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Current Oncology Reports Mar 2021Patients with neurofibromatosis type 1 (NF1) are at increased risk for benign and malignant neoplasms. Recently, targeted therapy with the MEK inhibitor class has helped... (Review)
Review
PURPOSE OF REVIEW
Patients with neurofibromatosis type 1 (NF1) are at increased risk for benign and malignant neoplasms. Recently, targeted therapy with the MEK inhibitor class has helped address these needs. We highlight recent successes with selumetinib while acknowledging ongoing challenges for NF1 patients and future directions.
RECENT FINDINGS
MEK inhibitors have demonstrated efficacy for NF1-related conditions, including plexiform neurofibromas and low-grade gliomas, two common causes of NF1-related morbidity. Active investigations for NF1-related neoplasms have benefited from advanced understanding of the genomic and cell signaling alterations in these conditions and development of sound preclinical animal models. Selumetinib has become the first FDA-approved targeted therapy for NF1 following its demonstrated efficacy for inoperable plexiform neurofibroma. Investigations of combination therapy and the development of a representative NF1 swine model hold promise for translating therapies for other NF1-associated pathology.
Topics: Animals; Benzimidazoles; Clinical Trials as Topic; Disease Models, Animal; Humans; Mitogen-Activated Protein Kinase Kinases; Neurofibroma, Plexiform; Neurofibromatosis 1; Precision Medicine; Protein Kinase Inhibitors; Signal Transduction; Swine
PubMed: 33721151
DOI: 10.1007/s11912-021-01032-y -
Indian Journal of Otolaryngology and... Jun 2023Lateral neck masses are common in children, ranging from simple benign diseases to pathologies with malignant potential. Plexiform neurofibromas are extremely rare...
Lateral neck masses are common in children, ranging from simple benign diseases to pathologies with malignant potential. Plexiform neurofibromas are extremely rare peripheral nerve sheath tumours involving multiple nerve sheath fascicles. They are typically seen in the paediatric population, with the majority affecting the craniofacial area and neck. Due to the close clinical and histological resemblance with other benign neck lesions such as lymphadenitis and branchial cysts, these cases can often go misdiagnosed. We describe a lesion in a young girl who presented with a progressive lateral neck swelling and how it was managed.
PubMed: 37274990
DOI: 10.1007/s12070-022-03434-1 -
BMC Surgery May 2020A large plexiform neurofibroma in patients with neurofibromatosis type I can be life threatening due to possible massive bleeding within the lesion. Although the...
Cardiac overload resolved by resection of a large plexiform neurofibroma on both the buttocks and upper posterior thighs in a patient with neurofibromatosis type I: a case report.
BACKGROUND
A large plexiform neurofibroma in patients with neurofibromatosis type I can be life threatening due to possible massive bleeding within the lesion. Although the literature includes many reports that describe the plexiform neurofibroma size and weight or strategies for their surgical treatment, few have discussed their possible physical or mental benefits, such as reducing cardiac stress. In addition, resection of these large tumors can result in impaired wound healing, partly due to massive blood loss during surgery.
CASE PRESENTATION
A 24-year-old man was diagnosed with neurofibromatosis type I and burdened with a large plexiform neurofibroma on the buttocks and upper posterior thighs. The patient was 159 cm in height and 70.0 kg in weight at the first visit. Cardiac overload was indicated by an echocardiography before surgery. His cardiac output was 5.2 L/min with mild tricuspid regurgitation. After embolism of the arteries feeding the tumor, the patient underwent surgery to remove the neurofibroma, followed by skin grafting. Follow-up echocardiography, performed 6 months after the final surgery, indicated a decreased cardiac output (3.6 L/min) with improvement of tricuspid regurgitation. Because the blood loss during the first surgery was over 3.8 L, malnutrition with albuminemia was induced and half of the skin graft did not attach. Nutritional support to improve the albuminemia produced better results following a second surgery to repair the skin wound.
CONCLUSION
Cardiac overload may be latent in patients with neurofibromatosis type I with large plexiform neurofibromas. As in pregnancy, the body may compensate for this burden. In these patients, one stage total excision may improve quality of life and reduce cardiac overload. In addition, nutritional support is likely needed following a major surgery that results in either an extensive skin wound or excessive blood loss during treatment.
Topics: Buttocks; Cardiac Output, High; Humans; Male; Neoplasms, Multiple Primary; Neurofibroma, Plexiform; Neurofibromatosis 1; Quality of Life; Skin Transplantation; Thigh; Young Adult
PubMed: 32423401
DOI: 10.1186/s12893-020-00761-4 -
The Oncologist Jul 2020Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type... (Review)
Review
Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. IMPLICATIONS FOR PRACTICE: Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.
Topics: Antineoplastic Agents; Child; Humans; Mitogen-Activated Protein Kinase Kinases; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors
PubMed: 32272491
DOI: 10.1634/theoncologist.2020-0069 -
Orphanet Journal of Rare Diseases Apr 2021The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should... (Review)
Review
BACKGROUND
The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications.
METHOD
A systematic retrospective data collection in a MNF1 cohort from one of two Danish national centers of NF1 Expertise was completed. Data collected included demographics, clinical features including NF1 diagnostic criteria and NF1-associated complications. Recent literature in the field was reviewed.
RESULTS
We identified 17 patients with MNF1 with a median age of 37 years [4; 66]. Eleven (65%) were females. Five patients (30%) had a plexiform neurofibroma. The median age at detection of plexiform neurofibroma was 30 years [14; 60]. Nine (53%) had at least one NF1-related complication; scoliosis, hypertension, ADHD, learning disability, language delay, autism and delay in gross and fine motor function development. We reviewed nine articles. In total, 126 cases were described within three case-series. Nineteen (15%) had a plexiform neurofibroma and in total, 23 NF1-associated complications were reported including language delay, learning disability and skeletal abnormalities. Furthermore, from the literature it was evident that the diagnosing of MNF1 varies among physicians and across countries.
CONCLUSION
Patients with MNF1 present with plexiform neurofibromas and other NF1-related complications with a frequency requiring that follow-up of MNF1 patients should be in accordance with the standard NF1 guideline in both childhood and adulthood. Physicians should be aware of cognitive impairment as a complication to MNF1. To develop a specific MNF1 follow-up guideline, there is a need for an international consensus on the diagnostic criteria for MNF1 and a follow-up study conducted in a larger MNF1 cohort.
Topics: Adult; Child; Female; Follow-Up Studies; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Retrospective Studies; Severity of Illness Index
PubMed: 33853649
DOI: 10.1186/s13023-021-01796-3 -
Radiologia Brasileira 2014The authors report the case of a plexiform neurofibroma located in the pelvis, affecting the bladder, prostate and spine (lumbar/sacral), followed-up for three years and...
The authors report the case of a plexiform neurofibroma located in the pelvis, affecting the bladder, prostate and spine (lumbar/sacral), followed-up for three years and six months. Surgical removal was contraindicated and the patient underwent biannual clinical and radiological follow-up that did not demonstrate any tumor increase. The clinical manifestations of neurofibromatosis type 1 are variable, and the medical team should be attentive to further investigations, considering possible unexpected rare findings. Large pelvic masses may correspond to plexiform neurofibromas, so the diagnostic hypothesis of neurofibromatosis should be taken into consideration.
PubMed: 25741110
DOI: 10.1590/0100-3984.2012.1648 -
Biomarker Research Apr 2021MAP/ERK kinase 1 and 2 (MEK 1/2) inhibitors (MEKi) are investigated in several trials to treat lesions that arise from pathogenic variants of the Neurofibromatosis type... (Review)
Review
MAP/ERK kinase 1 and 2 (MEK 1/2) inhibitors (MEKi) are investigated in several trials to treat lesions that arise from pathogenic variants of the Neurofibromatosis type 1 and type 2 genes (NF1, NF2). These trials showed that MEKi are capable to shrink volume of low grade gliomas and plexiform neurofibromas in NF1. Targeting other lesions being associated with a high morbidity in NF1 seems to be promising. Due to involvement of multiple pathways in NF2 associated lesions as well as in malignant tumors, MEKi are also used in combination therapies. This review outlines the current state of MEKi application in neurofibromatosis and associated benign and malignant lesions.
PubMed: 33863389
DOI: 10.1186/s40364-021-00281-0 -
Oncogene Mar 2023Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore...
Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.
Topics: Animals; Humans; Mice; Core Binding Factor Alpha 2 Subunit; eIF-2 Kinase; Endoplasmic Reticulum Stress; Neurofibroma; Neurofibroma, Plexiform; Neurofibromatosis 1; Unfolded Protein Response
PubMed: 36759572
DOI: 10.1038/s41388-023-02620-x -
American Society of Clinical Oncology... Jun 2024Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a... (Review)
Review
Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.
Topics: Humans; Neurofibromatosis 1; Nerve Sheath Neoplasms
PubMed: 38710002
DOI: 10.1200/EDBK_432242 -
Journal of Pediatric Genetics Jun 2022Plexiform neurofibroma (PN) involvement of the external genitalia in patients with neurofibromatosis type I (NF1) is a rare cause of nonhormonal clitoromegaly. We...
Plexiform neurofibroma (PN) involvement of the external genitalia in patients with neurofibromatosis type I (NF1) is a rare cause of nonhormonal clitoromegaly. We present a 3-year-old female with known NF1 who presented with clitoromegaly. She was identified with an extensive pelvic mass involving the bladder wall, perineum, labia, clitoris, rectum, and sacral foramina. A partial cystectomy was performed, and histopathology was consistent with PN. She has been initiated on a mitogen activated protein kinase enzyme kinase inhibitor, trametinib, which has been effective in of the bladder mass over 5 months. Additionally, she has experienced clinical response to trematinib with resolution of urinary urgency and frequency since initiating treatment.
PubMed: 35769967
DOI: 10.1055/s-0040-1715638