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Clinical Trials (London, England) Feb 2024Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance...
BACKGROUND/AIMS
Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials.
METHODS
After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation.
RESULTS
Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English.
CONCLUSION
The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.
Topics: Child; Humans; Aged; Neurofibromatosis 1; Neurofibroma, Plexiform; Quality of Life; Neurofibromatoses; Neurilemmoma; Skin Neoplasms
PubMed: 38140900
DOI: 10.1177/17407745231205577 -
Cancers Dec 2023: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline gene mutations that predispose patients to developing plexiform...
: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. : Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, = log[EFF/AC50], and (b) a relative score, , characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. was applied to data from high-throughput screening (HTS) of a drug panel tested on tumor cells, using immortalized non-tumor cells as a reference. : We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The technique used here, in tandem with a supplemental web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.
PubMed: 38136356
DOI: 10.3390/cancers15245811 -
Clinical Cancer Research : An Official... Mar 2024Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance,...
PURPOSE
Plexiform neurofibromas (PNF) are benign peripheral nerve sheath tumors (PNST) associated with neurofibromatosis type 1 (NF1). Despite similar histologic appearance, these neoplasms exhibit diverse evolutionary trajectories, with a subset progressing to malignant peripheral nerve sheath tumor (MPNST), the leading cause of premature death in individuals with NF1. Malignant transformation of PNF often occurs through the development of atypical neurofibroma (ANF) precursor lesions characterized by distinct histopathologic features and CDKN2A copy-number loss. Although genomic studies have uncovered key driver events promoting tumor progression, the transcriptional changes preceding malignant transformation remain poorly defined.
EXPERIMENTAL DESIGN
Here we resolve gene-expression profiles in PNST across the neurofibroma-to-MPNST continuum in NF1 patients and mouse models, revealing early molecular features associated with neurofibroma evolution and transformation.
RESULTS
Our findings demonstrate that ANF exhibit enhanced signatures of antigen presentation and immune response, which are suppressed as malignant transformation ensues. MPNST further displayed deregulated survival and mitotic fidelity pathways, and targeting key mediators of these pathways, CENPF and BIRC5, disrupted the growth and viability of human MPNST cell lines and primary murine Nf1-Cdkn2a-mutant Schwann cell precursors. Finally, neurofibromas contiguous with MPNST manifested distinct alterations in core oncogenic and immune surveillance programs, suggesting that early molecular events driving disease progression may precede histopathologic evidence of malignancy.
CONCLUSIONS
If validated prospectively in future studies, these signatures may serve as molecular diagnostic tools to augment conventional histopathologic diagnosis by identifying neurofibromas at high risk of undergoing malignant transformation, facilitating risk-adapted care.
Topics: Animals; Humans; Mice; Gene Expression Profiling; Nerve Sheath Neoplasms; Neurofibroma; Neurofibromatosis 1; Neurofibrosarcoma
PubMed: 38127282
DOI: 10.1158/1078-0432.CCR-23-2548 -
GMS Interdisciplinary Plastic and... 2023Neurofibromatosis type 1 (NF1) is an is an autosomal dominant heritable tumor predisposition syndrome.. Peripheral nerve sheath tumors (PNST) are a hallmark of NF1....
INTRODUCTION
Neurofibromatosis type 1 (NF1) is an is an autosomal dominant heritable tumor predisposition syndrome.. Peripheral nerve sheath tumors (PNST) are a hallmark of NF1. Plexiform neurofibromas (PNF) are neoplasms that are characteristic of NF1, often causing disfiguring effects (e.g., on the face), and are considered precancerous lesions. Previous studies have shown that facial PNF (FPNF) have an impact on the shape of facial bones. This study examines deviations of mandibular symmetry from cephalometric reference planes considering the topography of FPNF.
MATERIAL AND METHODS
The posterior-anterior (PA) cephalograms of 168 patients with NF1 were examined. We compared three groups: patients with FPNF (n=74), with disseminated cutaneous neurofibroma (DNF (n=94)), and control subjects without NF1 (n=23). The PNF group was subtyped with respect to facial PNST type and location. Typical mandibular cephalometric reference points were determined (condyle, antegonion, and menton).
RESULTS
The skeletal measurement points of the mandible in FPNF patients often differ significantly from those of the DNF group. It has been proven that typical asymmetries of the median-sagittal measurement points are indicators of PNF. Differences within the trigeminal tumor spread patterns are indicated in the measured values. A local tumor effect (PNF) on the relation of the measurement points to the reference planes is made plausible by the study results. The investigations prove that tumor type (FPNF) and the number of FPNF affected branches of the trigeminal nerve may correlate with significant deviations of mandible from symmetry on PA projections.
CONCLUSION
The presented study shows that characteristic patterns of mandibular deformity can be measured on standardized radiographs in NF1 patients with FPNF. Mandibular deformities imaged on standardized radiographs may be initial indicators of a previously unrecognized NF1. Tumor-associated alterations of the mandible should be considered in the classification systems of pathognomonic, diagnostically pioneering osseous findings in NF1. The radiological findings provide clues for planning mandibular osteotomies in NF1 patients, especially for assessing facial regions typically highly vascularized by tumor spread. Furthermore, the radiological findings are an indication of a tumor potentially invading and destroying adjacent masticatory and mimic muscle, findings that may have an influence on surgical measures (function, aesthetics, and wound healing).
PubMed: 38111842
DOI: 10.3205/iprs000181 -
Indian Journal of Dermatology 2023
PubMed: 38099114
DOI: 10.4103/ijd.ijd_47_23 -
Journal of Neurology Apr 2024Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The...
BACKGROUND
Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype-phenotype associations in a large Chinese cohort of NF1 patients.
METHODS
We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype-phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains.
RESULTS
A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18 years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy.
CONCLUSION
Our study suggested some novel genotype-phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.
Topics: Male; Female; Humans; Adolescent; Neurofibromatosis 1; Cross-Sectional Studies; Neurofibroma, Plexiform; Genetic Association Studies; Phenotype; China
PubMed: 38095723
DOI: 10.1007/s00415-023-12127-w -
International Journal of Surgery Case... Aug 2023This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on...
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.
PubMed: 38092617
DOI: 10.1016/j.ijscr.2023.108617 -
Radiology Case Reports Jan 2024Plexiform schwannoma is a rare subtype of schwannoma. In this report, we present a case of plexiform schwannoma arising from the sciatic, tibial, and peroneal nerves. A...
Plexiform schwannoma is a rare subtype of schwannoma. In this report, we present a case of plexiform schwannoma arising from the sciatic, tibial, and peroneal nerves. A 54-year-old man presented with a painful palpable mass extending from the left posterior thigh to the calf. Magnetic resonance imaging showed multiple bead-like nodular structures along the sciatic, tibial, and peroneal nerve pathway. The nodular lesions showed uniform signal intensity on T1-weighted imaging. On T2-weighted imaging, each nodule showed an eccentric area of relatively low signal intensity surrounded by an area of higher signal intensity and a low-intensity rim. Plexiform schwannoma or neurofibroma was considered as the preoperative diagnosis. Because of the patient's severe symptoms and strong desire for relief, tumor enucleation of the largest painful nodule was performed, and plexiform schwannoma was confirmed pathologically.
PubMed: 38028287
DOI: 10.1016/j.radcr.2023.10.009 -
BMC Neurology Nov 2023Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN...
Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey.
BACKGROUND
Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients.
METHODS
Adult patients and caregivers of paediatric patients self-enrolled in an online survey (March-April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL.
RESULTS
Mean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate-extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores. Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate-severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8).
CONCLUSIONS
NF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity.
Topics: Adult; Child; Humans; Caregivers; Cross-Sectional Studies; Health Status; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain; Quality of Life; Surveys and Questionnaires; United Kingdom
PubMed: 37996843
DOI: 10.1186/s12883-023-03429-7 -
Current Oncology Reports Dec 2023Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared... (Review)
Review
Neurofibromatosis type I (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis represent a diverse group of genetic tumor predisposition syndromes with a shared feature of tumors affecting the peripheral nerve sheaths. PURPOSE OF REVIEW: Many advancements have been made in understanding the biologic underpinnings of these conditions, and in 2016 the first drug was approved by the FDA to treat pediatric symptomatic unresectable plexiform neurofibromas. RECENT FINDINGS: Mek inhibitors have provided a much-needed therapeutic avenue for NF1 patients with unresectable plexiform neurofibromas (PN), both for reduction of tumor bulk and for improvement in symptoms. Selumetinib is the first FDA approved drug for PN, but is only approved for children. Some research suggests that alternative Mek inhibitors and other mixed tyrosine kinase inhibitors may have better efficacy in adults. Vascular endothelial growth factor (VEGF) inhibitor bevacizumab can prolong hearing and delay the need for surgery in NF2 patients with bilateral vestibular schwannomas. This article provides an update regarding considerations and approaches when treating the tumors associated with the neurofibromatoses (NF), including risk and prognosis metrics, clinical trial results, surgical techniques, and radiation therapy recommendations.
Topics: Adult; Humans; Child; Neurofibroma, Plexiform; Vascular Endothelial Growth Factor A; Neurofibromatoses; Neurofibromatosis 1; Peripheral Nervous System Neoplasms; Genetic Predisposition to Disease; Protein Kinase Inhibitors; Mitogen-Activated Protein Kinase Kinases
PubMed: 37906356
DOI: 10.1007/s11912-023-01451-z