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Journal of Patient-reported Outcomes Mar 2024Half 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...
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.
Topics: Adult; Humans; Quality of Life; Neurofibroma, Plexiform; Neurofibromatosis 1; Netherlands; Reproducibility of Results; Language; Patient Reported Outcome Measures
PubMed: 38499890
DOI: 10.1186/s41687-024-00714-y -
Cancers Feb 2024Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is... (Review)
Review
Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)-benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care.
PubMed: 38473354
DOI: 10.3390/cancers16050994 -
Epilepsy Research May 2024Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study,...
PURPOSE
Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood.
METHODS
Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model.
RESULTS
Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI=6-18%) and point prevalence 7% (CI= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI=3-65) and specificity of 99% (CI=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy.
CONCLUSIONS
In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.
Topics: Humans; Neurofibromatosis 1; Epilepsy; Male; Female; Adult; Prevalence; Young Adult; Electroencephalography; Phenotype; Middle Aged; Genotype; Adolescent; Magnetic Resonance Imaging; Prospective Studies
PubMed: 38471245
DOI: 10.1016/j.eplepsyres.2024.107336 -
Life Science Alliance May 2024Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK...
Plexiform neurofibromas (PNFs) are nerve tumors caused by loss of and dysregulation of RAS-MAPK signaling in Schwann cells. Most PNFs shrink in response to MEK inhibition, but targets with increased and durable effects are needed. We identified the anaphylatoxin C5a as increased in PNFs and expressed largely by PNF m acrophages. We defined pharmacokinetic and immunomodulatory properties of a C5aR1/2 antagonist and tested if peptide antagonists augment the effects of MEK inhibition. MEK inhibition recruited C5AR1 to the macrophage surface; short-term inhibition of C5aR elevated macrophage apoptosis and Schwann cell death, without affecting MEK-induced tumor shrinkage. PNF macrophages lacking C5aR1 increased the engulfment of dying Schwann cells, allowing their visualization. Halting combination therapy resulted in altered T-cell distribution, elevated Iba1+ and CD169+ immunoreactivity, and profoundly altered cytokine expression, but not sustained trumor shrinkage. Thus, C5aRA inhibition independently induces macrophage cell death and causes sustained and durable effects on the PNF microenvironment.
Topics: Humans; Cytophagocytosis; Macrophages; Mitogen-Activated Protein Kinase Kinases; Neurofibroma, Plexiform; Signal Transduction; Tumor Microenvironment
PubMed: 38458648
DOI: 10.26508/lsa.202302229 -
Clinical and Translational Medicine Mar 2024
Safety, pharmacokinetics and efficacy of selumetinib in Chinese adult and paediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas: The primary analysis of a phase 1 open-label study.
Topics: Adult; Humans; Child; Neurofibroma, Plexiform; Neurofibromatosis 1; Benzimidazoles; China
PubMed: 38456222
DOI: 10.1002/ctm2.1589 -
International Journal of Surgery Case... Mar 2024Neurofibromatosis type 1 is a benign peripheral nerve tumor, often manifests as plexiform neurofibroma that may cause severe dysfunction, pain, and disfigurement....
Case report: Remarkable efficacy of negative-pressure wound therapy in giant lower extremity elephantiasis neuromatosa for vascularization, skin grafting, and fluid control.
INTRODUCTION AND IMPORTANCE
Neurofibromatosis type 1 is a benign peripheral nerve tumor, often manifests as plexiform neurofibroma that may cause severe dysfunction, pain, and disfigurement. Bleeding has been reported as a complication of plexiform neurofibroma due to vascular fragility and vasculopathy that may develop into life-threatening bleeding especially after excision procedure. Consequently, post excision complications also include dehiscence and infection.
CASE PRESENTATION
We report a 23-year-old male with elephantiasis of the left lower extremity due to giant plexiform neurofibroma who underwent preoperative embolization followed by serial surgical mass reduction. There were postoperative complications consisting of hematoma, wound dehiscence, and infection.
CLINICAL DISCUSSION
Negative pressure wound therapy is often used to accelerate wound healing, including infected wounds. However, negative pressure wound therapy has been a debatable modality for wound care of neurofibroma due to reported risks of profuse bleeding during its use.
CONCLUSION
In this case, despite the size, negative-pressure wound therapy has shown good results for infected neurofibroma wounds and as an adjunct as wound dressing for defect closure of neurofibroma with split-thickness skin graft.
PubMed: 38428057
DOI: 10.1016/j.ijscr.2024.109428 -
Journal of Indian Association of... 2024This case report describes a 4-year-old girl with an isolated neurofibroma in the sacrococcygeal region. Although initially resembling sacrococcygeal teratoma,...
This case report describes a 4-year-old girl with an isolated neurofibroma in the sacrococcygeal region. Although initially resembling sacrococcygeal teratoma, histopathology revealed a benign nerve sheath tumor. Wide local excision was performed, and the final diagnosis was plexiform neurofibroma. Diagnostic challenges in rare childhood tumors require stepwise evaluation and multidisciplinary team discussions.
PubMed: 38405243
DOI: 10.4103/jiaps.jiaps_136_23 -
Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.Cancer Medicine Feb 2024The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to...
BACKGROUND
The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020.
METHODS
Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines.
RESULTS
We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces.
CONCLUSION
This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.
Topics: Humans; Child; Adult; Retrospective Studies; Canada; Neoplasms; Medical Oncology; Antineoplastic Agents; Therapies, Investigational
PubMed: 38400668
DOI: 10.1002/cam4.7033 -
Cureus Feb 2024Neurofibromatosis type 1 (NF-1) is the most common neurocutaneous syndrome. It is inherited in an autosomal dominant manner, with many patients having the syndrome as...
Neurofibromatosis type 1 (NF-1) is the most common neurocutaneous syndrome. It is inherited in an autosomal dominant manner, with many patients having the syndrome as the result of a de novo mutation. NF-1 is caused by a mutation in the NF-1 gene located on the chromosome 17q11.2. NF-1 gene mutations result in the absence or reduced function of neurofibromin protein, thereby promoting tumor development and other clinical findings. NF-1 is fully penetrant, and it is commonly manifested by café-au-lait macules, axillary and/or inguinal freckling, neurofibromas, and Lisch nodules in the eyes. Skeletal manifestations include scoliosis, short stature, long bone dysplasia, and pseudoarthrosis. Rarely, NF-1 can manifest lambdoid suture defects. This report describes the case of a 12-year-old neurofibromatosis patient who presented to the pediatric clinic with a palpable posterior scalp defect, as well as café-au-lait macules and Lisch nodules. Diagnosis of NF-1 was made clinically. MRI and CT scan were done, and the patient was diagnosed with a lambdoid suture defect that is not associated with plexiform neurofibroma. Moreover, whole exome sequence (WES) was done, and diagnosis of NF-1 was confirmed. Watchful waiting and continuous monitoring were the management of choice for this case.
PubMed: 38380111
DOI: 10.7759/cureus.54567 -
Journal of Pediatric Psychology Jun 2024Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors,...
OBJECTIVES
Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors, requiring care from birth through adulthood. Adolescents and young adults (AYAs) with NF1 face several barriers to transition from pediatric to adult care. This cross-sectional study aimed to assess transition readiness in this population and to evaluate relationships between specific NF1 symptoms and transition readiness.
METHODS
AYAs (aged 16-24) enrolled in existing studies related to NF1 were eligible. AYAs and their parents completed measures of transition readiness (Transition Readiness Assessment Questionnaire version 4 [TRAQ-4]), and AYAs also completed a transition readiness interview (UNC TRxANSITION).
RESULTS
Thirty-eight AYAs (mean age = 19.95 ± 2.68 years) participated in the study. Average TRAQ scores indicated that AYAs were still learning Self-Management skills (M = 3.37, SD = 1.08) and Self-Advocacy skills (M = 3.98, SD = 0.67). Older AYAs had higher TRAQ scores for Self-Management (r = 0.70, p < .001) and Self-Advocacy (r = 0.41, p = .011) than younger AYAs. Parents and AYAs had similar TRAQ scores. About one third of AYAs (37.8%, n = 14) expressed uncertainty about how NF1 might affect them in the future. The remaining AYAs mostly expressed concerns regarding tumor growth, pain, or cancer.
CONCLUSIONS
In this small study, preliminary findings suggest that AYAs with NF1 express confidence in many areas of transition readiness but continue to require support, particularly with Self-Management skills. Given the gaps in understanding of future health risks, AYAs with NF1 would benefit from early assessment, psychoeducation, and support for transition readiness to adult care.
Topics: Humans; Cross-Sectional Studies; Adolescent; Neurofibromatosis 1; Male; Neurofibroma, Plexiform; Female; Transition to Adult Care; Young Adult; Adult; Surveys and Questionnaires
PubMed: 38366576
DOI: 10.1093/jpepsy/jsae006