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A bstract Future dark matter (DM) direct detection searches will be subject to irreducible neutrino backgrounds that will challenge the identification of an actual WIMP signal in experiments without directionality sensitivity. We study the impact of neutrino-quark non-standard interactions (NSI) on this background, assuming the constraints from neutrino oscillations and the recent COHERENT experiment data, which are relevant for NSI mediated by light mediators, m m e d ≲ O GeV . We calculate the expected number of neutrino-nucleus elastic scattering events in a Xe-based ton-size dark matter detector, including solar neutrino fluxes from the pp chain and CNO cycle as well as sub-GeV atmospheric fluxes and taking into account NSI effects in both propagation and detection. We find that sizable deviations from the standard model expectation are possible, but are more pronounced for flavor-diagonal couplings, in particular for electron neutrinos. We show that neutrino NSI can enhance or deplete the neutrino-nucleus event rate, which may impact DM searches in multi-ton detectors.

Introduction The incidence of gastrointestinal (GI) cancer is rising and most patients with GI malignancies are discussed by a multidisciplinary team (MDT). We performed a systematic review to assess whether MDTs for patients with GI malignancies can correctly change diagnosis, tumor stage and subsequent treatment plan, and whether the treatment plan was implemented. Methods We performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We conducted a search of the PubMed, MEDLINE and EMBASE electronic databases, and included studies relating to adults with a GI malignancy discussed by an MDT prior to the start of treatment which described a change of initial diagnosis, stage or treatment plan. Two researchers independently evaluated all retrieved titles and abstracts from the abovementioned databases. Results Overall, 16 studies were included; the study quality was rated as fair. Four studies reported that MDTs changed the diagnoses formulated by individual physicians in 18.4–26.9% of evaluated cases; two studies reported that MDTs formulated an accurate diagnosis in 89 and 93.5% of evaluated cases, respectively; nine studies described that the treatment plan was altered in 23.0–41.7% of evaluated cases; and four studies found that MDT decisions were implemented in 90–100% of evaluated cases. The reasons for altering a treatment plan included the patient’s wishes, and comorbidities. Conclusions MDT meetings for patients with a GI malignancy are responsible for changes in diagnoses and management in a significant number of patients. Treatment plans formulated by MDTs are implemented in 90–100% of discussed patients. All patients with a GI malignancy should be discussed by an MDT.

Despite their indisputable importance in neuroblastoma (NB) pathology, knowledge of the bases of NB plasticity and heterogeneity remains incomplete. They may be rooted in developmental trajectories of their lineage of origin, the sympatho-adrenal neural crest. We find that implanting human NB cells in the neural crest of the avian embryo allows recapitulating the metastatic sequence until bone marrow involvement. Using deep single cell RNA sequencing, we characterize transcriptome states of NB cells and their dynamics over time and space, and compare them to those of fetal sympatho-adrenal tissues and patient tumors and bone marrow samples. Here we report remarkable transcriptomic proximities restricted to an early sympathetic neuroblast branch that co-exist with phenotypical adaptations over disease progression and recapitulate intratumor and interpatient heterogeneity. Combining avian and patient datasets, we identify a list of genes upregulated during bone marrow involvement and associated with growth dependency, validating the relevance of our multimodal approach. The roots of neuroblastoma plasticity and heterogeneity remain poorly understood. Here, the authors characterise the transcriptional states of neuroblastoma cells and their changes throughout development using avian embryo models, single-cell RNA-sequencing, and patient samples; they find transcriptomic changes related to early sympatho-adrenal development.

A bstract The existence of Dark Matter (DM) in the form of Strongly Interacting Massive Particles (SIMPs) may be motivated by astrophysical observations that challenge the classical Cold DM scenario. Other observations greatly constrain, but do not completely exclude, the SIMP alternative. The signature of SIMPs at the LHC may consist of neutral, hadron-like, trackless jets produced in pairs. We show that the absence of charged content can provide a very efficient tool to suppress dijet backgrounds at the LHC, thus enhancing the sensitivity to a potential SIMP signal. We illustrate this using a simplified SIMP model and present a detailed feasibility study based on simulations, including a dedicated detector response parametrization. We evaluate the expected sensitivity to various signal scenarios and tentatively consider the exclusion limits on the SIMP elastic cross section with nucleons.

Background Bone marrow dissemination of tumor cells, common in various cancers, including neuroblastoma, is associated with poor outcome, necessitating sensitive detection methods for bone marrow minimal residual disease (MRD) and offer detection of biomarkers for therapy stratification. Current standard-of-care diagnostics, involving cytomorphological and histological assessment of bone marrow aspirates and trephine biopsies, lack sensitivity, leading to undetected MRD in many patients, and do not allow molecular biomarker assessment. Methods This study evaluates advanced multi-modal high-sensitivity MRD detection techniques in 509 bone marrow specimens from 108 high-risk neuroblastoma patients across two centers. We employed automatic immunofluorescence plus interphase fluorescence in situ hybridization (AIPF) and reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) panels to quantify disseminated tumor cells (DTCs), disialoganglioside 2 (GD2) and CD56/Neural cell adhesion molecule (NCAM) levels, and adrenergic (ADRN) and mesenchymal (MES)-phenotype mRNA markers. Results This multi-modal analysis significantly improved MRD detection compared to standard-of-care methods; 395 samples yielded results for RT-qPCR-ADRN, AIPF and CM/histology and 223 showed concordant results (64 positive, 159 negative). 114 samples did not produce results as either no cytospins were prepared ( n  = 96) or results were inconclusive (all techniques n  = 18). AIPF and RT-qPCR complemented each other in detecting MRD and characterizing ADRN- and MES-phenotypes and GD2 immunotherapy target. RT-qPCR-ADRN alone frequently detected low tumor cell burden. High DTC infiltration at diagnosis showed bilateral bone marrow disease, whereas MRD settings often involved only one side. RT-qPCR-MES, despite lower sensitivity, identified 37 additional cases and showed delayed clearance of MES markers post-chemotherapy, with increases prior to relapse. Conclusions Our findings demonstrate the feasibility of integrating high-sensitivity techniques with standard-of-care assessments in an international multicenter setting. Advanced multi-modal MRD detection, monitoring phenotype switches and assessing immunotherapy targets are crucial for improving patient outcomes in neuroblastoma and other cancers.

Background Liquid biopsies offer less burdensome sensitive disease monitoring. Bone marrow (BM) metastases, common in various cancers including neuroblastoma, is associated with poor outcomes. In pediatric high-risk neuroblastoma most patients initially respond to treatment, but in the majority the disease recurs with only 40% long-term survivors, stressing the need for more sensitive detection of disseminated disease during therapy. Methods To validate sensitive neuroblastoma mRNA RT-qPCR BM testing, we prospectively assessed serial BM samples from 345 international high‐risk neuroblastoma patients, treated in trials NB2004 (GPOH) or NBL2009 (DCOG), using PHOX2B , TH , DDC , CHRNA3 , and GAP43 RT-qPCR mRNA markers and BM GD2-immunocytology. Association between BM-infiltration levels and event-free survival (EFS) and overall survival (OS) was estimated by using Cox regression models and Kaplan-Meier’s methodology. Results BM infiltration >10% by RT-qPCR at diagnosis was prognostic for survival (adjusted hazard ratio (HR) 1.82 [95%CI 1.25‐2.63] and 2.04 [1.33‐3.14] for EFS and OS, respectively). Any post-induction RT-qPCR positivity correlated with poor EFS and OS, with a HR of 2.10 [1.27-3.49] and 1.76 [1.01-3.08] and 5-years EFS of 26.6% [standard error 5.2%] versus 60.4% [6.7] and OS of 43.8% [5.9] versus 65.7% [6.6] for RT-qPCR-positive patients versus RT-qPCR-negative patients. In contrast, post-induction immunocytology positivity was not associated with EFS or OS (HR 1.22 [0.68-2.19] and 1.26 [0.54-2.42]). Conclusion This study validates the association of not clearing of BM metastases by sensitive RT-qPCR detection with very poor outcome. We therefore propose implementation of RT-qPCR for minimal residual disease testing in neuroblastoma to guide therapy.

Background Multidisciplinary cancer team meetings are intended to optimize the diagnosis of a patient with a malignancy. The aim of this study was to assess the number of correct diagnoses formulated by the multidisciplinary team (MDT) and whether MDT decisions were implemented. Methods In a prospective study, data of consecutive patients discussed at gastrointestinal oncology MDT meetings were studied, and MDT diagnoses were validated with pathology or follow-up. Factors of influence on the correct diagnosis were identified by use of a Poisson regression model. Electronic patient records were used to assess whether MDT decisions were implemented, and reasons to deviate from these decisions were hand-searched within these records. Results In 74 MDT meetings, 551 patients were discussed a total of 691 times. The MDTs formulated a correct diagnosis for 515/551 patients (93.4 %), and for 120/551 (21.8 %) patients the MDT changed the referral diagnosis. Of the MDT diagnoses, 451/515 (87.6 %) were validated with pathology. Patients presented to the MDT by their treating physician were 20 % more likely to receive a correct diagnosis [relative risk (RR) 1.2, 95 % confidence interval (CI) 1.1–1.5], while the number of patients discussed or the duration of the meeting had no influence on this (RR 1.0, 95 % CI 0.99–1.0; RR 1.0, 95 % CI 0.9–1.1; resp.). MDT decisions were implemented in 94.4 % of cases. Deviations of MDT decisions occurred when a patient’s wishes or physical condition were not taken into account. Conclusions MDTs rectify 20 % of the referral diagnoses. The presence of the treating physician is the most important factor to ensure a correct diagnosis and adherence to the treatment plan.

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC), which is usually adult-onset. HLRCC-related RCC tends to be aggressive and can metastasize even when the primary tumor is small. Data on children and adolescents are scarce. Herein, we report two patients from unrelated Dutch families, with HLRCC-related RCC at the ages of 15 and 18 years, and a third patient with an FH mutation and complex renal cysts at the age of 13. Both RCC’s were localized and successfully resected, and careful MRI surveillance was initiated to monitor the renal cysts. One of the patients with RCC subsequently developed an ovarian Leydig cell tumor. A review of the literature identified 10 previously reported cases of HLRCC-related RCC in patients aged younger than 20 years, five of them presenting with metastatic disease. These data emphasize the importance of recognizing HLRCC in young patients to enable early detection of RCC, albeit rare. They support the recommendations from the 2014 consensus guideline, in which genetic testing for FH mutations, and renal MRI surveillance, is advised for HLRCC family members from the age of 8–10 years onwards.

The CMS detector, including its muon system, has been operating at the CERN LHC in increasingly challenging conditions for about 15 years. The muon detector was designed to provide excellent triggering and track reconstruction for muons produced in proton-proton collisons at an instantaneous luminosity ( [Formula omitted]) of [Formula omitted] cm [Formula omitted]s [Formula omitted]. During the Run 2 data-taking period (2015-2018), the LHC achieved an instantaneous luminosity of twice its design value, resulting in larger background rates and making the efficient detection of muons more difficult. While some backgrounds result from natural radioactivity, cosmic rays, and interactions of the circulating protons with residual gas in the beam pipe, the dominant source of background hits in the muon system arises from proton-proton interactions themselves. Charged hadrons leaving the calorimeters produce energy deposits in the muon chambers. In addition, high-energy particles interacting in the hadron calorimeter and forward shielding elements generate thermal neutrons, which leak out of the calorimeter and shielding structures, filling the CMS cavern. We describe the method used to measure the background rates in the various muon subsystems. These rates, in conjunction with simulations, can be used to estimate the expected backgrounds in the High-Luminosity LHC. This machine will run for at least 10 years starting in 2029 reaching an instantaneous luminosity of [Formula omitted] and increasing ultimately to [Formula omitted]. These background estimates have been a key ingredient for the planning and design of the muon detector upgrade.

Introduction Ototoxicity is an adverse effect of childhood cancer treatment with a negative impact on speech‐language development and quality of life. This study aimed to retrospectively assess ototoxicity monitoring in a national cohort of pediatric patients with solid tumors, examining the frequency and determinants associated with hearing loss (HL). Methods This retrospective cohort study included 305 patients treated between 2015 and 2020 at the Princess Máxima Center. Patients receiving platinum agents, head and neck radiotherapy, and/or ear‐nose‐throat surgery were analyzed. Electronic patient files provided demographic, clinical, and audiological data. HL was defined as Muenster ≥ 2b or SIOP ≥ 2 grade. Associations between clinical characteristics and HL occurrence were analyzed using logistic regression analysis. Results Audiological monitoring was performed at baseline (62.6%), during treatment (79.0%), and at the end of treatment (82.1%). Post treatment, 51.2% and 36.5% experienced Muenster and SIOP‐defined HL, respectively. Multivariable analyses revealed that age at diagnosis (OR 0.9, 95% CI 0.9–1.0), total cumulative dose cisplatin per 100 mg/m2 (OR 1.6, 95% CI 1.4–2.0), and vincristine treatment (OR 3.3, 95% CI 1.4–7.8) remained significantly associated with Muenster grade ≥ 2b HL. Age at diagnosis in years (OR 0.9, 95% CI 0.8–1.0), total cumulative dose cisplatin per 100 mg/m2 (OR 1.5, 95% CI 1.2–1.8), and male sex (OR 2.7, 95% CI 1.4–5.3) were associated with SIOP ≥ 2 HL. Conclusion This study shows that more than half of the children treated with ototoxic cancer therapies develop HL by the end of treatment. Therefore, audiological monitoring during and after treatment is essential. Improved insight into clinical determinants aids in identifying patients at high risk for HL, who may benefit from prevention strategies that are currently being implemented.