Quality of life in individuals with neurofibromatosis type 1 associated cutaneous neurofibromas: validation of the Dutch cNF-Skindex.

BACKGROUND: Almost all patients with Neurofibromatosis type 1 (NF1) develop cutaneous neurofibroma (cNF), benign dermal tumours that have a large impact on the patient's Quality of Life (QoL). The French cNF-Skindex is the first questionnaire to specifically assess cNF-related QoL in patients with NF1. We aimed to adapt and validate a Dutch version of the cNF-Skindex. METHODS: The questionnaire was translated using forward and backwards translation, and subsequently administered to a sample of 59 patients on two separate occasions. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating internal consistency and test-retest reliability, by calculating Cronbach's alpha and Spearman's rank correlation coefficients. The EQ-5D-5L and SF-36 were used to evaluate convergent validity, using Spearman's rank correlation coefficients. An exploratory factor analysis was performed to study the data's internal structure. Multivariable linear regression was used to model the relationship between patient characteristics and the cNF-Skindex. RESULTS: The Dutch cNF-Skindex demonstrated excellent feasibility and reliability (Cronbach's alpha 0.96, test-retest correlation coefficient 0.88). Convergent validity was confirmed for the EQ-5D-5L and relevant SF-36 scales. All items and subdomains from the original questionnaire were confirmed following exploratory factor analysis. The patient characteristics included in the multivariable linear regression were not significantly associated with the cNF-Skindex score. CONCLUSIONS: The Dutch cNF-Skindex displayed excellent psychometric properties, enabling use in the Netherlands.

Cognition and health-related quality of life in long-term survivors of high-grade glioma: an interactive perspective from patient and caregiver.

BACKGROUND: The health-related quality of life (HRQoL) and cognition are important indicators for the quality of survival in patients with high-grade glioma (HGG). However, data on long-term survivors and their caregivers are scarce. We aim to investigate the interaction between cognition and HRQoL in long-term survivors, their caregivers' evaluations, and the effect on caregiver strain and burden. METHODS: 21 long-term HGG (8 WHO grade III and 13 WHO grade IV) survivors (survival ≥ 5 years) and 15 caregivers were included. Cognition (verbal memory, attention, executive functioning, and language), HRQoL, anxiety and depression, caregiver strain, and caregiver burden were assessed with standardized measures. Questionnaires were completed by patients and/or their caregivers. RESULTS: Mean survival was 12 years (grade III) and 8 years (grade IV). Cognition was significantly impaired with a large individual variety. Patients' general HRQoL was not impaired but all functioning scales were deviant. Patient-proxy agreement was found in most HRQoL subscales. Three patients (14%) showed indications of anxiety or depression. One-third of the caregivers reported a high caregiver strain or a high burden. Test scores for attention, executive functioning, language, and/or verbal memory were correlated with perceived global health status, cognitive functioning, and/or communication deficits. Caregiver burden was not related to cognitive deficits. CONCLUSIONS: In long-term HGG survivors maintained HRQoL seems possible even when cognition is impaired in a large variety at the individual level. A tailored approach is therefore recommended to investigate the cognitive impairments and HRQoL in patients and the need for patient and caregiver support.

The PlexiQoL, a patient-reported outcome measure on quality of life in neurofibromatosis type 1-associated plexiform neurofibroma: translation, cultural adaptation and validation into the Dutch language for the Netherlands.

BACKGROUND: Half of the patients with Neurofibromatosis type 1 (NF1) develop one or more tumours called plexiform neurofibromas, which can have a significant impact on Quality of Life (QoL). The PlexiQoL questionnaire is a disease-specific QoL measure for adults with NF1-associated plexiform neurofibromas. The aim of this study was to adapt and validate a Dutch version of the PlexiQoL for the Netherlands. METHODS: The PlexiQoL was translated using the dual-panel methodology, followed by cognitive debriefing interviews to assess face and content validity. The psychometric properties were evaluated by administering the questionnaire on two separate occasions to a sample of adults with NF1 and plexiform neurofibromas. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating Cronbach's alpha coefficient and test-retest reliability, using Spearman's rank correlation coefficients. Mann-Whitney U tests were used to check for known group validity. The Nottingham Health Profile (NHP) questionnaire was used as comparator questionnaire to evaluate convergent validity. RESULTS: The translation and cognitive debriefing interviews resulted in a Dutch version of the PlexiQoL that reflected the original concept and underlying semantic meanings of the UK English version. Forty participants completed the validation survey. The Dutch PlexiQoL demonstrated excellent internal consistency (Cronbach's α 0.825) and test-retest reliability (Spearman correlation coefficient 0.928). The questionnaire detected differences in PlexiQoL scores between participants based on self-reported general health and disease severity. Convergent validity was confirmed for relevant NHP subsections. CONCLUSIONS: The Dutch PlexiQoL demonstrated excellent psychometric properties and can be reliably used to measure plexiform neurofibroma-related QoL in adults with NF1 in the Netherlands.

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections.

CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observe that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3, favoring parenchymal CD4+ T cell accumulation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections.

[Symptomatic tumors in neurofibromatosis type 1: a diagnostic challenge]. / Symptomatische tumoren bij neurofibromatose type 1.

Neurofibromatosis type 1 (NF1) is a hereditary, progressive and unpredictable disease, which can involve many organs. Benign and malignant tumors arise due to unrestrained cell division and cell growth. Recognizing the symptoms of these tumors and using the correct diagnostics is of great importance. In this clinical lesson we show the disease course of 3 patients with NF1. In all 3, the disease course was complicated by a symptomatic tumor. Characteristic in these patients is the relatively long interval between the onset of symptoms and the final tumor diagnosis. In this clinical lesson we examine the causes of this in more detail and we emphasize the importance of the specific knowledge within the Dutch national NF1 care network.

Pannexin-1 channels promote CD8+ T cell effector and memory responses through distinct intracellular pathways.

Sensing of extracellular metabolites controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses to antigen, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 favors memory CD8+ T cell survival primarily through ATP export and induction of mitochondrial metabolism. CD8-specific Panx1 is also crucial for the effector expansion of CD8+ T cells, however this regulation occurs independently of eATP. Instead, our results suggest a connection between Panx1-induced extracellular lactate accumulation and the complete activation of effector CD8+ T cells. In summary, Panx1 regulates effector and memory CD8+ T cells through export of distinct metabolites and by engaging different metabolic and signaling pathways.

Endocrine and non-endocrine causes of fatigue in adults with Neurofibromatosis type 1.

Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes. Objective: To explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1. Design: Cross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated. Main outcome measure: Prevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue. Results: In our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue. Conclusions: Endocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An alternative explanation for fatigue might be deficits in cognitive functioning and other neuropsychological processes in NF1. Based on our results and review of the literature, we provide a clinical algorithm for the approach to fatigue in NF1 adults, including somatic and psychological assessment.

The Extracellular ATP Receptor P2RX7 Imprints a Promemory Transcriptional Signature in Effector CD8+ T Cells.

Development of CD8+ central memory T (Tcm) and resident memory T (Trm) cells, which promote immunity in the circulation and in barrier tissues, respectively, is not completely understood. Tcm and Trm cells may arise from common precursors; however, their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors, which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm cell formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Mechanistically, P2RX7 negatively regulates Zeb2 expression, at least partially through TGF-ß sensing in early effector CD8+ T cells. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate.