Pediatric Oncology

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Slide 1 : Dr. Giulia Ottaviani, University of Milano, Italy Dr. Giulia Ottaviani  PEDIATRIC ONCOLOGY I October 30, 2008 Istituto di Pediatria e Neonatologia Università degli Studi di Milano CORSO DI LAUREA IN MEDICINA E CHIRURGIAPEDIATRIA, 6° anno, Poli C ed F
Slide 2 : Dr. Giulia Ottaviani, University of Milano, Italy First Take Home point Childhood Cancer is a rare disease
Slide 3 : Dr. Giulia Ottaviani, University of Milano, Italy Clinical Research Clinical Trials Translational Research Translational Research Epidemiology Etiology Prevention Therapy Late Effects Genomics/Proteomics PEDIATRIC ONCOLOGY Basic Research
Slide 4 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 5 : Dr. Giulia Ottaviani, University of Milano, Italy 0-1 years Sudden infant death syndrome (SIDS) or Crib death Developmental and genetic conditions that were present at birth All conditions associated with prematurity and low birth weight TOP THREE CAUSES OF DEATH BY AGE GROUP
Slide 6 : Dr. Giulia Ottaviani, University of Milano, Italy 1-4 years Accidents Developmental and genetic conditions that were present at birth Cancer [Medline Plus: http://www.nlm.nih.gov/] TOP THREE CAUSES OF DEATH BY AGE GROUP
Slide 7 : Dr. Giulia Ottaviani, University of Milano, Italy 5-14 years Accidents Cancer Homicide [Medline Plus: http://www.nlm.nih.gov/] TOP THREE CAUSES OF DEATH BY AGE GROUP
Slide 8 : Dr. Giulia Ottaviani, University of Milano, Italy 15-24 years Accidents Homicide Suicide [Medline Plus: http://www.nlm.nih.gov/] TOP THREE CAUSES OF DEATH BY AGE GROUP
Slide 9 : Dr. Giulia Ottaviani, University of Milano, Italy Top 10 causes of death in children [Willen Daily Life, UK 1995]
Slide 10 : Dr. Giulia Ottaviani, University of Milano, Italy Male Female Total All malignancies 2.7 2.3 2.5 1. Leukemia 0.9 0.7 0.8 2. Brain/ Other Nervous System 0.8 0.7 0.7 3. Non-Hodgkin lymphoma 0.1 0.1 0.1 4. Soft tissue 0.1 0.1 0.1 5. Bone and Joint 0.1 0.1 0.1 6. Kidney and Renal pelvis 0.1 0.1 0.1 [American Cancer Society Inc. 2007] Rate Per 100,000 Cancer DEATH in Children 0-14 Yrs
Slide 11 : Dr. Giulia Ottaviani, University of Milano, Italy Cancer DEATHS in the United States, Ages 0–19 Other 13.5% Leukemias 25.5% Colon rectum 0.7% Brain/Nervous system 25% Endocrine 8.5% Soft tissue 7.4% Non-Hodgkin Lymphoma 7.4% Kidney/Renal Pelvis 2.7% Liver/Intrahepatic bile duct 2.5% Hodgkin Lymphoma 1% Bone & joint 8.9%
Slide 12 : Dr. Giulia Ottaviani, University of Milano, Italy Distribution of Pediatric Cancer by Age AML NHL Neuroblastoma Wilms’ Tumor Osteosarcoma Rhabdomyosarcoma Germ-cell/gonadal Malignant melanoma
Slide 13 : Dr. Giulia Ottaviani, University of Milano, Italy Trends All childhood adolescent Cancers Age < 20 [NCI. SEER Surveillance Epidemiology End Results. Ries at al. 2007] INCIDENCE: + 0.2%/year MORTALITY: - 1.3%/year
Slide 14 : Dr. Giulia Ottaviani, University of Milano, Italy 1 in 300 for males 1 in 333 for females [NCI. SEER Surveillance Epidemiology End Results. 2004] PROBABILITY FOR A NEWBORN OF DEVELOPING CANCER BY AGE 20 Adult : Pediatric 125-150 : 1
Slide 15 : Dr. Giulia Ottaviani, University of Milano, Italy Male Female Total All malignancies 15.7 13.9 14.8 1. Leukemia 5.1 4.5 4.8 2. Brain/ONS 3.4 3.1 3.3 3. Soft tissue 1.0 1.0 1.0 4. Non-Hodgkin lymphoma 1.2 0.6 0.9 5. Kidney and renal pelvis 0.8 1.0 0.9 6. Bone and Joint 0.7 0.6 0.7 7. Hodgkin lymphoma 0.7 0.4 0.5 [American Cancer Society Inc. 2007] Cancer INCIDENCE in Children 0-14 Yrs Rate per 100,000
Slide 16 : Dr. Giulia Ottaviani, University of Milano, Italy Cancer CASES in the United States, Ages 0–19 Other 26% Leukemias 26% Brain/Nervous system 17% Non-Hodgkin Lymphome 7% Soft tissue 6% Hodgkin Lymphoma 8% Kidney/Renal pelvis 4% Bone & joint 6%
Slide 17 : Dr. Giulia Ottaviani, University of Milano, Italy Trends in SURVIVAL Children 0-14 Years, All Sites Combined 5 - Year Relative Survival Rates (%) Age Year ofDiagnosis 1975 - 1977 1996 - 2002 1975 - 1977 1996 - 2002 0 – 4 Years 1975 - 1977 1996 - 2002 5 - 9 Years 10 – 14 Years [American Cancer Society Inc. 2007]
Slide 18 : Dr. Giulia Ottaviani, University of Milano, Italy Childhood Cancer Survival Data
Slide 19 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] CUMULATIVE INCIDENCE OF DEATH AND OF DEVELOPING A SECOND CANCER AFTER CHILDHOOD CANCER DIAGNOSIS 37.6% 3.5%
Slide 20 : Dr. Giulia Ottaviani, University of Milano, Italy Epidemiology: Incidence Mortality Survival EtiologyTherapy Clinical Cases: Acute Leukemia Medulloblastoma Neuroblastoma Wilm’s tumor Osteosarcoma NOTES on PEDIATRIC ONCOLOGY SUMMARY
Slide 21 : Dr. Giulia Ottaviani, University of Milano, Italy PEDIATRIC CANCER ETIOLOGY
Slide 22 : Dr. Giulia Ottaviani, University of Milano, Italy Cancer Neoplasia – Latin, ‘new growth’ Cancer – ‘crab’ Rupert Willis, 1950s: “an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the surrounding normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change” Uncontrolled growth Invasion and destruction of local tissues Potential to spread
Slide 23 : Dr. Giulia Ottaviani, University of Milano, Italy Death Genes Environment Health Cancer
Slide 24 : Dr. Giulia Ottaviani, University of Milano, Italy NEOPLASTIC CELLS Increased growth factor Increased growth factor receptors Increased signal transduction Increased activation of transcription
Slide 25 : Dr. Giulia Ottaviani, University of Milano, Italy Carcinogenesis Acquired environmental factors chemicals, radiation, viruses Changes in genome of somatic cells Activation of growth promoting proto-oncogenes Inactivation of cancer supressor genes Expression all altered gene products and loss of regular gene products MALIGNANT NEOPLASM Genetic factors
Slide 26 : Dr. Giulia Ottaviani, University of Milano, Italy Oncogenes bcl-2 -------------->Follicular & undiff. Lymphomas C-myc ---------------------->Burkitt’s lymphoma N-myc ----------------->Neuroblastoma ras ------------------->colon carcinoma L-myc ----------------->Lung cancer ret-------------->multiple endocrine neoplasia (MEN) types II & III
Slide 27 : Dr. Giulia Ottaviani, University of Milano, Italy Tumor Suppressor genes BRCA 1&2 ------> Breast & ovarian cancer Rb ----------------> Retinoblastoma, osteosarcoma p53 ---> most human CA, Li-Fraumeni syndrome WT1 ------------------> Wilm’s tumor APC -------------------> Colorectal cancer NF1 ----------------> Neurofibromatosis type 1 NF2 ----------------> Neurofibromatosis type 2 DPC -------------------> Pancreatic Cancer DCC ----------------------> Colon Cancer
Slide 28 : Dr. Giulia Ottaviani, University of Milano, Italy Oncogenic Viruses HTLV1 ---------------> Adult T cell Leukemia HBV, HCV -------> Hepatocellular carcinoma EBV ---------------->Burkitt’s lymphoma nasopharyngeal carcinoma HIV --------------> Lymphomas (Burkitt’s lymph), Kaposi’s sarcoma HPV ------------> Cervical carcinoma (16,18) penile/anal carcinoma HHV8 -------------> Kaposi’s sarcoma, body cavity fluid B cell lymphoma
Slide 29 : Dr. Giulia Ottaviani, University of Milano, Italy Chemical Carcinogens Aflatoxins ----------------- Liver (hepatocellular carcinoma) Vinyl chloride ----------------- Liver (angiosarcoma) Nitrosamines --------------- Esophagus, Stomach Asbestos ---------------------- Lung (mesothelioma & bronchogenic carcinoma) Arsenic ----------------------- Skin (squamous cell carcinoma) CCl4 ----------------- Liver (centrilobular necrosis, fatty change) Naphthalene (aniline) dyes ----------- Bladder (transitional cell carcinoma)
Slide 30 : Dr. Giulia Ottaviani, University of Milano, Italy Diseases & neoplasms Down syndrome Immunodef. states Xeroderma pigmentosum ALL, AML Lymphoma Melanoma, Basal squamous cell carcinomas of the skin Tuberous sclerosis (facial angiofibroma, seizures, etc.) Astocytoma; Cardiac rhabdomyoma
Slide 31 : Dr. Giulia Ottaviani, University of Milano, Italy Tumor nomenclature Benign Adenoma, Papilloma Hemangioma Leiomyoma Rhabdomyoma Osteoma Lipoma Mature teratoma Malignant Adenocarcinoma, Papillary Carcinoma Leukemia, Lymphoma Angiosarcoma Leiomyosarcoma Rhabomyosarcoma Osteosarcoma Liposarcoma Immature teratoma Epithelium Mesenchyme > 1 cell type Blood cells Blood vessels Smooth muscle Skeletal muscle Bone Fat
Slide 32 : Dr. Giulia Ottaviani, University of Milano, Italy Tumor Stage Site & Size of 1st lesion Regional lymph node spread Mets T= tumor size N= node involvement M= metastasis
Slide 33 : Dr. Giulia Ottaviani, University of Milano, Italy Tumor grade Histological appearance 1-4 based on degree of differentiation number of mitoses
Slide 34 : Dr. Giulia Ottaviani, University of Milano, Italy Need for immediate follow-up C = Change in bowel or bladder habits A = A sore that does not heal U = Unusual bleeding or discharge T = Thickening or lump I = Indigestion or difficulty in swallowing O = Obvious change in a wart or mole N = Nagging cough or hoarseness Cancer: Warning Signs
Slide 35 : Dr. Giulia Ottaviani, University of Milano, Italy Pediatric vs Adult Tumors
Slide 36 : Dr. Giulia Ottaviani, University of Milano, Italy Unique Aspects of Pediatric Oncology Usually otherwise healthy patients Overall Prognosis is Good Long Term Survivors Chemotherapy and radiation therapy Cardiac, Renal, and Pulmonary Toxicity Development and CNS function Reproductive Function Second Malignancies
Slide 37 : Dr. Giulia Ottaviani, University of Milano, Italy Age-specific Prognosis All Malignancies [SEER]
Slide 38 : Dr. Giulia Ottaviani, University of Milano, Italy RETINOBLASTOMA Flexner-Wintersteiner rosettes 60% nonhereditary and unilateral
Slide 39 : Dr. Giulia Ottaviani, University of Milano, Italy RETINOBLASTOMA Normal chromosomes 13 Normal RB1 gene Rb protein Chromosome 13 with RB1 locus deleted (germline mutation) Rb protein High risk for retinoblastoma Retinoblastoma cell Chromosome 13 with both RB1 loci deleted 15% hereditary and unilateral25% hereditary and bilateral
Slide 40 : Dr. Giulia Ottaviani, University of Milano, Italy LI-FRAUMENI SYNDROME P53 gene Mutation p17 Autosomal dominant
Slide 41 : Dr. Giulia Ottaviani, University of Milano, Italy Three criteria for diagnosis A proband diagnosed with sarcoma younger than 45 years; A first-degree relative with any cancer diagnosed younger than 45 years; Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed younger than 45 years or sarcoma diagnosed at any age. Li-Fraumeni Syndrome
Slide 42 : Dr. Giulia Ottaviani, University of Milano, Italy S G2 M G1 R p53 p53 p53 DNA damage checkpoint DNA damage checkpoint Spindle checkpoint Mitogenic and antimitogenic signals pRB pRB Li-Fraumeni Syndrome Hereditary Retinoblastoma
Slide 43 : Dr. Giulia Ottaviani, University of Milano, Italy RADIATION DOSE and OSTEOSARCOMA RISK Children Cancer Research Group Late Effect Study Group Observed Dose in Gy Osteosarcoma Risk [Le Vu B. et al. Int J Can 1998; 77: 370-377]
Slide 44 : Dr. Giulia Ottaviani, University of Milano, Italy SECOND PRIMARY MALIGNANT NEOPLASM FAMILY CHEMOTHERAPY RADIOTHERAPY SECONDPRIMARY CANCER HISTORY OF CANCER
Slide 45 : Dr. Giulia Ottaviani, University of Milano, Italy NOTES on PEDIATRIC ONCOLOGY SUMMARY Epidemiology: Incidence Mortality Survival EtiologyTherapy Clinical Cases: Acute Leukemia Medulloblastoma Neuroblastoma Wilm’s tumor Osteosarcoma
Slide 46 : Dr. Giulia Ottaviani, University of Milano, Italy Discussion with the family If the diagnosis is relatively certain, then preparing the patient and family is helpful Until the histological type is known, therapy and prognosis are very variable
Slide 47 : Dr. Giulia Ottaviani, University of Milano, Italy The longer part of therapy (maintenance) can often be done mostly at home Familiarity with port-a-caths helps Almost every patient has some serious side effect Co-managing the patient
Slide 48 : Dr. Giulia Ottaviani, University of Milano, Italy Treatment Neoadjuvant chemotherapy Don’t prolong interval between chemo Bone marrow transplant (BMT) if indicated Surgery if indicated Adjuvant chemotherapy Radiation if indicated
Slide 49 : Dr. Giulia Ottaviani, University of Milano, Italy Early Management Hydration and alkalinization are excellent initial measures in almost all cases Allopurinol or rasburicase should be considered Allopurinol 300 mg/m2/d divided TID Rasburicase 0.2 mg/kg times one Maintain the urine output In the case of fever, add a broad spectrum antibiotic for empiric coverage
Slide 50 : Dr. Giulia Ottaviani, University of Milano, Italy CHEMOTHERAPY: General Principles Addition of chemotherapy (1950s) has improved prognosis dramatically Combination Chemotherapy has been shown to be essential, especially in ALL Problems: Toxicity Drug Interaction Resistance
Slide 51 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 52 : Dr. Giulia Ottaviani, University of Milano, Italy CHEMIOTHERAPY: common problems Gastrointestinal side effects Cytopenias Anemia Neutropenia Thrombocytopenia Liver function tests Alopecia Febrile episodes Infections, e.g., chicken pox and herpes zoster Emergency room visits
Slide 53 : Dr. Giulia Ottaviani, University of Milano, Italy Surgery Surgery is an effective form of treatment for cancer, and yet the most aggressive. Surgery offers the greatest chance for cure for many types of cancer, especially those that have not yet spread to other parts of the body. 
Slide 54 : Dr. Giulia Ottaviani, University of Milano, Italy Endoprosthesisfor children andadolescents
Slide 55 : Dr. Giulia Ottaviani, University of Milano, Italy Radiation The primary purpose of radiation therapy is to eliminate or shrink localized cancers. The aim is to kill as many cancer cells as possible, while damaging minimal healthy tissues. In some cases, the purpose is to kill all cancer cells curing a patient. In other cases, when cures are not possible, the purpose is to alleviate symptoms by reducing the size of tumors causing the symptoms. Photon vs Proton
Slide 56 : Dr. Giulia Ottaviani, University of Milano, Italy Proton Radiotherapy The proton beam extracted from the cyclotron may have exclusive advantages in treatment of certain human malignant tumours. The depth dose distribution enables the concentration of radiation to the target volume and minimizes the dose to normal tissue surrounding the target.
Slide 57 : Dr. Giulia Ottaviani, University of Milano, Italy Advanced Tumor therapy New targeting therapy Immunotherapy Tumor vaccine
Slide 58 : Dr. Giulia Ottaviani, University of Milano, Italy NOTES on PEDIATRIC ONCOLOGY SUMMARY Epidemiology: Incidence Mortality Survival EtiologyTherapy Clinical Cases: Acute Leukemia Medulloblastoma Neuroblastoma Wilm’s tumor Osteosarcoma
Slide 59 : Dr. Giulia Ottaviani, University of Milano, Italy ALL AML Astrocytoma Medulloblastoma Glioma Craniopharyngioma Ependymoma
Slide 60 : Dr. Giulia Ottaviani, University of Milano, Italy [SEER, NCI] Age Specific Incidence rates for childhood cancer all races, both sexes Age at Diagnosis LLA * LMA * Lym * CNS *
Slide 61 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 1 4 y/o gir: 2 weeks of low grade fever (38 – 38.3), fatigue, achy legs Now with one day of easy bruising PE notable for tired-appearance, large cervical nodes, enlarged liver and spleen multiple bruises and petechiae ? Test
Slide 62 : Dr. Giulia Ottaviani, University of Milano, Italy Case #1 Labs WBC = 5.0 w 8% Neut, 92% lymphocytes Hgb = 6.5 Plt = 11, 000
Slide 63 : Dr. Giulia Ottaviani, University of Milano, Italy Peripheral smear
Slide 64 : Dr. Giulia Ottaviani, University of Milano, Italy Bone marrow
Slide 65 : Dr. Giulia Ottaviani, University of Milano, Italy Leukemia: Signs and Symptoms Bone marrow infiltration Anemia Pallor, lethargy Dyspnea, ?murmur ? Platelets Bleeding, petechiae, purpura Neutropenia Fevers and infections Bone pain Limp, ? walking, irritability
Slide 66 : Dr. Giulia Ottaviani, University of Milano, Italy Leukemia: Signs and Symptoms Extramedullary spread Lymphadenopathy Hepatosplenomegaly Orthopnea, cough mediastinal mass tracheal compression Facial nerve palsy Testicular enlargement Skin lesions Gingival hypertrophy • Fever of malignancy
Slide 67 : Dr. Giulia Ottaviani, University of Milano, Italy Childhood Acute Leukemia Approximately 3000 new cases of leukemia in patients under 18 years 500 AML and 2500 ALL Of the ALL cases, 70% are pre-B ALL, 15% are T-ALL and the rest mature B
Slide 68 : Dr. Giulia Ottaviani, University of Milano, Italy Acute lymphoblastic leukemia Acute myeloid leukemia
Slide 69 : Dr. Giulia Ottaviani, University of Milano, Italy Bone marrow BIOPSY needle
Slide 70 : Dr. Giulia Ottaviani, University of Milano, Italy TRU-CUT needle for bone marrow biopsy
Slide 71 : Dr. Giulia Ottaviani, University of Milano, Italy Bone marrow ASPIRATION needle
Slide 72 : Dr. Giulia Ottaviani, University of Milano, Italy Bone marrow aspiration needle
Slide 73 : Dr. Giulia Ottaviani, University of Milano, Italy Bone marrow aspiration needle
Slide 74 : Dr. Giulia Ottaviani, University of Milano, Italy Acute leukemia: bone marrow biopsy
Slide 75 : Dr. Giulia Ottaviani, University of Milano, Italy Normal bone marrow biopsy
Slide 76 : Dr. Giulia Ottaviani, University of Milano, Italy Acute Lymphoblastic Leukemia T-lineage ALL: Bad prognosis. B-lineage ALL: “B-cell precursor ALL”: Better prognosis. “B-cell ALL”: Bad prognosis. Immunophenotype
Slide 77 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 78 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 79 : Dr. Giulia Ottaviani, University of Milano, Italy B-cell ALL: starry sky pattern
Slide 80 : Dr. Giulia Ottaviani, University of Milano, Italy B-cell ALL: starry sky pattern
Slide 81 : Dr. Giulia Ottaviani, University of Milano, Italy ALL TdT+ TdT (deoxynucleotidyltransferase, a specialized DNA polymerase that is expressed only by pre-B and pre-T lymphoblasts, positive in >95% of ALL)
Slide 82 : Dr. Giulia Ottaviani, University of Milano, Italy Pre-B Cell Flow cytometry ALL
Slide 83 : Dr. Giulia Ottaviani, University of Milano, Italy Treatment Chemotherapy Bone marrow transplant Many children are cured! Prognostic factors Immunophenotype (T-cell: bad) Age (1-10: good) WBC (<10,000: good) Cytogenetics (hyperdiploidy: good) Acute Lymphoblastic Leukemia
Slide 84 : Dr. Giulia Ottaviani, University of Milano, Italy ALL - History
Slide 85 : Dr. Giulia Ottaviani, University of Milano, Italy ALL - Signs
Slide 86 : Dr. Giulia Ottaviani, University of Milano, Italy ALL - Physical Signs of anemia (pallor, tachycardia) and thrombocytopenia (petechiae, bruises) Hepatosplenomegaly Lymphadenopathy Testes may be involved in males CNS may be involved – H/A, vision change, meningismus
Slide 87 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 88 : Dr. Giulia Ottaviani, University of Milano, Italy Other Labs LDH – elevated Urate – elevated PO4 – elevated AST/ALT – elevated if sig. liver involvement CSF to look for malignant cells
Slide 89 : Dr. Giulia Ottaviani, University of Milano, Italy Assigning risk-ALL Age >1 and <10 WBC< 50,000 Steroid pre-treatment Extramedullary disease Phenotype T-cell phenotype (T-ALL) are now all placed on a high risk protocol
Slide 90 : Dr. Giulia Ottaviani, University of Milano, Italy Assigning Risk- Following Dx Response to therapy Rapid responders fare better overall Cytogenetics: Ph chromosome, MLL gene rearrangements, Numerical abnormalities Minimal residual disease studies Flow cytometry or PCR techniques
Slide 91 : Dr. Giulia Ottaviani, University of Milano, Italy ALL – assigning the risk
Slide 92 : Suspected Leukemia Marrow aspirate Immunophenotype Cytogenetics Marrow/blood samples submitted to Reference Labs for: Immunophenotype DNA Index FISH for trisomies 4, 10, 17, and MLL rearrangements RT-PCR to detect BCR-ABL, MLL-AF4, E2A-PBX1, TEL-AML1 MRD Host polymorphisms (optional) Cell Banking (optional) Local Institution Reference Laboratories Consent for collection of extra marrow Consent for: Diagnostic studies Tissue banking Host polymorphisms Required studies for entry onto therapeutic trials Standard Risk B-precursor ALL High Risk B-precursor ALL T-cell ALL Treatment Initiated AML
Slide 93 : Dr. Giulia Ottaviani, University of Milano, Italy “Normal” 26% 11q23 4% Ph 2% t(1;19) 4% 14q11 3% TEL-AML1 18% < 45 Chrom 1% 45 Chrom 3% Pseudodiploid 10% 47-50 Chrom 6% > 50 Chrom 26% ALL: Genetic Heterogeneity
Slide 94 : Dr. Giulia Ottaviani, University of Milano, Italy ALL - Cytogenetics
Slide 95 : Dr. Giulia Ottaviani, University of Milano, Italy 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 20 40 60 80 100 Probability 10/2001 TEL Years Followed t(4;11) t(9;22) t(1;19) Trisomies 4,10,17 B-precursor ALL ALL: Genotype Correlates with Outcome
Slide 96 : Dr. Giulia Ottaviani, University of Milano, Italy ALL: PROGNOSIS worsens with age [SEER registry data]
Slide 97 : Dr. Giulia Ottaviani, University of Milano, Italy Age at Diagnosis Age Specific Incidence rates for childhood cancer all races, both sexes [SEER, NCI] Neurobl * Ret * Wilms *
Slide 98 : Dr. Giulia Ottaviani, University of Milano, Italy 23 mo boy with ataxia X 1month NB NB Emesis, in am X 2weeks Vomiting am Seen by PCP for GERD without improvement No Fevers Increasing vomiting Case # 2 ? Test
Slide 99 : Dr. Giulia Ottaviani, University of Milano, Italy MRI
Slide 100 : Dr. Giulia Ottaviani, University of Milano, Italy Medulloblastoma
Slide 101 : Dr. Giulia Ottaviani, University of Milano, Italy Medulloblastoma Rosettes (Homer-Wright)
Slide 102 : Dr. Giulia Ottaviani, University of Milano, Italy CNS TUMORS Common childhood tumor Peak incidence at 5th decade Supratentorial in adult Infratentorial in child
Slide 103 : Dr. Giulia Ottaviani, University of Milano, Italy Brain Tumors of Childhood Infratentorial 50% < 6 y/o Supratentorial 50% > 8 y/o
Slide 104 : Dr. Giulia Ottaviani, University of Milano, Italy
Slide 105 : Dr. Giulia Ottaviani, University of Milano, Italy Nonlocalizing Signs of Brain Tumors Increased intracranial pressure (ICP) Obstructed CSF flow and hydrocephalus Child is often asymptomatic until critical threshold reached Medulloblastoma Can grow very large before detection
Slide 106 : Dr. Giulia Ottaviani, University of Milano, Italy Headaches, progressively worsening Vomiting (morning) Irritability Papilledema rare < 2 y/o - head can expand “Double vision” with 6th nerve palsy Head tilt Bulging fontanel (infant) Increased Intracranial Pressure (ICP) In a young child with ? brain tumor: Measure head circumference and observe gait
Slide 107 : Dr. Giulia Ottaviani, University of Milano, Italy CNS Tumors Signs depend on location and age like in adults; in addition: Younger child: Developmental delay or loss of milestones Older child: Deteriorating school performance Personality changes Endocrinopathies: DI, hypothyroidism, precocious puberty
Slide 108 : Dr. Giulia Ottaviani, University of Milano, Italy CNS tumors: General Considerations Primary – children - 50% infiltrative Limited space, Vital structures Location determines prognosis. Rare extra neural metastasis.
Slide 109 : Dr. Giulia Ottaviani, University of Milano, Italy Types of CNS Tumors Meninges: meningioma, hemangiopericytoma Glia: astrocytoma, oligodendroglioma, ependymoma, choroid plexus papilloma.. Vascular: hemangioblastoma. Primitive cells: neuroblastoma, germinoma, medulloblastoma, pineoblastoma, retinoblastoma Neuronal: ganglioglioma, gangliocytoma Pituitary: adenoma, craniopharyngioma Nerves: schwannoma, neurofibroma, MPNST in children
Slide 110 : Dr. Giulia Ottaviani, University of Milano, Italy Medulloblastoma Origin: primitive neuroectodermal cells Age: 1st decade of life. Most common brain tumor at this age. Site: vermis of cerebellum May cause hydrocephalus Subarachnoid dissemination
Slide 111 : Dr. Giulia Ottaviani, University of Milano, Italy Dr. Giulia Ottaviani  PEDIATRIC ONCOLOGY II December 18, 2008 Istituto di Pediatria e Neonatologia Università degli Studi di Milano CORSO DI LAUREA IN MEDICINA E CHIRURGIAPEDIATRIA, 6° anno, Poli C ed F
Slide 112 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 3 13 months/old girl with 1 month of fever Irritable Pale Periorbital ecchymoses ? Test
Slide 113 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 3 CT scan
Slide 114 : Dr. Giulia Ottaviani, University of Milano, Italy neuroblastoma
Slide 115 : Dr. Giulia Ottaviani, University of Milano, Italy neuroblastoma
Slide 116 : Dr. Giulia Ottaviani, University of Milano, Italy Embryonal tumors Neuroblastoma - cerebral hemispheresNeuroblastic (neuronal) differentiation Medulloblastoma - cerebellumNeuronal and glial differentiation Ependymoblastoma – ventriclesEpendymal differentiation Pineoblastoma- pineal regionRetinoblastic differentiation All commonly known as: Primitive neuroectodermal tumor (PNET)
Slide 117 : Dr. Giulia Ottaviani, University of Milano, Italy NEUROBLASTOMA 6% of childhood malignancies Most common cancer in children < 1 y.o. 2/3 are in children < 5 y.o. 70% of all patients have mets at dx
Slide 118 : Dr. Giulia Ottaviani, University of Milano, Italy Neuroblastoma: Signs and Symptoms Abdominal mass Often crosses midline Lower extremity weakness Spinal cord compression Thoracic abdominal Cervical, high thoracic mass Horner’s syndrome Miosis, ptosis, anhydrosis
Slide 119 : Dr. Giulia Ottaviani, University of Milano, Italy Signs of metastatic disease Irritability Weight loss Bone pain Fever Proptosis Bone lesions Periorbital ecchymoses Neuroblastoma: Signs and Symptoms
Slide 120 : Dr. Giulia Ottaviani, University of Milano, Italy Neuroblastoma Age 90% < 5 y/o; 50% < 2 y/o Occasional USG detection in utero Location: any neural crest tissue Adrenal Paraspinal sympathetic tissue Cervical, Thoracic, Pelvic Often metastatic at diagnosis Bone and/or bone marrow > 1 y/o: 70%
Slide 121 : Dr. Giulia Ottaviani, University of Milano, Italy Neuroblastoma: Signs & Symptoms Paraneoplastic syndromes Watery diarrhea – Vasoactive Intestinal Peptide Opsoclonus-myoclonus, cerebellar ataxia Cross-reacting antibodies ? Urinary catecholamines VMA/HVA – 85% ? BP – 25% Renal compression Catecholamine secretion
Slide 122 : Dr. Giulia Ottaviani, University of Milano, Italy More Periorbital Ecchymoses of Neuroblastoma 13 months old at diagnosis 1 month into therapy
Slide 123 : Dr. Giulia Ottaviani, University of Milano, Italy NEUROBLASTOMA: Clinical findings Originates in sympathetic NS: paraspinal ganglia or adrenal medulla Most common: mass effect, bone pain, proptosis/periorbital ecchymoses from retrobulbar mets Can invade neural foramina, ? paralysis Less commonly: fever, anemia Rarely: VIP secretion ? diarrhea, cerebellar ataxia, opsoclonus/myoclonus
Slide 124 : Dr. Giulia Ottaviani, University of Milano, Italy NEUROBLASTOMA: Prognostic factors Stage Age (<1 y.o. better except maybe <6 wks with no skin nodules) Primary tumor site ONLY for stage 3-4 (abd is worse) Primary tumor size NOT catecholamine levels
Slide 125 : Dr. Giulia Ottaviani, University of Milano, Italy NEUROBLASTOMA: Staging (INSS)
Slide 126 : Dr. Giulia Ottaviani, University of Milano, Italy Neuroblastoma: Work-up Bone scan CT/MR to look for nodes and evaluate liver Catecholamines Tumor biology, at least for myc-n and ploidy
Slide 127 : Dr. Giulia Ottaviani, University of Milano, Italy Neuroblastoma: Treatment & Prognosis 1: > 90%, still good even with local recurrence. Surgery only UNLESS: age > 2y, myc-n amplified, unfavorable histology, ? +LN 2: 75-90%. Bx/surg, chemo (4-6 mos of CTX/DOX), then definitive surg. 3, <1y: 80%. Surg +/- chemo 3, >1y: 50-70%. Surg + chemo, +/- XRT. May need SCT if myc-n amplified.4, <1y: 50-80%, avg. 60%; biology important (approaches 0 if myc-n; approaches 95% without) 4, >1y: 10-40%, avg. 15%*; SCT better than chemo alone 4S: 57-100%.
Slide 128 : Dr. Giulia Ottaviani, University of Milano, Italy Same patient: 5 years later 12 years later
Slide 129 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 4 3 y/o girl comes in for well-child check up 2 weeks of abdomenal distension Otherwise, healthy Large mass palpable in abdomen 2 days before dx ? Test
Slide 130 : Dr. Giulia Ottaviani, University of Milano, Italy CT scan
Slide 131 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 4 nephrectomy performed
Slide 132 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms Tumor
Slide 133 : Dr. Giulia Ottaviani, University of Milano, Italy Usually 3 cellular components: 1) Primitive blastema: very cellular with primitive round to oval cells with little cytoplasm. 2) Mesenchymal cells: usually myxoid and spindled but may form smooth or skeletal muscle 3) epithelial cells: form primitive tubules and glomeruli (can have papillary or fibroadenomatous architecture or be small and round) Wilms/ Nephroblastoma: Histology
Slide 134 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms tumor: Signs & Symptoms Associated with various syndromes– 15% Hemihypertrophy Aniridia - WAGR syndrome = Wilms/ Aniridia/GU malformation/ Mental Retardation Most common renal tumor of childhood
Slide 135 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms tumor: Signs & Symptoms More anomalies, syndromes GU anomalies Denys-Drash syndrome GU anomalies and renal failure Beckwith-Wiedemann syndrome
Slide 136 : Dr. Giulia Ottaviani, University of Milano, Italy Mass enlarges toward pelvis Wilms tumor: Signs and Symptoms But usually is isolated
Slide 137 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms/ Nephroblastoma - Genetics Wilms Tumor 1 (WT1) gene - chrom. 11p13 Tumor suppressor gene ?gene codes for a protein that regulates transcription Plays role in development of gonads Accounts for ~10% of Wilms tumors
Slide 138 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms - Staging I – limited to kidney, completely removed II – beyond kidney but completely removed Out of kidney bit within capsule Into blood vessel III – Residual disease confined to abdomen; spillage; nodes involved; margins not clear IV – distant spread V - bilateral
Slide 139 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms - Metastasis Metastasizes to: Lung (of Wilms that spread, lung is only other site ~80% of time) Regional nodes Liver – only ~15% of time, often with lung
Slide 140 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms - Treatment Based on stage, histology Everyone gets chemo As stage advances/ histology worsens prolong course, add more agents and radiation therapy
Slide 141 : Dr. Giulia Ottaviani, University of Milano, Italy Wilms - Outcome Depends on stage, anaplasia Favorable histology I – 95% II – 90% III – 75 - 88% IV – 70 - 80%
Slide 142 : Dr. Giulia Ottaviani, University of Milano, Italy Age Specific Incidence rates for childhood cancer all races, both sexes [SEER, NCI] Age at Diagnosis Hep * Bone * Soft * Germ *
Slide 143 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 5 14 y/o soccer player with 2 months of mid and distal thigh soreness No other symptoms Accidental minor fall -> E.R. P.E. notable for mass, knee decreased ROM
Slide 144 : Dr. Giulia Ottaviani, University of Milano, Italy Case # 5 Pain: 100% Mass: 50% Fracture:10%
Slide 145 : Dr. Giulia Ottaviani, University of Milano, Italy OSTEOSARCOMA
Slide 146 : Dr. Giulia Ottaviani, University of Milano, Italy Conventional X-ray Benign Appropriate management Diagnostic problem (poorly visualized bone matrix) Probably Malignant CT BIOPSY Treatment Staging examination MRI [WHO. Pathology and genetics of tumors of the soft tissue and bone. 2002] OSTEOSARCOMA DIAGNOSIS
Slide 147 : Dr. Giulia Ottaviani, University of Milano, Italy OSTEOSARCOMA
Slide 148 : Dr. Giulia Ottaviani, University of Milano, Italy OSTEOSARCOMA
Slide 149 : Dr. Giulia Ottaviani, University of Milano, Italy OSTEOSARCOMA
Slide 150 : Dr. Giulia Ottaviani, University of Milano, Italy Cancer CASES in the United States, Ages 0–19 Other 26% Leukemias 26% Brain/Nervous system 17% Non-Hodgkin Lymphome 7% Soft tissue 6% Hodgkin Lymphoma 8% Kidney/Renal pelvis 4% BONE & JOINT 6%
Slide 151 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Ries at al. 2007] INCIDENCE by Age Bone & Joint 28.7 16.5 11.5 13.0 10.1 8.6 7.8 3.8 100% 3,386 % <20 20-34 35-44 45-54 55-64 65-74 75-84 85+ Ages Cases
Slide 152 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Mascarenhas et al. 2004] BONE & JOINT CANCER
Slide 153 : Dr. Giulia Ottaviani, University of Milano, Italy [Linabery AM, Ross JA. Cancer 2008; 112: 416-432.] Cancer No.(%) rate Years APC (95%CI) per 1,000,000 annual percentage change Osteosarcoma 660 (3%) 4.7 1992-2004 0.2(-1.4,1.8) 0-19 yrs OSTEOSARCOMA INCIDENCE in SEER registries 1992-2004
Slide 154 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Gurney at al. 1999] OSTEOSARCOMA: INCIDENCE by RACE and AGE
Slide 155 : Dr. Giulia Ottaviani, University of Milano, Italy * * * * OSTEOSARCOMA INCIDENCE by ETHNICITY [NCI. SEER Surveillance Epidemiology End Results. Mascarenhas et al. 2004]
Slide 156 : Dr. Giulia Ottaviani, University of Milano, Italy [U.S. Cancer Statistics Working Group 2007] Rate per 1,000,000 OSTEOSARCOMA 0-19 yrs INCIDENCE by ETHNICITY in MALES Osteosarcomas 5.0 4.5 6.8 ~ ~ 5.2 All Races Whites Black Asian/Pacific Amer.Ind. Hispanic Islander Alaska Nat.
Slide 157 : Dr. Giulia Ottaviani, University of Milano, Italy per 1,000,000 [U.S. Cancer Statistics Working Group 2007] OSTEOSARCOMA 0-19 yrs INCIDENCE by ETHNICITY in FEMALES Rate per 1,000,000 Osteosarcomas 5.1 4.7 6.8 ~ ~ 6.8 All Races Whites Black Asian/Pacific Amer.Ind. Hispanic Islander Alaska Nat.
Slide 158 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Mascarenhas et al. 2004] OSTEOSARCOMA: GENDER by AGE AT DIAGNOSIS * * * + * * * * *
Slide 159 : Dr. Giulia Ottaviani, University of Milano, Italy MALES 5.0 /milion FEMALES 5.1 /milion YEAR 2007 OSTEOSARCOMA INCIDENCE by GENDER Ages 0-19All races
Slide 160 : Dr. Giulia Ottaviani, University of Milano, Italy [Linabery AM, Ross JA. Cancer 2008; 112: 416-432.] OSTEOSARCOMA INCIDENCE SEER 1992-2004 in MALES Cancer No.(%) rate Years per 1,000,000 Osteosarcoma 385 (3%) 5.4 1992-2004 0-19 yrs
Slide 161 : Dr. Giulia Ottaviani, University of Milano, Italy [Linabery AM, Ross JA. Cancer 2008; 112: 416-432.] OSTEOSARCOMA INCIDENCE SEER 1992-2004 in FEMALES Osteosarcoma 275 (3%) 4.0 1992-2004 Cancer No.(%) rate Years per 1,000,000 0-19 yrs
Slide 162 : Dr. Giulia Ottaviani, University of Milano, Italy [Damron TA et al. NCDB Report. CORR 2007;459:40-47] OSTEOSARCOMA GENDER by HISTOLOGICAL TYPE + * * * * * * *
Slide 163 : Dr. Giulia Ottaviani, University of Milano, Italy Rate per 1,000,000 OSTEOSARCOMA: INCIDENCE BY AGE Osteosarcomas ~ ~ 3.1 8.6 8.0 10-14 5-9 1-4 <1 15-19 [U.S. Cancer Statistics Working Group 2007]
Slide 164 : Dr. Giulia Ottaviani, University of Milano, Italy [Dahlin DC, Unni K. Charles C. Thomas, Springfield, IL 1986. Mayo Clinic] OSTEOSARCOMA: AGE and ANATOMIC SITE LOCATION
Slide 165 : Dr. Giulia Ottaviani, University of Milano, Italy [Damron TA et al. NCDB Report. CORR 2007;459:40-47] OSTEOSARCOMA ANATOMIC SITE DISTRIBUTION Primary Site Osteosarcomas (%) Long Bones – Upper limb 11.7 Short Bones – Upper limb 0.7 Long Bones – Lower limb 57.6 Short Bones – Lower limb 1.9 Overlapping lesions 0.1 Bone of limb, NOS 0.6 Bones – Skull and face 5.9 Mandibole 4.1 Vertebral column 2.5 Rib, sternum, clavicole 3.2 Pelvic bones 10.1 Overlapping lesions 0.2 Bone, NOS 1.4 Total cases 11,961
Slide 166 : Dr. Giulia Ottaviani, University of Milano, Italy Cancer DEATHS in the United States, Ages 0–19 Other 13.5% Leukemias 25.5% Colon rectum 0.7% Brain/Nervous system 25% Endocrine 8.5% Soft tissue 7.4% Non-Hodgkin Lymphoma 7.4% Kidney/Renal Pelvis 2.7% Liver/Intrahepatic bile duct 2.5% Hodgkin Lymphoma 1% BONE & JOINT 8.9%
Slide 167 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Ries at al. 2007] Trends MORTALITY All Cancers Age < 20 Rate per 100,000 American Indian/Alaska Native Asian/Pacific Islander
Slide 168 : Dr. Giulia Ottaviani, University of Milano, Italy Trends All childhood adolescent Cancers Age < 20 [NCI. SEER Surveillance Epidemiology End Results. Ries at al. 2007] OSTEOSARCOMA INCIDENCE: + 0.2%/year OSTEOSARCOMA MORTALITY: - 1.3%/year
Slide 169 : Dr. Giulia Ottaviani, University of Milano, Italy All Ages INCIDENCE MORTALITY SURVIVAL [NCI. SEER Surveillance Epidemiology End Results. Ries at al. 2007] Rate per 100,000 Bone/Joint 0.9 1.0 0.8 0.4 0.5 0.3 67.9 64.4 72.4
Slide 170 : Dr. Giulia Ottaviani, University of Milano, Italy NOTES on Epidemiology of Osteosarcoma CONCLUSIONS INCIDENCE 4.7/million/year; APC 0.2 (SEER) by age peak 10-14 yrs (US Working Group) by ethnicity more frequent in Blacks and Hispanics by gender M:F 5.0:5.1/million/yr (US Working Group) M:F 5.4:40 /million/yr (SEER) MORTALITY 8.9% mortality of all bone joint cancersDeath rate decreases 1.3%/yr
Slide 171 : Dr. Giulia Ottaviani, University of Milano, Italy OSTEOSARCOMA SURVIVAL by AGE [NCI. SEER Surveillance Epidemiology End Results. Mascarenhas et al. 2004] 62.3% <45% >65%
Slide 172 : Dr. Giulia Ottaviani, University of Milano, Italy [Damron TA et al. NCDB Report. CORR 2007;459:40-47] OSTEOSARCOMA SURVIVAL by HISTOLOGICAL TYPE 52.60% SURVIVAL 85.9% 49.5% 17.8%
Slide 173 : Dr. Giulia Ottaviani, University of Milano, Italy [Jeys LM et al. Ann Surg Oncol 2007; 14: 2887-95] 84.5% 62.3% (Years) OSTEOSARCOMA SURVIVAL infection vs noninfection in patients with endoprosthesis
Slide 174 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] CUMULATIVE INCIDENCE OF DEATH AND OF DEVELOPING A SECOND CANCER AFTER CHILDHOOD CANCER DIAGNOSIS 37.6% 3.5%
Slide 175 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] CUMULATIVE INCIDENCE OF DEVELOPING A SECOND CANCER in children with selected primary cancers
Slide 176 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] RISK OF SUBSEQUENT PRIMARY CANCERS following PEDIATRIC/ADOLESCENT OSTEOSARCOMA Rate per 10,000 O = Observed number O/E = Observed/ExpectedEAR = Excess Absolute Risk. Excess cancers per 10,000 person-years, calculated as [O-E/PYR x 10,000] being PYR=Person year at risk.
Slide 177 : Dr. Giulia Ottaviani, University of Milano, Italy NOTES on Etiology of Osteosarcoma Age Gender Ethnicity Height Genetic conditions Paget’s disease Other preexisting bone abnormalities HOST FACTORS ENVIRONMENTAL FACTORS Ionizing radiation Alkylating agents Weight Prenatal exposure Viruses Prior trauma
Slide 178 : Dr. Giulia Ottaviani, University of Milano, Italy [Le Vu B. et al. Int J Can 1998; 77: 370-377] RADIATION DOSE and OSTEOSARCOMA RISK Children Cancer Research Group Late Effect Study Group Observed Dose in Gy Osteosarcoma Risk
Slide 179 : Dr. Giulia Ottaviani, University of Milano, Italy [Le Vu B. et al. Int J Can 1998; 77: 370-377] SECOND OSTEOSARCOMA BY TYPE OF FIRST CHILDHOOD CANCER
Slide 180 : Dr. Giulia Ottaviani, University of Milano, Italy Osteosarcoma Genes Environment Health Other cancers or diseases
Slide 181 : Dr. Giulia Ottaviani, University of Milano, Italy LONG TERM SURVIVORS Late effects and complications of treatments Heart problems Hearing loss Osteopenia, osteoporosis Kidney and liver impairments Decreased fertility Functional disability secondary to surgical procedure* Hepatitis C / HIV Second malignant neoplasm
Slide 182 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] CUMULATIVE INCIDENCE OF DEVELOPING A SECOND CANCER in children with selected primary cancers
Slide 183 : Dr. Giulia Ottaviani, University of Milano, Italy [NCI. SEER Surveillance Epidemiology End Results. Inskin PD et al. 2006] RISK OF SUBSEQUENT PRIMARY CANCERS following PEDIATRIC/ADOLESCENT OSTEOSARCOMA Rate per 10,000 O = Observed number O/E = Observed/ExpectedEAR = Excess Absolute Risk. Excess cancers per 10,000 person-years, calculated as [O-E/PYR x 10,000] being PYR=Person year at risk. rischio di successivo tumore 0.15%/anno!
Slide 184 : Dr. Giulia Ottaviani, University of Milano, Italy SUMMARY Epidemiology: Pediatric cancer is rare – but a major cause of pediatric morbidity and mortality Pediatric cancers are different from adult cancers Etiology: genetics plays an important role Clinical Cases: common pediatric cancers: diagnosis staging treatment Success comes with a price
Slide 185 : Dr. Giulia Ottaviani, University of Milano, Italy CONCLUDING REMARKS MAJOR ADVANCES HAVE BEEN ACHIEVED IN THE CONQUEST OF PEDIATRIC CANCER APPROXIMATELY ONE IN EVERY 640 YOUNG ADULTS IS A PEDIATRIC CANCER SURVIVOR! [Aziz NM. et al. Cancer 2006;107:841-848]
Slide 186 : Dr. Giulia Ottaviani, University of Milano, Italy ISA 2006 Scientific Committee Membership Houston, Texas
Slide 187 : Dr. Giulia Ottaviani, University of Milano, Italy THANK YOU FOR YOUR ATTENTION http://users.unimi.it/giuliaottaviani/

 


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