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European Journal of Cancer (Oxford,... Dec 2022As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of... (Review)
Review
Paediatric Strategy Forum for medicinal product development in mitogen-activated protein kinase pathway inhibitors: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.
As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors. Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined. Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging. Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary. Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development. Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer.
Topics: United States; Adolescent; Adult; Child; Humans; United States Food and Drug Administration; Prospective Studies; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Glioma; Mitogen-Activated Protein Kinases
PubMed: 36335782
DOI: 10.1016/j.ejca.2022.09.036 -
Neurology Feb 2023Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most...
BACKGROUND AND OBJECTIVES
Internal neurofibromas, including plexiform neurofibromas (PNF), can cause significant morbidity in patients with neurofibromatosis type 1 (NF1). PNF growth is most pronounced in children and young adults, with more rapid growth thought to occur in a subset of PNF termed distinct nodular lesions (DNL). Growth behavior of internal neurofibromas and DNL in older adults is not well documented; yet knowledge thereof is important for patient risk stratification and clinical trial design. The primary objective of this study was to evaluate the long-term growth behavior of internal neurofibromas in adults with NF1. Secondary objectives were to correlate tumor growth behavior with patient-specific, tumor-specific, and patient-reported variables.
METHODS
In this prospective cohort study, internal neurofibromas were identified on coronal short TI inversion recovery sequences on baseline and follow-up whole-body MRIs (WBMRIs). Tumor growth and shrinkage were defined as a volume change ≥20%. The association between tumor growth and patient-specific (baseline age, sex, and genotype), tumor-specific (morphology, location, DNL presence on baseline WBMRI, and maximum standardized uptake value on baseline PET imaging), and patient-reported variables (endogenous and exogenous hormone exposure, pain intensity, and quality of life) was assessed using the Spearman correlation coefficient and Kruskal-Wallis test.
RESULTS
Of 106 patients with a baseline WBMRI obtained as part of a previous research study, 44 had a follow-up WBMRI. Three additional patients with WBMRIs acquired for clinical care were included, generating 47 adults for this study. The median age during baseline WBMRI was 42 years (range 18-70). The median time between WBMRIs was 10.4 years. Among 324 internal neurofibromas, 62.8% (56% of PNF and 62.1% of DNL) shrank spontaneously without treatment and 17.1% (17.9% of PNF and 13.8% of DNL) grew. Growth patterns were heterogeneous within participants. Patient-specific, tumor-specific, and patient-reported variables (including endogenous and exogenous hormone exposure) were not strong predictors of tumor growth.
DISCUSSION
Internal neurofibroma growth behavior in older adults differs fundamentally from that in children and young adults, with most tumors, including DNL, demonstrating spontaneous shrinkage. Better growth models are needed to understand factors that influence tumor growth. These results will inform clinical trial design for internal neurofibromas.
Topics: Child; Young Adult; Humans; Aged; Adolescent; Adult; Middle Aged; Neurofibromatosis 1; Follow-Up Studies; Prospective Studies; Quality of Life; Neurofibroma, Plexiform; Neurofibroma; Magnetic Resonance Imaging
PubMed: 36332985
DOI: 10.1212/WNL.0000000000201535 -
Gastroenterology and Hepatology From... 2022Herein, we report an extremely rare case of histopathologically proven neurofibromatosis of the liver. A 15-year-old male, a known case of type I neurofibromatosis...
Herein, we report an extremely rare case of histopathologically proven neurofibromatosis of the liver. A 15-year-old male, a known case of type I neurofibromatosis (NF1), referred to our hospital with a complaint of right upper quadrant pain. He had a café-au-lait spot and positive family history of NF1 in his mother. Laboratory data was within normal limits, and computed tomography (CT) revealed a large predominantly less attenuated infiltrative liver mass along the porta hepatis with extension to both lobes of the liver. Magnetic resonance imaging showed a large hypo-signal mass in T1-weighted images and hypersignal lesion in T2-sequences with faint enhancement, periportal distribution, and encasing of major branches of the portal vein without evidence of narrowing and invasion. A CT-guided biopsy was taken from both liver lobe lesions, and pathological diagnosis of the biopsy specimens confirmed plexiform neurofibromas of the liver. According to the extensive intrahepatic extension and periportal infiltration, the mass was unrespectable. Radiologists need to be familiar with the typical imaging features of the uncommon hepatic neoplasms. If imaging findings are not typical or diagnostic, a further biopsy should be performed again.
PubMed: 36311967
DOI: 10.22037/ghfbb.v15i3.2047 -
Balkan Journal of Medical Genetics :... Nov 2021Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by mutations on the gene, which is located at chromosome 17q11.2. Although an autosomal dominant...
Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by mutations on the gene, which is located at chromosome 17q11.2. Although an autosomal dominant inheritance pattern is well-established, about half of new cases are the result of mutations. Neurofibromatosis type 1 has an incidence rate of 1/2600-3000 individuals, making it a major public health problem. The product of the gene, the neurofibromin protein, is known to play a critical role in cellular differentiation and in tumor suppression. Due to widespread expression of neurofibromin in numerous tissues, particularly in cutaneous and nervous systems, mutations cause a wide variety of clinical symptoms, including cutaneous and ocular lesions such as café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling and internal tumors. In this article, we report the cases of two siblings with NF1, a 21-year-old male and his 24-year-old sister, who have the same c.5392C>T mutation on the gene (p.Gln1798 Ter). Café au lait macules and freckling were the prominent clinical features in both siblings. However, a plexiform neurofibroma was also observed on the left arm of the sister, which is known to carry potential risk for malignant transformation. Although the mutation was previously described once, to the best of our knowledge, no case report has been published since then.
PubMed: 36249525
DOI: 10.2478/bjmg-2021-0021 -
Cureus Sep 2022Neurofibromatosis type 1 is characterized by multiple cutaneous neurofibromas of varying sizes along with skeletal, neurologic, and ophthalmic features. Solitary...
Neurofibromatosis type 1 is characterized by multiple cutaneous neurofibromas of varying sizes along with skeletal, neurologic, and ophthalmic features. Solitary swellings in neurofibromatosis type 1 are not commonly encountered except in the form of plexiform neurofibromas. We report two cases with neurofibromatosis type 1 presenting with solitary swelling in the ankles which were proven to be the diffuse type of neurofibroma, radiologically and histopathologically. Diffuse type neurofibroma presenting as ankle swelling in type 1 neurofibromatosis has not been reported before.
PubMed: 36237736
DOI: 10.7759/cureus.28938 -
Journal of Clinical Medicine Sep 2022Nodular plexiform neurofibromas in individuals with neurofibromatosis type 1 often cause significant symptoms and are treated with surgical excision despite the...
BACKGROUND
Nodular plexiform neurofibromas in individuals with neurofibromatosis type 1 often cause significant symptoms and are treated with surgical excision despite the potential risk of complications. This study aimed to clarify the surgical outcomes of deep-seated nodular plexiform neurofibromas and identify the factors associated with postoperative complications.
METHODS
We retrospectively reviewed patients with neurofibromatosis type 1 who underwent surgical excision for deep-seated nodular plexiform neurofibromas in our hospital from 2015 to 2021. Enucleation while preserving the nerve fascicles was attempted first, and en bloc resection, ligating the nerve origin in cases in which the parent nerve was entrapped by the tumor, making the tumor difficult to dissect, was performed.
RESULTS
In 15 patients, 24 nodular plexiform neurofibromas received surgical excision. Sixteen tumors were enucleated, and eight were en bloc resected. The symptoms of all 10 patients with preoperative symptoms resolved after surgery. Four patients developed new neurological deficits immediately after surgery, two of whom had retained neurological symptoms at the last visit, but these symptoms were mild.
CONCLUSIONS
The present study demonstrates that surgical treatment of nodular plexiform neurofibromas, even deep-seated neurofibromas, is safe with a low risk of severe complications and improvement in preoperative symptoms.
PubMed: 36233563
DOI: 10.3390/jcm11195695 -
World Journal of Clinical Cases Jul 2022Peripheral nerve sheath tumors (PNSTs), a rare group of neoplasms in the orbit, comprise only 4% of all orbital tumors. At present, there are very few studies detailing...
BACKGROUND
Peripheral nerve sheath tumors (PNSTs), a rare group of neoplasms in the orbit, comprise only 4% of all orbital tumors. At present, there are very few studies detailing the features of these tumors identified using imaging technology.
AIM
To compare the differences in location, morphology, magnetic resonance imaging (MRI) signal intensity/computed tomography (CT) value, and enhancement degree of tumors of different pathological PNSTs types.
METHODS
Clinical, pathological, CT, and MRI data were analyzed retrospectively in 34 patients with periorbital sheath tumors diagnosed using histopathology from January 2013 to August 2021.
RESULTS
Among 34 cases of orbital peripheral nerve sheath tumors, 21 were schwannomas, 12 were neurofibromas, and 1 was a plexiform neurofibroma. Common clinical symptoms presented by patients with these types of tumors include eyelid swelling, exophthalmos, and limited eye movement. Schwannomas mostly occur in the intramuscular space with small tumor volume and rare bone involvement. Neurofibromas develop in the extrapyramidal space with larger tumor volume and more bone involvement. Radiologically, schwannomas and neurofibromas are characterized by regular morphology and uneven density and signal. One case of plexiform neurofibroma showed tortuous and diffuse growth along the nerve, with a worm-like appearance on imaging.
CONCLUSION
Different pathological types of orbital peripheral nerve sheath tumors have unique imaging characteristics. Comprehensive consideration of the patient's clinical and imaging manifestations is of great value in the diagnosis of orbital peripheral nerve sheath tumors.
PubMed: 36158022
DOI: 10.12998/wjcc.v10.i21.7356 -
Cancers Sep 2022Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the gene and subsequent... (Review)
Review
BACKGROUND
Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes.
METHODS
We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas.
CONCLUSIONS
In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.
PubMed: 36139671
DOI: 10.3390/cancers14184513 -
JCI Insight Sep 2022To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop...
To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor-like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.
Topics: Animals; Humans; Mice; NF-kappa B; Neurofibroma, Plexiform; Neurofibromatosis 1; Schwann Cells; Tumor Microenvironment
PubMed: 36134665
DOI: 10.1172/jci.insight.154513 -
Cureus Aug 2022Neurofibromatosis type 1 (NF1) is the most common form of neurofibromatosis. It is associated with neurofibromas, gliomas, neurofibrosarcomas, and neuroendocrine and...
Neurofibromatosis type 1 (NF1) is the most common form of neurofibromatosis. It is associated with neurofibromas, gliomas, neurofibrosarcomas, and neuroendocrine and hematopoietic tumors. We present a case of scalp plexiform neurofibromatosis associated with intrathoracic fibrosarcoma. An 18-year-old female presented with a 15-year history of plexiform scalp mass. She had multiple café-au-lait patches on her trunk and extremities and a first-degree relative with a plexiform right shoulder mass. She was managed by a multidisciplinary team of plastic and reconstructive surgeons, neurosurgeons, cardiothoracic surgeons, otorhinolaryngologists, ophthalmologists, pulmonologists, and pathologists. The histology of the excised scalp mass was that of a malignant peripheral nerve sheath tumor (neurofibrosarcoma). She subsequently developed upper chest and back pain with associated breathlessness and was found to have an intra-thoracic tumor. She had two sessions of exploratory right thoracotomy with subtotal excision of an aggressive, highly hemorrhagic, infiltrative mucinous tumor. The histology was a fibrosarcoma. The patient died a few hours following the second thoracotomy. NF1 is associated with several tumors, among which are neurofibrosarcomas. Intra-thoracic fibrosarcoma requires aggressive surgical resection; recurrence may be delayed with radiotherapy and chemotherapy. The prognosis is however poor, and survival beyond one year is unusual. Once one tumor is found, other body systems should be evaluated for the possibility of other tumors.
PubMed: 36110436
DOI: 10.7759/cureus.27853