Presented By:

Dr. Vandana

Deptt. of Radiotherapy

CSMMU, Lucknow

Introduction The origin of Medulloblastoma is from medulla (Latin for marrow), blastos

(Greek word for germ) and oma (Greek for tumor);

means “tumor of primitive undeveloped cells located inside the cerebellum”.

Most common malignant primary brain tumor of child age group.

First described by Harvey Cushing and Percival Bailey in 1930.

Initially described as “spongioblastoma cerebelli” - a soft, suckable tumor usually arising in the vermis of cerebellum.

In 1925, changed name to medulloblastoma - from “medulloblast” - a hypothetical multipotent cell.

OriginA highly malignant primary brain tumor that originates in the

cerebellum vermis or posterior fossa.

Arise in cerebellum and projects into 4th ventricle.

Originate from embryonal cells k/a medulloblast of cerebellar stem cells. The exact cell of origin, or “medulloblast” has yet to be identified.

It is currently thought that it arises from Germinative neuroepithelial cells in the external granular layer of cerebellum.

Anatomy

Posterior fossa contains hindbrain which consists of cerebellum, pons and medulla.

The cavity of hindbrain is fourth ventricle. This is bounded in front by pons and medulla and behind by cerebellum.

The vermis separates two lateral lobes or cerebellar hemspheres.

Because of the location of the fourth ventricle, ventral to the cerebellum, mass lesions or swelling of the cerebellum can cause obstructive hydrocepahalus.

Relevant Neuroanatomy

CSF PathwaysLateral Ventricle

Foramen of Munro

Third Ventricle

Foramen of Luschka

Foramen of Magendie

Central canal of Spinal Cord

Subarachnoid Space

CSF is produced by modified ependymal cells in choroid plexus

It circulates from lateral ventricles into the third ventricle through the foramen of munro.

It then passes into the fourth ventricle through the narrow cerebral aqueduct.

From the fourth ventricle, it passes slowly through median aperture (foramen of magendie) and lateral foramina (foramen of luschka) and enters the subarachnoid space over brain and spinal cord.

It is reabsorbed into venous sinus blood via arachnoid granulations.

Epidemiology Overall account ~ 7% all

brain tumors 10-20% of brain tumors in

pediatric age group 0.4%–1% of all adult central

nervous system tumors 40% of tumors of the

posterior fossa Peak incidence at the age of 5

–6 yrs In children and 25 yrs in adults

Approximately 20% of Medulloblastoma present in infants younger than 2 years old;.

male : female (3:2)

Figure: Distribution of pediatric central nervous system (CNS) tumors by location in the CNS and by tumor type.

Adult vs. Paediatric MedulloblastomaChild Adult

Usual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs

Shorter clinical History (~ 3 months) Longer history ( ~ 5 months)

Classical type predominates Desmoplastic type relativelycommoner

Median cerebellar syndromepredominates

Lateral cerebellar syndrome seen

Biologically more agressive Biologically less aggressivePoorer resectability - median location Greater resectability - lateral location

Higher surgical morbidity andmortality

Lower surgical morbidity and mortality - impact of location and age

Poorer RT tolerance Better RT tolerance

Poorer long term survival Better long term survival

Natural HistoryArising in the

midline cerebellar vermis (roof of the

4th ventricle)

Grows into the 4th ventricle

Fills into the 4th ventricle

Spread around the 4th ventricle

Invasion of ventricular

floor

Invasion of brain stem

Invasion of brachium

pontis

CSF Spread

Extra neural spread :Young age, males and diffuse subarachnoid disease

Mode of Spread

Contagiously- cerebellar peduncle Floor of forth ventricle Ant-brain stem Inf –cervical spine Sup- above tentorium

CSF(30%) – Intracranially Leptomeninges Spinal cord

Extraneural (5%) Most common CNS tumor to spread Hematogenous MC sites are Long Bones and Ribs(10-15%) LN(4-6%)

Pathological Features

Highly cellular tumorHigh N:C ratioCells arranged in typical Homer -

Wright rosettesMultiple histological subtypes

1. Classic medulloblastomas- 70-80%

2. Desmoplastic/nodular- 7%

3. Medulloblastoma with extensive nodularity (MBEN) - 3%

4. Anaplastic

5. Large Cell

WHO classification - 2007

large cell / anaplastic (LCA) 10% to 22%.

Classic Medulloblastoma: densely packed cells, hyperchromatic nuclei

classic medulloblastoma

medulloblastoma with extensive nodularity

Medulloblastoma with extensive nodularity – (MBEN): occurs in infants and is associated with a good prognosis.

large cell medulloblastoma

anaplastic medulloblastoma

Large cell medulloblastoma: Large nuclei, abundant cytoplasm.

These ‘large cells’ tend to mix with cells with nuclear pleomorphism and k/a ‘anaplastic’ cells.

Diffuse anaplasia is associated with poor prognosis.

Desmoplastic/nodular: nodular, reticulin-free zones or ‘pale islands’. Surrounded by densely packed mitotically active cells.

Chang Surgical classification 1969 T1 Tumour < 3 cm in diameter and limited to classic position in

vermis, roof of fourth ventricle, or cerebellar hemisphere

T2 Tumour > 3 cm in diameter and further invading one adjacent structure or partially filling the fourth ventricle

T3a Tumour further invading two adjacent structures or completely filling the fourth ventricle, with extensions into aqueduct or foramina of Magendie or Luschka with marked internal hydrocephalus

T3b Tumour arising from the floor of fourth ventricle or brain stem and filling the fourth ventricle

T4 Tumour penetrates aqueduct to involve third ventricle or midbrain or extends to cervical cord

No N Stage

M0 No metastases

M1 Microscopic evidence of tumour cells in CSF.

M2 Macroscopic metastases in cerebellar and/or cerebral subarachnoid space and/or supratentorial ventricular system

M3 Macroscopic metastases to spinal subarachnoidal space

M4 Metastases outside the central nervous system

Clinical FeaturesRaised ICT: Due to obstructive or non

communicating hydrocephalus

Pressure Syndrome: Nocturnal or morning head-ache, nausea and vomiting and papilledema.

Symptoms usually precede presentation by no more than 2 months.

Presenting symptoms are related to the age of the patient. infants with open cranial sutures, irritability, anorexia,

failure to thrive, macrocephaly and setting sun sign. The younger, nonverbal patient presents with

behavioral changes, listlessness, irritability, vomiting, and decreased social interactions.

Older children and adults complain of headache, especially upon awakening in the morning.

Decerebrate rigidity, head tilt, stiff neck s/o herniation

Cerebellar Signs: In children, tumor involve cerebellar vermis causes gait ataxia. In Adults, desmoplastic variant arises in cerebellar hemisphere

causing ipsilateral dysmetria. Worsening handwriting ,difficulty with hoping or running, slurring

speech and hypotonia.

Neighbourhood syndrome: focal deficit due to pressure effect. Brain stem : diplopia, 6th cranial nerve palsy, positional

dizziness, nystagmus, tinnitus, hearing loss, facial sensory and motor loss .

Leptomeningeal dissemination: Rarely the symptoms are present. Patients can complain of radiculopathy

Bone mets- painExtra neural site- lymph node.

Diagnostic Work up

Detailed Clinical history: Morning headaches, nausea, vomitting, confusion, visual changes, unsteady walking.

Physical examination: Gait, signs of raised ICT, double vision, stiff neck

General examination

CNS examinationo Higher mental examo Cerebeller examo Sensory examo Motor examo Cranial N. exam

Ophthalmoscopy examination for papilloedema

Resection of tumor

VP Shunting +Biopsy

High dose steroids + Neuro radiological examination

Patient stable

Medulloblastoma

Histopathological examination

Patient extremelysomnolent

Confirmation of diagnosis NeuroRadiological examination Biopsy

Neuro Radiological examination

CT finding

Hyperattenuated, well-defined vermian cerebellar mass

Surrounding vasogenic edema

Cyst formation

Evidence of hydrocephalus

Fig: A, Axial noncontrast CT image demonstrates a large lobulated hyperdense round tumor (arrow) with an internal hypodense cavity. An ill-defined faintly hypodense band surrounding the hyperdense mass represents white matter edema.

MRI features: MRI is the gold standard.

Iso- to- hypointense relative to adjacent cerebellar vermis (T1

images)

Iso intense to slightly Hyperintense on T2 weighted images

Homogeneous enhancement (but may be irregular and patchy)

following contrast

MRI with contrast enhancement is very sensitive for detection of

tumor spread, metastatic seeding in the cranial and spinal

subarachnoid spaces.

Fig: (B,) non-contrast axial T1-weighted (C,) T2-weighted MR images; the solid portion of the tumor appears mildly hypointense on T1-weighting and mildly hyperintense on T2-weighting (arrow). Following intravenous gadolinium, an axial T1-weighted image (D,) demonstrates irregular patchy contrast enhancement of the solid areas of the tumor (arrow).

Adult Medulloblastoma Poorly defined masses

located in the cerebellar hemisphere.

Cyst like regions are morecommonly seen

Fig: (A,) Axial T2-weighted MR image demonstrates a poorly circumscribed mass with a heterogeneous signal pattern in the anteroinferior portion of the right cerebellar hemisphere. (B,) After intravenous administration of gadolinium, the tumor demonstrates homogeneous contrast enhancement with well-circumscribed margins (arrow). Punctate intratumoral hypointensities represent enlarged vascular channels and/or focal calcifications.

Spinal MRI

Fig: Sagittal and axial MRI, T1 weighted Gadolinium contrast enhancement – Medulloblastoma with metastatic spread to the meninges within the posterior fossa and with a large intramedullary deposit.

Most sensitive for spinal cord mets

Frequency of spinal seeding

at diagnosis is 30-35%.

M.C.seen in the lumbosacral and thoracic areas and are best seen on post-contrast T1-weighted images.

MRI spine should be obtained whenever possible pre-operatively or else at least 2-3 weeks post-operatively.

Advantage of MRI over CT

Highly sensitiveHigh resolution in diagnosing posterior

fossa tumor because of high quality coronal images without artifacts, associated with beam hardening through bone in CT.

Sagittal images can be used in RT planning.MRI better delineates tumor induced

edema.

CSF examination: Important for stagingLumber puncture: most common method for obtaining

CSF.can’t be obtained pre-operatively because of raised ICT.

More commonly obtained at 3 weeks post operatively. To avoid risk of misinterpretation due to post operative changes.

Routine Investigations: Hemogram, KFT, LFT, Serum electrolyte, Chest X-ray, USG abdomen (Not mandatory)

Skeleton imaging: In case of Bone mets.

Risk Factor

• At diagnosis, 2/3rd of patients are standard risk and 1/3 are high risk.

• Standard Risk: 5yr. Survival is more than 80%• High Risk: 5 yr survival is 30-60%

• M stage is a crucial staging component.

• Several studies had shown that the T stage of the Chang's system did not

correlate with survival- so replaced by the definition of the post operative residual tumor volume concept.

Risk Factor Standard Risk High Risk

Age > 3 yrs. < 3 yrs

Residual Tumor < 1.5 cm2 (Complete or near total resection)

> 1.5 cm2 (subtotal or biopsy)

Mets M0 M1 - M4

Treatment Medulloblastoma is well managed by multimodal approach.

Surgery“Surgery is usually the first step and mainstay of treatment.”

Objective: Remove or Reduce as much of the tumor's bulk as possible. Relieve ICT & local pressure effect ,i.e. Shunting. Tissue Diagnosis and staging – Biopsy.

Suboccipital Craniotomy

Surgery is classified as: No evidence of residual tumor at surgery and negative postoperative

imaging : Gross total resection

> 90% : Total or near total 51 - 90% : Subtotal resection 11 - 50% : Partial resection < 10% : Biopsy

ComplicationEdema in the brainHematomaAseptic meningitis Cervical instabilityPosterior fossa syndrome/ cerebellar mutism syndrome:

15% of children Difficulty in swallowing, truncal ataxia, mutism, and, less

often, respiratory failure noted after a 12 to 24 hour often improve dramatically, sometimes over many months

after surgery.

Advantage: Longer recurrence-free interval (Gross total resection).

“Exception is Brainstem involvement”. restores natural CSF pathways.

Ventriculoperitoneal ShuntVP shunting done for hydrocephalous

reduction if repeated drainage fails to release symptoms.

Complication:Blood clot or bleeding in the brainBrain swellingThe shunt may stop working and

fluid will begin to build up in the brain again.

The shunt may become infected. Infection in the brainDamage to brain tissueSeizuresThrough VP shunt, tumor can spread.

RADIOTHERAPY Highly radio-sensitive. RT plays a central role.

Objective: To treat microscopic cancer cells / residual tumor with

the goal of reducing its size or stopping its progression.

Prevent or treat spread through CSF. Covering the entire subarachnoid space is an essential component in the management of medulloblastoma. So We do Craniospinal irradiation (CSI).

Cont…CSI is a very complex techniqueGoal is to achieve uniform dosage throughout the

subarachnoid space, encompassing the entire intracranial vault and spinal canal.

Fundamental is the use of opposed lateral fields including the cranium

and upper cervical spinal canal, matching a posterior spinal field including the full spinal

subarachnoid space with cranial field in larger children, the upper posterior spinal field

matching with a separate lower posterior spinal field

Target Volume:Entire brain and its meningeal coverings with the CSF

Spinal cord and the leptomeninges with CSFPosterior fossa – boost

Energy4-6 MV linac or Co60

PortalsWhole Brain: Two parallel opposed lateral field.Spine: Direct Posterior field

Scheduling of radiotherapy:Starting time : within 28 days following surgeryDuration of treatment : 45 to 47 days

Dose CSI (Phase I)

30- 36 Gy in 18 - 21 # over 4 weeks to the cranium @ 1.5-1.8 Gy per #

30-36 Gy in 18-21 # over 4 weeks to the spine @ 1.5-1.8 Gy per #

Posterior fossa boost (Phase II)18-20 Gy in 10-11# over 2 weeks to the posterior fossa

PLANNING STEPS Positioning Immobilization Simulation Field arrangement Matching of CSI Aligning of spinal field Implementation of plan

Patient position Prone (preferred): Supine:

More patient comfort. In-anaesthetic patient

Head position Slightly extended and the

shoulders pulled down to avoid beam divergence

into the mandibule & dentition.

Facilitates the use of a moving junction between the cephalad border of post. Spine field and the lower borders of cranial fields.

Lumbar and Thoracic spine ll to couch.

Immobilization method1.Orfit cast for immobilization of

the head, cervical spine & shoulder

2.Small children –inverted full body plaster cast with facial area open for access for anesthesia

3.Alpha cradle4.Vacuum devices

Different RT techniques for CSI Initially entire CNS is irradiated at one

stretch with a single field. Pt. is prone below a shielded screen on top of RT table. It is known as Patterson FARR technique. Co60 source exposes the entire craniospinal axis at a focus distance of 125 c.m.

Moving Field technique: Table and pt. moves longitudinally in relation to a perpendicular Co60 beam which is stationary at 50 cm focal skin distance.

Hockey Stick technique: Pt. prone with head turned to one side. Field at base of brain is defined by cribriform

plate and is above both orbital cavities. Include middle cranial fossa and to exclude

orbit and lens. Each side of head is treated on alternate

days.

German Helmet Technique

German Helmet Technique: Field set so that beam flashes over entire head in ant , post, & sup directions and only the

caudal margin is defined by collimator by RT machine .

Caudal margin is set up so that it follows a line drawn from Eyebrow through the ext. auditory canal to the post aspect of the skull At C2-C3 jt.

Here we shield extra-Cranial structure in the subfrontal region,facial structures, teeth and lens.

Field ArrangementsWhole brain

o In the simulator, opposing lateral fields are applied to the whole brain with a collimator rotation of 7-11o to match the divergence of the direct posterior spinal field.

SFOP guidelines- The recommended placement of block is:o 0.5 cm below the orbital roof .o 1 cm below and 1 cm in front

of the lower most portion of the temporal fossa .

o 1 cm away from the extreme edges of the calvaria.

In Medulloblastoma nearly 15-20% of recurrences occur at cribriform plate site which is attributed to overzealous shielding ,because of its proximity to ocular structure it often get shielded.

SPINAL FIELD Laterally - 1 cm margin

beyond the pedicles, to cover the spinal cord and meninges along the nerve roots upto the spinal ganglia

Caudal-1 cm below the termination of the thecal sac i.e. L5 –S3.

2 spinal fields are used if the length is > 36 cm.

In Dorsal Region, block lat. Field to cover heart and lungs.

In Lumber Region, reduce field to spare BM and Gonads.

SSD techniqueGantry Angle = 0 degree

IMP point is length and depth of spinal fields.

Field of approx.4–6 cm wide box over the spinal cord/vertebral bodies extends from C2 –S2 .

Post fossa boostVolume includes entire

Infratentorial compartment.Field arrangement :

Two lat opposing fields .

SFOP Guidelines : Ant -0.5 cm in front of clivus Upper -1 cm above midpoint

b/w line joining foramen magnum and the skull.

Post- ll to ant margin in air . Lower – 1 cm below occipital

foramen.

TECHNIQUES OF MATCHING CS FIELDS

Collimator/Couch rotation

Half beam block Asymetric jaws Moving Junction

technique

Collimator Couch rotation Classically described technique.

Divergence of the spinal field

into the cranial field is overcome

with collimator rotation

Divergence of the cranial fields

into the spinal fields is

overcome with couch rotation

(rotated so that the foot end

moves towards the gantry).

Collimator rotation allowscranial field to match

spinal field divergence

Coll θ = arc tan (L1 /2 x SSD)For Co60 SSD = 80

Zone of overlap of spinal field if collimator rotation isnot applied in cranial field

SSD

L1

Collimator rotation : While treating cranial field rotate Collimator of lateral field so that its inferior border is parallel to divergence of sup. Aspect of spinal field .

θ

In order to avoid the overlap resulting from inf. Divergence of cranial field, rotate the couch towards the collimator so that fields margins of two fields become parallel.

Degree of couch rotation depends upon the length of lateral cranial fields and SAD

Θ couch = arc tan (1/2 x L2 /SAD)L2 = Cranial field length

COUCH ROTATION

Fig: Rotation of the couch toward the gantry is necessary to match the caudal margin of the lateral cranial fields with the cephalad margin of the posterior spinal field.

COUCH ROTATION

Couch θ = arc tan (L2/2 x SAD)For Co60 SAD = 80

L2 ( Length of cranial field)

Cranial field

SAD

Zone ofoverlap

Spinal field

Couch rotationduringtreatment ofcranial field

θ

Disadvantage of Couch Collimator rotation

The lesser separation at the neck can increase the dose to the spinal cord.

Due to the couch rotation the cranial portions of the skull can move away and get treated a greater SSD (resulting in under dosage)

Conversely in case of

the spinal cord the

lower SSD will result

in an increased

dose.

Areas of the opposite

lower temporal lobe

can get lower dose if

customized blocks

are used - lower

border of the cranial

fields need to be

more generous.

Figure: This figure illustrates a potential complication of the craniospinal setup. A couch angle on the lateral cranial fields can cause the contralateral temporal lobe to be underdosed

Half Beam Blocking

Actual Field LengthSpinal field

Moving junction in CSI

Feathering after every 5-7 fraction smoothes out any over or underdose over a longer segment of cord .

Usually shifted by 1-2cm at each shift .

Either in cranial or caudal direction.

Lower border of sup. Spinal field & sup. Border of inf. Spinal field are also shifted superiorly , maintaining the calculated gap b/w them.

“Feathering” refers to movement of the junction of the two fields across the treatment length.

Aligning Spinal field Abutting fields : will result in

heterogenous dose to the spinal cord . To overcome this various techniques are

available o Gap technique o Double junction technique o Moving junction technique

Fixed or calculated gap spinal fields

Gap calculation formulaS= ½ x L1(d/SSD1)+1/2xL2(d/SSD2)

Cold Spot Hot Spot

SSD 2 SSD 1

L2 S L1

Double junction techniques

The post field divided into two halves.

An overlapping segment is treated with two diff. fields on alternate days.

The junction is therefore automatically feathered onalternate days

Upper Spine Lower Spine

Day of Planning

Upper Spine Lower Spine

Day 1: The upper spinalfield is shortened

Upper Spine Lower Spine

Day 2: The lower spinal field isshortened

Junction on D 1 Junction on D 2

RADIATION TOXICITY ACUTE TOXICITY

Nausea, vomitingneutropenia,

thrombocytopeniaFatigue, headache,

drowsiness Alopecia, mild

dermitis Serous otitis mediamucositis,

oesophagitis (exit dose from spinal cord)

Spinal cord Chronic progressive myelitis

Brain Radiation necrosis

Intellectual deficit

Lens of eye Cataract formation

Retina Radiation retinopathy

Optic nerve Optic neuritis

Inner ear Sensorineural hearing loss 

Hypothalamic-pituitary axis

Endocrinopathies ( hypothyroidism and decreased growth hormone secretion)

Secondary Malignancy

LATE TOXICITY

CHEMOTHERAPY chemo-sensitive Indication for CT :

1. As Adjuvant with Surgery in child <3 yrs to delay/avoid RT.

2. In Recurrent /Progressive disease .3. In patients with Extra cranial mets .4. High risk Pt. to improve cure rates5. In avg. risk group to allow reduced RT dose.

Chemotherapy regimenSingle agent CCNU

Lomustine 100-130 mg/m2 x 6 wks

PCV Procarbazine 60-75 mg/m2 PO D18-21 CCNU 110-130 mg/m2 PO D1 Vincristine 1.4mg/m2 IV D8 &D29

Cisplatin & Etoposide Cisplatin 30mg/m2 IV D1-D3 Etoposide 100 mg/m2 IV D1-D3

PCV (Most commonly used) CCNU 75 mg/m2 Cisplatin 75 mg/ m2 Vincristine 1.5 mg/m2

8 in 1 Regimen: MethylPDN 300 mg/m2 Vincristine 1.5 mg/m2 CCNU 75 mg/m2 Procarbazine 75 mg/m2 Hydroxyurea 1500 mg/m2 Cisplatin 60 mg/m2 Cytarabine 300 mg/m2 Endoxan 300 mg / m2

CVP x 6 weekly CCNU 75 mg/m2 D1 Vincristine 1.5 mg/m2 wklyx 3wks Prednisolone 40 mg / m2 x 14 days

Follow up

In standard risk : Brain MRI - every 3 months, for the first 2 years Spinal MRI - every 6 months, for the first 2 years;

then Brain MRI every 6 months up to 3 years and spinal MRI every year for 3 yrs.

In high-risk :

brain and spinal MRI - every 3 months for the first 2 years then every 6 months.

RecurrenceRelapses occur in nearly 75% of paediatric cases within 2 years.Predicted by collins rule of recurrence=age at diagnosis +9monthSites

• Post. Fossa • supratentorial region including cribriform plate • spinal cord • ventricular walls

Diagnosed by neuroimaging; occasionally, clinical progression precedes neuroimaging

findings.Treatment at relapse: Localized brain recurrence: Surgery“radiation therapy

combined with various chemotherapy schedules.”Disseminated disease: Chemotherapy or best supportive

care including radiation.

RECENT ADVANCESCSI followed by chemotherapy is the standard of care for

both average and high-risk children ages 3 and olderCurrent standard approach:Standard risk: Surgical

resection CSI 23.4 Gy at 1.8-Gy/fx with PF boost to 54 Gy with concurrent vincristine PCV chemo. DFS ~80%

High risk: Surgical resection post-op CSI 36–39 Gy at 1.8-Gy/fx, with entire PF and mets >1 cm boosted to 54 Gy with concurrent vincristine PCV chemo. DFS ~60%

Infants<3-year old: Surgery intensive chemo. Reserve RT for salvage

Contemporary CSI treatment & planning approach uses MRI and CT simulations (3D RTP).

Posterior boost also benefits from 3D-RTP and the use of highly-conformal 3D-CRT or IMRT techniques.

Ongoing Trials

In average-risk disease, lowering of the craniospinal dosage to 18 Gy, conformal posterior fossa radiotherapy to the tumor volume and intensification of chemotherapy with autologous peripheral blood stem cell support.

Use of Proton in treatment to reduce exit dose.The current SIOP (PNET 4) and UK-CCSG (CNS 2001) are

addressing hyperfractionated and accelerated hyperfractionated delivery, respectively, in standard-risk

SummaryMedulloblastoma is pediatric age group tumor.Raised ICT is the most common presentation.CT, MRI have important role in diagnosis and

treatment.Surgery is the primary modality of treatment .RT has central role in treatment.Standard risk:

surgery CranioSpinal Radiation or concurrent chemo RT followed by post radiation

chemotherapy.High risk: CranioSpinal radiation and post RT

chemotherapy.Infants pt treated with intent to avoid or delay the RT.Long term neurological sequalae seen in CSI.

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