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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 -
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 -
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 -
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 -
BMC Oral Health Apr 2021A dentigerous cyst (DC) is a pathology embracing the crown of an unerupted tooth at risk of malignant transformation. The causal tooth is usually removed together with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A dentigerous cyst (DC) is a pathology embracing the crown of an unerupted tooth at risk of malignant transformation. The causal tooth is usually removed together with the cyst. However, if there are orthodontic contraindications for extraction, two questions arise. (1) Which factors favor spontaneous eruption? (2) Which factors imply the necessity of applying orthodontic traction? This systematic review aimed to identify factors conducive/inconducive to the spontaneous eruption of teeth after dentigerous cyst marsupialization.
METHODS
In accordance with the PRISMA guidelines, the main research question was defined in the PICO format (P: patients with dentigerous cysts; I: spontaneous tooth eruption after surgical DC treatment; C: lack of a spontaneous tooth eruption after surgical DC treatment; O: determining factors potentially influencing spontaneous tooth eruption). The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for keywords combining dentigerous/odontogenic/follicular cysts with teeth and/or orthodontics, as well as human teeth and eruption patterns/intervals/periods/durations. The following data were extracted from the qualified articles (4 out of 3005 found initially): the rate of tooth eruption after surgical treatment of the cyst, the age and sex of the patients, the perpendicular projection distance between the top of the tooth cusp and the edge of the alveolar process, tooth angulation, the root formation stage, the cyst area, and the eruption space. The articles were subjected to risk of bias and quality analyses with the ROBINS-I protocol and the modified Newcastle-Ottawa QAS, respectively. Meta-analyses were performed with both fixed and random effects models. The GRADE approach was used to evaluate the quality of the evidence. The systematic review was registered in PROSPERO under ID CRD42020189044.
RESULTS
Nearly 62% of DC-associated premolars erupted spontaneously after cyst marsupialization/decompression. Young age (mean = 10 years) and root formation not exceeding 1/2 of its fully developed length were the factors likely to favor spontaneous eruption.
CONCLUSION
The small number of published studies, as well as their heterogeneity and the critical risk of bias, did not allow the creation of evidence-based protocols for managing teeth with DC after marsupialization. More high-quality research is needed to draw more reliable conclusions.
Topics: Bicuspid; Child; Dentigerous Cyst; Humans; Tooth Eruption; Tooth, Impacted; Tooth, Unerupted
PubMed: 33827533
DOI: 10.1186/s12903-021-01542-y -
Harmful Algae Jan 2020Many phytoplankton species, including many harmful algal bloom (HAB) species, survive long periods between blooms through formation of benthic resting stages. Because... (Review)
Review
Many phytoplankton species, including many harmful algal bloom (HAB) species, survive long periods between blooms through formation of benthic resting stages. Because they are crucial to the persistence of these species and the initiation of new blooms, the physiology of benthic stages must be considered to accurately predict responses to climate warming and associated environmental changes. The benthic stages of dinoflagellates, called resting cysts, germinate in response to the combination of favorable temperature, oxygen-availability, and release from dormancy. The latter is a mechanism that prevents germination even when oxygen and temperature conditions are favorable. Here, evidence of temperature-mediated control of dormancy duration from the dinoflagellates Alexandrium catenella and Pyrodinium bahamense-two HAB species that cause paralytic shellfish poisoning (PSP)-is reviewed and presented alongside new evidence of complementary, temperature-based control of cyst quiescence (the state in which cysts germinate on exposure to favorable conditions). Interaction of the two temperature-based mechanisms with climate is explored through a simple model parameterized using results from recent experiments with A. catenella. Simulations demonstrate the importance of seasonal temperature cycles for the synchronization of cysts' release from dormancy and are consistent with biogeography-based inferences that A. catenella is more tolerant of warming in habitats that experience a larger range of seasonal temperature variation (i.e., have higher temperature seasonality). Temperature seasonality is much greater in shallow, long-residence time habitats than in deep, open-water ones. As warming shifts species' ranges, cyst beds may persist longer in more seasonally variable, shallow inshore habitats than in deep offshore ones, promoting HABs that are more localized and commence earlier each year. Recent field investigations of A. catenella also point to the importance of new cyst formation as a factor triggering bloom termination through mass sexual induction. In areas where temperature seasonality restricts the flux of new swimming cells (germlings) to narrow temporal windows, warming is unlikely to promote longer and more intense HAB impacts-even when water column conditions would otherwise promote prolonged bloom development. Many species likely have a strong drive to sexually differentiate and produce new cysts once concentrations reach levels that are conducive to new cyst formation. This phenomenon can impose a limit to bloom intensification and suggests an important role for cyst bed quiescence in determining the duration of HAB risk periods.
Topics: Cysts; Dinoflagellida; Harmful Algal Bloom; Humans; Shellfish Poisoning; Temperature
PubMed: 32057345
DOI: 10.1016/j.hal.2019.101728 -
Ugeskrift For Laeger Jan 2024This case report presents a 69-year-old male patient with a subcutaneous tumour in the left parietal region. Initially, the tumour was identified as a lipoma or benign...
This case report presents a 69-year-old male patient with a subcutaneous tumour in the left parietal region. Initially, the tumour was identified as a lipoma or benign cyst by the general practitioner. However, a subsequent MRI scan revealed a sarcoma metastasis with a significant intracranial component. Radical excision of the tumour was not possible due to its critical localisation. Therefore, the patient received palliative radiotherapy. This case emphasises the importance of accurate clinical assessment and highlights the clinical features that should lead to suspicion of malignancy.
Topics: Male; Humans; Aged; Sarcoma; Lipoma; Soft Tissue Neoplasms; Magnetic Resonance Imaging; Cysts
PubMed: 38327198
DOI: 10.61409/V10230622