UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA...

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UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemell i” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi CANCER SUSCEPTIBILITY AND MANAGEMENT IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 Second primary cancer and familiar cancer syndromes Rome, 27 January 2012

Transcript of UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA...

Page 1: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

UNIVERSITÀ CATTOLICA DEL SACRO CUOREFacoltà di Medicina e Chirurgia “A. Gemelli” - ROMA

ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi

CANCER SUSCEPTIBILITY AND MANAGEMENT IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

Second primary cancer and familiar cancer syndromes

Rome, 27 January 2012

Page 2: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1 - EPIDEMIOLOGY

• NF1 is one of the most common genetic disorders in the general population

• Population prevalence: 1 of 3.500 live births

• Sex ratio 1:1

• All racial groups are equally affected

Page 3: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1: A MULTISYSTEMIC GENETIC DISORDER

• Autosomal dominant disorder • Many affected persons inherit the disorder, however 30 – 50% of new cases

result from a spontaneous genetic mutation of unknown cause

• Variable phenotypic expression: signs can range from benign cutaneous manifestations to life-threatening or sever disfigurement

• Complete clinical manifestations at 8-10 years of age

• Symptoms and severity of the disorder may vary among members of an affected family

Page 4: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1: A TUMOUR-SUPPRESSOR GENE

NF1: tumour-suppressor gene located on chromosome 17q11.2

NF1 encodes neurofibromin, a cytoplasmic protein that is expressed in neurons, schwann cells, oligodendrocytes, astrocytes and leukocytes

Neurofibromin is a negative regulator of the Ras oncogene, the inactivation of which leads to cell proliferation and tumour development

Page 5: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1- DIAGNOSTIC CRITERIA

Two or more of the features listed:

1. Six or more café au lait macules• larger than 5 mm in greatest diameter in prepubertal individuals • larger than 15 mm in greatest diameter in postpubertal individuals

2. Freckling in the axillary or inguinal regions3. Optic pathway glioma4. Two or more Lisch nodules 5. A distinctive osseous lesion, such as

sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis

6. A first-degree relative with NF-1 according to the above criteria7. Two or more neurofibromas of any type or 1 plexiform neurofibroma

Page 6: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NEUROFIBROMAS

• Most common benign tumor of NF-1

• It can form at any place along a nerve

• Three subtypes of neurofibroma : cutaneous, subcutaneous, and plexiform

• Cutaneous lesions and subcutaneous lesions are circumscribed. These nodules may be brown, pink, or skin colored. They may be soft or firm to the touch

• Plexiform neurofibromas are non circumscribed, thick, and irregular, and they can cause disfigurement by entwining important supportive structures

cutaneous neurofibromas

Plexiform neurofibroma

Page 7: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1 - BONE ABNORMALITIES

• Scoliosis: 10-30%

• Pseudarthrosis: 1 à 3 %

Page 8: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1 - NEUROPSYCHOLOGICAL DISORDERS

• Mental retardation : 4 - 8 %

• Learning disabilities: 40-60%

• Epilepsy: 11 %

• Headache

Page 9: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

OTHER CLINICAL FEATURES OF NF-1

• congenital heart defects

• Hypertension. In NF1 it can also result from renovascular disease, tumors that secrete vasoactive compounds, and coarctation of the aorta

• Hypoglycemia

• Fibromas in Iris

• Glaucoma – rare

Page 10: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

HEALTH SUPERVISION GUIDELINES FOR CHILDREN WITH NF1

   INFANCY

 

 

EARLY CHILDHOOD

Annual evaluation

 

LATE CHILDHOOD

 Annual

evaluation

 

ADOLESCENCE 

Annual evaluation

   1 mo

 

 2 mo

 4 mo

 6 mo

 9 m

 12 m

 15 m

 18 m

 24 m

 3-5 y

 6-12 y

 13-21y

Counseling genetico Medical evaluation Growth Blood pressure Skin examiantion Bone examiantion Neurologicexamination Vision screening Sexual maturation 

Psychosocial evaluation Development/behaviorSchool performancePsychological/social adjustment

X  XXXXX    

X   

   XXXXX    

   XXXXX    

   XXXXX    

   XXXXX    

   XXXXXX   

X X

   XXXXX    

X X

   XXXXX    

X X

   XXXXXX   

X X 

   XXXXXX   

X X

   XXXXX

X*X  

XXX 

   XXXXX

X*X  

XXX

* Biannual vision screening since the age of 7 years

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NF1 AND NEOPLASTIC RISK

• Patients with NF-1 have about a 3-15% additional risk of malignant disease in their lifetime

• In NF1-related tumours, biallelic NF1 inactivation results in complete loss of functional neurofibromin activity. Most tumour suppressor genes are inactivated according to the two-hit model

• Malignant tumours can arise in the nervous and non-nervous system in either childhood or adulthood

• Malignant tumours are the most common cause of death in individuals with NF1

• The systematic medical follow-up of children with NF1 is necessary due to developments of malignancies related to the disease

Brems et al. Lancet Oncol 2009; 10:508–515

Page 12: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

TUMOURS IN NF1 PATIENTS RELATIVE RISK

Brain tumours

Optic pathway glioma 920

Meningioma 155

Astrocytoma 31.1

Medulloblastoma 11.4

Ependymoma 6.6

Other gliomas 24

Sarcomas

MPNST (Malignant Peripheral Nerve Sheath Tumour) 9000

Rabdomyosarcoma 23.4

Other sarcomas 20

Tumours of the sympathetic nervous system

Neuroblastoma 3.1

Pheochromocytoma 1000

Leukemia

Acute lymphoblastic leukemia 2.7

Chronic myeloid leukemia 71.4

Lymphoma

Hodgkin lymphoma 8

Non-Hodgkin lymphoma 3.4

Page 13: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MANAGEMENT OF OPTIC PATHWAY GLIOMAS IN CHILDREN WITH NF1

Page 14: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

OPG IN CHILDREN WITH NF1

• Incidence of OPG in patients with NF1: 15 - 20 %

• OPG are associated with NF1 in 50 %-70 % of cases

• Diagnosis below the age of 6 years: 60-70 % of cases

• Histologically, OPG are almost uniformly pilocytic astrocytoma (WHO grade I)

• The majority of OPGs are slow growing

• The prognosis is reportedly much better in children with NF1 than in those without (3-years progression free survival: 82% vs 42%)

• Spontaneous regression has been reported in OPG associated with NF1

Page 15: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

CHILDREN WITH NF1:

- the most common site of involvement is the orbital nerve- bilateral optic nerve involvement is seen almost exclusively in NF1 patients- the tumor is smaller than in the non-NF patients and the original shape of the optic pathway is preserved- cystic components are uncommon

CHILDREN WITHOUT NF1:

- the chiasm and hypothalamus are the most common sites of involvement- cystic components are frequently seen

DIFFERENT FEATURES OF OPG IN CHILDREN WITH AND WITHOUT NF1

Kornreich et al. Am J Neuroradiol 2001; 22:1963–1969

Page 16: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

A SPECIFIC RADIOLOGICAL FEATURE OF NF1: UNIDENTIFIED BRIGHT OBJECTS (UBOs)

• UBOSs: areas of increased signal intensity on T2-weighted images

• 60% of affected children

• lesions well circumscribed and nonenhancing, located in the brainstem, cerebellum, basal ganglia, and thalamus

• the lesions are not space occupying and tend to disappear in adulthood

Page 17: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

VISION SCREENING IN CHILDREN WITH NF1

• Ophthalmic screening is recommended in children with NF1

• The protocol includes visual acuity testing and fundoscopy every year + colour vision and visual fields when the child can co-operate

Listernick et al. Ann Neurol 2007;61:189–198

ASYMPTOMATIC CHILDREN < 8 YEARS:annual screening

ASYMPTOMATIC CHILDREN > 8 YEARS:screening every 2 years until 18 years of age

The first 6 years of life constitute the time of maximal risk for OPG development.In children younger than 1 year visual examinations may be unreliable!

Page 18: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MRI: USEFUL SCREENING TOOL IN CHILDREN WITH NF1?

• Some specialists recommend an initial MRI study to determine if an optic glioma is present when the diagnosis of NF1 is made, based on the difficulty in detecting visual changes in young children

• Although potentially helpful in establishing an early diagnosis,based on the benign nature of most OPG and the need to sedate the child neuroimaging of the brain may not be warranted

- Neuroimaging of asymptomatic children has not been shown to improve clinical

outcomes nor does early detection reduce the incidence of visual loss due to OPG

- MRI does not predict clinical behaviour or preclude the later development of an OPG

- Incidentally identified NF1-associated OPGs rarely require treatment

Page 19: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

AN INTEGRATED APPROACH TO THE TREATMENT OF OPGs

• Do we need to treat?

• If yes, when?

• And how?

Page 20: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

OPG IN CHILDREN WITH NF1 - MANAGEMENT

• Absolutely mandatory pre-therapeutic multidisciplinary discussion

• Let’s be careful about the real need for treatment– Imaging is not the only criteria to start the treatment – We treat a child not an MRI

• Treatment in patients with clinical and/or radiological progression (visual progression, defined as a two-line decrement in visual acuity, is an indication for chemotherapy)

• Surgery is reserved for large tumors causing mass effect or hydrocephalus and tumors confined to the orbit or unilateral optic nerve

• When a non surgical treatment is needed, decision should take into account:– Age– NF1– Tumour site– Tumour volume

Page 21: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

etoposide increased risk of second tumours !!!

Page 22: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

RADIOTHERAPY IN CHILDREN WITH OPG AND NF1

In chidren with NF1 RT is not recommended leading to serious complications: • Increased risk of second tumors

• Neurovascular sequelae, moyamoya syndrome

Page 23: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

SECOND CANCERAS IN IRRADIATED AND NON IRRADIATED NF1 PATIENTS

Sharif S et al. J Clin Oncol. 2006 1;24:2570-5.

Page 24: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Targeted therapy is addressed to key pathways involvedwith the development of tumors in NF1:

• Ras/mitogen-activated protein kinase (MAPK) • Akt/mammalian target of rapamycin (mTOR)

TARGETED THERAPY

Page 25: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Recently, mTOR inhibitors such as everolimus have shown encouraging benefit for patients with

subependymal giant cell astrocytoma

Page 26: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.
Page 27: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MALIGNANT PERIPHERAL NERVE SHEATH TUMOUR IN CHILDREN WITH NF1

Page 28: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

• The lifetime risk of a malignant peripheral nerve sheath tumour (MPNST) in patients with NF1 is 8–13%

• Annual incidence: 0.16% (compared with 0.001% in the general population)

• In patients with NF1 MPNSTs are difficult to diagnose because many of these patients have multiple benign tumors of the peripheral nervous system

• Most NF1-associated MPNSTs arise within preexisting plexiform neurofibromas and may not produce symptoms until distant metastases occurr

Cecen et al, Childs Nerv Syst (2011) 27:1885–1893

MPNST IN CHILDREN WITH NF1

Plexiform neurofibromas that become painful or begin to grow rapidly should be investigated for the

risk of malignant transformation!!!

Page 29: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MPNST show increased glucose uptake on FDG-PET

FDG-PET can differentiate most benign neurofibromas from MPNSTs

Brems et al. Lancet Oncol 2009; 10:508-515

Page 30: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

• Inactivation of both NF1 alleles is thought to be sufficient to form a benign neurofibroma but not an MPNST

• Most MPNSTs have a complex karyotype with many gains and losses of chromosomal material

• The tumour suppressor genes CDKN2A and TP53 have an important role in the malignant transformation of neurofi broma to MPNST

Brems et al. Lancet Oncol 2009; 10:508-515

MPNST - MECHANISMS OF ONCOGENESIS

Page 31: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MPNST IN NF1 PATIENTS: TREATMENT AND PROGNOSIS

• Complete surgical resection is the mainstay of the successful treatment of MPNSTs

• Radiotherapy can improve local control

• Poor prognosis in children with NF1 compared to sporadic cases (5-year survival rate 21% vs 42%):

– occurrence of larger, more invasive, and less resectable tumors in NF1 patients

– tumours less responsive to chemotherapy (17% vs 55% in non-NF1 cases)

– potential biological differences between MPNST patients with and without NF1

Page 32: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

RABDOMYOSARCOMA IN CHILDREN WITH NF1

Page 33: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

RMS IN CHILDREN WITH NF1

• The prevalence of RMS associated with NF1 is about 20 times higher than that in the general population

• The pathogenesis of RMS in NF1 patients appears less clear than for MPNST

• RMS arising in NF1 patients tend to have peculiar features:1. embryonal histotypes 2. genitourinary tract or pelvic (paravesical) location 3. onset in early age

Embryonal rhabdomyosarcoma (bothyroid type) protruding from the vaginal meatus

Page 34: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

CONCLUSION

• The development of malignancies is a feature of NF1

• The clinical course of malignancy in NF1 is often different from that of similar tumor types in the general population

• Careful follow-up in patients with NF1 is required to enable the early diagnosis of malignancies

Page 35: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.
Page 36: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

CASE REPORT

20 days-old child is brought to the pediatrician for a check up

Clinical examination: healthy baby

7 café au lait macules larger than 5 mm in greatest diameter

Family history: father and paternal grandmother with NF1

IS THE CHILD AFFECTED BY NF1?

Page 37: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NF1- DIAGNOSTIC CRITERIA

Two or more of the features listed:

1. Six or more café au lait macules• larger than 5 mm in greatest diameter in prepubertal individuals • larger than 15 mm in greatest diameter in postpubertal individuals

2. Two or more neurofibromas of any type or 1 plexiform neurofibroma3. Freckling in the axillary or inguinal regions4. Optic pathway glioma5. Two or more Lisch nodules 6. A distinctive osseous lesion, such as sphenoid dysplasia or thinning of

the long bone cortex, with or without pseudoarthrosis7. A first-degree relative with NF-1 according to the above criteria

Page 38: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

HEALTH SUPERVISION GUIDELINES FOR CHILDREN WITH NF1

   INFANCY

 

 

EARLY CHILDHOOD

Annual evaluation

 

LATE CHILDHOOD

 Annual

evaluation

 

ADOLESCENCE 

Annual evaluation

   1 mo

 

 2 mo

 4 mo

 6 mo

 9 m

 12 m

 15 m

 18 m

 24 m

 3-5 y

 6-12 y

 13-21y

Counseling genetico Medical evaluation Growth Blood pressure Skin examiantion Bone examiantion Neurologicexamination Vision screening Sexual maturation 

Psychosocial evaluation Development/behaviorSchool performancePsychological/social adjustment

X  XXXXX    X   

   XXXXX    X 

   XXXXX    X 

   XXXXX    X 

   XXXXX    X 

   XXXXXX   X X

   XXXXX    X X

   XXXXX    X X

   XXXXXX   X X 

   XXXXXX   X X

   XXXXX

X*X  XXX 

   XXXXX

X*X  XXX

* Biannual vision screening since the age of 7 years

Page 39: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

CLINICAL HISTORY

• At 4 years of age: occurrence of headache and reduction of visual acuity

• Brain scan showed a optic pathway mass, confirmed by IRM

BIOPSY?

The association between OPG and NF1 is a well-known phenomenon.

Diagnosis of OPG based on IRM.

Page 40: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

• Treatment according to SIOP LGG 2004 protocol

(start on 28/05/2005; end on 18/06/2006)

• Stable disease until July 2007

• MRI on 25/09/2007: – increase of the cystic component,

without mass effect

– no progressive visual impairment

• MRI on 07/01/08:– reduction of the cystic component

– no progressive visual impairment

TREATMENT CLINICAL AND RADIOLOGICAL EVOLUTION

TREATMENT ?

WAIT AND SEE

Page 41: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Sagittal MRI T2 flair scan of brain- at six months of age showing huge mass in optic chiasmatic region (a)- at four years of age showing significant regression of optic chiasmatic mass (b)

EXAMPLES OF SPONTANEOUS REGRESSION - 1

Page 42: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Coronal (a) and axial (b) T1 weighted MRI imaging after contrast administration, disclosing a chiasmatic tumor, performedwhen the boy was 2 years old.

Coronal (c) and axial (d) T1 weightedMRI imaging after Gadolinium administration, 9 months later,demonstrate the complete regression of the chiasmatic lesion.

EXAMPLES OF SPONTANEOUS REGRESSION - 2

Page 43: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

LET’S BE CAREFUL ABOUT THE REAL NEED FOR TREATMENT!

• Imaging is not the only criteria to start the treatment ! We treat a child not an IRM

• Treatment in patients with clinical and/or radiological progression

Page 44: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Now the child is 11 years old– off - therapy for 5.5 years– stable disease– visual acuity deficit persists

OUTCOME

To date, no specific therapy is available for optic glioma – induced visual loss

NEUROPROTECTION ?

Page 45: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NERVE GROWTH FACTOR (NGF)

• NGF is the first discovered neurotrophin involved in the development and survival of sympathetic, sensory, and forebrain cholinergic neurons

• given its actions favoring neuronal survival, NGF has been proposed for the treatment of some traumatic, ischemic, and neurodegenerative brain diseases

• exogenous NGF has a neuroprotective effects on the visual system due to the presence of NGF receptors on the conjunctiva, cornea, as well as in the retinal pigment epithelium, photoreceptors, and retinal ganglion cells

• NGF promotes: – protective activity against neural apoptosis – neuronal repair and– axonal regeneration

Page 46: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

TREATMENT BY NGFpurified and lyophilized

from male mouse submandibular glands

1 mg of NGF diluted in 5 mL of saline solution was administered onto the conjunctiva of both eyes

for 10 consecutive days 3 times a day

Page 47: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

Five patients with OPGs and advanced optic nerve atrophy were assessed beforeand after a single 10-day course of 1 mg murine NGF topical administration by clinical evaluation, visual-evoked potentials(VEPs), and MRI

After NGF treatment:

- median VEPs amplitude showed a progressive increase from the baseline values (p < 0.01)

- perception of spontaneous visual phosphenes was noted

Page 48: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

NGF: A PROMISING RESCUING STRATEGY

Eye drop NGF administration appears tobe a promising rescuing strategy for the treatment of

children with optic glioma – induced visual loss

RISK TUMOUR PROGRESSION ?

No significant change in tumor volumeafter NGF treatment was found

Page 49: UNIVERSITÀ CATTOLICA DEL SACRO CUORE Facoltà di Medicina e Chirurgia “A. Gemelli” - ROMA ISTITUTO DI CLINICA PEDIATRICA Direttore: Prof. Riccardo Riccardi.

MRI of the brain -at baseline (A and B)

-4 months after NGF administration (C and D)

No significant change in tumor volumeafter NGF treatment