imaging features in this multicenter retrospective study. This is likely related to acquisition variations, which is a major problem for feature reproducibility and thus model generalizability.Peer reviewe

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Biogeography and contemporary climatic differentiation among Moroccan Salamandra algira

The opening of the Gibraltar land bridge occurred at the end of the Messinian Salinity Crisis approximately 5.3 Mya, and was one of the main causes of vicariance between European and north-west African amphibians, resulting in the origin of several new species. However, little is currently known about the causes for post-Messinian amphibian differentiation in the Maghreb, although it is acknowledged that the Pleistocene glaciations probably had considerable influence on several species. The current study uses both species distribution modelling (MAXENT) and information from a total of 694 bp of mitochondrial data (351 from cytochrome b and 342 from 12S rRNA) from 36 representatives of all three recognized subspecies of Moroccan Salamandra to infer the phylogeny and biogeography of Salamandra algira tingitana, which is characterized by both viviparous and ovoviviparous populations. According to the results, the split between S. a. tingitana and S. a. algira from the Rif and Middle Atlas mountains took place approximately 1.6 Mya, and could have been caused by a shift towards a colder and drier climate that occurred during the upper Pliocene, which may have resulted in the isolation of Salamandra at increasingly higher altitudes, or in other climatically favourable areas. Several lineages within S. a. tingitana originated during the Pleistocene climatic oscillations, one of which gave rise to the viviparous populations north of the Oued Martil. It is suggested that the origin of viviparity in S. a. tingitana occurred during the last 600 000 years. In order to further understand the origin of the unique viviparous population of S. algira from North Africa, predictive distribution models of the viviparous and ovoviviparous populations of S. a. tingitana were created using MAXENT to assess environmental differences. Niche divergence was subsequently determined using Schoener's D and Warren et al.'s I niche similarity metrics. Predictive modelling and niche divergence analyses revealed significant environmental differences between the two reproductive types, which could have influenced the transition from ovoviviparity to viviparity. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society.The mtDNA work was funded by grant CGL2009-11663/BOS from the Ministerio de Educación y Ciencia, Spain. S.C. is a member of the Grup de Recerca Emergent of the Generalitat de Catalunya: 2009SGR1462.Peer Reviewe

Structural and functional correlates of subthalamic deep brain stimulation-induced apathy in Parkinson's disease

Background: Notwithstanding the large improvement in motor function in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role. Objective: We studied whether apathy in DBS-treated PD patients could be a stimulation effect. Methods: In 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy. Results: Average apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex. Conclusions: The present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms

Prenatal Origins of Temperament: Fetal Growth, Brain Structure, and Inhibitory Control in Adolescence

Objective Individual differences in the temperamental dimension of effortful control are constitutionally based and have been associated with an adverse prenatal developmental environment, with structural brain alterations presenting a potential mechanism. We investigated this hypothesis for anatomically defined brain regions implicated in cognitive and inhibitory motor control. Methods Twenty-seven 15–16 year old participants with low, medium, or high fetal growth were selected from a longitudinal birth cohort to maximize variation and represent the full normal spectrum of fetal growth. Outcome measures were parent ratings of attention and inhibitory control, thickness and surface area of the orbitofrontal cortex (lateral (LOFC) and medial (MOFC)) and right inferior frontal gyrus (rIFG), and volumetric measures of the striatum and amygdala. Results Lower birth weight was associated with lower inhibitory control, smaller surface area of LOFC, MOFC and rIFG, lower caudate volume, and thicker MOFC. A mediation model found a significant indirect effect of birth weight on inhibitory control via caudate volume. Conclusions Our findings support a neuroanatomical mechanism underlying potential long-term consequences of an adverse fetal developmental environment for behavioral inhibitory control in adolescence and have implications for understanding putative prenatal developmental origins of externalizing behavioral problems and self-control