Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course

Background The pathophysiological origin of juvenile idiopathic arthritis (JIA) is largely unknown. However, individuals with presumably pathogenic mutations in FAMIN have been reported, associating this gene with a rare subtype of this disorder. FAMIN, that is formerly also referred to as LACC1 or C13orf31, has recently been shown to play a crucial role in immune-metabolic functions and is involved in regulation of inflammasome activation and promotion of ROS production. Case presentation We describe two siblings with severe familial forms of juvenile arthritis in which whole-exome-sequencing revealed a novel homozygous frameshift mutation (NM_153218.2:c.827delC¸. p.(T276fs*2) in FAMIN. Conclusions The observation of a new deleterious mutation adds further evidence that pathogenic mutations in FAMIN are causal for a monogenic form of JIA. Furthermore the associated phenotype is not restricted to systemic JIA, but can also be found in other forms of familial juvenile arthritis

Professional quality of life and burnout amongst radiation oncologists:The impact of alexithymia and empathy

Background and purpose: Different factors may influence the professional quality of life of oncology professionals. Among them, personality traits, as alexithymia and empathy, are underinvestigated. Alexithymia is about deficits in emotion processing and awareness. Empathy is the ability to understand another's 'state of mind'/emotion. The PROject on BurnOut in RadiatioN Oncology (PRO BONO) assesses professional quality of life, including burnout, in the field of radiation oncology and investigates alexithymia and empathy as contributing factors. Material and methods: An online survey was conducted amongst ESTRO members. Participants completed 3 validated questionnaires for alexithymia, empathy and professional quality of life: (a) Toronto Alexithymia Scale; (b) Interpersonal Reactivity Index; (c) Professional Quality of Life Scale. The present analysis, focusing on radiation/clinical oncologists, evaluates Compassion Satisfaction (CS), Secondary Traumatic Stress (STS) and Burnout and correlates them with alexithymia and empathy (empathic concern, perspective taking and personal distress) with generalized linear modeling. Significant covariates on univariate linear regression analysis were included in the multivariate linear regression model. Results: A total of 825 radiation oncologists completed all questionnaires. A higher level of alexithymia was associated to decreased CS (beta:-0.101; SE: 0.018; p <0.001), increased STS (beta: 0.228; SE: 0.018; p <0.001) and burnout (beta: 0.177; SE: 0.016; p <0.001). A higher empathic concern was significantly associated to increased CS (beta: 0.1.287; SE: 0.305; p = 0.001), STS (beta: 0.114; SE: 0.296; p <0.001), with no effect on burnout. Personal distress was associated to decreased CS (beta:-1.423; SE: 0.275; p <0.001), increased STS (beta: 1.871; SE: 0.283; p <0.001) and burnout (beta: 1.504; SE: 0.245; p <0.001). Conclusions: Alexithymic personality trait increased burnout risk, with less professional satisfaction. Empathic concern was associated to increased stress, without leading to burnout, resulting in higher professional fulfillment. These results may be used to benchmark preventing strategies, such as work-hour restrictions, peer support, debriefing sessions, and leadership initiatives for professionals at risk. (c) 2020 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 147 (2020) 162-16

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

BACKGROUND Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. METHODS Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). RESULTS As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. In all patients, the 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with Grade 3-4 in 3 patients. No new safety signals were identified. CONCLUSIONS In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile

PET imaging of hypoxia using [F-18]HX4: a phase I trial

 Download the images using these instructions and this DOI : 10.1007/s00259-010-1437-x Background and purposeNon-invasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [18F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging.MethodsPatients with a..

Molecular analysis of NKX2-1 in patients with congenital hypothyroidism and associated choreathethosis

Das NKX2-1 Gen kodiert für einen Transkriptionsfaktor, der eine wichtige Rolle in der Organogenese von ZNS, Schilddrüse und Lunge spielt. Mutationen führen zu einer Malformation und damit Dysfunktion der entsprechenden Organe. Mit der vorliegenden Arbeit wurden im bisher größten kohärenten Kollektiv Patienten mit suspektem Phänotyp systematisch hinsichtlich Mutationsfrequenz und –qualität, sowie des phänotypischen Spektrums von NKX2-1 Mutationen untersucht. Mittels Sanger Sequenzierung und arraybasierter comparativer genomischer Hybridisierung (Array CGH) wurden Veränderungen des Gens bzw der genomischen Region identifiziert. Im weiteren wurden die Mutationen mittels EMSA und Mini Gene Reporter Assay funktionell charakterisiert, sowie außerdem Expressionsanalysen embryonaler Mausgewebe von NKX2-1 als auch des genomisch benachbart liegenden MBIP durchgeführt. In 101 untersuchten Patienten konnten 17 heterozygote Punktmutationen und 10 heterozygote Deletionen identifiziert werden. Neurologische Symptome, meist in Form einer Choreathetose, fanden sich bei allen Patienten (100%), diese war interindividuell unterschiedlich kombiniert mit pulmonaler Affektion (78%) und Schilddrüsendysfunktion (75%). Es wurden außerdem bisher nicht in Zusammenhang mit NKX2-1 Mutationen beschriebene Symptome wie verändertes Längenwachstum, unklare Fieberepisoden und Herzseptumdefekte nachgewiesen. Zudem ergaben sich Hinweise, dass eine nur verminderte DNA-Bindungskapazität bei einer der nachgewiesenen Mutationen einen milderen Phänotyp verursacht. Zwei heterozygote Deletionen hingegen betrafen nicht NKX2-1 selbst, sondern MBIP, welches - durch die gezeigte räumliche und zeitliche Koexpression in Mausembryonen - möglicherweise eine Rolle in der Entwicklung der betroffenen Organsysteme spielt. Die hohe Inzidenz von NKX2-1 Mutationen in der untersuchten Kohorte legt eine routinemäßige Untersuchung von Patienten mit korrespondierenden Symptomen nahe. Jedoch sollte eine Analyse sich nicht auf die primäre Gensequenz beschränken, sondern vielmehr - unter Verwendung von „Next Generation Sequencing“ (NGS)-Technologien - auch die umliegende genomische Region und mögliche regulatorische Sequenzen miteinbeziehen.NKX2-1 encodes a transcription factor with large impact on the development of brain, lung and thyroid. Germline mutations of NKX2-1 can lead to dysfunction and malformations of these organs. Starting from the largest coherent collection of patients with a suspected phenotype to date, we systematically evaluated frequency, quality and spectrum of phenotypic consequences of NKX2-1 mutations. After identifying mutations by Sanger sequencing and array CGH, we comprehensively reanalysed the phenotype of affected patients and their relatives. We employed electrophoretic mobility shift assay (EMSA) to detect alterations of NKX2-1 DNA binding. Gene expression was monitored by means of in situ hybridisation and compared with the expression level of MBIP, a candidate gene presumably involved in the disorders and closely located in close genomic proximity to NKX2-1. Within 101 index patients, we detected 17 point mutations and 10 deletions. Neurological symptoms were the most consistent finding (100%), followed by lung affection (78%) and thyroidal dysfunction (75%). Novel symptoms associated with NKX2-1 mutations comprise abnormal height, bouts of fever and cardiac septum defects. In contrast to previous reports, our data suggest that missense mutations in the homeodomain of NKX2-1 not necessarily modify its DNA binding capacity and that this specific type of mutations may be associated with mild pulmonary phenotypes such as asthma. Two deletions did not include NKX2-1, but MBIP, whose expression spatially and temporarily coincides with NKX2-1 in early murine development. The high incidence of NKX2-1 mutations strongly recommends the routine screen for mutations in patients with corresponding symptoms. However, this analysis should not be confined to the exonic sequence alone, but should take advantage of affordable NGS technology to expand the target to adjacent regulatory sequences and the NKX2-1 interactome in order to maximise the yield of this diagnostic effort

The role of alexithymia and empathy on radiation therapists' professional quality of life.

Background and purpose Physical and mental well-being are crucial for oncology professionals as they affect performance at work. Personality traits, as alexithymia and empathy, may influence professional quality of life. Alexithymia involves diminished skills in emotion processing and awareness. Empathy is pertinent to the ability to understand another's 'state of mind/emotion'. The PROject on Burn-Out in RadiatioN Oncology (PRO BONO) investigates professional quality of life amongst radiation oncology professionals, exploring the role of alexithymia and empathy. The present study reports on data pertinent to radiation therapists (RTTs). Material and methods An online survey targeted ESTRO members. Participants were asked to fill out 3 questionnaires for alexithymia, empathy and professional quality of life: (a) Toronto Alexithymia Scale (TAS-20); (b) Interpersonal Reactivity Index (IRI); (c) Professional Quality of Life Scale (ProQoL). The present analysis focuses on RTTS to evaluate compassion satisfaction (CS), secondary traumatic stress (STS) and Burnout and their correlation with alexithymia and empathy, using generalized linear modeling. Covariates found significant at univariate linear regression analysis were included in the multivariate linear regression model. Results A total of 399 RTTs completed all questionnaires. The final model for the burnout scale of ProQoL found, as significal predictors, the TAS-20 total score (β = 0.46, p < 0 0.001), and the individual's perception of being valued by supervisor (β = -0.29, p < 0.001). With respect to CS, the final model included TAS-20 total score (β = -0.33, p < 0.001), the Empatic Concern domain (β = 0.23, p < 0.001) of the IRI questionnaire and the individual's perception of being valued by colleagues (β = 0.22, p < 0.001). Conclusions Alexithymia increased the likelyhood to experience burnout and negatively affected the professional quality of life amongst RTTs working in oncology. Empathy resulted in higher professional fulfillment together with collegaues' appreciation. These results may be used to benchmark preventing strategies and implement organization-direct and/or individual-directed interventions

Molecular tumor therapy: phase I/II network structure of the Society for Pediatric Oncology and Hematology in Germany

Background To enable the rapid and efficient implementation of early clinical trials for pediatric patients and provide comprehensive access to novel treatment options for pediatric relapse or high-risk patients, five regional phase I/II trial networks have been established under the auspices of the Society for Pediatric Oncology and Hematology (GPOH). The network structure secures, bundles and organizes required competencies and resources and has established processes to optimize operational trial efficiency. The INFORM study is a population-based molecular diagnostic study for children and adolescents with recurrent cancer in Germany and 11 other countries. Preliminary data show that precision medicine in pediatric oncology is possible in an international multicenter setting, provides clinical benefit for subgroups of patients and helps to identify hereditary predispositions, to refine diagnoses and to match patients in suitable phase I/II clinical trials. Conclusions The portfolio of innovative biomarker driven phase I/II clinical trials for children and adolescents with recurrent tumor diseases in Germany is currently limited. Therefore, the development of innovative, targeted therapy concepts and combination therapies is an important task in the coming years

Forecasting the effect of the change in timing of the ABR diagnostic radiology examinations: results of the ACR survey of practice leaders

The results of a survey sent to practice leaders in the ACR Practice of Radiology Environment Database show that the majority of responding groups will continue to hire recently trained residents and fellows even though they have been unable to take the final ABR diagnostic radiology certifying examination. However, a significant minority of private practice groups will not hire these individuals. The majority of private practices expect the timing change for the ABR certifying examinations to affect their groups' function. In contrast, the majority of academic medical school practices expect little or no impact. Residents and fellows should not expect work time off or protected time to study for the certifying examination or for their maintenance of certification examinations in the future