Molecular pathogenesis of CNS tumors lecture covers the following key points in 3 sentences:
The lecture discusses the molecular underpinnings and classification of various CNS tumors including gliomas, medulloblastoma, and meningiomas. It covers important molecular markers and genetic alterations that drive tumor pathogenesis, such as IDH1/2 mutations and 1p/19q codeletion in gliomas, and WNT and Sonic Hedgehog pathways in medulloblastoma classification. The lecture also reviews diagnostic techniques like FISH, IHC, and gene sequencing that are used to detect these molecular alterations and inform tumor grading and targeted therapy approaches.
Medulloblastoma- A primitive neuroectodermal tumors (PNETs) is the most common malignant brain tumor of childhood (WHO IV)
arising from the vermis in the inferior medullary velum.
It comprises up to 18% of all pediatric brain tumors.
WNT and Shh pathway plays major role in its pathogenesis.
c-erbB-2 (HER2/neu) oncogene expression has prognostic value. Norcantharidin, Vismodegib, Sonidegib are the future in medulloblastoma.
This is not a original work of mine based on Various text books, Journals and also Power Point presentations too
This is a WHO Classification 2021 Update and with brief about all tumor types.also added are the changes that are made in this classification
helpful for Neurology and Neurosurgery Residents
This Power Point Presentation is useful to revise the final exam
various cutaneous lymphomas though having low incidence but need to be diagnosed accurately. they can be mimiced by many non neoplastic conditions of skin. so discussing both T and B cell lymphomas
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
Medulloblastoma- A primitive neuroectodermal tumors (PNETs) is the most common malignant brain tumor of childhood (WHO IV)
arising from the vermis in the inferior medullary velum.
It comprises up to 18% of all pediatric brain tumors.
WNT and Shh pathway plays major role in its pathogenesis.
c-erbB-2 (HER2/neu) oncogene expression has prognostic value. Norcantharidin, Vismodegib, Sonidegib are the future in medulloblastoma.
This is not a original work of mine based on Various text books, Journals and also Power Point presentations too
This is a WHO Classification 2021 Update and with brief about all tumor types.also added are the changes that are made in this classification
helpful for Neurology and Neurosurgery Residents
This Power Point Presentation is useful to revise the final exam
various cutaneous lymphomas though having low incidence but need to be diagnosed accurately. they can be mimiced by many non neoplastic conditions of skin. so discussing both T and B cell lymphomas
Allogeneic hematopoietic stem cell transplantation (allo HSCT) from an HLA-matched related donor provides the most potent anti-leukemic effect of any post-remission therapy in AML, as demonstrated by the lowest rates of relapse.
Graft vs leukemia plays and important role here.
Provides the best chance of long-term survival
Aim of this ppt presentation:
To understand the standard of care for both GBM and anaplastic glioma.
To know what is the new advances and modifications to the standard of care?
Contents:
Introduction: 2 slides.
GBM:
Epidemiology: 1 slide.
Molecular biology & New trends: 5 slides
EORTC/NCIC trial: 10 slides.
MGMT: 1 slide.
Evidence-based medicine: 6 slides.
Avastin in GBM: 2 slides.
Novocure (TTF): 2 slides.
Gliadel (BCNU) wafers: 1 slide.
Anaplastic astrocytoma: 7 slides
Take home message.
Central nervous system (CNS) lymphoma is a disease in which malignant (cancer) cells form in the lymph tissue of the brain and/or spinal cord
Fatal Condition
x-rays, MRI and computed tomography (CT) scans
Lack technique for early diagnosis
This is a PDF of a presentation given to the Radiation Oncology department at the University of Minnesota in October 2015. This PDF focuses on evaluation, management, and state-of-the-art approach to gliomas from a medical neuro-oncology perspective.
Radiotherapy in low grade gliomas benefit with local control advantage
Patients with high risk factors need immediate radiation after surgery
RT dose of 50-54 Gy in 2 Gy/Fr
Fractionated radiosurgery in optic nerve glioma and small volume disease
Michael Buckland, Neuropathology, RPA Hospital & Brain and Mind Research Institute presents at the Brain Tumour Patient Forum, hosted by the Cure Brain Cancer Foundation.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
4. Hallmarks of cancer. (Adapted from Hanahan D, Weinberg RA.Hallmarks of cancer: the next generation. Cell 2011; 144:646.)
5. Epidemiology of CNS tumors
• Primary cerebral malignancy* -
• 4 to 10/lac general population
• 1.6% of all primary tumors
• 2.3% of all cancer related deaths
• 2nd most common cancer in children
• 20% of all cancers in children <15 yrs
• Therapeutic X-irradiation has been unequivocally linked
with brain tumors (7–9 years)
*Francis Ali-Osman, Brain tumors, 2005
6. Distribution of Primary Brain and CNS Tumors by Behavior (N = 356,858), CBTRUS Statistical Report:
NPCR and SEER, 2008-2012
7. Distributiona in Children (Age 0-14 years) of Primary Brain and CNS Tumors by CBTRUS Histology Groupings
and Histology (N = 16,366), CBTRUS Statistical Report: NPCR and SEER, 2008-2012
8. Cell of Origin
• Glial cells
• Neural stem cells (NSC): proposed that carcinogenesis is
dependent on a small population of cells termed ‘‘cancer stem
cells*’’ (CSCs)
• Genes that are expressed in NSC are Nestin, EGFR, PTEN,
Hedgehog etc : Neurogenesis and Gliogenesis
• Aberrant activation of developmental genetic programs in NSCs
gives rise to CNS tumors
*Ignatova et al. 2002; Shen et al. 2004
11. Gliomas
• Gliomas (a primary tumor of glial cell origin) are the
most common intracranial neoplasm
• Astrocytomas, glioblastomas, and oligodendrogliomas
accounting for more than 80%
• Grade I to Grade IV tumors
• GBMs: most aggressive and deadly of these tumors, are
the most common of the gliomas (55%)
12. Distributiona of Primary Brain and CNS Gliomasb by Histology Subtypes (N = 97,910), CBTRUS Statistical
Report: NPCR and SEER, 2008-2012
13. Gliomas
• 1985 : Epidermal growth factor receptor (EGFR) gene
amplification in glioblastoma
• Subsequent discoveries :
• Phosphatase and tensin homolog (PTEN) gene
• Mutations in the TP53 gene
• BRAF fusion
• MGMT gene
• IDH mutations
14. Molecular markers: Glioma
• 1p/19q co-deletion in oligodendroglial tumors
• Mutations in the IDH1/2 genes in diffuse gliomas
• Hypermethylation of the MGMT gene promoter in
glioblastomas
• Alterations in the EGFR and PTEN genes, and 10q deletions
in GBMs
• BRAF alterations in pilocytic astrocytomas
MGMT: O6-methylguanine DNA methyltransferase ;, BRAF :v-raf murine sarcoma viral oncogene
homologe B1, IDH: isocitrate dehydrogenase; PTEN: Phosphatase and tensin homolog
16. Gliomas
1. 1p/19q CODELETION:
• Loss of the short arm of chromosome 1 (1p), along with the long
arm of chromosome 19 (19q); "genetic signature" of
oligodendrogliomas
• Early genetic event in oligodendroglial tumorigenesis
• 80% to 90% in oligodendrogliomas (WHO grade II)
• 60% in anaplastic oligodendrogliomas (WHO grade III)
• 30% to 50% in oligoastrocytomas
• Partial loss of chromosome 1p in oligodendrogliomas has an
opposite prognostic significance when compared with tumors
that have a complete 1p/19q loss
• Almost all oligodendrogliomas with a 1p/19q codeletion are also
positive for IDH1 or IDH2 mutations
17. Gliomas
• The first allele is lost (1st Hit) due to an imbalanced reciprocal translocation between
chromosomes 1 and 19
• The second allele is disrupted (2nd Hit) by a somatic mutation capable of inhibiting protein
function
18. Gliomas
1. 1p/19q CODELETION:
• The CIC gene is a tumor suppressor gene present in the Chr 19
• Encodes for protein capicua homolog
• Member of the high mobility group (HMG)-box superfamily of
transcriptional repressors
• Loss of CIC gene results in loss of transcription repressor function
19. Gliomas
1. 1p/19q CODELETION:
• The status of the 1p/19q loci detected by:
• FISH
• PCR
• Loss of heterozygosity (LOH) analysis or virtual karyotyping
• Comparative genomic hybridization array
• Single nucleotide polymorphism array
• Cairncross et al.: (1998) : better response to procarbazine-
lomustine-vincristine chemotherapy and a longer survival in
patients with anaplastic oligodendroglioma
• Co-deletions (ie, 9p or 10q loss) may lead to poor outcome
independent of the 1p/19q status
20. Gliomas
2. IDH1 AND IDH2 MUTATIONS
• Mutations in the IDH1 gene were discovered in 2008 during a
genome-wide analysis of 22 glioblastomas as a part of the Cancer
Genome Atlas Project
• Presence of the mutation is associated with young age, a
secondary-type GBM, and increased overall survival
• 60% to 90% of secondary glioblastomas that developed from
lower-grade tumors
• IDH1 mutations are rare in primary GBMs and are completely
absent in pilocytic astrocytomas
• Mutations in IDH2 gene were detected in a smaller proportion of
gliomas (5%), mostly in oligodendroglial tumors
22. Gliomas
2. IDH1 AND IDH2 MUTATIONS
• Sanger sequencing analysis: most commonly used method for
detection of IDH1 and IDH2 mutations. It allows for detection of
all mutational variants
• Pyrosequencing : better sensitivity than Sanger sequencing
• Real-time PCR amplification: fast, less laborious, and more
sensitive; allows detection of as little as 10% mutant alleles or
20% of cells with mutations in a background of normal DNA
• Immunohistochemistry: monoclonal antibodies for detection of
IDH1 R132H mutation. Convenient detection of mutations in
tissue sections. IHC will miss approximately 10% of gliomas
carrying less-common mutations of IDH1 and all of the IDH2
mutations
24. Gliomas
3. MGMT METHYLATION :
• The MGMT gene is located at chromosome 10q26 and encodes
for a DNA repair protein
• Epigenetic silencing of this gene by promoter hypermethylation
leads to reduced expression of the MGMT protein
• MGMT gene silencing improves survival in patients with
glioblastoma who are treated concurrently with alkylating drug
temozolomide and radiation therapy
• Prognostic and predictive marker
• Hegi and colleagues (2005): reported that 49% of patients with
glioblastoma and methylated MGMT were alive at 2 years after
treatment with temozolomide and radiotherapy, as compared
with 15% of patients with unmethylated MGMT
MGMT: Methylguanine-DNA-methyltransferase
25. Gliomas
3. MGMT METHYLATION :
• Most of the methods for MGMT analysis are based on evaluation
of the methylation status of the ‘CG island’ of the MGMT gene
• Methylation-specific PCR (MSP) : methylation status at 6 to 9
CpGs
• Real-time PCR
• Methylation-specific Pyrosequencing
• IHC: assessment of MGMT methylation by IHC has failed to
correlate with disease outcome
CG : Cytosine/Guanine
26. Gliomas
4. BRAF/KIAA1549 FUSION :
• Part of the mitogen-activated protein kinase (MAPK) pathway
• Serine/threonine kinase, modulates cell proliferation and survival
• First BRAF mutation reported in papillary thyroid carcinomas
• In gliomas: BRAF activation is by gene duplication or point
mutation
• Fusion between the KIAA1549 and BRAF genes
• Identified in 60% to 80% of pilocytic astrocytomas
• Rare in diffuse astrocytic gliomas
• Prognostic significance is still under investigation
• RAF inhibitors (vemurafenib and dabrafenib)
• Interphase FISH: currently the best method for testing for this
fusion
• IHC : anti-BRAF V600E (VE1) antibody
27. Gliomas
5. EGFR AND PTEN ALTERATIONS:
• Cell surface receptors for Endothelial growth factors
• EGFR affects cell proliferation and growth through the activation
of downstream effector molecules in the MAPK and PI3K-AKT
pathways
• EGFR gene : located on chromosome 7p12
• Activation of EGFR signaling through gene amplification or
mutations is found in about 30% to 40% of primary glioblastomas
• Mutant EGFR: characterized by a deletion of 267 amino acids in
the extracellular domain of the EGFR protein
• Truncated protein: EGFRvIII receptor : lacks an extracellular
domain but remains constitutively activated
• Detection of either EGFR amplification or EGFRvIII is indicative of
high-grade glioma and can be used diagnostically
28. Gliomas
5. EGFR AND PTEN ALTERATIONS:
• Attractive target for new therapies in gliomas
• anti-EGFR tyrosine kinase inhibitors
• anti-EGFRvIII vaccine: addition of vaccine to radiation and
chemotherapy resulted in increased overall survival*
• EGFR amplification: FISH
• EGFRvIII analysis: performed by RT-PCR amplification
• Phosphatase and tensin homolog (PTEN) : tumor suppressor
gene located on the long arm of chromosome 10
• Counteracts one of the most critical cancer-promoting pathways,
the PI3K-AKT signaling pathway
• Genetic alterations: LOH at 10q frequently found in high-grade
gliomas (15-40%)
• Poor prognostic marker for anaplastic astrocytomas and
glioblastoma
• Detected in FFPE tissue by LOH analysis or FISH
*Heimberger AB, Sampson JH. The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients. Expert Opin Biol Ther. 2009;9(8):1087–1098. 84. Yoshimoto K, Dang J, Zhu S, et al.
Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples. Clin Cancer Res. 2008; 14(2):488–493
30. Medulloblastomas
• Second most frequent BT in children after pilocytic astrocytoma
• First decade of life, second peak in the early 20s
• Genetic tumor syndrome: Turcot syndrome, Gorlin syndrome
• Embryonal tumor of the brain, analogous to Wilms tumor of the
kidney
• Origin: stem cells located in the subependymal matrix and the
external granular layer (EGL) of the cerebellum
• Medulloblastomas are tumors of the cerebellum, arising more
frequently in the midline, especially in the posterior vermis,
adjacent to the roof of the fourth ventricle
Medulloblastoma: molecular pathways and histopathological classifcation ; Anna Borowska, Jarosław Jóźwiak ; Arch Med Sci 2016; 12, 3: 659–666
31. Medulloblastomas
• Molecular pathogenesis:
• Previously, thought to represent a subset of primitive
neuroectodermal tumor (PNET) of the posterior fossa
• Gene expression profiling: distinct molecular profile and are distinct
from other PNET tumors
• Five histological subtypes:
1. Classical type (CMB)
2. Desmoplastic/nodular type (DN),
3. Medulloblastoma with extensive nodularity (MBEN),
4. Anaplastic type
5. Large cell Medulloblastoma (LC)
• Four molecular subgroups:
1. Wnt subgroup
2. Sonic hedgehog subgroup
3. Group 3
4. Group 4
32. Medulloblastomas
1. WNT subgroup:
• The Wnt/β-catenin pathway participates in the control of
vertebrate development
• Rarest subgroup of medulloblastoma, accounting for 11%
• Patients with Turcot syndrome: predisposition to Wnt MB
• Germline mutation of Apc gene
• Thought to arise from ‘mossy-fiber neuron precursors’, involved
in the formation of synapses in the developing cerebellum
34. Medulloblastomas
1. WNT subgroup:
• Includes mainly classic MB
• Large cell/anaplastic MB (good prognosis)
• Monosomy of chromosome 6 is present in about 100% of
Wnt tumors
• Overall excellent long term prognosis (90% 5 year survival
rate)
35. Medulloblastomas
1. WNT subgroup:
• IHC: monoclonal antibodies against the C-terminal domain of β-
catenin
• CTNNB1 (β-catenin encoding gene) mutation analysis by direct
gene sequencing
• Cantharidin and norcantharidin: drugs on trial against Wnt
associated medulloblastoma
36. (A) Classic MB with nuclear
β-catenin immunostaining
(B) Nodular MB with cytoplasmic β-
catenin immunostaining
(C) Anaplastic MB with cytoplasmic
β-catenin immunostaining
37. Medulloblastomas
2. Shh Medulloblastomas
• Account for 28% of all medulloblastomas
• Intermediate prognosis
• Dichotomous age distribution: common in both children
(<4 years) and adults (>16 years)
• Gorlin syndrome : germline mutations in PTCH gene*
• Sonic hedgehog (Shh) pathway: plays a key role in normal
cerebellar development, induces proliferation of neuronal
precursor cells in the developing cerebellum and other
tissues
• Normal conditions: The Shh ligand is secreted by Purkinje
neurons and promotes formation of the external germinal
layer in the cerebellum
PTCH: patched 1
39. Medulloblastomas
2. Shh Medulloblastomas
• Molecular analysis of sporadic medulloblastomas commonly
shows Patched-1 (PTCH1) mutations
• Desmoplastic/nodular and MBEN are almost exclusively
associated with Shh pathway activation
• IHC: GLI1, and GAB1 have been proposed
• Hh pathway inhibitor: Cyclopamine, Vismodegib, Saridegib
• SMO inhibitors: SANT1–SANT4
• Arsenic compounds: targets GLI1
SFRP1: secreted frizzled related protein 1; GLI1: glioblastoma family protein; GAB1: GRB2-associated-binding protein 1
40. Medulloblastomas
3. Group 3 Medulloblastomas
• 28% of all medulloblastomas
• Associated with the worst prognosis of all the subgroups and
are frequently metastatic
• Predominantly found in infants/children
• Relatively little is known about the molecular pathogenesis
• Associated with MYC amplification
• Further categorized in to 3α and 3β, depending on MYC
expression
• 3α – tumors: increased MYC expression and worse prognosis
• 3β – tumors: normal MYC expression and better prognosis
• Mostly associated with classic or large cell/anaplastic
morphology
• Detected by transcriptional profiling, although IHC for NPR3*
has been proposed
*NPR3: Natriuretic peptide receptor
41. Medulloblastomas
4. Group 4 Medulloblastomas
• Most common “typical” subgroup of medulloblastoma,
accounting for around 34%
• Rarely affect infants (0–3 years) and mainly affect children,
with a peak age of 10 years
• Intermediate prognosis
• Classic histology
• Associated with isochromosome 17q (2/3rd cases)
• Associated with CDK6 and MYCN amplification but minimal
MYC over-expression
• Chromosome X loss is seen in 80% of females
42. Medulloblastomas
4. Group 4 Medulloblastomas
• Currently detected by gene expression profiling
• Immunohistochemistry for KCNA* has been proposed
*Potassium Voltage-Gated Channel Subfamily A
45. Ependymal Tumors
Third most common pediatric brain tumors
50% of cases arising in children under 5 years of age
Ependymal neuroepithelium of the ventricles and spinal
canal
Occur in three distinct locations:
Supratentorial brain comprising the cerebral hemispheres
Brain stem and cerebellum
Spinal cord
Pediatric: Intracranial, cerebellum and brain stem
Adult: Spinal cord
46. Ependymal Tumors
1. Myxopapillary ependymoma Grade I
2. Subependymoma Grade I
3. Ependymoma Grade II
1. Cellular
2. Papillary
3. Clear cell
4. Tanycytic
4. Anaplastic ependymoma Grade III
48. *Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8 (4):323-335
CDKN2A: cyclin-dependent kinase Inhibitor 2A
49. Ependymal Tumors
2. Molecular Genetic Aberrations
Taylor et al*, aCGH profiles of 103 ependymomas, three
molecularly distinct subtypes of ependymomas depending on
tumor location:
1. Supratentorial ependymomas : CDKN2A deletion in >90%
cases, poor prognosis
2. Spinal tumors: Deletion of chromosome 22q12,
3. Posterior fossa ependymomas : chromosome 1q gain, good
prognosis
*Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8
(4):323-335
50. Ependymal Tumors
2. Molecular Genetic Aberrations
RELA fusion positive ependymomas:
Subset of supratentorial ependymomas
Fusion between C11orf95, a gene with unknown function, and
RELA gene on Chr 11q13
RELA encodes RelA (p65), protein which interacts with IκB and
p50 in the central signaling complex in the NF-κB pathway
Amenable to targeted therapy
Supratentorial ependymomas of childhood carry C11orf95–RELA fusions leading to pathological activation of the NF-κB signaling pathway: Acta
Neuropathol (2014) 127:609–611
RELA: v-rel avian reticuloendotheliosis viral oncogene homolog A
51. Ependymal Tumors
2. Molecular Genetic Aberrations
RELA fusion positive ependymomas:
*NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) ; IKK: IĸB kinase
RELA Fusion gene protein
52. Ependymal Tumors
3. Epigenetics:
Methylation status of the hypermethylated in cancer 1 (HIC-1)
putative tumor suppressor gene: downregulation in 81% of
cases, correlated with non-spinal localization and pediatric age
The RAS association domain family 1 isoform A (RASSF1A) gene:
silenced by methylation in 86% of ependymoma, results in loss
of cell cycle control, enhanced genetic instability and cell
motility, and resistance to K-Ras and TNF-α induced apoptosis
53. Ependymal Tumors
4. Gene expression profiling:
112 abnormally expressed genes* in ependymoma
WNT5A, TP53 homologue, TP63, ZIC1, VEGF and
Fibronectin1
Cell cycle, proliferation, adhesion, and extracellular matrix
regualtion
*Suarez Merino B, Hubank M, Revesz T, et al. Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four
transcripts at 22q12.1 -q13.3 [J]. Neuro Oncol, 2005,7(1):20-31
**Taylor MD, Poppleton H, Fuller C, et al. Radial glia cells are candidate stem cells of ependymoma [J]. Cancer Cell, 2005,8 (4):323-335
55. Meningioma
• Meningiomas are mostly benign, slow-growing tumors of the
CNS
• Most common CNS tumor in adults
• Originate from Arachnoidal cap cells
• Annual incidence of meningiomas is 2.3 per 100,000
• Peaks in the 7th decade of life
• Associated risk factors:
• Deletions of the neurofbromatosis Type 2 (NF2) gene
• Ionizing radiation
56.
57.
58. Meningioma
• Benign meningiomas are slow growing and have a 5-
year recurrence rate of 5% following gross-total
resection
• Atypical meningiomas have 5-year recurrence rate of
40%
• Anaplastic meningiomas have recurrence rates of up to
80%
• Surgical resection and radiotherapy, mainstay
treatment
59. Meningioma
• Cytogenetic abnormality:
• Monosomy 22 is the most frequent genetic abnormality
• Association between the long arm of chromosome 22 (22q)
and meningiomas was first studied in patients with NF2
• Bilateral vestibular schwannomas, multiple meningiomas,
and other CNS tumors
• Allelic losses in 22q12.2: Nearly all NF2-associated
meningiomas, and 70% of sporadic meningiomas
• NF2 gene encodes the tumor suppressor merlin, critical role
in controlling cell growth and motility
NF2: Neurofibromatosis 2
60. Schematic diagram of merlin's role in tumourigenesis.
C. O. Hanemann Brain 2008;131:606-615
62. Meningioma
• Cytogenetic abnormality:
• Chr 1p deletions comprise the second most common
chromosomal abnormality
• Found in:
• 13%–26% of Grade I
• 40%–76% of Grade II
• 70%–100% of Grade III
• Loss of 1p is also associated with a 30% recurrence rate
63. Meningioma
• Sex steroids:
• The incidence of meningiomas is more than 2-fold
greater in women than in men
• Increased growth during pregnancy and the luteal phase
of the menstrual cycle
• Expression of the progesterone receptor is most
frequently observed
• Progesterone receptor is expressed in 81% of women
and 40% of men with meningiomas
• Expression is highest in benign meningiomas (50%–80%)
• PR status can help to describe the biological behavior of
meningiomas
66. Primary CNS lymphoma
• Accounts for less than 5% of all primary brain tumors
• Lymphoma occurring in the brain, leptomeninges, spinal cord, or
eyes without evidence of lymphoma outside the CNS
• Majority are high-grade B-cell lymphomas
• 95%-98% diagnosed as high-grade DLBCL
• 05% of cases include Burkitt, Burkitt-like, and lymphoblastic B-cell
lymphomas as well as T-cell lymphomas
• Patients with AIDS develop PCNSL at a rate 3600-fold
higher than the general population and have a lifetime risk of CNS
lymphoma that approaches 20%
67. Primary CNS lymphoma
• Age group: 60 yrs
• Intracranial mass lesion, 70% cases are supratentorial
• Basal ganglia, the corpus callosum, and/or the periventricular
subependymal tissues
• Periventricular location, facilitating leptomeningeal seeding
• Extend across the corpus callosum and involve both cerebral
hemispheres
68. Primary CNS lymphoma
• Pathogenesis :
• Gain on chromosome 12
• EBV
• Chemokines
• Protooncogene mutation
• Ectopic expression of Interleukin-4
• Promoter hypermethylation of the CDKN2A gene
• STAT6 overexpression
• Unfolded protein response pathway
• Somatic mutations in Ig variable region genes
• Allelic deletions of the long arm of chromosome 6
69. Primary CNS lymphoma
• Gain on chromosome 12 :
• Comparative genomic hybridization
• Most frequent alteration
• Gain in a region of 12q
• MDM2, CDK4, and GLI1 overexpression
70. Primary CNS lymphoma
• EBV:
• Immunocompromised individuals
• Proliferation of EBV infected B-cells is usually suppressed by
normal T-cell immunity
• EBV infected clone may progress to malignant lymphoma
• EBV extracted from the CSF via PCR
71. Primary CNS lymphoma
• Chemokines:
• Class of molecules that regulate the trafficking of leukocytes as
well as their proliferation and adhesion
• BCA1 (CXCL13) : expressed at significant levels in PCNSL tumors
• Promotes B-cell homing to secondary lymphoid organs
• Helicobacter pylori–induced MALTomas as well as in gastric
lymphoma
BCA1: B-cell attracting chemokine1
72. Primary CNS lymphoma
• Protooncogene mutation:
• Somatic mutation of PIM1 and MYC oncogene
• High level of expression of PIM1 and MYC proteins
• Ectopic expression of Interleukin-4:
• Interleukin4 is not expressed in the vasculature of normal brain
• Expression by tumor associated endothelia in PCNSL
• May contribute to the angiotropic growth pattern of lymphoma
cells within the CNS
73. Primary CNS lymphoma
• Hypermethylation of the CDKN2A gene:
• Established molecular event
• Produces p14ARF
CDKN2A: cyclin-dependent kinase Inhibitor 2A
HDM2: human double minute 2 (HDM2)
78. Summary
• First impression is not the last impression
• Not only a morphological diagnosis, but also molecular
data
• Prognosis and response to treatment
• 1p/19q assessment, IHC for IDH1 and β-catenin*
The Molecular Pathology of Primary Brain Tumors; David S. Hersh et al, Pathol Case Rev 2013;18: 210-220