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Oncogene Apr 2022Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of... (Review)
Review
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, invasive cancer that comprise around 10% of all soft tissue sarcomas and develop in about 8-13% of patients with Neurofibromatosis Type 1. They are associated with poor prognosis and are the leading cause of mortality in NF1 patients. MPNSTs can also develop sporadically or following exposure to radiation. There is currently no effective targeted therapy to treat MPNSTs and surgical removal remains the mainstay treatment. Unfortunately, surgery is not always possible due to the size and location of the tumor, thus, a better understanding of MPNST initiation and development is required to design novel therapeutics. Here, we provide an overview of MPNST biology and genetics, discuss findings regarding the developmental origin of MPNST, and summarize the various model systems employed to study MPNST. Finally, we discuss current management strategies for MPNST, as well as recent developments in translating basic research findings into potential therapies.
Topics: Biology; Humans; Nerve Sheath Neoplasms; Neurofibromatosis 1; Neurofibrosarcoma; Sarcoma
PubMed: 35393544
DOI: 10.1038/s41388-022-02290-1 -
Neuro-oncology Nov 2022Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant... (Review)
Review
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.
Topics: Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Nerve Sheath Neoplasms; Protein Kinase Inhibitors
PubMed: 35657359
DOI: 10.1093/neuonc/noac146 -
The Journal of Clinical Investigation Jan 2021Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral...
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
Topics: Animals; Cell Line; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Nude; Mice, Transgenic; Mutation; Neoplasms, Experimental; Neurofibroma; Neurofibromin 1
PubMed: 33108355
DOI: 10.1172/JCI139807 -
Cell Stem Cell Aug 2021NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve...
NF1-associated malignant peripheral nerve sheath tumors (MPNSTs) are the major cause of mortality in neurofibromatosis. MPNSTs arise from benign peripheral nerve plexiform neurofibromas that originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discover and characterize a rare MPNST cell population with stem-cell-like properties, including quiescence, that is essential for tumor initiation and relapse. Following isolation of these cells, we derive a cancer-stem-cell-specific gene expression signature that includes consensus embryonic neural crest genes and identify Nestin as a marker for the MPNST cell of origin. Combined targeting of cancer stem cells along with antimitotic chemotherapy yields effective tumor inhibition and prolongs survival. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to MPNST therapy development.
Topics: Animals; Disease Models, Animal; Mice; Neoplasm Recurrence, Local; Neurofibromatosis 1; Neurofibrosarcoma
PubMed: 34010628
DOI: 10.1016/j.stem.2021.04.029 -
World Journal of Gastroenterology Feb 2022Pancreatic cystic lesions (PCLs) are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population. It has become... (Review)
Review
Pancreatic cystic lesions (PCLs) are becoming more prevalent due to more frequent abdominal imaging and the increasing age of the general population. It has become crucial to identify these PCLs and subsequently risk stratify them to guide management. Given the high morbidity associated with pancreatic surgery, only those PCLs at high risk for malignancy should undergo such treatment. However, current diagnostic testing is suboptimal at accurately diagnosing and risk stratifying PCLs. Therefore, research has focused on developing new techniques for differentiating mucinous from non-mucinous PCLs and identifying high risk lesions for malignancy. Cross sectional imaging radiomics can potentially improve the predictive accuracy of primary risk stratification of PCLs at the time of detection to guide invasive testing. While cyst fluid glucose has reemerged as a potential biomarker, cyst fluid molecular markers have improved accuracy for identifying specific types of PCLs. Endoscopic ultrasound guided approaches such as confocal laser endomicroscopy and through the needle microforceps biopsy have shown a good correlation with histopathological findings and are evolving techniques for identifying and risk stratifying PCLs. While most of these recent diagnostics are only practiced at selective tertiary care centers, they hold a promise that management of PCLs will only get better in the future.
Topics: Cyst Fluid; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Pancreas; Pancreatic Cyst; Pancreatic Neoplasms
PubMed: 35317424
DOI: 10.3748/wjg.v28.i6.624 -
Pediatric Radiology Aug 2022Aneurysmal bone cyst (ABC) is a benign but locally aggressive lesion that predominantly affects children and young adults. ABC, which accounts for approximately 70% of... (Review)
Review
Aneurysmal bone cyst (ABC) is a benign but locally aggressive lesion that predominantly affects children and young adults. ABC, which accounts for approximately 70% of the cases, is now recognized to be a true neoplasm, whereas ABC-like changes associated to other bone neoplasms (also referred in the literature as secondary ABC) accounts for the remaining 30%. The solid variant of ABC is also considered a true neoplasm but is rare. ABC can involve any bone in the body, and although it has a metaphyseal preference, it can involve any part of a bone and soft tissues. As with any bone tumor, the initial evaluation of ABCs should be done with radiographs followed by magnetic resonance imaging or less frequently computed tomography for further characterization. The imaging appearance of ABC is variable; however, a lytic and expansile lesion with fluid-fluid levels is the most common presentation. The main differential diagnosis of an ABC in the pediatric population is unicameral bone cyst (UBC) and telangiectatic osteosarcoma, therefore a biopsy is recommended before treatment. The therapeutic options of ABC range from curettage with or without adjuncts such as phenol, liquid nitrogen, argon laser and bone grafting or bone substitutes to more recently employed alternatives such as image-guided sclerotherapy with various sclerosing agents and monoclonal antibodies (e.g., Denosumab).
Topics: Bone Cysts; Bone Cysts, Aneurysmal; Bone Neoplasms; Child; Humans; Osteosarcoma; Tomography, X-Ray Computed; Young Adult
PubMed: 35941207
DOI: 10.1007/s00247-022-05396-6 -
Cell Jul 2022Mouse germline cysts, on average, develop into six oocytes supported by 24 nurse cells that transfer cytoplasm and organelles to generate a Balbiani body. We showed that...
Mouse germline cysts, on average, develop into six oocytes supported by 24 nurse cells that transfer cytoplasm and organelles to generate a Balbiani body. We showed that between E14.5 and P5, cysts periodically activate some nurse cells to begin cytoplasmic transfer, which causes them to shrink and turnover within 2 days. Nurse cells die by a programmed cell death (PCD) pathway involving acidification, similar to Drosophila nurse cells, and only infrequently by apoptosis. Prior to initiating transfer, nurse cells co-cluster by scRNA-seq with their pro-oocyte sisters, but during their final 2 days, they cluster separately. The genes promoting oocyte development and nurse cell PCD are upregulated, whereas the genes that repress transfer, such as Tex14, and oocyte factors, such as Nobox and Lhx8, are under-expressed. The transferred nurse cell centrosomes build a cytocentrum that establishes a large microtubule aster in the primordial oocyte that organizes the Balbiani body, defining the earliest oocyte polarity.
Topics: Animals; Apoptosis; Cell Enlargement; Cell Lineage; Cysts; Cytoplasm; Drosophila melanogaster; Female; Gene Expression Regulation, Developmental; Mice; Oocytes; Ovary
PubMed: 35623357
DOI: 10.1016/j.cell.2022.05.001 -
The Lancet. Oncology Jul 2019Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment...
Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.
BACKGROUND
Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
METHODS
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
FINDINGS
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.
INTERPRETATION
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
FUNDING
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
Topics: Adolescent; Benzimidazoles; Central Nervous System Neoplasms; Child; Child, Preschool; Disease Progression; Female; Glioma; Humans; Male; Neoplasm Grading; Neoplasms, Multiple Primary; Neurofibromatosis 1; Proto-Oncogene Proteins B-raf; Young Adult
PubMed: 31151904
DOI: 10.1016/S1470-2045(19)30277-3 -
European Endodontic Journal Jan 2023Inflammatory radicular cysts (IRCs) are chronic lesions that follow the development of periapical granulomas (PGs). IRCs result from multiple inflammatory reactions led... (Review)
Review
Inflammatory radicular cysts (IRCs) are chronic lesions that follow the development of periapical granulomas (PGs). IRCs result from multiple inflammatory reactions led initially by several pro-inflammatory interleukins and growth factors that provoke the proliferation of epithelial cells derived from epithelial cell rests of Malassez present in the granulomatous tissue, followed by cyst formation and growth processes. Multiple theories have been proposed to help explain the molecular process involved in the development of the IRC from a PG. However, although multiple studies have demonstrated the presence of epithelial cells in most PGs, it is still not fully understood why not all PGs turn into IRCs, even though both are stages of the same inflammatory phenomenon and receive the same antigenic stimulus. Histopathological examination is currently the diagnostic gold standard for differentiating IRCs from PGs. Although multiple studies have evaluated the accuracy of non-invasive or minimally invasive methods in assessing the histopathological nature of the AP before the intervention, these studies' results are still controversial. This narrative review addresses the biological insights into the complex molecular mechanisms of IRC formation and its histopathological features. In addition, the relevant inflammatory molecular mediators for IRC development and the accuracy of non-invasive or minimally invasive diagnostic approaches are summarised. (EEJ-2022-03-041).
Topics: Humans; Radicular Cyst; Epithelial Cells; Inflammation; Periapical Granuloma; Intercellular Signaling Peptides and Proteins
PubMed: 36748442
DOI: 10.14744/eej.2022.26918 -
JAMA Network Open Mar 2021Neurofibromatosis type 1 (NF1) is a complex genetic disorder that is associated with not only neurofibromas, but also an increased susceptibility to other neoplasms. (Comparative Study)
Comparative Study
IMPORTANCE
Neurofibromatosis type 1 (NF1) is a complex genetic disorder that is associated with not only neurofibromas, but also an increased susceptibility to other neoplasms.
OBJECTIVE
To evaluate the prevalence of neoplasia and outcomes among patients with NF1.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted among patients with NF1 at a single academic cancer center from 1985 to 2020 with median (range) follow-up of 2.9 years (36 days to 30.5 years). Of 2427 patients evaluated for NF1, 1607 patients who met the National Institutes of Health consensus criteria for NF1 were included. This group was compared with estimates from Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1975 to 2015 and SEER participants database unless otherwise specified. Data were analyzed from August 2018 to March 2020.
MAIN OUTCOMES AND MEASURES
Disease-specific survival (DSS) was measured from diagnosis date to date of neoplasm-specific death or censorship and calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Deaths from disease were considered a DSS end point; other deaths were considered censored observations. Secondary outcome measures were comparisons of (1) overall survival of patients with NF1 with neurofibroma neoplasms vs those without nonneurofibroma neoplasms, (2) neoplasm prevalence in the NF1 group vs general population estimates, and (3) age at diagnosis in the NF1 group vs general population estimates for the most common neoplasms in the NF1 group.
RESULTS
Among 1607 patients with NF1, the median (range) age at initial visit was 19 years (1 month to 83 years) and 840 (52.3%) were female patients. Among 666 patients who developed other neoplasms in addition to neurofibromas (41.4%), 295 patients (18.4%) developed glioma and 243 patients (15.1%) developed malignant peripheral nerve sheath tumor (MPNST), the most common neoplasms. Patients with NF1, compared with the general population, developed several neoplasms at a younger mean (SD) age (low-grade glioma: 12.98 [11.09] years vs 37.76 [24.53] years; P < .0001; high-grade glioma [HGG]: 27.31 [15.59] years vs 58.42 [19.09] years; P < .0001; MPNST: 33.88 [14.80] years vs 47.06 [20.76] years; P < .0001; breast cancer: 46.61 [9.94] years vs 61.71 [13.85] years; P < .0001). Patients with NF1 developed neoplasms more frequently compared with the general population (odds ratio, 9.5; 95% CI, 8.5-10.5; P < .0001). Among patients with NF1, significantly lower 5-year DSS rates were found among those with undifferentiated pleomorphic sarcoma (1 of 5 patients [20.0%]), HGG (8 of 34 patients [23.1%]), MPNST (72 of 228 patients [31.6%]), ovarian carcinoma (4 of 7 patients [57.1%]), and melanoma (8 of 12 patients [66.7%]) compared with those who had neoplasms classified as other (110 of 119 patients [92.4%]) (all P < .001) .
CONCLUSIONS AND RELEVANCE
This cohort study found that among patients with NF1, those who developed undifferentiated pleomorphic sarcoma, HGG, MPNST, ovarian carcinoma, or melanoma had significantly lower DSS rates compared with those who developed other neoplasms. This study also found that patients with NF1 developed some neoplasms more frequently and at a younger age compared with individuals without NF1. HGGs and MPNST were noteworthy causes of death among patients NF1. This information may be useful for NF1 patient counseling and follow-up.
Topics: Academic Medical Centers; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Male; Middle Aged; Neoplasms; Neoplasms, Multiple Primary; Neurofibromatosis 1; Prevalence; Time Factors; Young Adult
PubMed: 33734413
DOI: 10.1001/jamanetworkopen.2021.0945