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Cerebral palsy (CP) is a non-progressive neurologic pathology representing a leading cause of spasticity and concerning gait impairments in children. Robotic-assisted gait training (RAGT) is widely employed to treat this pathology to improve children’s gait pattern. Importantly, the effectiveness of the therapy is strictly related to the engagement of the patient in the rehabilitation process, which depends on his/her psychophysiological state. The aim of the study is to evaluate the psychophysiological condition of children with CP during RAGT through infrared thermography (IRT), which was acquired during three sessions in one month. A repeated measure ANOVA was performed (i.e., mean value, standard deviation, and sample entropy) extracted from the temperature time course collected over the nose and corrugator, which are known to be indicative of the psychophysiological state of the individual. Concerning the corrugator, significant differences were found for the sample entropy (F (1.477, 5.907) = 6.888; p = 0.033) and for the mean value (F (1.425, 5.7) = 5.88; p = 0.047). Regarding the nose tip, the sample entropy showed significant differences (F (1.134, 4.536) = 11.5; p = 0.041). The findings from this study suggests that this approach can be used to evaluate in a contactless manner the psychophysiological condition of the children with CP during RAGT, allowing to monitor their engagement to the therapy, increasing the benefits of the treatment.

Mucosal high-risk (HR) human papillomaviruses (HPV) are associated with anogenital carcinogenesis. The products of two early genes, E6 and E7, act as major viral oncoproteins. Functional studies in experimental models showed that HPV16 E6 induces degradation of the PDZ protein, the Na+/H+ exchanger regulatory factor-1 (NHERF-1). Here, we determined NHERF-1 protein levels by immunohistochemistry (IHC) in (i) benign anogenital warts (n = 8) (ii) premalignant lesions (L-SIL and H-SIL) (n = 43) and (iii) invasive cervical squamous cell carcinomas (SCC) (n = 17). A decrease of NHERF-1 protein level was not observed in genital warts in comparison to healthy epithelium. Conversely, a clearly decrease in NHERF-1 protein levels was observed in HPV16-positive pre-malignant and malignant lesions, while the phenomenon was much attenuated in lesions induced by other HR HPV types. In conclusion, these findings show that mucosal HPV types differently impact on NHERF-1 protein level in benign and malignant anogenital lesions.

Treatment advances for metastatic breast cancer (mBC) have improved overall survival (OS) in some mBC subtypes; however, there remains no cure for mBC. Considering the use of progression-free survival (PFS) and other surrogate endpoints in clinical trials, we must understand patient perspectives on measures used to assess treatment efficacy.To explore global patient perceptions of the concept of PFS and its potential relation to quality of life (QoL).Virtual roundtables in Europe and the United States and interviews in Japan with breast cancer patients, patient advocates, and thought leaders. Discussions were recorded, transcribed, and analyzed thematically.Lengthened OS combined with no worsening or improvement in QoL remain the most important endpoints for mBC patients. Time when the disease is not progressing is meaningful to patients when coupled with improvements in QoL and no added treatment toxicity. Clinical terminology such as "PFS" is not well understood, and participants underscored the need for patient-friendly terminology to better illustrate the concept. Facets of care that patients with mBC value and that may be related to PFS include relief from cancer-related symptoms and treatment-related toxicities as well as the ability to pursue personal goals. Improved communication between patients and providers on managing treatment-related toxicities and addressing psychosocial challenges to maintain desired QoL is needed.While OS and QoL are considered the most relevant endpoints, patients also value periods of time without disease progression. Incorporation of these considerations into the design and conduct of future clinical trials in mBC, as well as HTA and reimbursement decision-making, is needed to better capture the potential value of a therapeutic innovation.

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour. UCP2 is shown in yeast and mammalian cells to transport aspartate out of mitochondria, thus enabling KRAS-mutated pancreatic ductal adenocarcinoma cells to perform glutaminolysis to support cancer growth.

Objective Real‐time quaking‐induced conversion (RT‐QuIC) assays detect prion‐seeding activity in a variety of human biospecimens, including cerebrospinal fluid and olfactory mucosa swabs. The assay has shown high diagnostic accuracy in patients with prion disorders. Recently, advances in these tests have led to markedly improved diagnostic sensitivity and reduced assay times. Accordingly, an algorithm has been proposed that entails the use of RT‐QuIC analysis of both sample types to diagnose sporadic Creutzfeldt‐Jakob disease with nearly 100% accuracy. Here we present a multi‐center evaluation (ring trial) of the reproducibility of these improved “second generation” RT‐QuIC assays as applied to these diagnostic specimens. Methods Cerebrospinal fluid samples were analyzed from subjects with sporadic Creutzfeldt‐Jakob (n = 55) or other neurological diseases (n = 45) at multiple clinical centers. Olfactory mucosa brushings collected by multiple otolaryngologists were obtained from nine sporadic Creutzfeldt‐Jakob disease cases and 19 controls. These sample sets were initially tested blindly by RT‐QuIC by a coordinating laboratory, recoded, and then sent to five additional testing laboratories for blinded ring trial testing. Results Unblinding of the results by a third party indicated 98‐100% concordance between the results obtained by the testing of these cerebrospinal fluid and nasal brushings at the six laboratories. Interpretation This second‐generation RT‐QuIC assay is highly transferrable, reproducible, and therefore robust for the diagnosis of sporadic Creutzfeldt‐Jakob disease in clinical practice.

Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options. Significance: These findings provide preclinical evidence that a drug repurposing approach to prevent metastatic disease in TNBC exploits lipid anabolism as a metabolic vulnerability against CSCs in primary tumors.

Background Jehovah's Witnesses (JWs) refuse blood transfusions due to religious issues. This situation may impact kidney transplantation (KT) outcomes in case of hemorrhagic complications. We evaluated demographic characteristics of this population, hematologic safety, and graft outcomes. Methods This was a retrospective, single-center study comparing KT outcomes in JW patients versus a non-JW control group. Hematologic endpoints included clinical indication for blood transfusion (hemoglobin 2 g/dL or hematocrit >5% in the first week after KT, hemorrhagic complications requiring surgery, and de novo prescription of erythropoiesis-stimulating agents. Secondary endpoints included delayed graft function, treated biopsy-proven acute rejection, renal function, mortality, and graft survival at 12 months. Results From January 1989 to September 2018, we identified 143 JW (10 pediatric) and selected 142 matched control (non-JW) patients. There were no differences in the incidence of clinical indication for transfusion (13.3% versus 11.3%, P = 0.640), but a higher proportion of non-JW patients received transfusions (2.1% versus 9.2%, P = 0.010). There were no differences in the proportion of patients with decreased hemoglobin concentration, in reinterventions due to hemorrhagic complications, in the use of erythropoiesis-stimulating agents at hospital discharge, in the incidence of acute rejection, in renal function, and in mortality or graft survival rate at 12 months. Conclusions In summary, this matched control cohort study suggests that, when clinically indicated, blood transfusions can be safely avoided in the majority of JW kidney transplant, who achieve and maintain comparable hemoglobin concentrations during the first year after transplantation compared with non-JW patients.

The SARS-CoV-2 pandemic is not only a threat to physical health but is also having severe impacts on mental health. Although increases in stress-related symptomatology and other adverse psycho-social outcomes, as well as their most important risk factors have been described, hardly anything is known about potential protective factors. Resilience refers to the maintenance of mental health despite adversity. To gain mechanistic insights about the relationship between described psycho-social resilience factors and resilience specifically in the current crisis, we assessed resilience factors, exposure to Corona crisis-specific and general stressors, as well as internalizing symptoms in a cross-sectional online survey conducted in 24 languages during the most intense phase of the lockdown in Europe (22 March to 19 April) in a convenience sample of N = 15,970 adults. Resilience, as an outcome, was conceptualized as good mental health despite stressor exposure and measured as the inverse residual between actual and predicted symptom total score. Preregistered hypotheses (osf.io/r6btn) were tested with multiple regression models and mediation analyses. Results confirmed our primary hypothesis that positive appraisal style (PAS) is positively associated with resilience (p

Purpose This study aimed to standardize the operative technique of indocyanine green (ICG) near-infrared fluorescence (NIRF) laparoscopic partial nephrectomy (LPN) and compare it with the standard technique. Methods In the last 4 years, we performed 22 LPN (14 right-sided, 8 left-sided) in children with non-functioning moiety of duplex kidney. Patients included 12 girls and 10 boys with a median age of 3.9 years (range 1–10). Patients were grouped according to the use of ICG-NIRF: G1 included 12 patients operated using ICG-NIRF and G2 included 10 patients receiving the standard technique. We standardized the technique of injection of ICG in three different steps. Results The median operative time was significantly lower in G1 [87 min (range 68–110)] compared with G2 [140 min (range 70–220)] (p = 0.001). One intra-operative complication occurred in G2. At post-operative ultrasound (US), the residual moiety was normal in all patients. An asymptomatic renal cyst related to the site of surgery was visualized at US in 8/22 (36%), with a significantly higher incidence in G2 (6/10, 60%) compared with G1 (2/12, 16.6%) (p = 0.001). Renogram demonstrated no loss of function of residual moiety. No allergic reactions to ICG occurred. Conclusion ICG-NIRF LPN is technically easier, quicker, and safer compared with the standard technique. The main advantages of using ICG-NIRF during LPN are the clear identification of normal ureter, vasculature of non-functioning pole, and demarcation line between the avascular and the perfused pole. The main limitation of ICG technology remains the need for specific laparoscopic equipment that is not always available.

Background Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. Methods We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. Results We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. Conclusions This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.

Objective: The development of integrated multimedia operating rooms has made possible to record surgical procedures mainly in minimally invasive surgery (MIS) and robotic surgery. This modality of video storage allows the trainees to study surgical procedures based on video analysis. The aim of this study is to compare two learning methods of surgical procedures, operative textbooks and video-based coaching, in a group of 10 pediatric surgery trainees. Patients and Methods: We selected five surgical procedures to study: Three MIS procedures, Nissen fundoplication, partial nephrectomy, and cholecystectomy; and two robotic procedures, Lich-Gregoir reimplantation for vesicoureteral reflux and Henderson-Hynes pyleoplasty for ureteropelvic junction obstruction. Ten trainees were divided into two groups of 5 each, Group 1 (G1) and Group 2 (G2). G1 studied the procedures analyzing videos, G2 studied the same procedure classically reading textbooks. Tutors prepared a questionnaire of 100 multianswered questions that was submitted to both groups, divided into 20 questions for each surgical technique. The questionnaire focused on the different steps of surgical techniques. Results: Analyzing the 10 questionnaires, G1 (video group) obtained a median result of 82 exact answers (74-97), whereas G2 (textbook group) obtained a median result of 64.2 correct answers (53-79). Analyzing statistically the results of two groups, using unpaired t-Student's test with a level of statistical significance >95%, the results of G1 were statistically significantly better that G2 with a P = .0265 for the average scores. Conclusion: Video-based coaching to learn surgical techniques is a novel, feasible, and excellent modality for supplementing surgical techniques learning for pediatric surgery trainees. Objective evaluation using a multianswered questionnaire demonstrates that video-based coaching in pediatric surgery is statistically better than textbook classic education. We suggest to adopt this teaching modality in every surgical training program above all to teach MIS and robotic surgery.

IMPORTANCE: Rechallenge therapy with anti–epidermal growth factor receptor (EGFR) drugs has been suggested in patients with chemo-refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC) after initial response to anti–EGFR-based first-line treatment. The association of treatment with cetuximab plus avelumab with overall survival (OS) may be worthy of investigation in this setting. OBJECTIVE: To assess the efficacy and safety of cetuximab rechallenge therapy plus avelumab. DESIGN, SETTING, AND PARTICIPANTS: This single-arm, multicenter phase 2 trial enrolled patients from August 2018 to February 2020. Eligible patients with RAS WT mCRC had a complete or partial response to first-line chemotherapy plus anti-EGFR drugs, developed acquired resistance, and failed second-line therapy. Baseline circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R mutation analysis was done. INTERVENTIONS: Patients received avelumab (10 mg/kg every 2 weeks) and cetuximab (400 mg/m(2) and, subsequently, 250 mg/m(2) weekly) until disease progression or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: The primary end point was OS. Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: Seventy-seven patients were enrolled (42 men, 35 women; median age, 63 years); 71 had microsatellite stable tumors (MSS), 3 microsatellite instability-high tumors (MSI-H), 3 unknown. The study met the primary end point, with median OS (mOS) of 11.6 months (95% CI, 8.4-14.8 months). Median PFS (mPFS) was 3.6 months (95% CI, 3.2-4.1 months). Common grade-3 adverse events were cutaneous eruption, 11 (14%), and diarrhea, 3 (4%). For 67 of 77 (87%) patients, baseline analysis of plasma circulating tumor DNA (ctDNA) for KRAS, NRAS, BRAF, and EGFR-S492R variations was feasible. Forty-eight patients had WT disease, whereas 19 had mutations. Patients with RAS/BRAF WT ctDNA had mOS of 17.3 months (95% CI, 12.5-22.0 months) compared with 10.4 months (95% CI, 7.2-13.6 months) in patients with mutated ctDNA (hazard ratio [HR], 0.49; 95% CI, 0.27-0.90; P = .02). The mPFS was 4.1 months (95% CI, 2.9-5.2 months) in RAS/BRAF WT patients compared with 3.0 months (95% CI, 2.6-3.5 months) in patients with mutated ctDNA (HR, 0.42; 95% CI, 0.23-0.75; P = .004). CONCLUSIONS AND RELEVANCE: The findings of this single-arm phase 2 trial suggest that cetuximab plus avelumab is an active, well tolerated rechallenge therapy in RAS WT mCRC. Plasma ctDNA analysis before treatment may allow selection of patients who could benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04561336

Hypophosphatasia should be considered for any patient who presents with multiple metatarsal stress fractures and a low alkaline phosphatase.

The cardiovascular system is designed to distribute a steady flow through its elastic properties. With ageing, fatigue and fracture of elastin lamellae cause a loss of elasticity defined arterial stiffness. Arterial stiffness causes changes of the pulse wave propagation through the arterial tree, which volumetric counterpart can be assessed non-invasively through photoplethysmography (PPG). PPG may be employed in combination with electrocardiography (ECG). It is here reported an implementation of analysis of multisite PPG and single lead ECG relying on Deep Convolutional Neural Networks (DCNNs). DCNNs generate peculiar filters allowing for data-driven automated selection of the features of interest. The ability of a DCNN to predict subject's age from PPG (left and right brachial, radial and tibial arteries plus fingers) and ECG (Lead I) in a healthy male population (age range: 20–70 years) was investigated. A performance in age prediction of 7 years of root mean square error was obtained, which was superior to other feature-based procedures. The accuracy in age prediction of the machinery in the healthy population may serve for the generation of age-matched normal ranges for the identification of outliers suggesting cardiovascular diseases manifesting as fastened cardiovascular ageing which is recognized as a risk factor for ischemic diseases.

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase CELA2A. We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target., Editorial summary: Exome sequencing identifies loss-of-function CELA2A mutations in families with early-onset atherosclerosis and metabolic syndrome. Functional studies show that CELA2A is a circulating enzyme that reduces platelet activation, triggers insulin secretion and degradation, and increases insulin sensitivity.

Purpose: Pegylated liposomal doxorubicin (PLD) combined with bortezomib is an effective salvage regimen for relapsed refractory multiple myeloma (RRMM). Carfilzomib, a second-generation proteasome inhibitor, has clinical efficacy even among bortezomib-refractory patients. Patients and Methods: We performed a phase I/II trial of carfilzomib, PLD, and dexamethasone (KDD) with the primary endpoints being safety and efficacy (NCT01246063). Twenty-three patients were enrolled in the phase I portion and the MTD of carfilzomib was determined to be 56 mg/m2 (days 1, 2, 8, 9, 15, and 16) when combined with PLD (30 mg/m2 on day 8) and dexamethasone (20 mg on days 1, 2, 8, 9, 15, and 16). Seventeen additional patients were enrolled in the phase II portion. Results: KDD was determined to be well tolerated with the only common grade 3/4 nonhematologic adverse events of infection. Grade 3/4 hematologic toxicity included lymphopenia (63%), thrombocytopenia (40%), anemia (40%), and neutropenia (28%). In the cohort of patients treated at the MTD, where median prior therapies were 2% and 42% were refractory to bortezomib, the overall response rate was 83% (20/24) with 54% (13/24) having a very good partial response or better. The median progression-free survival was 13.7 months (95% CI, 5.0–21.7). Conclusions: This trial is the first to report outcomes using a triplet regimen of high-dose carfilzomib. KDD was well tolerated and appears efficacious in RRMM. Additional study is needed to more precisely determine patient outcomes with this regimen and its utility compared with other carfilzomib containing salvage regimens.

Metastatic cancer cells are highly plastic for the expression of different tumor phenotype hallmarks and organotropism. This plasticity is highly regulated but the dynamics of the signaling processes orchestrating the shift from one cell phenotype and metastatic organ pattern to another are still largely unknown. The scaffolding protein NHERF1 has been shown to regulate the expression of different neoplastic phenotypes through its PDZ domains, which forms the mechanistic basis for metastatic organotropism. This reprogramming activity was postulated to be dependent on its differential phosphorylation patterns. Here, we show that NHERF1 phosphorylation on S279/S301 dictates several tumor phenotypes such as in vivo invasion, NHE1-mediated matrix digestion, growth and vasculogenic mimicry. Remarkably, injecting mice with cells having differential NHERF1 expression and phosphorylation drove a shift from the predominantly lung colonization (WT NHERF1) to predominately bone colonization (double S279A/S301A mutant), indicating that NHERF1 phosphorylation also acts as a signaling switch in metastatic organotropism.

Objectives To evaluate the performance of a simplified-ABLATE score (sABLATE) in predicting complications and outcome in respect to RENAL, mRENAL and ABLATE scores. Methods This study included 136 renal lesions in 113 patients (M:F ratio=2.5; mean age 70.8 years). 98 tumors underwent cryoablation at San Raffaele hospital between 01/2015 and 03/2020, 37 microwave ablation at San Paolo or Policlinico hospitals between 07/2016 and 03/2020. RENAL, mRENAL, ABLATE and sABLATE scores were calculated using preprocedural imaging. Data regarding complications and follow-up were registered. Mann-Whitney U test, ROC analyses, and logistic regression analyses were used for complications. Cox-regression analyses were performed for outcome Results Mean tumor diameter was 23.2mm. Mean and median RENAL, mRENAL, ABLATE and sABLATE scores were 6.8 and 7, 6.9 and 7, 5.3 and 5, and 3.5 and 3, respectively. During a mean follow-up of 21.9 months (range 1-73) we registered 7 complications, 3 cases of residual disease and 10 local tumor progressions. Mann-Whitney U test p-values for complications for RENAL, mRENAL, ABLATE and sABLATE were 0.51, 0.49, 0.66 and 0.056 respectively. ROC analyses for complications showed an AUC for RENAL, mRENAL, ABLATE and sABLATE of 0.57, 0.57, 0.55 and 0.71 respectively. Regarding outcome, HR and p-values of Cox-regression analyses were 1.30 and 0.36 for RENAL, 1.33 and 0.35 for mRENAL, 2.16 and 0.01 for ABLATE, 2.29 and 0.004 for sABLATE.Conclusion sABLATE was the only score close to significance for complications, representing a progress even if not definitive. Regarding outcome, ABLATE confirmed its value, and sABLATE maintained validity despite being a simplification.

Objective To evaluate effects of remote monitoring of adjuvant chemotherapy related side effects via the Advanced Symptom Management System (ASyMS) on symptom burden, quality of life, supportive care needs, anxiety, self-efficacy, and work limitations. Design Multicentre, repeated measures, parallel group, evaluator masked, stratified randomised controlled trial. Setting Twelve cancer centres in Austria, Greece, Norway, Republic of Ireland, and UK. Participants 829 patients with non-metastatic breast cancer, colorectal cancer, Hodgkin’s disease, or non-Hodgkin’s lymphoma receiving first line adjuvant chemotherapy or chemotherapy for the first time in five years. Intervention Patients were randomised to ASyMS (intervention; n=415) or standard care (control; n=414) over six cycles of chemotherapy. Main outcome measures The primary outcome was symptom burden (Memorial Symptom Assessment Scale; MSAS). Secondary outcomes were health related quality of life (Functional Assessment of Cancer Therapy—General; FACT-G), Supportive Care Needs Survey Short-Form (SCNS-SF34), State-Trait Anxiety Inventory—Revised (STAI-R), Communication and Attitudinal Self-Efficacy scale for cancer (CASE-Cancer), and work limitations questionnaire (WLQ). Results For the intervention group, symptom burden remained at pre-chemotherapy treatment levels, whereas controls reported an increase from cycle 1 onwards (least squares absolute mean difference −0.15, 95% confidence interval −0.19 to −0.12; P Conclusions Significant reduction in symptom burden supports the use of ASyMS for remote symptom monitoring in cancer care. A “medium” Cohen’s effect size of 0.5 showed a sizable, positive clinical effect of ASyMS on patients’ symptom experiences. Remote monitoring systems will be vital for future services, particularly with blended models of care delivery arising from the covid-19 pandemic. Trial registration Clinicaltrials.gov NCT02356081 .

Introduction: Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models. Methods: We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments. Results: The addition of selumetinib or cetuximab to osimertinib in second-line therapy reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50% to 80%, and a median progression-free survival (mPFS) of first- plus second-line of therapy of 28 weeks. The early use of combinations in first-line therapy increased the RR to 90%, with an mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0.005) as compared to osimertinib, achieving in first-line therapy an mPFS time of 17 to 18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found Hedgehog pathway activation and we showed that therapy with an SMO inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells. Conclusions: We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.

There has been controversy regarding whether headgear use in women's lacrosse will affect the rate of head and musculoskeletal injuries. The purpose of this study was to investigate the effect of mandated headgear use on the rate of head and musculoskeletal injuries in high school women's lacrosse.This was a prospective cohort study of eight high school women's lacrosse teams and their game op-ponents who were mandated to wear F3137 headgear for the 2017 and 2018 seasons. Athletic trainers documented all injuries that occurred as a result of participation on the lacrosse teams. Injury rates in the headgear cohort were compared to a retrospective (control) cohort from the High School Reporting Information Online injury data reports.Over the study period, 17 total injuries were reported in the headgear cohort during 22,397 exposures for an injury rate of 0.76 injuries per 1,000 athlete-exposures. The headgear cohort demonstrated significant decreases in rates of in-game head and face injury (RR 0.141, 95% CI [0.004, 0.798]), in-game concussion (RR 0.152, 95% CI [0.004, 0.860]), and practice trunk and extremity injury (RR 0.239, 95% CI [0.049, 0.703]) when compared to the control cohort.Mandated use of headgear was shown to be effective at lowering the rate of head or face injury and concussions in women's lacrosse. Additionally, mandated headgear use was also shown to lower the rate of injury to body locations other than the head or face during practice. To our knowledge, this is the first study to demonstrate a decrease in injury rates associated with ASTM approved headgear in women's lacrosse.

BACKGROUND Neuronal hyperexcitability characterizes the early stages of Alzheimer’s disease (AD). In animals, early misfolded tau and amyloid-β (Aβ) protein accumulation — both central to AD neuropathology — promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau — and its associated neuroinflammation — and cortical Aβ aggregations remains unknown. METHODS We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle–aged individuals (50–69 years; 45 women and 19 men). We assessed whole-brain [18F]THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. RESULTS We found that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability (r = 0.29, P = 0.02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = –0.20, P = 0.11). CONCLUSION These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. TRIAL REGISTRATION EudraCT 2016-001436-35. FUNDING F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.

Modern lifestyle curtails sleep and increases nighttime work and leisure activities. This has a deleterious impact on vigilance and attention, exacerbating chances of committing attentional lapses, with potential dramatic outcomes. Here, we investigated the brain signature of attentional lapses and assessed whether cortical excitability and brain response propagation were modified during lapses and whether these modifications changed with aging. We compared electroencephalogram (EEG) responses to transcranial magnetic stimulation (TMS) during lapse and no-lapse periods while performing a continuous attentional/vigilance task at night, after usual bedtime. Data were collected in healthy younger (N = 12; 18–30 years) and older individuals (N = 12; 50–70 years) of both sexes. The amplitude and slope of the first component of the TMS-evoked potential were larger during lapses. In contrast, TMS response scattering over the cortical surface, as well as EEG response complexity, did not significantly vary between lapse and no-lapse periods. Importantly, despite qualitative differences, age did not significantly affect any of the TMS–EEG measures. These results demonstrate that attentional lapses are associated with a transient increase of cortical excitability. This initial change is not associated with detectable changes in subsequent effective connectivity—as indexed by response propagation—and are not markedly different between younger and older adults. These findings could contribute to develop models aimed to predicting and preventing lapses in real-life situations.

As reported in the literature, benzopyrones (alpha and gamma) have important effects on the microcirculation through various mechanisms. Coumarins are an alpha-benzopyrone as derivatives of Melilotus Officinalis, while bioflavonoids are a gamma-benzopyrone and include Rutin. Alpha-benzopyrones have two fundamental pharmacological effects: they have pro-lymphokinetic action by activating contractility of lymphangions; and the activation of macrophages to provide a proteolytic effect. Gamma-benzopyrones, such as Rutin, have an important anti-exuding and membrane stabilizing effect. Bromelain is known for its anti-inflammatory effect. The present study enrolled 52 patients with primary and/or secondary lymphedema in clinical stages I or II (according to the ISL classification) with 31 cases involving the lower limbs and 21 cases involving the upper limbs. All subjects were given for six months a natural compound consisting of 100 mg of natural Melilotus, that contains 20 grams of Coumarin, 300 mg of Rutin and 100 mg of Bromelain. The following parameters were studied at zero time (T0), after three months (T1), and after six months of treatment (T2): pitting, Stemmer's sign, measurement of limb circumferences, measurement of superficial tissue thickness in the affected limbs using ultrasound, and blood tests to evaluate hepatic function (ALT, AST, GGT, total and fractional bilirubin). At the end of the treatment (T2), the following results were observed: disappearance of pitting in 72% of the cases; unchanged Stemmer's sign; average decrease in limb circumferences of 4.2 cm; and average reduction of the superficial thickness of 29%. There was no variation in the liver function parameters examined. The combination of natural compounds (Melilotus, Rutin, and Bromelain) has been shown to be a valuable aid in the clinical control of both primary and secondary lymphedema of clinical stages I and II as well as in control of inflammatory phenomena related to chronic stasis. There were no side effects and no alteration of liver function parameters found.

RENAL score has been validated on predicting adverse events and relapses in percutaneous treatments of renal lesions. To better fit interventional issues a modified score (mRENAL) has been introduced, but the only difference from the RENAL score is on the dimensional parameter. However, it remains of surgical derivation while a specific interventional score is missing. This study aims to obtain a specific score (ABLATE) to better quantify the risk of complications and relapses in percutaneous kidney ablation procedures compared to the existing surgical scores. Taking inspiration from previous papers, a score was built to quantify the real difficulties faced in percutaneous treatment of renal lesions. The ABLATE score was used on 71 cryoablations to evaluate its predictivity of complications and relapses. Logistic regression was used to predict complication incidence; Cox-regression was used for relapses; ROC analysis was used to evaluate the accuracy of the different scores. Between January 2014 and November 2019, 71 lesions in 68 patients were treated. Overall, malignant histology was found in 62 lesions (87.3%). Mean and median RENAL, mRENAL, and ABLATE scores were 7.04 and 7, 7.19 and 7, and 5.11 and 4, respectively. Out of 71 treatments, we experienced 3 bleeding with anemia (4.2%), only 2 of which needed further treatment (2.82%). The mean and median RENAL, mRENAL, and ABLATE scores in those with complications were 7.66 and 7.01 (p = 0.69), 8.0 and 7.1 (p = 0.54), and 6.6 and 5.0 (p = 0.38), respectively. Out of 62 malignant lesions, we experienced 2 persistent and 6 recurrent lesions (3.2% and 8.4%, respectively). At Cox-regression analyses, mABLATE score outperformed both RENAL and mRENAL scores in predicting recurrences (HR 1.48; p

In the last years, increasing efforts have been devoted to investigating the role of small extracellular vesicles (sEVs) in cardiovascular diseases. These nano-sized particles (30-150 nm), secreted by different cell types, contain signalling molecules that enable participation in intercellular communication processes. In this study, we examined the course of circulating sEVs in patients undergoing surgical aortic valve replacement (SAVR) and correlated them with echocardiographic and standard blood parameters. Peripheral blood samples were collected from 135 patients undergoing SAVR preoperatively and at three follow-up points. Circulating sEVs were precipitated using Exoquick™ exosome isolation reagent and analyzed by nanoparticle tracking analysis (NTA). Our findings indicate that no more than 7 days after SAVR, there was a marked increase of circulating sEVs before returning to initial values after 3 months. Further, shear stress is not a trigger for the formation and release of circulating sEVs. Moreover, we pointed out a correlation between circulating sEVs and erythrocytes as well as LDH and creatinine levels in peripheral blood. Finally, all patients with a moderate prosthesis-patient mismatch as well as with an impaired left ventricular mass regression had lower levels of circulating sEVs 3 months after SAVR compared to their respective status before surgery. We conclude that in patients with aortic valve stenosis (AVS), sEVs may play an important part in mediating cell-cell communication and SAVR may have a crucial and lasting impact on their circulating levels. Besides, lower levels of sEVs portend to be associated with inferior recovery after major surgical interventions. The additional use of circulating sEVs beyond echocardiographic and laboratory parameters could have a prognostic value to estimate adverse outcomes in patients undergoing SAVR.

Background and purpose The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC.

Background It has been shown that active surveillance (AS) is feasible and effective in a subset of patients with recurrent low-grade (LG) non–muscle-invasive bladder cancer (NMIBC). Objective To update a previous preliminary series and investigate pathological outcomes for patients who failed to remain on AS. Design, setting, and participants Prospective observational cohort study started in February 2008, and currently still active, at a tertiary university hospital, including patients with pathologically confirmed NMIBC who experienced recurrence during follow-up. Intervention AS monitoring consisted of cytology and in-office flexible cystoscopy every 3 mo for the first year, and every 6 mo thereafter. Outcome measurements and statistical analysis The primary endpoint was pathological results for patients who failed to remain on AS. The secondary outcome was an update of clinical results from our previous series. Data were complemented by descriptive statistical analysis and univariable and multivariable proportional hazards Cox regression. Results and limitations Overall, 167 patients were included. Of 181 AS events, 61 (33.7%) were deemed to require treatment because of positive cytology (n = 10), gross haematuria (n = 11), and increases in the tumour number (n = 15), or size (n = 17), or both (n = 8). The median time on AS was 12 mo (interquartile range 4–26). Pathological specimens from AS failures did not show any malignancy in 20 cases. Histopathology identified urothelial hyperplasia and oedema, submucosal vascular ectasia, mucosal erosion, polypoid cystitis, von Brunn nest hyperplasia, and squamous metaplasia. The time from first transurethral resection to AS start was inversely associated with recurrence-free survival (hazard ratio 0.97, 95% confidence interval 0.96–1.00; p = 0.024). The study lacks statistical subanalyses focusing on patients with failure and negative neoplastic pathological outcomes. Conclusions AS might be a reasonable strategy in patients presenting with small LG pTa/pT1a recurrent bladder tumours. Approximately 30% of patients deemed to have AS failure did not harbour any neoplastic lesion, strengthening the role of AS. Patient summary Patients with small low-grade pTa/pT1a recurrent papillary bladder tumours could benefit from an active surveillance protocol with no significant risk of pathological progression to muscle-invasive cancer.

Background: Alzheimer’s disease (AD) is a form of dementia characterized by failure of memory that becomes more severe with the progression of the disease. The Free and Cued Selective Reminding Test (FCSRT) is a clinical test used to evaluate such a deficit. However, since the cognitive performances could depend also on the psychophysiological state of the individual, it is important to monitor that state through the peripheral autonomic activity during the execution of the test. Thermal infrared imaging has been used for this kind of assessment in order to preserve the free and unbiased interaction between doctor and patient, thanks to the contactless features of the technique. Objective: To investigate whether the variation of facial temperature parameters during the FCSRT is indicative of different autonomic states in the early AD with respect to healthy controls (HC). Results: At a group level, a greater sympathetic activity for the HC with respect to AD during the execution of the test was found, indicative of a suppression of anxiety associated with the performances of the FCSRT in AD patients. Conclusion: These results indicate that AD and HC may present different autonomic activity associated with the execution of a cognitive task, thus suggesting a different modulation of high-cognition and emotion network.

Preformed anti-human leukocyte antigen (HLA) antibodies may be present in the blood of kidney transplant candidates. The production of these antibodies may occur in the post-transplant period, with the possible development of donor-specific antibodies (DSA). Luminex-based tests, such as the single antigen (SA) assay and the Luminex crossmatch (Xm-DSA) assay are the most commonly used tools to detect anti-HLA antibodies, due to their high sensitivity and specificity. This cross-sectional study aimed to compare the findings of two methods for the detection of DSAs after kidney transplant: SA and Xm-DSA. A total of 122 patients who underwent deceased donor kidney transplant at Hospital de Clínicas de Porto Alegre were included. The SA assay detected anti-class I HLA DSAs in 17 patients (13.9%) and anti-class II HLA DSAs in 22 patients (19.6%), whereas the Xm-DSA detected DSAs in 18 patients (14.8%) both against class I and class II antigens. There was agreement between the two methods for class I (kappa = 0.66, p = 0.001) and class II (kappa = 0.54, p = 0.025) antigens. The incidence of DSAs as obtained by the SA assay was 15.57%, and the most prevalent DSAs were those against HLA-DR antigens. Patient survival at 3 years was 92%. The two techniques assessed in this study provide important information on the presence of DSAs and may help in the post-transplant patient monitoring and in immunosuppressive strategy.

Background Chemotherapy-induced alopecia (CIA) ranks among the psychologically most devastating effects of cancer treatment for oncological patients, with an overall incidence of 65%. Nowadays trichoscopy is largely employed in the diagnosis of alopecia, but no description of CIA trichoscopic pattern is present in literature. Aims We want to create an organic description of CIA trichoscopic aspects. Methods Oncological patients candidate to chemotherapy drugs, afferent to our trichological outpatient were studied. Anamnesis, clinical exam, clinical global photography, pull test, trichogram, and trichoscopy were conducted at the different moments of therapeutic treatment. Results A definite trichoscopic pattern in the different phases of treatment was observed. After the first 3 weeks of chemotherapy rare and scattered black dots, broken hairs, flame hairs and pohl pinkus appeared. At the end of chemotherapy besides the features described above, numerous thin hair in regrowth were detected, together to rare terminal hair, scattered black dots and circle hair. Three months after chemotherapy a progressive increase of follicular units and elongation of the existing hair were visible. Conclusions We propose an description of CIA trichoscopic pattern and its evolution during the different phases of chemotherapy.

The diuretic response has been shown to be a robust independent marker of cardiovascular outcomes in acute heart failure (ADHF) patients. The objectives of this clinical research, will aim are to: a) include diuresis in the formula for diuretic response (R-to-D); b) add to R-to-D the value of a pre-discharged determination of galectin-3 and BNP in predicting mid-term clinical outcome.Consecutive patients discharged alive after an ADHF were enrolled. All patients underwent BNP and galectin-3, a 6 min walk test and an echocardiogram together with diuresis and body weight during diuretic administration. Death by any cause, cardiac transplantation and worsening HF requiring readmission to the hospital were considered cardiovascular events.141 patients (98 males, age 73.8) were analysed (follow-up 17 months). During the follow-up 45 (31.9%) events were scheduled (19 cardiac deaths, 26 re-hospitalisation for HF). Patients who experienced CV-event had a worst renal function (p = 0.003), an higher BNP (p = 0.006) and galectin-3 (p = 0.008). At multivariate analysis, only R-to-D, galectin-3 and BNP showed a significant correlation with worst clinical prognosis (respectively p = 0.043; OR 6.01; p = 0.01; OR 8.9; p = 0.02 OR 10.38), independently of age and renal function. Kaplan-Meier curves depicted a powerful stratification using an R-to-D1.2 kg/40 mg furosemide (log rank 10.96; p = 0.0009). Adding R-to-D1.2 mg/40 mg furosemide to galectin-317.6 pg/mL and BNP500 pg/mL the predictive value improved (log rank 23.59; p = 0.0001).Adding R-to-D to Gal-3 and BNP, a single pre-discharge strategy testing seemed to obtain a satisfactorily predictive value in alive HF patients discharged after an ADHF episode.

OBJECTIVE: Measures of rapid automatized naming (RAN) have been used for over 50 years to capture vision-based aspects of cognition. The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation for detection of concussion and other neurological disorders. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. Recent changes to the MULES test have been made to improve ease of use on the athletic sidelines. Originally an 11 × 17-inch single-sided paper, the test has been reduced to a laminated 8.5 × 11-inch double-sided version. We identified performance changes associated with transition to the new, MULES, now sized for the sidelines, and examined MULES on the sideline for sports-related concussion. METHODS: We administered the new laminated MULES to a group of adult office volunteers as well as youth and collegiate athletes during pre-season baseline testing. Athletes with concussion underwent sideline testing after injury. Time scores for the new laminated MULES were compared to those for the larger version (big MULES). Results: Among 501 athletes and office volunteers (age 16 ± 7 years, range 6–59, 29% female), average test times at baseline were 44.4 ± 14.4 s for the new laminated MULES (n = 196) and 46.5 ± 16.3 s for big MULES (n = 248). Both versions were completed by 57 participants, with excellent agreement (p < 0.001, linear regression, accounting for age). Age was a predictor of test times for both MULES versions, with longer times noted for younger participants (p < 0.001). Among 6 athletes with concussion thus far during the fall sports season (median age 15 years, range 11–21) all showed worsening of MULES scores from pre-season baseline (median 4.0 s, range 2.1–16.4). CONCLUSION: The MULES test has been converted to an 11 × 8.5-inch laminated version, with excellent agreement between versions across age groups. Feasibly administered at pre-season and in an office setting, the MULES test shows preliminary evidence of capacity to identify athletes with sports-related concussion.

Metastatic colorectal cancer; RAS analysis; Prognostic biomarker Cáncer colorrectal en metástasis; Análisis RAS; Biomarcador como pronóstico Càncer colorectal en metàstasi; Anàlisi RAS; Biomarcador com a pronòstic Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS‐mutant allele fraction (MAF) in plasma in mCRC. Forty‐seven plasma samples from 37 RAS‐mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first‐ and/or second‐line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19‐9 levels, primary site location, and treatment line) and clinical outcome [progression‐free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI‐GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first‐line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease (P = 0.007). Patients with low MAFs at baseline in the CAPRI‐GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5–9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07–5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice. This work was supported partially by the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) and `Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa' grants [FIS PI12-01589 to RS] and RETICC Cancer.

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1–G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4–10.8; vs. 12.3 months; CI 95%, 10.4–14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

Sialadenitis by iodinated contrast medium (i.c.m) oriodine mumps (IM) is a rare and late benign manifestation that occurs independently of intravenous or endoarterial administration modality. If renal function is normal, i.c.m. does not reach salivary glands concentrations able to induce sialadenitis. However, a critical glomerular filtration reduction may lead to salivary ducts edema and glandular swelling after i.c.m. injection. We report a rare case report of IM in a patient on chronic hemodialysis.A 72-year-old woman affected by chronic kidney disease on chronic hemodialysis, underwent to endoscopic removal of a rectal cancer. For disease staging, a total body TC with i.c.m. was performed. The following morning, patient showed a soft and aching bilateral paroditidis swelling. Salivary glands ultrasound was diagnostic for sialadenitis. The patient was rapidly treated with betamethasone following by a 240 minutes post-dilution online hemodiafiltration session.Within the next 24h, a complete remission of IM was obtained.In our patient, a compensatory hyperactivity of the sodium / iodine symporter (NIS) on salivary gland cells may have played a crucial role in IM induction. An high efficiency hemodialysis session within the few following hours after i.c.m injection is a fundamental tool in patients on renal replacement treatment to prevent IM that is an epiphenomenon of i.c.m. accumulation.

Aim: Regorafenib induces radiological changes in liver metastasis among patients with metastatic colorectal cancer (mCRC). The standard criteria used to evaluate solid tumor response (Response Evaluation Criteria in Solid Tumors) may be limited in assessing response to biologic agents with anti-angiogenic action. Patients & methods: A total of 67 hepatic lesions in 32 selected patients were analyzed to evaluate tumor attenuation as measured by Hounsfield unit (HU) and size changes. Results: Following two cycles of regorafenib, tumor HU values decreased in the in 73.1% (49/67) of lesions (average HU changes -25.6%) while tumor size increased in 64.2% (43/67) of them (average size changes +25.4%). Conclusion: The computed tomography density changes evaluation may be an additional tool, in combination with tumor sizing, to evaluate tumor response in patients treated with regorafenib.

Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa−/− satellite cells to regenerate muscle damage. Gaa−/− mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa−/− muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa−/− mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa−/− animals. Surprisingly, both young and old Gaa−/− mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa−/− mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa−/− mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa−/− mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa−/− satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease. Electronic supplementary material The online version of this article (10.1186/s40478-018-0620-3) contains supplementary material, which is available to authorized users.

SUMMARY: LRP5 loss-of-function mutations have been shown to cause profound osteoporosis and have been associated with impaired insulin sensitivity and dysregulated lipid metabolism. We hypothesized that gain-of-function mutations in LRP5 would also affect these parameters. We therefore studied individuals with LRP5 gain-of-function mutations exhibiting high bone mass (HBM) phenotypes and found that while there was no detected change in insulin sensitivity, there was a significant reduction in serum LDL. INTRODUCTION: Wnt signaling through LRP5 represents a newly appreciated metabolic pathway, which potentially represents a target for drug discovery in type 2 diabetes and hyperlipidemia. Studies in animal models suggest a physiologic link between LRP5 and glucose and lipid homeostasis; however, whether it plays a similar role in humans is unclear. As current literature links loss-of-function LRP5 to impaired glucose and lipid metabolism, we hypothesized that individuals with an HBM-causing mutation in LRP5 would exhibit improved glucose and lipid homeostasis. Since studies in animal models have suggested that Wnt signaling augments insulin secretion, we also examined the effect of Wnt signaling on glucose-stimulated insulin secretion on human pancreatic islets. METHODS: This was a matched case-control study. We used several methods to assess glucose and lipid metabolism in 11 individuals with HBM-causing mutations in LRP5. Affected study participants were recruited from previously identified kindreds with HBM-causing LRP5 mutations and included 9 males and 2 females. Two subjects that were being treated with insulin for type 2 diabetes were excluded from our analysis, as this would have obscured our ability to determine the impact of gain-of-function LRP5 mutations on glucose metabolism. The mean age of the evaluated study subjects was 55 ± 7 with a mean BMI of 27.2 ± 2.0. Control subjects were matched and recruited from the general community at an equivalent ratio, with 18 males and 4 females (mean age 56 ± 4; mean BMI 27.2 ± 1.0). Study testing was conducted at an academic medical center. RESULTS: There were no statistically significant differences between affected and matched control populations for HbA1c (p = 0.06), eAG (p = 0.06), insulin (p = 0.82), HOMA-B (p = 0.34), or HOMA-IR (p = 0.66). The mean Insulin Sensitivity Index (ISI) was also similar between control and affected individuals. Total cholesterol (p = 0.43), triglycerides (TG) (p = 0.56), and HDL (p = 0.32) were not different between the same two groups. In a small subset of studied subjects, intramyocellular and hepatic lipid content were similar in the affected individuals and controls when quantified by proton magnetic resonance spectroscopy (MRS). However, the mean value for serum LDL was significantly lower (p = 0.04) in affected individuals. In primary human islets, there were no differences between control and Wnt treatment groups for insulin secretion measured as area under the curve (AUC) for first phase (p = 0.17) or second phase (p = 0.33) insulin secretion. CONCLUSIONS: Although our sample size was small, our data do not support the hypothesis that HBM-causing LRP5 mutations, associated with increased Wnt signaling, improve glucose metabolism in humans. However, it does appear that LRP5 variants may affect LDL metabolism, a major risk factor for coronary artery disease. The molecular mechanisms underpinning this effect warrant further study.

Introduction Re-emergent tremor (RET) is a postural tremor that appears after a variable delay in patients with Parkinson's disease (PD). The aim of the present study was to evaluate the occurrence and the clinical characteristics of RET in a population of patients with PD. Methods We consecutively assessed 210 patients with PD. We collected the patients' demographic and clinical data. RET was clinically characterized in terms of latency, severity and body side affected. We also investigated a possible relationship with motor and non-motor symptoms and differences in the clinical features in patients with and without RET. Results RET was present in 42/210 patients. The mean latency of RET was 9.20 ± 6.8 seconds. Mean severity was 2.4 ± 1.9. RET was unilateral in 21 patients. Patients with RET had less severe speech, posture and gait disorders and upper limb and global bradykinesia than patients without RET. Similar findings were observed when we compared patients with RET with patients with tremor at rest associated with action tremor, patients with isolated action tremor and patients with no tremor. By contrast, patients with RET tremor did not clinically differ from those with isolated tremor at rest. Conclusion Our results suggest that patients with RET and patients with isolated tremor at rest represent the same clinical subtype, whereas patients with action tremor (whether isolated or associated with tremor at rest) might belong to a distinct subtype that is clinically worse. Patients with RET represents a benign subtype of PD, even within the tremor-dominant phenotype.

Background Previous studies showed that troponin blood levels may increase after exercise. In this study we assessed whether, among patients admitted with suspected unstable angina, the increase in high-sensitive troponin T (hs-TnT) levels after exercise stress test (EST) might help identify those with obstructive coronary artery disease (CAD) and predict symptom recurrence during short term follow-up. Methods Maximal treadmill EST was performed in 69 consecutive patients admitted to the emergency room with a suspicion of unstable angina (acute chest pain but confirmed normal serum levels of cardiac troponins) was measured before and 4 hours after EST. Coronary angiography was performed in 22 patients (32.8%). Results hs-TnT increased after EST compared to baseline in the whole population (from 0.84±0.65 to 1.17±0.87 ng/dL, p

With the European Parliament elections having taken place in May 2019 and a new European Commission (EC) taking office in November 2019, this year is critical for European policymakers, as goals and priorities of the European Union (EU) for the next five years will be discussed and agreed upon. This Manifesto issued by the Transforming Breast Cancer Together initiative calls upon policymakers to improve services for patients in an area still of high unmet need and reduce the societal impact of breast cancer by elevating it as a health policy priority to improve breast cancer prevention, diagnosis and care across Europe.

Acute uncomplicated diverticulitis (AUD) is an inflammation of the colon diverticulum. We tested the efficacy of Lactobacillus reuteri 4659 (L. reuteri) in treating AUD. Primary outcome was reduced abdominal pain and inflammatory markers (C-RP). Secondary outcome was reduced hours of hospitalization. A double-blind, placebo RCT was conducted with 88 (34M/54F mean age 61.9 ± 13.9) patients with a diagnosis of AUD. Group A (44 patients, 26F): ciprofloxacin 400 mg/bid and metronidazole 500 mg/tid for 1 week, plus L. reuteri/bid for 10 days. Group B (44 patients, 28F): same antibiotic therapy for 1 week, plus placebo/bid for 10 days. All patients completed a daily visual analog scale (VAS) for abdominal pain. Between days 1 and 3, the group A pain decreased by 4.5 points; group B decreased by 2.36 points (p

According to embodied simulation theories, others’ emotions are recognized by the unconscious mimicking of observed facial expressions, which requires the implicit activation of the motor programs that produce a specific expression. Motor responses performed during the expression of a given emotion are hypothesized to be directly linked to autonomic responses associated with that emotional behavior. We tested this hypothesis in 9 children (Mage=5.66) affected by Moebius syndrome (MBS) and 15 control children (Mage=6.6). MBS is a neurological congenital disorder characterized by underdevelopment of the VI and VII cranial nerves, which results in paralysis of the face. Moebius patients’ inability to produce facial expressions impairs their capacity to communicate emotions through the face. We therefore assessed Moebius children’s autonomic response to emotional stimuli (video cartoons) by means of functional infrared thermal (fIRT) imaging. Patients showed weaker temperature changes compared to controls, suggesting impaired autonomic activity. They also showed difficulties in recognizing facial emotions from static illustrations. These findings reveal that the impairment of facial movement attenuates the intensity of emotional experience, probably through the diminished activation of autonomic responses associated with emotional stimuli. The current study is the first to investigate emotional responses in MBS children, providing important insights into the role of facial expressions in emotional processing during early development.

The Mobile Universal Lexicon Evaluation System (MULES) is a test of rapid picture naming under investigation. Measures of rapid automatic naming (RAN) have been used for over 50 years to capture aspects of vision and cognition. MULES was designed as a series of 54 grouped color photographs (fruits, random objects, animals) that integrates saccades, color perception and contextual object identification. We examined MULES performance in youth, collegiate and professional athletes at pre-season baseline and at the sidelines following concussion.Our study teams administered the MULES to youth, collegiate and professional athletes during pre-season baseline testing. Sideline post-concussion time scores were compared to pre-season baseline scores among athletes with concussion to determine degrees and directions of change.Among 681 athletes (age 17 ± 4 years, range 6-37, 38% female), average test times at baseline were 41.2 ± 11.2 s. The group included 280 youth, 357 collegiate and 44 professional athletes; the most common sports were ice hockey (23%), soccer (17%) and football (11%). Age was a predictor of MULES test times, with longer times noted for younger participants (P .001, linear regression). Consistent with other timed performance measures, significant learning effects were noted for the MULES during baseline testing with trial 1 test times (mean 49.2 ± 13.1 s) exceeding those for trial 2 (mean 41.3 ± 11.2 s, P .0001, paired t-test). Among 17 athletes with concussion during the sports seasons captured to date (age 18 ± 3 years), all showed increases (worsening) of MULES time scores from pre-season baseline (median increase 11.2 s, range 0.6-164.2, P = .0003, Wilcoxon signed-rank test). The Symptom Severity Score from the SCAT5 Symptom Evaluation likewise worsened from pre-season baseline following injury among participants with concussion (P = .002).Concussed athletes demonstrate worsening performance on the MULES test compared to their baseline time scores. This test samples a wide network of brain pathways and complements other vision-based measures for sideline concussion assessment. The MULES test demonstrates capacity to identify athletes with sports-related concussion.

Objective Alzheimer's disease (AD) is characterized by progressive memory failures and visuospatial impairment. Moreover, AD can be accompanied by autonomic system alterations, which, among other impacts, affect thermoregulatory activity. We here investigate differences in autonomic activity between AD patients and healthy controls (HC), employing a complexity analysis of functional infrared imaging (fIRI) data acquired at rest and during the execution of clinical cognitive and mnemonic tests. Approach fIRI allows for contactless monitoring of autonomic activity and its thermoregulatory expression without interfering with the psychophysiological state of the subject, preserving free interaction with the doctor. The signal complexity analysis, based on the sample entropy, was compared to a standard frequency-based analysis of autonomic-related signals. Main results AD patients exhibited lower complexity of fIRI signals during the tests, which could be indicative of a stronger sympathetic activity with respect to HC. No significant effects were found at rest. No differences were found on employing frequency-based analysis. Significance This study confirms that AD patients may exhibit peculiar autonomic responses associated with the execution of cognitive tasks that can be measured through fIRI. Moreover, these responses could be highlighted by a nonlinear metric of signal predictability such as the sample entropy establishing autonomic impairment of AD patients.