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Background: Collaterals are a strong determinant of clinical outcome in acute ischemic stroke (AIS) patients undergoing Endovascular Treatment (EVT). Careggi Collateral Score (CCS) is an angiographic score that demonstrated to be superior to the widely suggested ASITN/SIR score. Multi-phase CT-Angiography (mCTA) could be alternatively adopted for collateral assessment. We investigated whether mCTA had an equivalent predictive performance for functional outcome compared to CCS. Methods: Consecutive AIS patients undergoing EVT for large vessel occlusion within 24 h from onset were analyzed. Receiver operating characteristic curves and multivariable logistic regression were investigated to evaluate the predictive performance of mCTA collateral score (range 0–5) and CCS (range 0–4) for good functional outcome (three-months modified Rankin Scale 0–2). Results: We included 201 subjects (59.7% females, mean age 75), of whom 96 (47.7%) had good outcome at three-months. Both CCS (OR = 14.4, 95% CI = 6.3–33.8) and mCTA (OR = 23.8, 95% CI = 10.1–56.4) collateral scores were independent predictors of outcome. The AUC of CCS was 0.80 (95% CI 0.73–0.86) and the best cut-off was ≥ 3 (87% sensitivity, 71% specificity), while the AUC of mCTA collateral score was 0.84 (95% CI 0.78–0.90) with an optimal cut-off of ≥ 4 (85% sensitivity, 87% specificity). Patients with good mCTA collaterals experienced smaller (16.6 vs. 63.7 mL, p < 0.001) infarct lesion as compared to those with mCTA poor collaterals. Conclusion: mCTA discriminative ability for three-months 0–2 mRS was found to be comparable to CCS. mCTA appears a valid, non-invasive imaging modality for evaluating collaterals of AIS patients potentially eligible for EVT. [ABSTRACT FROM AUTHOR]

Given a couple of subspaces Y ⊂ X of the complex plane C satisfying some mild conditions (a “nice couple”), and given a PMQ-pair (Q , G) , consisting of a partially multiplicative quandle (PMQ) Q and a group G, we introduce a “Hurwitz–Ran” space Hur (X , Y ; Q , G) , containing configurations of points in X \ Y and in Y with monodromies in Q and in G, respectively. We further introduce a notion of morphisms between nice couples, and prove that Hurwitz–Ran spaces are functorial both in the nice couple and in the PMQ-group pair. For a locally finite PMQ Q we prove a homeomorphism between Hur ((0 , 1) 2 ; Q +) and the simplicial Hurwitz space Hur Δ (Q) , introduced in previous work of the author: this provides in particular Hur ((0 , 1) 2 ; Q +) with a cell stratification in the spirit of Fox–Neuwirth and Fuchs. [ABSTRACT FROM AUTHOR]

We consider for d ≥ 1 the graded commutative Q -algebra A (d) : = H ∗ (Hilb d (C 2) ; Q) , which is also connected to the study of generalised Hurwitz spaces by work of the first author. These Hurwitz spaces are in turn related to the moduli spaces of Riemann surfaces with boundary. We determine two distinct, minimal sets of ⌊ d / 2 ⌋ multiplicative generators of A (d) . Additionally, we prove when the lowest degree generating relations occur. For small values of d, we also determine a minimal set of generating relations, which leads to several conjectures about the necessary generating relations for A (d) . [ABSTRACT FROM AUTHOR]

Background: Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0. Methods: The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples. Results: A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population. Conclusions: Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide. Despite recent improvements in treatment and prevention, most of the current therapeutic options are weighted by side effects impacting patients' quality of life. Better patient selection towards systemic treatments represents an unmet clinical need. The recent multidisciplinary and molecular advancements in the treatment of CRC patients demand the identification of efficient biomarkers allowing to personalise patient care. Currently, core tumour biopsy specimens represent the gold-standard biological tissue to identify such biomarkers. However, technical feasibility, tumour heterogeneity and cancer evolution are major limitations of this single-snapshot approach. Genotyping circulating tumour DNA (ctDNA) has been addressed as potentially overcoming such limitations. Indeed, ctDNA has been retrospectively demonstrated capable of identifying minimal residual disease post-surgery and post-adjuvant treatment, as well as spotting druggable molecular alterations for tailoring treatments in metastatic disease. In this review, we summarise the available evidence on ctDNA applicability in CRC. Then, we review ongoing clinical trials assessing how liquid biopsy can be used interventionally to guide therapeutic choice in localised, locally advanced and metastatic CRC. Finally, we discuss how its widespread could transform CRC patients' management, dissecting its limitations while suggesting improvement strategies. [ABSTRACT FROM AUTHOR]

In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients' risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these "big data" in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association and agreement between magnetic resonance dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and computed tomography perfusion (CTP) in determining vascularity and permeability of primary and secondary brain tumors. Material and methods: DSC-PWI and CTP studies from 97 patients with high-grade glioma, low-grade glioma and solitary brain metastasis were retrospectively reviewed. Normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), capillary transfer constant (nK2) and permeability surface area product (nPS) values were obtained. Variables among groups were compared, and correlation and agreement between DSC-PWI and CTP were tested. Results: All DSC-PWI and CTP parameters were higher in high-grade than in low-grade gliomas (p < 0.01 and p < 0.001). Metastases had greater DSC-PWI nCBV (p < 0.05), nCTP-CBF (p < 0.05), nCTP-CBV (p < 0.01) and nCTP-PS (p < 0.0001) than low-grade gliomas and more elevated nCTP-PS (p < 0.01) than high-grade gliomas. The correlation was strong between DSC-PWI nCBF and CTP nCBF (r = 0.79; p < 0.00001) and between DSC-PWI nCBV and CTP nCBV (r = 0.83; p < 0.00001), weaker between DSC-PWI nK2 and CTP nPS (r = 0.29; p < 0.01). Bland–Altman plots indicated that the agreement was strong between DSC-PWI nCBF and CTP nCBF, good between DSC-PWI nCBV and CTP nCBV and poorer between DSC-PWI nK2 and CTP nPS. Conclusion: DSC-PWI and CTP CBF and CBV maps were comparable and interchangeable in the assessment of tumor vascularity, unlike DSC-PWI K2 and CTP PS maps that were more discordant in the analysis of tumor permeability. CTP could be an alternative method to quantify tumor neoangiogenesis when MRI is not available or when the patient does not tolerate it. [ABSTRACT FROM AUTHOR]

Open-plan workspaces are becoming common because of their compact footprint, economic advantages, and capacity for fostering communication. However, users of open-plan workspaces often report a high level of distraction, undermining their performance especially on individual cognitive tasks. Existing common solutions require recurrent physical changes, which are neither practical for companies and employees nor desired by interior architects. In this paper, we examine the use of augmented reality (AR) midair pervasive displays and visual separators to address the problem of visual distractions in open-plan workspaces. While past applications of AR in workspaces mostly focused on content creation and manipulation, we use AR to superimpose visual barriers—what we refer to as virtual partitions. To evaluate the impact of virtual partitioning on the occupants' cognitive performance, we conducted two user studies with a total of 48 participants. The design of assessed virtual partitions was informed by interviews that we conducted with 11 professional space designers. The analysis of collected data suggests that virtual partitions can reduce visual distractions and enable users to personalize the visual attributes of their space leading to an improved experience of shared workspaces. [ABSTRACT FROM AUTHOR]

The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants' gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity. [ABSTRACT FROM AUTHOR]

Since Saul Kripke's and Hilary Putnam's groundbreaking work in the Seventies, the idea has emerged that natural kind terms are semantically special among common nouns. Stephen P. Schwartz, for example, has argued that an artifactual kind term like "pencil" functions very differently from a natural kind term like "tiger." This, however, blatantly violates a principle that I call Semantic Uniformity. In this paper, I defend the principle. In particular, I outline a picture of how natural kind terms function based on Kripke's and Putnam's considerations, and I use it to rebut Schwartz's arguments, showing that if it works for natural kind terms, it can work for artifactual kind terms too (and, arguably, for common nouns in general), or at least that Schwartz did not provide good enough reasons to the contrary. [ABSTRACT FROM AUTHOR]

Climate policies encourage the search for greenhouse gas (GHG) mitigation options in all economic sectors and peatland rewetting is one of the most efficient mitigation measures in agriculture and land use. The benefits shown in the national GHG inventories, however, depend not only on the actual mitigation actions on the ground but also how well the effects can be reported. Currently there are no specific emission factors for reporting GHG emissions from rewetted agricultural soils as the current emission factors are aggregated for several pre-rewetting land use types. Also, rewetting can aim at either restoration or different forms of paludiculture which may differ in their GHG profile and thus demand disaggregated emission factors. We compiled the current knowledge on GHG emissions on sites where rewetting has occurred on former agricultural peatland in temperate or boreal climate zones. The recent data suggest that on average the current emission factors for rewetting nutrient-rich sites published by the Intergovernmental Panel for Climate Change (IPCC) provide a good estimate for reporting emissions from rewetting in the temperate zone. However, the total GHG balances differed widely in restoration, Sphagnum farming and production of emergent plants in paludiculture and it is evident that disaggregated emission factors will be needed to improve the accuracy of reporting the effects of mitigation measures in the GHG inventories. [ABSTRACT FROM AUTHOR]

Amidst the current health crisis and social distancing, telemedicine has become an important part of mainstream of healthcare, and building and deploying computational tools to support screening more efficiently is an increasing medical priority. The early identification of cervical cancer precursor lesions by Pap smear test can identify candidates for subsequent treatment. However, one of the main challenges is the accuracy of the conventional method, often subject to high rates of false negative. While machine learning has been highlighted to reduce the limitations of the test, the absence of high-quality curated datasets has prevented strategies development to improve cervical cancer screening. The Center for Recognition and Inspection of Cells (CRIC) platform enables the creation of CRIC Cervix collection, currently with 400 images (1,376 × 1,020 pixels) curated from conventional Pap smears, with manual classification of 11,534 cells. This collection has the potential to advance current efforts in training and testing machine learning algorithms for the automation of tasks as part of the cytopathological analysis in the routine work of laboratories. [ABSTRACT FROM AUTHOR]

Liquid biopsy recently gained widespread attention as a noninvasive alternative/complementary technique to tissue biopsy in patients with cancer. As technological advances have improved both feasibility and turnaround time, liquid biopsy has expanded tumor molecular analysis with acknowledgement of both spatial and temporal heterogeneity, overcoming many limitations of traditional tissue biopsy. Because of its diagnostic, prognostic, and predictive value, liquid biopsy has been extensively studied also in metastatic colorectal cancer. Indeed, as personalized medicine establishes its role in cancer treatment, genetic biomarkers unveiling the emergence of early resistance are needed. Among the wide variety of tumor analytes amenable to collection, circulating DNA and circulating tumor cells are the most adopted approaches, and both carry clinical relevance in colorectal cancer. However, few studies focused on comparing feasibility between these two approaches. In this review, we discuss the potential implications of liquid biopsy in metastatic colorectal cancer, assessing the advantages and drawbacks of circulating DNA and circulating tumor cells, and highlighting the most relevant trials for clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Cerebrovascular disease (CVD) is considered a major risk factor for fatal outcome in COVID-19. We aimed to evaluate the possible association between computed tomography (CT) signs of chronic CVD and mortality in infected patients. Materials and methods: We performed a double-blind retrospective evaluation of the cerebral CT scans of 83 COVID-19 patients looking for CT signs of chronic CVD. We developed a rapid visual score, named CVD-CT, which summarized the possible presence of parietal calcifications and dolichosis, with or without ectasia, of intracranial arteries, areas of chronic infarction and leukoaraiosis. Statistical analysis was carried out with weighted Cohen's K test for inter-reader agreement and logistic regression to evaluate the association of in-hospital mortality with CVD-CT, chest X-ray (CXR) severity score (Radiographic Assessment of Lung Edema-RALE) for radiological assessment of pulmonary disease, sex and age. Results: CVD-CT (odds ratio 1.6, 95% C.I. 1.2-2.1, p = 0.001) was associated with increased risk of mortality. RALE showed an almost significant association (odds ratio 1.05, 95% C.I. 1-1.1, p 0.06), whereas age and sex did not. Conclusion: CVD-CT is associated with risk of mortality in COVID-19 patients. The presence of CT signs of chronic CVD may be correlated to a condition of fragility of the circulatory system, which constitutes a key risk factor for death in infected patients. [ABSTRACT FROM AUTHOR]

Hutchinson-Gilford progeria syndrome is a genetic disease caused by an aberrant form of Lamin A resulting in chromatin structure disruption, in particular by interfering with lamina associated domains. Early molecular alterations involved in chromatin remodeling have not been identified thus far. Here, we present SAMMY-seq, a high-throughput sequencing-based method for genome-wide characterization of heterochromatin dynamics. Using SAMMY-seq, we detect early stage alterations of heterochromatin structure in progeria primary fibroblasts. These structural changes do not disrupt the distribution of H3K9me3 in early passage cells, thus suggesting that chromatin rearrangements precede H3K9me3 alterations described at later passages. On the other hand, we observe an interplay between changes in chromatin accessibility and Polycomb regulation, with site-specific H3K27me3 variations and transcriptional dysregulation of bivalent genes. We conclude that the correct assembly of lamina associated domains is functionally connected to the Polycomb repression and rapidly lost in early molecular events of progeria pathogenesis. Hutchinson-Gilford progeria syndrome is a genetic disease where an aberrant form of Lamin A disrupts chromatin by interfering with lamina associated domains. Here, the authors present the SAMMY-seq, a method for genome-wide characterization of heterochromatin dynamics and detect early stage alterations of heterochromatin structure in progeria primary fibroblasts, accompained by Polycomb dysfunctions. [ABSTRACT FROM AUTHOR]

Background: Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy.Methods: In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan-Meier method and Cox hazards regression models were used for survival analyses.Results: A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36-2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57-2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models.Conclusion: PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy. [ABSTRACT FROM AUTHOR]

Purpose: To present the application of custom-made 3D-printed subperiosteal implants for fixed prosthetic restoration of the atrophic posterior mandible of elderly patients. Methods: Between January 2017 and June 2018, all partially edentulous patients aged over 65 years, with two or more missing teeth in the posterior atrophic mandible, and who did not want to undergo bone regenerative procedures, were included in this study. These patients were rehabilitated with custom-made subperiosteal implants, designed from cone beam computed tomography (CBCT) and fabricated in titanium by means of direct metal laser sintering (DMLS). The outcome measures were fit and stability of the implants at placement, duration of the intervention, implant survival, and early and late complications. All patients were followed for 1 year after surgery. Results: Ten patients (four males, six females; mean age 69.6, SD ± 2.8, median 69, 95% CI 67.9–71.6) were included in the study. The fit of the implants was satisfactory, with a mean rating of 7 out of 10 (SD ± 1.6, median 7, 95% CI 6–8). Only two implants had insufficient fit, because of the presence of scattering in the CBCT; however, they were adapted to the sites during the interventions. The mean duration of the intervention was 44.3 min (SD ± 19.4, median 37, 95% CI 32.3–56.3). At the one-year follow-up, no implants were lost (survival rate 100%). One implant presented immediate postoperative complications with pain, discomfort and swelling, and two patients experienced late complications, having their provisional restorations fractured during the temporisation phase. All these complications were minor in nature, but the final complication rate amounted to 30% (three of ten patients). Conclusions: Although this study has limits (small patient sample and short follow-up), DMLS has proven to be an effective method for fabricating accurate subperiosteal implants, with high survival rates. This may represent an alternative treatment procedure in elderly patients with a severely atrophic posterior mandible, since it allows avoidance of regenerative bone therapies. Further studies are needed to confirm these outcomes. [ABSTRACT FROM AUTHOR]

The approval of targeted therapies for metastatic colorectal cancer (mCRC) has led to important improvements in patient outcomes. However, it is still necessary to increase individualisation of treatments based on tumour genetic profiles to optimise efficacy, while minimising toxicity. As such, there is currently great focus on the discovery and validation of further biomarkers in mCRC, with many new potential prognostic and predictive markers being identified alongside developments in patient molecular profiling technologies. Here, we review data for validated and emerging biomarkers impacting treatment strategies in mCRC. We completed a structured literature search of the PubMed database to identify relevant publications, limiting for English-language publications published between 1 January 2014 and 11 July 2018. In addition, we performed a manual search of the key general oncology and CRC-focused congresses to identify abstracts reporting emerging mCRC biomarker data, and of ClinicalTrials.gov to identify ongoing clinical trials investigating emerging biomarkers in mCRC and/or molecular-guided clinical trials. There is solid evidence supporting the use of BRAF status as a prognostic biomarker and DYPD, UGT1A1, RAS, and microsatellite instability as predictive biomarkers in mCRC. There are a number of emerging biomarkers that may prove to be clinically relevant in the future to have prognostic (HPP1 methylation), predictive (HER3, microRNAs, anti-angiogenic markers, and CRC intrinsic subtypes), or both prognostic and predictive values (HER2, CpG island methylator phenotype, tumour mutational load, gene fusions, and consensus molecular subtypes). As such, new biomarker-led treatment strategies in addition to anti-epidermal growth factor receptor and anti-angiogenetic treatments are being explored. Biomarkers that are not recommended to be tested in clinical practice or are unlikely to be imminently clinically relevant for mCRC include thymidylate transferase, ERCC1, PIK3CA, and PTEN. We highlight the clinical utility of existing and emerging biomarkers in mCRC and provide recommended treatment strategies according to the biomarker status. An update on ongoing molecular-guided clinical trials is also provided. [ABSTRACT FROM AUTHOR]

Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRCresistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT–APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance. [ABSTRACT FROM AUTHOR]

FDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients. Materials and methods Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease). Results Eighty-six patients (211 FDG PET/CTscans) were included in this analysis. Median patient age was 58 years (range, 35-66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4. Conclusions IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value.Objective: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s).Patients and Methods: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%).Results: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06).Conclusions: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment. [ABSTRACT FROM AUTHOR]

Infantile neuronal axonal dystrophy (INAD) is characterized by progressive cerebellar atrophy. MRI has been recommended as a marker of disease progression in cerebellar diseases. We performed a longitudinal brain volumetry study in a couple of bicorial twins with PLA2G6-positive INAD. Brain volumetry was calculated with FreeSurfer software on 3T T1-weighted images acquired at age 28 ( t ) and 36 months ( t ) in patient 1 and at age 22 ( t ) and 31 months ( t ) in patient 2. Data at t were compared to those obtained in 18 control children aged 14-44 months with normal MRI. At t , both patients showed markedly lower cerebellar volume compared to controls. At t , both patients exhibited a remarkable decrease of cerebellar volume (−25.8% in patient 1; −16.5% in patient 2) and of frontal (−6.8% in patient 1 and −3.3% in patient 2) and occipital (−9.8% in patient 1 and −9.1% in patient 2) cortical GM volume. Our MRI morphometry study indicates that INAD is characterized by a remarkably fast progression of cerebellar atrophy and mild atrophy of the frontal and occipital cortex presumably secondary to deafferentation in the cortical-pons-cerebellum-rubro-thalamus-cortical circuit and visual pathways. [ABSTRACT FROM AUTHOR]

Purpose: FDG PET/CT is able to detect active disease in patients with multiple myeloma (MM) and can be helpful for staging and assessing therapy response, but no standard interpretation criteria have been proposed for the evaluation of FDG PET/CT in MM. Methods: A group of Italian nuclear medicine physicians and haematologists met to propose new visual interpretation criteria to standardize FDG PET/CT evaluation in MM patients (Italian Myeloma criteria for PET USe; IMPeTUs) and the reproducibility of these criteria was tested. This Italian multicentre protocol was set up as a subprotocol of EMN02, an international prospective multicentre trial of the European Myeloma Network. The criteria were agreed at multidisciplinary consensus meetings. They include a description of the metabolic state of the bone marrow (BM), number and site of focal PET-positive lesions, the number of osteolytic lesions, and the presence and site of extramedullary disease, paramedullary disease and fractures. A visual degree of uptake was defined for the target lesion and extramedullary lesions according to modified Deauville criteria. MM patients who had undergone FDG PET/CT at baseline (PET-0), after induction (PET-AI) and at the end of treatment (PET-EoT) were enrolled. The patients had been prospectively enrolled in EMN02 and their PET scans were a posteriori reinterpreted in a blinded independent central review process managed by WIDEN®. Five expert nuclear medicine physicians scored the scans according to the new criteria. A case was considered read when four out of the five reviewers completed the report. Concordance among reviewers on different metrics was calculated using Krippendorff's alpha coefficient. Results: A total of 17 consecutive patients were enrolled. On PET-0, the alpha coefficients for the BM score, the score for the hottest focal lesion, the number of focal lesions and the number of lytic lesions were 0.33 and 0.47, 0.40 and 0.32, respectively. On PET-AI, the alpha coefficients were 0.09 and 0.43, 0.22 and 0.21, respectively, and on PET-EoT, the alpha coefficients were 0.07, 0.28, 0.25 and 0.21, respectively. BM was generally difficult to score since grades 2 and 3 are difficult to discriminate. However, since neither of the two grades is related to BM myelomatous involvement, the difference was not clinically relevant. Agreement on focal lesion scores and on the number of focal lesions was good. Conclusion: The new visual criteria for interpreting FDG PET/CT imaging in MM patients, IMPeTUs, were found to be feasible in clinical practice. [ABSTRACT FROM AUTHOR]

The article provides information on the features of neuropathological study that focuses on the neurodegenerative disease Friedreich's ataxia (FRDA). Particular focus is given to the patients with FRDA underwent autopsy procedure through the dorsal root ganglia perikarya and thoracic spinal cord cross-section.

Objective: To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity. Materials and methods: Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide). Results: MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals. Conclusion: A T-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases. [ABSTRACT FROM AUTHOR]

Famously, both Saul Kripke and Keith Donnellan opposed description theories and insisted on the role of history in determining the reference of a proper name token. No wonder, then, that their views on proper names have often been assimilated. By focusing on reference borrowing-an alleged phenomenon that Kripke takes to be fundamental-we argue that they should not be. In particular, we claim that according to Donnellan a proper name token never borrows its reference from preceding tokens which it is historically connected to. On the contrary, its reference is always fixed anew on who or what the speaker has in mind when he or she produces it. In fact, what is important to realize is that Donnellan and Kripke took two different histories to be relevant: that of the proper name token produced by the speaker (Kripke), and that of the cognitive status of the speaker when he or she produces it (Donnellan). We end by suggesting that this difference between Kripke's and Donnellan's accounts of proper names rests on a more general difference in their approach to language. [ABSTRACT FROM AUTHOR]

Introduction: Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography is not yet accepted as a standard pretreatment evaluation of thymic epithelial neoplasm (TEN). Statistical correlation between standardized uptake value of tumor/mediastinum ratio and patients' WHO risk class has been reported. PET metabolic tumor volume (MTV) and total glycolytic volume (TGV) have been reported as additional prognostic imaging biomarkers in several human tumors. Purpose of study was to establish whether MTV and TGV add prognostic information in TEN. Materials and methods: A retrospective dynamic cohort study of prospectively collected data (2006-2012) on 23 consecutive patients with pathologically proven TEN (no thymic carcinoma) was conducted. All patients underwent chest CT, and PET for staging. SUV T/M ratio, semi-quantitative and volumetric analyses of TEN were calculated. Patients were categorized according to WHO classification (low-risk and high-risk thymomas). Statistical analysis was performed with bootstrap method. Multi-collinearity was established using Pearson correlation coefficient. Cut-off point for TGV was compared using Mantel Cox log rank test. Results: SUV T/M ratio, MTV, and TGV correlate with low- and high-risk TEN. However, the statistical correlation between TGV and WHO classification ( ρ = 0.897) was higher than SUV T/M ratio ( ρ = 0.873). Since sample distributions were not uniformly smooth, only one cut-off value was identified: a TGV of 383 served as a cut-off value between low-risk and high-risk TEN. Conclusion: TGV is a PET reproducible imaging marker in patients with TEN, provides prognostic information, and could be useful in pretreatment stratification of patients. Nevertheless, it needs validation in larger cohort studies. [ABSTRACT FROM AUTHOR]

The interplay of magnetic and charge fluctuations can lead to quantum phases with exceptional electronic properties. A case in point is magnetically-driven superconductivity, where magnetic correlations fundamentally affect the underlying symmetry and generate new physical properties. The superconducting wavefunction in most known magnetic superconductors does not break translational symmetry. However, it has been predicted that modulated triplet p-wave superconductivity occurs in singlet d-wave superconductors with spin-density-wave (SDW) order. Here we report evidence for the presence of a spatially inhomogeneous p-wave Cooper pair-density wave in CeCoIn5. We show that the SDW domains can be switched completely by a tiny change of the magnetic field direction, which is naturally explained by the presence of triplet superconductivity. Further, the Q-phase emerges in a common magneto-superconducting quantum critical point. The Q-phase of CeCoIn5 thus represents an example where spatially modulated superconductivity is associated with SDW order. [ABSTRACT FROM AUTHOR]

The introduction into clinical practice of KRAS mutational status for selection of patients has dramatically improved the results from use of anti-EGFR monoclonal antibodies cetuximab or panitumumab for metastatic colorectal cancer. More refined selection of patients by means of other molecular alterations, for example BRAF, PIK3CA, and NRAS has enabled further increases in responses to first-line and other therapy for metastatic disease. Elucidation of differences among specific subtypes of KRAS mutations affecting sensitivity, and identification of other mechanisms by which tumor cell resistance is acquired, revealing 'druggable' molecular targets to overcome resistance, are clearly a priority of clinical research. Recent data have revealed potentially different activity of the G13D KRAS mutation in conferring resistance to cetuximab. This review examines the most recent evidence available on codon 13 mutation in metastatic colorectal cancer, including both preclinical and available clinical data, indicating differences between codon 13 and other KRAS mutations and analyzing its prognostic and predictive use in EGFR-targeted therapy. [ABSTRACT FROM AUTHOR]

A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. [ABSTRACT FROM AUTHOR]

The article the case of a 12-year-old girl with aquaporin-4 immunoglobulin G antibodies (AQP4IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) who presented with three episodes of isolated recurrent myelitis when she was between seven and nine years old. Topics discussed include no further relapses after rituximab was introduced, possible presentation of NMOSD as selective and recurrent spinal cord damage, and importance of AQP4IgG detection in differential diagnosis.

Everyone knows what David Lewis' possible worlds are, what role they play in his account of possibility and necessity, and Saul Kripke's criticisms. But what, instead, are Kripke's possible worlds, and what role do they play in his account of possibility and necessity? The answers are not so obvious. Recently, it has even been claimed that, contrary to what is standardly assumed, Kripke's approach to modality has not always been consistently metaphysical. In particular, an interpretation of the famous passage in the preface to Naming and Necessity with Kripke's discussion of the dice example has been put forward, according to which he purports there to clarify the modal notions in terms of that of possible world, model-theoretically construed, in a way which is reminiscent of Carnap's. In this paper, I shall point out some internal difficulties of this interpretation, and offer a different one, according to which in the dice passage Kripke is trying, consistently with his metaphysical approach, to legitimize the technically useful notion of possible world starting from modal notions, to be accounted for in another way (arguably, in an essentialistic framework). My final goal, however, will be philosophical elucidation rather than mere exegesis. Indeed, I am interested in shedding some light on what possible worlds might possibly be, if something like Kripke's metaphysical approach is on the right track. [ABSTRACT FROM AUTHOR]

The introduction of KRAS testing as a diagnostic tool to select patients for epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies for metastatic colorectal cancer is widely regarded as a key advance in the field of personalized cancer medicine. Oncologists are now facing emerging issues in the treatment of metastatic colorectal cancer, including: (i) the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients; (ii) the explanation of rare cases of patients carrying KRAS-mutated tumors who have been reported to respond to either cetuximab or panitumumab and (iii) the discovery of mechanisms of secondary resistance to anti-EGFR antibody therapies. Here we discuss the potential role of comprehensive dissection of the key oncogenic nodes in the EGFR signaling cascade to predict resistance and sensitivity to EGFR monoclonal antibodies in metastatic colorectal cancer. Current data suggest that, together with KRAS mutations, the evaluation of BRAF and PIK3CA/PTEN alterations could also be useful for selecting patients with reduced chance to benefit from EGFR-targeted therapy. Furthermore, measuring EGFR gene copy number also appears relevant to positively identify responders. Up until now, each of these markers has been mainly assessed as a single event, often in retrospective analyses and patients' series. As these molecular alterations display overlapping patterns of occurrence, this adds considerable complexity to the drawing of an algorithm suitable for clinical decision-making. We suggest that in the near future comprehensive molecular analysis of the entire oncogenic pathway triggered by the EGFR should be performed, thus enhancing the prediction ability of individual markers. [ABSTRACT FROM AUTHOR]

Clinical studies showed that only 10% of patients with metastatic colorectal cancer (mCRC) respond to treatment with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies panitumumab or cetuximab, regardless of the line of treatment. The current tool used to select patients, i.e. immunohistochemistry (IHC) evaluation of EGFR expression by EGFR pharmDx™ Kit, is not reliable in predicting response. Retrospective analyses of factors such as increased EGFR gene copy number and KRAS and/or BRAF mutations showed that such molecular changes could affect clinical benefit from anti-EGFR monoclonal antibodies. We report here the case of a 66-year-old man with chemorefractory mCRC, considered not eligible to salvage treatment with the anti-EGFR monoclonal antibody cetuximab and irinotecan because the primary adenocarcinoma of the rectum was found not expressing EGFR protein by IHC. However, FISH analysis of EGFR gene copy number and evaluation of KRAS and/or BRAF specific mutations by gene sequencing showed characteristics associated with favourable clinical outcome to anti-EGFR therapy. Based on the EGFR protein expression by IHC in a liver metastasis, the patient was then treated with cetuximab plus irinotecan, obtaining symptoms improvement and a dramatic objective tumor response in all sites of disease, lasting 4.2 months. We also discuss literature findings about the role of different biological characteristics in predicting clinical benefit from anti-EGFR therapy in patients with mCRC. [ABSTRACT FROM AUTHOR]

A correction to this paper has been published: https://doi.org/10.1007/s11523-021-00812-7 [ABSTRACT FROM AUTHOR]

Background: Radiomics is expected to improve the management of metastatic colorectal cancer (CRC). We aimed at evaluating the impact of liver lesion contouring as a source of variability on radiomic features (RFs). Methods: After Ethics Committee approval, 70 liver metastases in 17 CRC patients were segmented on contrast-enhanced computed tomography scans by two residents and checked by experienced radiologists. RFs from grey level co-occurrence and run length matrices were extracted from three-dimensional (3D) regions of interest (ROIs) and the largest two-dimensional (2D) ROIs. Inter-reader variability was evaluated with Dice coefficient and Hausdorff distance, whilst its impact on RFs was assessed using mean relative change (MRC) and intraclass correlation coefficient (ICC). For the main lesion of each patient, one reader also segmented a circular ROI on the same image used for the 2D ROI. Results: The best inter-reader contouring agreement was observed for 2D ROIs according to both Dice coefficient (median 0.85, interquartile range 0.78–0.89) and Hausdorff distance (0.21 mm, 0.14–0.31 mm). Comparing RF values, MRC ranged 0–752% for 2D and 0–1567% for 3D. For 24/32 RFs (75%), MRC was lower for 2D than for 3D. An ICC > 0.90 was observed for more RFs for 2D (53%) than for 3D (34%). Only 2/32 RFs (6%) showed a variability between 2D and circular ROIs higher than inter-reader variability. Conclusions: A 2D contouring approach may help mitigate overall inter-reader variability, albeit stable RFs can be extracted from both 3D and 2D segmentations of CRC liver metastases. [ABSTRACT FROM AUTHOR]

Movshovich et al. suggest that our calorimetric observation of the FFLO superconducting phase boundary and its angular dependence are inconsistent with their own data reporting the possible presence of an FFLO phase, and that we have incorrectly used magnetothermal measurements to identify the order of the FFLO transition. They also contest that the correlation of the magnetization steps with the calorimetrically identified FFLO superconducting phase of CeCoIn5 is coincidental. We consider each of these points in turn. [ABSTRACT FROM AUTHOR]