- Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer deaths.
- It arises from primitive neural crest cells of the sympathetic nervous system and the abdomen is the most common primary site.
- Staging systems include the International Neuroblastoma Staging System and the International Neuroblastoma Risk Group Staging System, which classify disease as localized, metastatic, or multifocal based on imaging.
- Treatment involves chemotherapy, surgery, radiation therapy, stem cell transplant, and immunotherapy depending on risk stratification as low, intermediate, or high risk based on age, stage, biology, and other factors.
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.
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.
Neuroblastoma diagnosis, treatment, complications, and further management. The main contents of this review have been accessed from MedScape. Please do not reprint or copy this material without permission from the copyright owner.
Neuroblastoma diagnosis, treatment, complications, and further management. The main contents of this review have been accessed from MedScape. Please do not reprint or copy this material without permission from the copyright owner.
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 non-glioma tumors from a medical neuro-oncology perspective.
Neuroblastoma is the most common cancer in babies and the third-most common cancer in children after leukemia and brain cancer, proper diagnosis, treatment must be done in appropriate time. As it a fatal condition psychosocial support is most important for patient and family.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
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 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 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
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
2. • Most common
• Extracranial solid tumor in children
• Malignancy in infants <1 year old.
• The median age at diagnosis is 17 months.
• Males>Females
• Abdomen is most common primary site (50%–80%)
• Other common sites
• Adrenal gland (35%)
• Low-thoracic or abdominal paraspinal ganglia (30%–35%)
• Posterior mediastinum (20%)
• Pelvis (2%), cervical spine (1%), and other sites (12%)
3. • Neuroblastoma, a small round blue cell tumor
Others: Lymphoma, all other “blastomas,” small cell
carcinoma of the lung, PNET and Ewing’s sarcoma,
and rhabdomyosarcoma
• Benign ganglioneuroma (well-differentiated,
favorable prognosis)
• Ganglioneuroblastoma (moderately differentiated,
unfavorable prognosis)
• Neuroblastoma (poorly differentiated, favorable to
poor prognosis)
4. • Arises from primitive
neural crest cells of the
sympathetic nervous
system
• Spinal ganglion
• Dorsal spinal nerve roots,
and
• Adrenal medulla.
• Homer-Wright
pseudorosettes are found
in 15–50% of cases.
5.
6. Immunohistochemistry (IHC)
•Positive for
• Neuron-specific enolase
• Chromogranin A
• Neurofilament protein
• S100, and
• Synaptophysin
• Negative for
• Leukocyte common antigen
• Vimentin
• Myosin and Actin
• Desmin
7. Genetics:
• N-myc protein amplification - short arm of chromosome 2 (20-25%)
• Cytogenetic abnormalities associated with poorer prognosis:
• LOH 1p, 11q, or isolated 17p; gain of 1q or 17q
• Diploid tumors (DNA index 1)
• Increased telomerase activity through TERT promoter rearrangement
• ALK copy number gain and gene amplification.
• Favorable factors
• Hyperdiploidy or
• TRK-A amplification.
8. Biochemistry
• In 90% of cases, elevated levels of catecholamines or
their metabolites are found in the urine or blood.
• Catecholamines and their metabolites
• Dopamine
• Homovanillic acid (HVA), and/or
• Vanillylmandelic acid (VMA)
9. Screening
• Screening Urine catecholamines in asymptomatic infants at three
weeks, six months, and one year has been performed in Japan,
Canada, Austria and Germany since the 1980s.
• Screening was halted in Japan in 2004 after studies in Canada and
Germany showed no reduction in deaths due to neuroblastoma.
• The high spontaneous regression rate led to overdiagnosis of clinically
insignificant disease.
• Screening does not change the mortality rate of neuroblastoma, as
confirmed in international trials.
11. • Abdominal mass, abdominal pain, fever, malaise, weight loss, micturition, dyspnea,
and dysphagia.
• 1/3 experience fatigue, anorexia, irritability, and pallor.
• Bone pain frequent in pts with skeletal mets (Skull/Posterior orbit).
• Excess catecholamines can produce flushing, sweating, and HTN (rare).
• 70% of patients present with metastatic disease with bone marrow mets seen in
80% to 90% & LN+ in 35%.
• Spontaneous regression may occur, especially in infants with 4S disease.
• 5-yr OS is 71% in modern era
• Mainly to increased cure rates in pts with less aggressive disease.
14. Work-up
• H&P, Labs include urine catecholamines, vanillylmandelic acid, and homovanillic acid, CBC,
BUN/Cr, and LFTs.
Imaging: CT/MRI of primary, MIBG scan, and CXR.
• CXR/CT chest for metastases.
• Primary tumor is calcified on X-ray in 80–90% of cases (vs. 5–10% in Wilms’).
• MIBG Scan:
• Meta-iodobenzylguanidine scan uptake in 90 to 95% of all neuroblastomas (MIBG-avid) [Sensitivity 97% &
Specificity 92%]
• The mechanism is that MIBG is taken up by sympathetic neurons, and is a functioning analog of the
neurotransmitter norepinephrine.
• When it is radio-iodinated with I-131 or I-123, it is a very good radiopharmaceutical for diagnosis and
monitoring of response to treatment for this disease.
• Bone scan if primary tumor is not MIBG Avid.
• Biopsy the primary or involved nodes.
• All patients should have a bilateral bone marrow biopsy and aspirate.
18. • Shimada classification: Favorable (FH)/Unfavorable (UH)
• Age
• Amount of Schwann cell stroma (Stromal pattern)
• Nodular vs. diffuse pattern
• Degree of neuroblastic differentiation
• Mitosis karyorrhexis index (MKI- Fragmentation of the nucleus)
• Favorable Shimada:
• Young age
• Rich stroma with non-nodular pattern
• Mature neuroblast differentiation
• Low MKI
19. • The International Neuroblastoma Staging System (INSS) used to stage
neuroblastomas and it attempts to combine the previously used Evans and
Pediatric Oncology Group (POG) staging systems.
• This was initially developed in 1986 and revised in 1993 and takes into account
the results of surgery to remove the tumor.
• The INSS staging system was further classified into low, intermediate, and
high-risk groups by the Children’s Oncology Group (COG).
• The International Neuroblastoma Staging System (INSS) is based on
surgicopathologic findings.
22. • 60% of patients <1 year present with localized disease.
• 70% of patients >1 year present with metastases.
• London (JCO 2005):
• Retrospective analysis of 3666 patients on POG and CCG
studies from 1986 to 2001 demonstrated prognostic
contribution of age to outcome is continuous.
• 460-day cutoff selected to maximize the outcome difference
between younger and older patients.
23. • INRG developed a staging system (INRGSS) based on
preoperative evaluation and extent of disease as determined
by imaging defined risk factors (IDRFs).
• INRGSS simplifies staging into localized (L1/L2) versus
metastatic disease (M/MS).
• The International Neuroblastoma Risk Group (INRG)
classification system is used to develop pretreatment risk
stratification to help standardize patients enrolled on trial.
International Neuroblastoma Risk Group Staging System(INRGSS)
24. International Neuroblastoma Risk Group
(INRGSS)
• L1: Localized tumor not involving vital structures as defined by the list
of imagedefined risk factors and confined to one body compartment
• L2: Locoregional tumor with presence of one or more image-defined
factors
• M Distant: metastatic disease (except stage MS)
• MS: Metastatic disease in children younger than 18 months with
metastasis confined to the skin, liver, and/or bone marrow
25. INRGSS image-defined risk factors
Ipsilateral tumor extension
within two body compartments
Neck-chest, chest-abdomen, or abdomen-pelvis
Neck Encasing carotid and/or vertebral artery and/or internal jugular vein.
Extending to the base of skull.
Compressing the trachea.
Cervicothoracic junction Encasing brachial plexus roots.
Encasing subclavian vessels and/or vertebral and/or carotid artery.
Compressing the trachea
Thorax Encasing the aorta and/or major branches.
Compressing the trachea and/or principal bronchi.
Lower mediastinal tumor, infiltrating the costovertebral junction between T9 and T12.
Thoracoabdominal Encasing the aorta and/or vena cava.
Abdomen/pelvis Infiltrating porta hepatis and/or the hepatoduodenal ligament.
Encasing branches of the SMA at the mesenteric root.
Encasing the origin of the celiac axis and/or the SMA.
Invading one or both renal pedicles.
Encasing aorta and/or vena cava.
Encasing iliac vessels.
Pelvic tumor crossing the sciatic notch.
Intraspinal tumor extension More than one-third of the spinal canal in the axial plane is invaded, and/or the perimedullary
leptomeningeal spaces are not visible, and/or the spinal cord signal is abnormal
Infiltration of adjacent organs/structures Pericardium, diaphragm, kidney, liver, duodeno-pancreatic block, and mesentery
Conditions to be recorded, but not
considered IDRFs
Multifocal primary tumors
Pleural effusion, with or without malignant cells
Ascites, with or without malignant cells
26.
27. 5year EFS cutpoints for the INRG pretreatment risk groups:
• Very low: >85%
• Low: 75–85%
• Intermediate: 50–75%
• High: <50%
29. • Treatment is determined by risk stratification
• Low
• Intermediate
• High risk
• COG risk grouping:
• Stage
• Age
• N-myc
• DNA ploidy
• Shimada histology.
• Pts with amplified N-myc are either low or high risk
• Pts with 11q aberration are intermediate to high risk
• Pts with stage I disease are low risk
30.
31. • POG 8104 (Nitschke, JCO 1988):
• 101 patients with POG A (INSS 1) disease.
• Gross total resection → observation
• 2-year DFS 89%.
• CCG 3881 (Perez, JCO 2000):374 patients treated with Evans I–II
(INSS 1–2B)
• Surgery alone (plus RT for spinal cord compression).
• Recurrences managed with surgery or multimodality therapy.
At 4-years EFS OS
stage I 93% 99%
stage II 81% 98%
Low Risk
32. • If GTR: Surgery → observation.
• If STR/unresectable, or recurrence after GTR → Chemo for 6–12 weeks.
• Chemotherapy regimens: Carboplatin, VP-16, CY, ADR, and/or Topotecan and
Cyclophosphamide.
• If patient has severe symptoms from spinal cord compression, respiratory
compromise, or GI/GU obstruction
• Start chemotherapy immediately (Early radiation in symptomatic/ progressive cases) →
Surgery
• RT (1.5/21 Gy) is used for symptoms that do not respond to chemotherapy or for
massive hepatomegaly causing respiratory distress (1.5/4.5 Gy).
• For clinically stable stage 4S low-risk patients, observe after biopsy unless massive
hepatomegaly causes respiratory distress (then treat with chemotherapy ± RT).
33. • Castleberry, POG (Castleberry, JCO 1991):
• 62 patients >1 year old with POG C (INSS 2B-3)
• Randomized to post-op chemotherapy ± concurrent RT → second-look
surgery → chemotherapy.
• RT was to the primary and regional nodes(1.5/24 Gy for <2 years old or 1.5/30
Gy for >2 years old).
• Chemo-RT improved DFS (31 → 58%) and CR rate (45 → 67%).
• POG 8742 & 9244 (Eur J Cancer 1997): 49 patients >1 year old with
INSS 2B-3
• Surgery → chemotherapy × 5c → second-look surgery → RT for viable residual
tumor → chemotherapy.
• RT was 1.5/24 Gy for age 1–2 years, 1.5/30 Gy for age >2 years.
• Two-year EFS
• 85% after GTR vs. 70% after STR
• 92% for FH vs. 58% for UH
INTERMEDIATE RISK
34. • RT was shown to increase both EFS and OS when added to
adjuvant CHT in the Castleberry study of POG C pts.
• The current intermediate-risk pts, are not the same pts as
those in the Castleberry study.
• RT is not a standard component of first-line therapy.
• As in low-risk pts, RT is typically reserved for pts with
residual disease refractory to CHT, recurrent disease, or
those who remain symptomatic.
35. • Maximal safe resection with lymphadenectomy →
chemotherapy for 12–24 weeks depending on biology.
• Chemotherapy regimens consist of carboplatin, VP-16, CY, ADR,
and/or topotecan and cyclophosphamide.
• Unresectable tumors may require preoperative
chemotherapy to convert them to resectable status.
• Radiation controversial in intermediate-risk disease
• If PR to chemotherapy → second-look surgery. If viable
residual disease present → RT to primary (1.5/24 Gy)
• If stage 4S with respiratory distress → RT to liver (1.5/4.5 Gy)
36. CCG 3891 (NEJM 1999; IJROBP 2003; JCO 2009):
539 high-risk patients
• After induction CHT, pts without progression underwent delayed primary surgery with nodal assessment followed by RT to
gross residual disease.
• Induction CHT consisted of cisplatin, doxorubicin, etoposide, and cyclophosphamide x five cycles.
• RT dose was 20 Gy/10 fx to extra-abdominal disease and 10 Gy/5 fx to mediastinal and intra-abdominal tumors.
• Pts were subsequently randomized to receive consolidation CHT or myeloablative CHT + TBI with SCT.
• Consolidation CHT consisted of three cycles of cisplatin, etoposide, doxorubicin, ifosfamide.
• Myeloablative CHT was carboplatin and etoposide.
• TBI was 10 Gy/3 fx daily.
• Following SCT or consolidation CHT, pts without disease progression were randomized to six cycles of 13-cis-retinoic acid
(isotretinoin) or no further therapy.
• 2009 update:
• ABMT + TBI improved 5-year EFS (19 → 30%)
• Cis-retinoic acid improved 5-year EFS (31 → 42%)
• Trend toward improved OS for both.
HIGH RISK
37. • ANBL0532 (Park, ASCO 2016): 652 patients with high-risk NB
• Induction chemotherapy and surgery with randomization to single
vs. tandem ASCT
• Tandem SCT improved 3-yr EFS from 48.8% to 61.8% (p = .008)
with a nonsignificant improvement in OS (69.0%–73.8%, p = .256).
• 249 pts received postconsolidation immunotherapy, which also
improved both EFS and OS
• Immunotherapy: anti-GD2 antibody with isotretinoin vs. isotretinoin alone
• EFS 55.4% vs. 73.7%, p < .001
• OS 75.7% vs. 86.3%, p = .016).
38. • High-dose induction chemotherapy (ifosfamide and cisplatin)
+/- 131 I-MIBG → attempt maximal safe resection.
• After surgery → high-dose chemotherapy and tandem
transplant.
• All patients then
→ RT (1.8/21.6 Gy) to the postchemotherapy,
presurgical extent of tumor
→ +/− 1.8/14.4 Gy boost to gross residual disease
→ cis-retinoic acid +/− antibody therapy for 6 months.
39. Radiation
• Indications:
• Highrisk: RT is delivered to the primary tumor and persistent metastatic sites.
• Intermediate-risk: RT is delivered to recurrent or gross residual disease.
• Adjuvant RT: Not indicated for low- or intermediate-risk disease
• Urgent symptomatic (life/organ threatening) concerns without
significant response to CHT
• Eg: Liver mets with respiratory compromise or cord compression.
40. Simulation and Field Design
• CT and/or MRI used for planning 3DCRT or IMRT plans.
• Treat the postchemotherapy, presurgical tumor extent with
a 1–1.5 cm margin, adjusted for pushing borders.
• If lymph node involvement is suspected or proven, cover
involved LN.
• Do not give elective nodal RT because of morbidity and lack of
benefit.
• Always cover full width of vertebrae to avoid scoliosis.
41. DOSE PRESCRIPTIONS
• Intermediate risk = 24 Gy/1.5 Gy/# (controversial)
• High risk = 21.6 Gy/12# plus 14.4 Gy/8# @1.8 Gy/# (boost to gross residual
disease)
• 4S liver involvement = 4.5 Gy/ 3# @ 1.5 Gy/# (Hepatic metastasis causing
respiratory compromise)
DOSE LIMITATIONS
• Ipsilateral kidney: D25% <18 Gy, D100% <14.4 Gy
• Contralateral kidney: D75% <18 Gy
• Liver: mean <15 Gy, D85% <30 Gy
• Lung: ipsilateral D70% <20 Gy, contralateral D10% <20 Gy
• Vertebral bodies: min 18 Gy if overlaps with PTV
• Spine: 36 Gy after induction with bleomycin and mitomycin
42. COMPLICATIONS:
• Acute: Diarrhea, nausea, vomiting, erythema, fatigue, myelosuppression.
• Late: Site irradiated and the total dose of both radiation and chemotherapy
agents used.
• Age at the time of treatment may influence the risk and severity of skeletal anomalies, which
may include spinal deformities such as kyphosis, scoliosis, or limb shortening.
• Younger children are more prone to late radiation injury than older children. (<6months)
• Both laminectomy and RT dose >17.5 Gy were risk factors for development of scoliosis in
children with abdominal neuroblastoma.
• A report from the Childhood Cancer Survivor Study showed the 20-year cumulative
incidences of neurologic, sensory, endocrine, and musculoskeletal toxicities were 29.8%,
8.6%, 8.3%, and 7.8%.
• The cumulative incidence of secondary malignancies was 3.5% at 25 years after diagnosis.
43. • For cord compression, CHT is preferred followed by surgical
decompression.
• For widespread disease, 131I-MIBG scan, chemotherapy, or bone
marrow transplantation could be considered.
• Iobenguane I-131 (COG ANBL1531) is essentially therapeutic MIBG
including I-131 (diagnostic MIBG includes I-123) and has shown
dramatic responses in relapsed/refractory cases.
• Crizotinib is active against ALK mutated tumors.
44. • Targeted radionuclides:
• I-131 MIBG therapy, response rates of 30-40% pts
• Being investigated before resection or in combination with SCT for
consolidation.
• Differentiation therapy:
• Neuroblastoma cell lines can be induced to terminally differentiate with
retinoids.
• Risk of relapse is reduced in pts who receive isotretinoin.
• Immunotherapy:
• Neuroblastoma cells express disialoganglioside GD2 on their surface.
• Dinutuximab, a chimeric anti-GD2 antibody (ch14.18) is FDA-approved for
adjuvant first-line therapy
• Significant acute toxicity - capillary leak syndrome and pain.
Other modalities
aid distinction from other similar tumors (non-Hodgkin’s lymphoma, Ewing’s, sarcomas).
The prognostic implications of a tumor’s biologic indices, such as MYCN amplification and DNA index, may warrant more aggressive therapy in young patients with otherwise a favorable stage.
However, in the modern era, additional genetic/biologic risk-stratification factors (such as N-myc status) are used to better risk-stratify pts.
Induction CHT consisted of cisplatin, doxorubicin, etoposide, and cyclophosphamide x five cycles.
After induction CHT, pts without progression underwent delayed primary surgery with nodal assessment followed by RT to gross residual disease.
RT dose was 20 Gy/10 fx to extra-abdominal disease and 10 Gy/5 fx to mediastinal and intra-abdominal tumors.
Pts were subsequently randomized to receive consolidation CHT or myeloablative CHT + TBI with SCT.
Consolidation CHT consisted of three cycles of cisplatin, etoposide, doxorubicin, ifosfamide.
Myeloablative CHT was carboplatin and etoposide.
TBI was 10 Gy/3 fx daily.
Following SCT or consolidation CHT, pts without disease progression were randomized to six cycles of 13-cis-retinoic acid (isotretinoin) or no further therapy.
5-yr EFS and OS for all pts were 26% and 36%, respectively.
5-yr LRR was 51% for pts treated with CHT versus 33% for pts treated with SCT (p = .0044).
3-yr EFS with CHT was 22% versus 34% with SCT.
3-yr EFS after the second randomization was 46% among the 130 pts who received 13-cis-retinoic acid versus 29% among the 128 who received no further therapy (p = .027).
2009 update demonstrated 5-yr EFS of 19% for pts treated with consolidation CHT versus 30% for pts treated with SMT (p = .04).
5-yr EFS from second randomization was higher for isotretinoin than no further therapy, although not significant (42% vs. 31%).
Conclusions: This study set the standard treatment regimen for high-risk neuroblastoma, which includes both autologous SCT and isotretinoin.