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Presenter: Asadullah Advisor: Dr. dr. Joni Wahyuhadi, SpBS (K) Dr. dr. Rahadian Indarto S. SpBS (K) dr. Irwan Barlian I. H, SpBS (K) 0

Introduction - Tumor otak, Kanker otak, Gejala tumor otak

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Page 1: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Presenter:AsadullahAdvisor:Dr. dr. Joni Wahyuhadi, SpBS (K)Dr. dr. Rahadian Indarto S. SpBS (K)dr. Irwan Barlian I. H, SpBS (K) 0

Page 2: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Introduction

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

1

Page 3: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Introduction

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

2

20% dari seluruh kasus tumor susunan sarafpusat pada anak

Pertama kali diperkenalkan oleh Harvey Cushing dan Percival Bailey pada tahun 1925

Berpotensi untuk menyebar melalui celah sub arachnoid dan bahkan pada beberapa kasus

dapat bermetastasis keluar dari susunan sarafpusat

Page 4: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Epidemiologi

• Insiden medulloblastoma

Usia 0-3 : 12%

Usia 4-9 : 44%

Usia 10-16 : 23%

Usia >16 : 21%

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

3

Sales

0-3th 4-9th 10-16th >16th

Page 5: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Epidemiologi

• Central Brain Tumor Registry (CBTRUS) high grade glioma (secaratotal) > medulloblastoma

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

4

Page 6: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

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FK UNAIR – RSUD dr Soetomo

5

• Cushing mendeskripsikan medulloblastoma sebagai tumor yang tumbuh dari vermis cerebellum dan dapat bermetastasis ke lokasiyang jauh serta lebih cenderung terjadi pada laki-laki usia muda

Page 7: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• Based on histological similarity between medulloblastomas and other small round blue cell tumors arising in areas outside of the posterior fossa, it was proposed that these tumors be classified together under the umbrella group of primitive neuroectodermal tumors (PNETs)

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FK UNAIR – RSUD dr Soetomo

6

Page 8: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis

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FK UNAIR – RSUD dr Soetomo

7

Page 9: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Etiology

• Non-fresh peaches and similar fruits (OR = 0.5, 95% CI: 0.3, 0.8), non-chocolate candy (OR = 1.7, 95% CI: 1.0, 3.0), french fries (OR = 2.4, 95% CI: 1.2, 4.9) and chili peppers (OR = 1.8, 95% CI: 1.0, 3.0) were associated with medulloblastoma/PNET.

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

8

Page 10: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Etiology

• Neurotropic JC virus (JCV) is able to induce cerebellar neoplasms in rodents that exhibit a phenotype similar to that of human medulloblastomas

• By using PCR techniques we demonstrate that 11 of 23 samples of tumor tissue contain DNA sequences corresponding to three different regions of the JCV genome

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FK UNAIR – RSUD dr Soetomo

9

Page 11: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Etiology

• HCMV encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation

• HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumorformation in vivo

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10

Page 12: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Etiology

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

11

Page 13: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Histology

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FK UNAIR – RSUD dr Soetomo

12

Klasik Medulloblastoma Desmoplastik Nodular

Large-cell Anaplastic Melanotic

Medullomyoblastoma

Page 14: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Histology

• Klasik medulloblastoma (70%)

Sel pada tumor tampak sangat padat dengan nukleus berbentuk bulatatau oval dengan gambaran hiperkromatik

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FK UNAIR – RSUD dr Soetomo

13

Page 15: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Histology

• Desmoplastic-Nodular (15%)

• Tumor memiliki gambaran retikulen-free nodul dengan densitas lebihrendah pada daerah internodular. Desmoplasia terjadi pada daerahinternodular.

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FK UNAIR – RSUD dr Soetomo

14

Page 16: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Histology

• Large-cell anaplastic (10%)

• Sel yang berukuran besar dengan nucleus bulat dan prominen sertaproporsi sitoplasma yang lebih banyak dari jenis klasik

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FK UNAIR – RSUD dr Soetomo

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Page 17: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Patofisiologi

• Cusing melihat adanya sel neural dan glia pada medulloblastoma yang mengesankan bahwa medulloblastoma berasal dari sel yang lebihprimitif yaitu embryonic neuroepithelial cell yang kemudiandinamakan “medulloblast”

Ilmiah Divisi Neuro-OnkologiDepartemen Bedah Saraf

FK UNAIR – RSUD dr Soetomo

16

Page 18: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Patofisiologi

• Cancer stem cell

Self renewal

Differentiation

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Page 19: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Patofisiologi

• Cerebellum berasal dari beberapa regio termasuk bagian atasrhombic lip dan zona ventricular di sekeliling ventrikel empat yang berkembang selama fase embrio dan mencapai maturase pada beberapa bulan setelah kelahiran

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Page 20: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Patofisiologi

• Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes

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Page 21: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Sonic Hedgeog

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Page 22: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Sonic Hedgeog

• Gli1 dan Gli2 berperan penting pada pembentukan dan regulasipembelahan sel pada cancer

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Page 23: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Wingless

• Adanya TCF menyebabkanaktivasi transkripsi gen c-mycdan Cylin D1 yang berperandalam proliferasi gen dan bersifat proto-oncogenes

22Ilmiah Divisi Neuro-Onkologi

Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo

Page 24: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Patofisiologi

• Aktivasi berlebihan pada kedua jalur diatas baik Shh dan Wnt dapat memicuterjadinya medulloblastoma akibat terbentuknya proto oncogene dan kegagalan seluntuk keluar dari kondisiproliferative dan masukpada proses deferensiasi

23Ilmiah Divisi Neuro-Onkologi

Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo

Page 25: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Classification (Histology)

• More than 70% of patients have classic MB

• Their response to treatment is highly variable

• Histological classification may have limited prognostic value.

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Histological Sub-Type

Anaplastic

Large cell

Classic

Extensive nodular

Desmoplastic

Page 26: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Classification (Risk Stratification)

• High risk

Residual tumors (>1.5 cm2)

<3 years of age at diagnosis

presence of metastatic disease

• Average risk

Other

Cure rates of average and high-risk patients are 85 and 70%

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25

Age at diagnosis

Metastatic status

Extend of resection

Average risk

High risk

Page 27: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Classification (Molecular)

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Page 28: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Anamnesis

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Page 29: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Physical diagnostik

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Page 30: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Work-up

Imaging

Sitologi

Screening extra cranial metastasis

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Page 31: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Imaging

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Cranio-axis MRI Not AvailableCranio-axis MRI 2

week post op

Page 32: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Radiogenomic

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Page 33: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Sitologi CSF

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32

• With the use of either CSF cytology or spinal MRI alone, LMD would be missed in up to 14% to 18% of patients with medulloblastoma or PNET

Page 34: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

• 3:1 male/female ratio

• Bone was the most frequent site of metastases in adults (77%) and children (78%) Followed by lymph nodes (33%) in both children and adults. Lung metastases were more common in adults (17%), but liver metastases occurred more frequently in children (15%)

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Sign of metastasis (abnormality blood count)

High Risk (under 3 year)

Screening (ex. Bone Scan)

Page 35: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Session 2

34Ilmiah Divisi Neuro-Onkologi

Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo

Page 36: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Management

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FK UNAIR – RSUD dr Soetomo

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Surgery

RadiotherapyChemoterapy

Targetted ??

Page 37: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• Pembedahan pada medulloblastoma di era Cushing awalnya memilikitingkat mortalitas yang sangat tinggi (>30%)

• Selain mortalitas akibat pembedahan yang tinggi prognosis pada pasien medulloblastoma juga buruk karena angka rekurensi dan metastasis yang tinggi

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FK UNAIR – RSUD dr Soetomo

36

Extend of tumor resection

Better survival outcome

Evolution in neurosurgical

technique

Poor prognosis

Page 38: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• Prognosis pasien dengan medulloblastoma tetap buruk sampaidiperkenalkannya radiasi kraniospinal oleh Paterson dan Farr pada tahun 1953 (survival rate 3th mencapai 65% )

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FK UNAIR – RSUD dr Soetomo

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Page 39: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

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FK UNAIR – RSUD dr Soetomo

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Survival rate ↑↑Efek sampingradioterapi

Gangguanneurokognitif

Disfungsi endokrin

Tumor sekunder

Page 40: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

Reduction in the IQ score as high as 40 points

Endocrine deficits occurred in 45%

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FK UNAIR – RSUD dr Soetomo

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Page 41: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

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Improve Survival + Minimal

side effect

Surgery

KemoterapiRadioterapi

Page 42: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group(p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85)

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41

Page 43: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• 5-year overall survival ± SE and progression-free survival ± SE for M+ patients treated at the RP2D on regimen A was 82% ± 9% and 71% ±11% versus 68% ± 10% and 59% ± 10% on regimen B (P = .36)

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Page 44: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

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FK UNAIR – RSUD dr Soetomo

43

Improve Survival + Minimal

side effect

Surgery

Kemoterapi

Radioterapi

Targeted

Page 45: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

History

• Despite the body of literature describing the molecular subgroups, these findings have yet to translate directly to the clinical realm. Standard of care treatment remains maximal up front surgical resection followed by radiation and chemotherapy.

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Page 46: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Surgery

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Gross Total Resection Near Total Resection

High Risk

Page 47: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Surgical approach

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46

Transcortical

Cerebellum

Transvermian

Telovelar

Ventricle IV

Page 48: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Transvermian/Median Sub-Occipital

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• Splitting the inferior vermis on the sub-occipital surface. The incision extends a variable distance through the uvula, pyramid, tuber, and folium of the vermis, depending on the location and size of the lesion

• Retracting the two halves of the lower vermis laterally, then opening the telachoroidea and the inferior medullary velum, exposing the full length of the floor from the aqueduct to the obex

Page 49: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Telovelar

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• Examine the access to the fourth ventricle achieved by opening the tela choroidea and inferior medullary velum without incising or removing part of the cerebellum.

Page 50: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Telovelar

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• The medullotonsillar space of the cerebellomedullary fissure and the uvulotonsillar space are sharply dissected to release the tonsils from the uvula and the medulla oblongata bilaterally.

• The two cerebellar tonsils are then retracted laterally to expose the floor of the fissure. The telachoroidea is incised from the foramen of the magendie and then followed laterally to the foramen of the luschka on both sides

Page 51: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Recommendation

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• The transvermian approach has a higher risk of postoperative cerebellar mutism syndrome particularly in children

Page 52: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Radioteraphy

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• This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning.

Page 53: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Radioteraphy

• Patient > 3th average-risk

36 Gy craniospinal irradiation (dose-reduction to 18 Gy in children aged 3 to 7 years), and a boost to the posterior fossa for a total dose of 54 G

• Patient > 3th high-risk

36 Gy craniospinal irradiation with a boost to both the posterior fossa and focal sites of metastatic disease to 55.8 Gy

52Ilmiah Divisi Neuro-Onkologi

Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo

Page 54: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Chemoteraphy

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FK UNAIR – RSUD dr Soetomo

53

Page 55: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Targeted terapy

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54

Page 56: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Targeted terapy

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Page 57: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Targetted terapy

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• Our findings suggest that norcantharidin has potential therapeutic applications in the treatment of medulloblastoma as a result of its ability to cross the blood-brain barrier and its impairment of Wnt-β-catenin signaling

Page 58: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Targetted terapy

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• Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC

• Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down-regulation of MYC.

Page 59: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Complication

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Complication

Surgery

RadiotherapyChemotherapy

Targeted

Page 60: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Surgery

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• Cerebellar mutism: decreased speech, hypotonia, ataxia and emotional instability

• First presented at the 13th Annual Meeting of Japanese Society for Paediatric

• Pathophysiology of cerebellar mutism has not been well clarified yet

• Incidence is 11%–29%

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Posterior fossa syndrome

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Cerebellar Mutism

Brain stem invasion

Midline Tu

Aggressive surgery

Page 62: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Radiotherapy

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• Low IQ

• Endocrine dysfunction

• Secondary neoplasm

• Radiation necrosis

• Behavior abnormalities

• Stroke

• Steno-occlusive disease

• Vascular malformation

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Chemotherapy

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• Ototoxicity

• Renal toxicity

• Hepatotoxicity

• Pulmonary fibrosis

• Gastrointestinal disturbance

Page 64: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Prognosis

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• With current means of therapy, children with nondisseminatedmedulloblastoma 80% or more will be alive 5 years after diagnosis and treatment, with many free of the disease

Page 65: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Prognosis 5yr Survival

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Average Risk: 80%

High Risk: <40%

<3th: 30-70%

Page 66: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Issue

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65

Goal

Improve Survival at Any CostOld

New Improve Survival +

Quality of Life

Page 67: Introduction - Tumor otak, Kanker otak, Gejala tumor otak

Terimakasih

66Ilmiah Divisi Neuro-Onkologi

Departemen Bedah SarafFK UNAIR – RSUD dr Soetomo