DOCSLIB.ORG

Malignant Transformation of Low Grade Gliomas Into Glioblastoma a Series of 10 Cases and Review of the Literature

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Malignant Transformation of Low Grade Gliomas Into Glioblastoma a Series of 10 Cases and Review of the Literature Romanian Neurosurgery (2010) XVII 4: 403 – 412 403 Malignant transformation of low grade gliomas into glioblastoma a series of 10 cases and review of the literature D. Rotariu1, S. Gaivas1, Z. Faiyad1, D. Haba2, B. Iliescu1, I. Poeata1 Departments of Neurosurgery1 and Radiology2 , “Gr.T. Popa” University of Medicine and Pharmacy, Iasi, Romania Abstract astocytoma in 6 cases, oligoastocytoma in 2 Background: Diffuse infiltrative low-grade cases and in oligodendroglioma in 2 cases. gliomas (LGG) of the cerebral hemispheres The mean patient age was 46.1± 0.9 years in the adult are tumors with distinct and the most frequent symptom was clinical, histological and molecular represented by seizures 70%, the mean time characteristics. WHO (World Health from the first symptom to diagnosis was Organization) classification recognizes 11,2 months. 40% of the cases had subtotal grade II astrocytomas, oligodendrogliomas resection and 60% had total resection and oligoastrocytomas. Conventional MRI (defined by the surgeon at the time of is used for differential diagnosis, guiding operation). 5 patients received radiotherapy surgery, planning radiotherapy and postoperatively, 2 received both radio and monitoring treatment response. chemotherapy and 3 had no adjuvant Advanced imaging techniques are treatment. In our series the median time to increasing the diagnostic accuracy. Low- malignant transformation was 32,5 months. grade gliomas have been documented to Conclusions: Younger age, normal undergo transformation into high-grade neurological examination and gliomas, and the time interval of this oligodendroglial histology are favorable transformation has been reported to prognostic factors, total/near total resection generally occur within 5 years in about 50% can improve seizure control, progression- of patients diagnosed with low-grade free and overall survival, mean while gliomas. reducing the risk of malignant Methods: We have reviewed all adult transformation. Early post-operative patients operated on for hemispheric radiotherapy improves progression free but glioblastoma at N Oblu Hospital in Iasi not overall survival. Chemotherapy can be between 2006 and 2009 and in particular useful both at recurrence after radiotherapy those patients with secondary glioblastoma. and as initial treatment after surgery to Results: from the total 110 cases of delay the risk of late neurotoxicity from glioblastoma, ten of them were secondary large-field radiotherapy. to malignant transformation of an Keywords: astrocytoma, low-grade previously operated low grade glioma. Of glioma, glioblastoma, oligodendroglioma, the 10 patients with secondary malignant transformation glioblastoma, the initial histology was: gr II 404 D. Rotariu et al Malignant transformation of low grade gliomas Low-grade gliomas are primary brain The factors consistently shown to be tumors classified as Grade I and II by the associated with improved survival8 for WHO grading system (14, 27) and occur patients with gliomas are younger age, (13, primarily in children and young adults. The 23) higher KPS scores, (18) most common LGGs are the WHO Grade I oligodendroglioma pathology, (17) pilocytic astrocytomas and the WHO Grade postoperative radiation therapy, (25) and II diffuse astrocytomas (include fibrillary, GTR. (1, 15, 26) gemistocytic and protoplasmic variants), The only factors that have been oligodendrogliomas, and mixed consistently shown to be associated with oligoastrocytomas. It is important to tumor recurrence (8) or malignant separate gemistocytic astrocytoma, because degeneration are preoperative contrast it is more prone to malignant progression enhancement, (11, 12) tumor size, (1, 11) Patients with low-grade gliomas have a and STR. (1, 3) more favorable prognosis than patients with high grade glioma The median survival for Methods patients with low-grade gliomas is between We have analised all the patients 5 and 10 years (6, 9, 10, 13, 19) compared operated on at 3rd Neurosurgical with a survival of only 14 months in Department in N Oblu Hospital for patients with malignant glioma (GBM) malignant glioma between 2006 and 2009 (28). Despite this more favorable prognosis, and from the total of 110 cases ten percent patients with LGGs may survive for up to of the malignant glioma were secondary to a 20 years, in 50–75% of patients with low- malignant transformation of a low grade grade gliomas the tumors grow glioma. Our point of interest was continuously and tend to progress to a represented by the patients with initial higher grade, leading to neurological diagnostic of low grade gliomas.. Patients ≥ disability and ultimately to death (8, 24) In 18 years old with tissue-proven diagnosis of adults there are numerous prognostic a hemispheric WHO Grade I or II glioma factors reported in various prospective (FA, oligodendroglioma, or mixed glioma) studies that have been shown to affect (14) at the initial diagnosis, supratentorial survival in patients with LGG, the most tumor location and adequate (> 6 months) consistent are histological type, patient age, clinical follow-up and imaging reports were extent of resection (using postoperatively included in the study. MRI imaging), and tumor size. Pilocytic Patients with, WHO Grade III or IV astrocytomas, regardless of site (cerebral glioma including anaplastic astrocytoma, hemispheres, cerebellum, or spinal cord), glioblastoma multiforme, anaplastic are associated with a 10-year patient oligodendroglioma, or anaplastic mixed survival rate of ~ 80%, (6, 11, 14) but the oligoastrocytoma at the initial operation; rate is 100% in the subset of patients with nonsupratentorial tumor location including brain tumors who undergo GTR. (3, 22) optic chiasm, optic nerve(s), pons, medulla, Within the diffuse LGG group there is a cerebellum, or spinal cord; prior significant difference in patient outcome malignancy unless disease free ≥ 5 years based on histological tumor type. were excluded. Romanian Neurosurgery (2010) XVII 4: 403 – 412 405 The clinical, operative, and hospital oligoastrocytoma. The mean patient age course records were reviewed. Information was 46.1± 0.9 years, and 8 (80%) patients collected from clinical notes included were male. The initial symptom was patient demographics, age, presenting represented by seizures in 7 cases followed symptoms and signs, the interval between by motor impairment in 2 cases and rise the first symptom and diagnostic, pre- and intracranial hypertension in 1 case. The postoperative neuroimaging, extent of mean time from the initial symptom to resection, postoperative neurological diagnosis was 11.2±1.6 months. In our function, adjuvant therapy (radiotherapy series 80% of the tumors were limited to a and chemotherapy)medication history such single cerebral lobe and in 20% there were as steroids and anticonvulsants. involved 2 lobes, the most frequent affected Preoperative MR images, including T1- lobe was the frontal lobe (6 cases) followed weighted images with and without contrast by the parietal lobe (5 cases). All of our enhancement as well as T2-weighted cases had involvement of functional images (and FLAIR images when available), structures , in 6 cases there were functional were required. The preoperative tumor areas involved, 2 cases involved the bazal presence or absence of contrast ganglia and another 2 cases involved enhancement was recorded. Perioperative vascular structures (cavernous sinus, carotid death was defined as death within 30 days artery). As treatment 4 patients had subtotal of surgery. surgical resection and 6 total resection (as Tumor recurrence was defined as any defined by the neurosurgeon at the time of definitive evidence of tumor recurrence or surgery) . The main complication was progressive growth on MR imaging as per represented by hematoma in the tumoral the neuroradiology reports. Malignant bed wich was observed in 30% of the cases. degeneration was defined as either a notable 50% had radiotherapy postoperatively 20% increase in tumor contrast enhancement had both radio and chemotherapy while and/or a histopathologically proven 30% recived non of them. The median time malignant degeneration in tissue acquired to malignant transformation in our series during biopsy or resection (WHO Grade III was 32.5 months. (Figure 1 and Table 1) or IV). Results From all of low grade gliomas operated on between 2006 – 2009 ten of them have suffered malignant transformation. All the patients have underwent primary and secondary resection, 60 percent of the cases were secondary to grade II astrocytomas (diffuse astrocytoma), 20 percent were secondary to oligodendroglioma and another 20 percent were secondary to Figure 1 Time to malignant transformation 406 D. Rotariu et al Malignant transformation of low grade gliomas Table 1 Characteristics of malignant transformed low grade gliomas series Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case9 Case 10 Sex M M M F M M M M M F Age 42 41 37 55 59 45 60 39 50 33 1st Sign Seizures Seizures Seizures Left Seizures Partial Jacksonian Olfactive Right Ricp Hemiparesis Seizures Seizures Seizures Hemiplegia Sindrome T To Dg 2 36 30 1 2 2 10 3 `2 1 (Months) Loc F FTP F P P P F FTI P FTI Funct - 1 1 1 1 - 1 - 1 - Areas Bazal - 1 - - - - - 1 - - Ganglia Vascular - - - - - - - 1 - 1 Srtucture Biopsy - - - - - - - - - - Str - 1 - 1 1 - - 1 - - Gtr 1 - 1 - - 1 1 - 1 1 Dg Ap Gr II Gr II Gr II Oligodendro- Oligodendro- Gr II Oligoastro- Oligoastro- Gr II Gr II Astro- Astro- Astro- glioma glioma Astrocytoma cytoma cytoma Astrocytoma
Load more

Recommended publications
  • Central Nervous System Tumors General ~1% of Tumors in Adults, but ~25% of Malignancies in Children (Only 2Nd to Leukemia)
    Last updated: 3/4/2021 Prepared by Kurt Schaberg Central Nervous System Tumors General ~1% of tumors in adults, but ~25% of malignancies in children (only 2nd to leukemia). Significant increase in incidence in primary brain tumors in elderly. Metastases to the brain far outnumber primary CNS tumors→ multiple cerebral tumors. One can develop a very good DDX by just location, age, and imaging. Differential Diagnosis by clinical information: Location Pediatric/Young Adult Older Adult Cerebral/ Ganglioglioma, DNET, PXA, Glioblastoma Multiforme (GBM) Supratentorial Ependymoma, AT/RT Infiltrating Astrocytoma (grades II-III), CNS Embryonal Neoplasms Oligodendroglioma, Metastases, Lymphoma, Infection Cerebellar/ PA, Medulloblastoma, Ependymoma, Metastases, Hemangioblastoma, Infratentorial/ Choroid plexus papilloma, AT/RT Choroid plexus papilloma, Subependymoma Fourth ventricle Brainstem PA, DMG Astrocytoma, Glioblastoma, DMG, Metastases Spinal cord Ependymoma, PA, DMG, MPE, Drop Ependymoma, Astrocytoma, DMG, MPE (filum), (intramedullary) metastases Paraganglioma (filum), Spinal cord Meningioma, Schwannoma, Schwannoma, Meningioma, (extramedullary) Metastases, Melanocytoma/melanoma Melanocytoma/melanoma, MPNST Spinal cord Bone tumor, Meningioma, Abscess, Herniated disk, Lymphoma, Abscess, (extradural) Vascular malformation, Metastases, Extra-axial/Dural/ Leukemia/lymphoma, Ewing Sarcoma, Meningioma, SFT, Metastases, Lymphoma, Leptomeningeal Rhabdomyosarcoma, Disseminated medulloblastoma, DLGNT, Sellar/infundibular Pituitary adenoma, Pituitary adenoma,
    [Show full text]
  • Inhibition of Mir-1193 Leads to Synthetic Lethality in Glioblastoma
    Zhang et al. Cell Death and Disease (2020) 11:602 https://doi.org/10.1038/s41419-020-02812-3 Cell Death & Disease ARTICLE Open Access Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs Jing Zhang1,LiJing1,SubeeTan2, Er-Ming Zeng3, Yingbo Lin4, Lingfeng He 1, Zhigang Hu 1, Jianping Liu1 and Zhigang Guo1 Abstract Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and has the highest mortality rate among cancers and high resistance to radiation and cytotoxic chemotherapy. Although some targeted therapies can partially inhibit oncogenic mutation-driven proliferation of GBM cells, therapies harnessing synthetic lethality are ‘coincidental’ treatments with high effectiveness in cancers with gene mutations, such as GBM, which frequently exhibits DNA-PKcs mutation. By implementing a highly efficient high-throughput screening (HTS) platform using an in-house-constructed genome-wide human microRNA inhibitor library, we demonstrated that miR-1193 inhibition sensitized GBM tumor cells with DNA-PKcs deficiency. Furthermore, we found that miR-1193 directly targets YY1AP1, leading to subsequent inhibition of FEN1, an important factor in DNA damage repair. Inhibition of miR-1193 resulted in accumulation of DNA double-strand breaks and thus increased genomic instability. RPA-coated ssDNA structures enhanced ATR checkpoint kinase activity, subsequently activating the CHK1/p53/apoptosis axis. These data provide a preclinical theory for the application of miR-1193 inhibition as a potential synthetic lethal approach targeting GBM cancer cells with DNA-PKcs fi 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; de ciency. Introduction In response to DNA damage, cells activate the DNA Glioblastoma multiforme (GBM), exhibits highly damage response (DDR) network, allowing DNA repair aggressive invasion, a high mortality rate, and high resis- through the regulation of cell-cycle progression, DNA tance to radiation and cytotoxic chemotherapy, and thus damage repair or apoptosis4.
    [Show full text]
  • Meningioma ACKNOWLEDGEMENTS
    AMERICAN BRAIN TUMOR ASSOCIATION Meningioma ACKNOWLEDGEMENTS ABOUT THE AMERICAN BRAIN TUMOR ASSOCIATION Meningioma Founded in 1973, the American Brain Tumor Association (ABTA) was the first national nonprofit advocacy organization dedicated solely to brain tumor research. For nearly 45 years, the ABTA has been providing comprehensive resources that support the complex needs of brain tumor patients and caregivers, as well as the critical funding of research in the pursuit of breakthroughs in brain tumor diagnosis, treatment and care. To learn more about the ABTA, visit www.abta.org. We gratefully acknowledge Santosh Kesari, MD, PhD, FANA, FAAN chair of department of translational neuro- oncology and neurotherapeutics, and Marlon Saria, MSN, RN, AOCNS®, FAAN clinical nurse specialist, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA; and Albert Lai, MD, PhD, assistant clinical professor, Adult Brain Tumors, UCLA Neuro-Oncology Program, for their review of this edition of this publication. This publication is not intended as a substitute for professional medical advice and does not provide advice on treatments or conditions for individual patients. All health and treatment decisions must be made in consultation with your physician(s), utilizing your specific medical information. Inclusion in this publication is not a recommendation of any product, treatment, physician or hospital. COPYRIGHT © 2017 ABTA REPRODUCTION WITHOUT PRIOR WRITTEN PERMISSION IS PROHIBITED AMERICAN BRAIN TUMOR ASSOCIATION Meningioma INTRODUCTION Although meningiomas are considered a type of primary brain tumor, they do not grow from brain tissue itself, but instead arise from the meninges, three thin layers of tissue covering the brain and spinal cord.
    [Show full text]
  • The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy
    International Journal of Molecular Sciences Review The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy Fiona A. Desland and Adília Hormigo * Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, Department of Neurology, Box 1137, 1 Gustave L. Levy Pl, New York, NY 10029-6574, USA; fi[email protected] * Correspondence: [email protected] Received: 28 August 2020; Accepted: 29 September 2020; Published: 5 October 2020 Abstract: Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Its aggressive nature is attributed partly to its deeply invasive margins, its molecular and cellular heterogeneity, and uniquely tolerant site of origin—the brain. The immunosuppressive central nervous system (CNS) and GBM microenvironments are significant obstacles to generating an effective and long-lasting anti-tumoral response, as evidenced by this tumor’s reduced rate of treatment response and high probability of recurrence. Immunotherapy has revolutionized patients’ outcomes across many cancers and may open new avenues for patients with GBM. There is now a range of immunotherapeutic strategies being tested in patients with GBM that target both the innate and adaptive immune compartment. These strategies include antibodies that re-educate tumor macrophages, vaccines that introduce tumor-specific dendritic cells, checkpoint molecule inhibition, engineered T cells, and proteins that help T cells engage directly with tumor cells. Despite this, there is still much ground to be gained in improving the response rates of the various immunotherapies currently being trialed. Through historical and contemporary studies, we examine the fundamentals of CNS immunity that shape how to approach immune modulation in GBM, including the now revamped concept of CNS privilege.
    [Show full text]
  • Rehabilitation of Adult Patients with Primary Brain Tumors: a Narrative Review
    brain sciences Review Rehabilitation of Adult Patients with Primary Brain Tumors: A Narrative Review Parth Thakkar 1, Brian D. Greenwald 2,* and Palak Patel 1 1 Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA; [email protected] (P.T.); [email protected] (P.P.) 2 JFK Johnson Rehabilitation Institute, Edison, NJ 08820, USA * Correspondence: [email protected] Received: 22 May 2020; Accepted: 25 July 2020; Published: 29 July 2020 Abstract: Rehabilitative measures have been shown to benefit patients with primary brain tumors (PBT). To provide a high quality of care, clinicians should be aware of common challenges in this population including a variety of medical complications, symptoms, and impairments, such as headaches, seizures, cognitive deficits, fatigue, and mood changes. By taking communication and family training into consideration, clinicians can provide integrated and patient-centered care to this population. This article looks to review the current literature in outpatient and inpatient rehabilitation options for adult patients with PBTs as well as explore the role of the interdisciplinary team in providing survivorship care. Keywords: primary brain tumor; neuro-oncology; brain cancer; rehabilitation 1. Introduction About 80,000 people in the United States are diagnosed with a primary brain tumor (PBT) every year [1]. PBTs vary widely in their clinical presentations and can carry devastating prognoses for patients. The average survival rate for patients with malignant brain tumors is 35%, and the five-year survival rate for glioblastoma multiforme, the most common form of primary malignant brain tumor in adults, is 5.6%. There are an estimated 700,000 Americans living with a PBT, of which approximately 70% are benign and 30% are malignant [2].
    [Show full text]
  • Information Sheet 4: High-Grade Glioma Brain Tumours and Treatment Options
    Information Sheet 4: High-Grade Glioma brain tumours and treatment options This information document on high grade brain tumours simply provides a basis for discussion with the healthcare professionals with whom you are in contact. It should not in any way be used as a substitute for professional care. What is a Glioma? There are nearly 100 different types of brain tumours. Most primary brain tumours develop from the cells that support the nerve cells of the brain. These are called glial cells. So a tumour of glial cells is given the collective name of a glioma. About half of all primary brain tumours are gliomas. Low-grade or high-grade? Brain tumours are put into groups according to how fast they are likely to grow. There are four groups, called Grades 1–4. The cells are examined under a microscope, and the more normal they look, the more slowly the brain tumour is likely to develop and the lower the grade. The more abnormal the cells look, the more quickly the brain tumour is likely to grow and the higher the grade. You may have been told you have a benign tumour or a malignant tumour. Low-grade tumours are generally regarded as benign and high-grade as malignant. Malignant So, generally speaking, malignant means that: The tumour is relatively fast growing It may come back after surgery, even if completely removed It may spread to other parts of the brain or spinal cord It cannot just be treated with surgery and will need further treatments, such as radiotherapy or chemotherapy, to try to stop it from returning.
    [Show full text]
  • Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current Trends in Diagnosis and Management with a Focus on Novel Medical Therapies
    Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current trends in Diagnosis and Management with a focus on Novel Medical Therapies Simone Lisa Ardern-Holmes MBChB, MSc, FRACP A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Health Sciences, The University of Sydney February 2018 1 STATEMENT OF ORIGINALITY This is to certify that this submission is my own work and that, to the best of my knowledge, it contains no material previously published or written by another person, or material which to a substantial extent has been accepted for the award of any other degree or diploma of the university or other institute of higher learning, except where due acknowledgement has been made in the text. Simone L. Ardern-Holmes 2 SUMMARY Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are distinct single gene disorders, which share a predisposition to formation of benign nervous system tumours due to loss of tumour suppressor function. Since identification of the genes encoding NF1 and NF2 in the early 1990s, significant progress has been made in understanding the biological processes and molecular pathways underlying tumour formation. As a result, identifying safe and effective medical approaches to treating NF1 and NF2-associated tumours has become a focus of clinical research and patient care in recent years. This thesis presents a comprehensive discussion of the complications of NF1 and NF2 and approaches to treatment, with a focus on key tumours in each condition. The significant functional impact of these disorders in children and young adults is illustrated, demonstrating the need for coordinated care from experienced multidisciplinary teams.
    [Show full text]
  • Proceedings from the 2009 NF Conference: New Frontiers Joseph L
    CONFERENCE REPORT What’s New in Neurofibromatosis? Proceedings From the 2009 NF Conference: New Frontiers Joseph L. Kissil,1 Jaishri O. Blakeley,2 Rosalie E. Ferner,3 Susan M. Huson,4 Michel Kalamarides,5 Victor-Felix Mautner,6 Frank McCormick,7 Helen Morrison,8 Roger Packer,9 Vijaya Ramesh,10 Nancy Ratner,11 Katherine A. Rauen,7 David A. Stevenson,12 Kim Hunter-Schaedle,13* and Kathryn North14 1The Wistar Institute, Philadelphia, Pennsylvania 2Johns Hopkins University, Baltimore, Maryland 3Guy’s and St Thomas’!NHS Trust, London, United Kingdom 4St. Mary’s Hospital, University of Manchester, Manchester, United Kingdom 5Hopital Beaujon, APHP, Clichy, France and Inserm U674 6University Eppendorf, Hamburg, Germany 7University of California, San Francisco, California 8Leibniz Institute for Age Research, Jena, Germany 9Children’s National Medical Center, Washington, District of Columbia 10Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 11Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 12University of Utah, Salt Lake City, Utah 13Children’s Tumor Foundation, New York, New York 14University of Sydney and The Children’s Hospital at Westmead, Sydney, Australia Received 30 September 2009; Accepted 17 October 2009 The NF Conference is the largest annual gathering of researchers and clinicians focused on neurofibromatosis and has been con- How to Cite this Article: vened by the Children’s Tumor Foundation for over 20 years. The Kissil JL, Blakeley JO, Ferner RE, Huson SM, 2009 NF Conference was held in Portland, Oregon from June 13 to Kalamarides M, Mautner V-F, McCormick F, June 16, 2009 andco-chaired by Kathryn North from the University Morrison H, Packer R, Ramesh V, Ratner N, of Sydney and The Children’s Hospital at Westmead, Sydney, Rauen KA, Stevenson DA, Hunter-Schaedle Australia; and Joseph Kissil from the Wistar Institute, Philadel- K, North K.
    [Show full text]
  • Clinical and Genetic Patterns Ofneurofibromatosis 1 and 2
    662 BritishJournalofOphthalmology 1993; 77: 662-672 PERSPECTIVE Br J Ophthalmol: first published as 10.1136/bjo.77.10.662 on 1 October 1993. Downloaded from Clinical and genetic patterns of neurofibromatosis 1 and 2 Nicola K Ragge General introduction to the neurofibromatoses Neurofibromatosis type 1 The diseases traditionally known as neurofibromatosis have now been formally separated into two types: neurofibromato- CLINICAL ASPECTS sis type 1 or NFl (the type described by von Recklinghausen) Neurofibromatosis type 1 (NFI) is the commonest form of and neurofibromatosis type 2 or NF2 (a much rarer form).' It neurofibromatosis and has a frequency of about 1 in 3000 to is now recognised that although they have overlapping 1 in 3500.192° Although the gene is almost 100% penetrant, features, including an inherited propensity to neurofibromas the disease itselfhas extremely variable expressivity.20 About and tumours of the central nervous system, they are indeed 50% ofindex cases and 30% ofall NFl cases are considered to separate diseases and map to different chromosomes - 17 for be new mutations. The high mutation rate may be due in part NFl and 22 for NF2. Furthermore, developmental abnor- to the large size of the gene and its transcript, or possibly to malities such as hamartomas occur in both types of neuro- the presence of sequences within the gene highly susceptible fibromatosis, illustrating a need to define the role of the to mutation. normal NF genes in development. There may also be further forms of neurofibromatosis, including NF3, NF4, multiple meningiomatosis, and spinal Clinicalfeatures schwannomatosis, that do not fit precisely into current Particular clinical features are critical for establishing the diagnostic classifications.
    [Show full text]
  • Current FDA-Approved Therapies for High-Grade Malignant Gliomas
    biomedicines Review Current FDA-Approved Therapies for High-Grade Malignant Gliomas Jacob P. Fisher 1,* and David C. Adamson 2,3 1 Division of Biochemistry, Southern Virginia University, Buena Vista, VA 24416, USA 2 Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA; [email protected] 3 Atlanta VA Healthcare System, Decatur, GA 30033, USA * Correspondence: Jacob.fi[email protected] Abstract: The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.
    [Show full text]
  • Current Understanding of Neurofibromatosis Type 1, 2, And
    International Journal of Molecular Sciences Review Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis Ryota Tamura Department of Neurosurgery, Kawasaki Municipal Hospital, Shinkawadori, Kanagawa, Kawasaki-ku 210-0013, Japan; [email protected] Abstract: Neurofibromatosis (NF) is a neurocutaneous syndrome characterized by the development of tumors of the central or peripheral nervous system including the brain, spinal cord, organs, skin, and bones. There are three types of NF: NF1 accounting for 96% of all cases, NF2 in 3%, and schwannomatosis (SWN) in <1%. The NF1 gene is located on chromosome 17q11.2, which encodes for a tumor suppressor protein, neurofibromin, that functions as a negative regulator of Ras/MAPK and PI3K/mTOR signaling pathways. The NF2 gene is identified on chromosome 22q12, which encodes for merlin, a tumor suppressor protein related to ezrin-radixin-moesin that modulates the activity of PI3K/AKT, Raf/MEK/ERK, and mTOR signaling pathways. In contrast, molecular insights on the different forms of SWN remain unclear. Inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1 are considered responsible for a majority of cases. Recently, treatment strategies to target specific genetic or molecular events involved in their tumorigenesis are developed. This study discusses molecular pathways and related targeted therapies for NF1, NF2, and SWN and reviews recent clinical trials which involve NF patients. Keywords: neurofibromatosis type 1; neurofibromatosis type 2; schwannomatosis; molecular tar- geted therapy; clinical trial Citation: Tamura, R. Current Understanding of Neurofibromatosis Int. Type 1, 2, and Schwannomatosis. 1. Introduction J. Mol. Sci. 2021, 22, 5850. https:// doi.org/10.3390/ijms22115850 Neurofibromatosis (NF) is a genetic disorder that causes multiple tumors on nerve tissues, including brain, spinal cord, and peripheral nerves [1–3].
    [Show full text]
  • Genetic Testing for Neurofibromatosis and Related Disorders
    Corporate Medical Policy Genetic Testing for Neurofibromatosis and Related Disorders AHS – M2134 File Name: genetic_testing_for_neurofibromatosis_and_related_disorders Origination: 01/2019 Last CAPReview: 07/2021 Next CAP Review: 07/2022 Last Review: 07/2021 Description of Procedure or Service Neurofibromatoses are a group of three clinically and genetically distinct disorders that cause tumors to form on nerve tissue. Neurofibromatosis type 1 (NF1) is caused by autosomal dominant mutations in the neurofibromin (NF1) gene and is characterized by multiple café-au-lait macules and neurofibromas (Korf, 2021). Neurofibromatosis type (NF2) is caused by autosomal dominant mutations in the merlin, also known as schwannomin, (NF2) gene, and is characterized by multiple tumors of the nervous system, including the more common bilateral vestibular schwannomas as well as intracranial and spinal meningiomas, intrinsic ependymomas, and other spine tumors (Evans, 2020). Schwannomatosis is caused by inactivating mutations in SMARCB1 and LZTR and is characterized by multiple schwannomas and pain arising in adulthood (Yohay & Bergner, 2019). Legius syndrome is an NF1-like disorder caused by autosomal dominant mutations in the sprout-related EVH1 [enabled/vasodilator-stimulated phosphoprotein homology 1] domain-containing protein 1 (SPRED1) gene, resulting in café-au-lait macules. Constitutional mismatch repair-deficiency syndrome (CMMR-D), caused by mutations in mismatch repair genes, can also result in café-au-lait macules, axillary freckling, and Lisch nodules similar to NF1; however, unlike NF1, CMMR-D can also result in a variety of different malignancies, including glioblastoma and colorectal cancer (Korf, 2021). Related Policies Prenatal Screening AHS-G2035 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.
    [Show full text]