1 -Presentación Dr. Silva.pptx

INMUNO-ONCOLOGIA
Estado actual y futuro
Cáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión
Dr. Carlos Silva
Hospital Británico de Buenos Aires-Hospital Universitario Austral
Universidad Católica Argentina

Declaración de Intereses
• Doy o he dado conferencias convocado por: Astra Zéneca, Bristol
Myers, MSD, Pfizer, Roche.
• Pertenezco o he pertenecido a Advisory Boards de Astra Zéneca,
Bristol Myers, MSD, Pfizer, Roche.
• He percibido honorarios por estas actividades.
• No he sido ni soy medical advisor de ningún laboratorio.
• He asesorado al Ministerio de Salud de la República Argentina.
• He sido auditor de uno de los tres sistemas privados de salud más
grandes de Argentina (SPM-Galeno).

Agenda
• Bases biológicas de la Inmuno Oncología
• Impacto de la Inmuno Oncología en el tratamiento del cáncer
• Tratamiento del Cáncer Renal avanzado primera línea
• Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada
• Tratamiento del Cáncer de Pulmón en segunda línea
• Biomarcadores
• Futuro no tan futuro

Hoy encontramos 10 hitos fundamentales
relacionados con la formación del cáncer
Hanahan & Weinberg. Cell 2011
Inhibidores
vía EGFR
Inhibidores quinasas
dependiente ciclinas
Inhibidores
glicólisis aerobia
Activación Inmune
Anti CTLA4
Drogas antiinflamat
selectivas
Inhibidores
HGF/c-Met
Inhibidores
vía VEGF
Inhibidores
PARP
Pro-apoptóticos
BH3 miméticos
Señal
proliferativa
sostenida
Evadiendo
señales
supresoras
Evadiendo
inmunidad
Pemitiendo
Inmortalidad
replicativa
Inhibidores
telomerasa
Metabolismo
celular
desregulado
Inflamación
promovida
por tumor
Activación
Invasión y
metástasis
Inducción
angiogénesis
Inestabilidad
y mutación
genómica
Resistencia
muerte
celular

¿QUE ES INMUNO-ONCOLOGĺA?
• La Inmuno-Oncología comprende el desarrollo y utilización de nuevos
componentes que aprovechan el sistema inmune del propio paciente para combatir
el cáncer
• Impulsan las propiedades únicas del sistema inmune
(especificidad, memoria, adaptabilidad, efectos sistémicos)
• Distintos de la cirugía, radioterapia, y modalidades citotóxicas/modalidades
blanco que impactan al tumor
• Se ha identificado un número blancos terapéuticos basado en nuestra mejor
comprensión del sistema inmune en el cáncer y los mecanismos que el tumor utiliza
para evadirlo
• El objetivo es volcar el balance en favor de la inmunidad, llevando a la erradicación
del tumor o la supresión por largo tiempo del crecimiento tumoral
• Tiene el potencial de proveer sobrevida durable y a largo témino con una buena
calidad de vida para los pacientes con varios tumores sólidos y hematológicos
• Tiene el potencial de volverse una modalidad nueva e innovadora y los cimientos
sobre los cuales construir nuevas estrategias de tratamiento
Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; De Vita VT, et al. N Engl J Med. 2012;366:2207–2214;
Eggermont A. Ann Oncol. 2012;23 Suppl 8:viii53–viii57.
6

Somatic Mutations May Give Rise to Patient-Specific Tumor Neoantigens
Presented By Leisha Emens at 2015 ASCO Annual Meeting

ACTIVACIÓN DE LINFOCITOS T CITOTÓXICOS
MODELO DE LAS TRES SEÑALES

MDX010-20: 1- and 2-Year Survival Rates, OS1
Survival Rate Median OS, mo
1 Year 2 Year (95%CI)
Ipi + gp100 44% 22% 10.0 (8.5, 11.5)
Ipi + pbo 46% 24% 10.1 (8.0, 13.8)
gp100 + pbo 25% 14% 6.4 (5.5, 8.7)
1. Hodi FS, et al. N Engl J Med 2010;363:711-23.
Patients at risk
Ipi + gp100 403 297 223 163 115 81 54 42 33 24 17 7 6 4 0
Ipi + pbo 137 106 79 56 38 30 24 18 13 13 8 5 2 1 0
Gp100 + pbo 136 93 58 32 23 17 16 7 5 5 3 1 0 0 0
1.0
0.8
0.6
0.4
0.2
0.0
Proportion
alive
0 1 2 3 4
Years

Ipilimumab: Association of Response With Survival in
Melanoma
Wolchok JD, et al. Clin Cancer Res. 2009;15:7412-7420.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Proportion
Alive
0 1 2 3 4 5 6 7 8 9 10 11121314 1516171819 2021 22232425262728293031323334
Mos
CR/PR/SD (by WHO criteria)
irPR/irSD (by the irRC)
PD and unknown response

Consistent Survival Benefit in Subpopulations1
Pre-specified Subgroups in MDX010-20
ALL PATIENTS
Gender Male
Female
Age < 65 years
≥ 65 years
Female < 50 years
Female ≥ 50 years
M-stage at Study Entry M0, M1A, M1B
M1C
Baseline LDH ≤ ULN
> ULN
≤ 2x ULN
> 2x ULN
Prior Use of IL-2 Yes
No
Favors: Ipi + gp100 gp100 Ipi gp100
Hazard Ratio and 95% CI
1. Hodi FS, et al. N Engl J Med 2010;363:711-23.
0.2 0.5 1 2 5 0.2 0.5 1 2 5

Patients at Risk
Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0
Proportion
Alive
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
0 12 24 36 48 60 72 84 96 108 120
N = 1861
Median OS (95% CI): 11.4 mo (10.7-12.1)
3-year OS Rate (95% CI): 22% (20% to 24%)
Ipilimumab
CENSORED
Hodi S, et al. 2013 European Cancer Congress. Abstract LBA 24.
Ipilimumab: Pooled Survival Analysis from Phase II/III
Trials in Advanced Melanoma

Nivolumab: Duration of Response
Months since initiation of response
Proportion
progression-free
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33
22 21 16 14 12 8 5 2 2 1 1 0
33 33 30 27 19 15 12 9 5 0 0 0
10 10 10 9 5 3 2 2 2 1 0 0
No. at Risk
Med., mo. (95%CI)
NSCLC (n=22) 17.0 (9.7 - NE)
Melanoma (n=33) 24.0 (17.0 - NE)
RCC (n=10) 12.9 (11.4 - NE)
Censored
Topalian SL, et al. ASCO 2013. Abstract 3002.
NSCLC
MEL
RCC

Ways to enhance T cell attack
Presented By Michael Postow at 2017 ASCO Annual Meeting

Targeting regulatory T cells:
• Depleting (Denileukin diftitox, CD25-specific antibody, cyclophosphamide)
• Blocking trafficking (CCL22-specific antibody)
• Blocking differentiation and signalling (blocking FOXP3 signal)
Targeting suppressive molecules:
• Blocking suppressive molecules (B7-H1, B7-H4, IDO, arginase) on APCs
• Blocking suppressive molecules (CTLA4, PD1) on T cells
• Blocking soluble suppressive molecules (TGFβ, IL-10, VEGF, COX2
• Surgical debulking
• Radiation therapy
• Chemotherapy
• Anti-angiogenic therapy
• Tumour-associated antigens
(tumour peptides)
• APC vaccination
(dendritic cells)
• Adoptive T-cell transfusion
(effector T cells)
• Cytokine and/or chemokine
administration
(IL-7, IL-15 and IL-21)
Human tumour
Combinatorial therapy
Traditional
tumour therapy
Novel tumour
immunotherapy
Conventional
immunotherapy
Weiping Zou 2006. Nat Rev. Immunol. 6:295-307.
PERSPECTIVAS DE LA INMUNOTERAPIA PARA EL CÁNCER

¿Todos los pacientes deben
ser tratados de inicio?

Treatment Patterns: Untreated Patients
• In a large prospective cohort of mRCC patients, median time to treatment initiation
was 7.2 months, and 20% of patients remained untreated at 4 years
.
Bains P et al. Poster presentation at ASCO GU 2015. 424.
Factors predicting later initiation of
targeted therapy:
• History of radiation therapy
• Older age at time of metastatic disease
• Presence of brain metastases only
• Presence of bone metastases
• Indolent disease
• High number of metastatic sites
Initiation of
therapy within:
N=920
6 months 47%
1 year 57%
2 years 68%
3 years 74%
4 years 80%
5 years 83%

¿Cuál es la evidencia de la
efectividad de la
inmunoterapia para frenar
la enfermedad?

Long-Term Overall Survival With Nivolumab
in Patients With mRCC
• In CheckMate 003, minimum follow-up was 50.5 months
34 28 24 18 14 13 12 12 11 8 6 6 2 1 0
Number of patients at risk
Nivolumab
Median OS, months
(95% CI)
Nivolumab 22.4 (12.5–NE)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
Overall
Survival
(Probability)
Months
38%
34%
.
McDermott DF et al. Oral presentation at ASCO 2016. 4507.

CA209-025/CheckMate 025
* Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well-tolerated.2
1. Clinicaltrials.gov. NCT01668784. https://clinicaltrials.gov/ct2/show/NCT01668784?term=NCT01668784&rank=1. Accessed on October 2, 2015.
2. CA209-025 clinical protocol. August 27, 2014.
Phase III, randomized, open-label trial of nivolumab vs everolimus in subjects with
advanced or metastatic clear cell RCC who have received prior antiangiogenic therapy1
Nivolumab
3 mg/kg IV q2w
Until
progression*,
unacceptable
toxicity,
withdrawal of
consent, or end
of trial
Key Inclusion Criteria
• Advanced/metastatic clear cell RCC
• No more than 3 total prior regimens in
advanced/metastatic setting
• 1 or 2 prior antiangiogenic therapy
regimens in advanced/metastatic
setting
• Karnofsky PS ≥70%
• No CNS metastases
• No prior therapy with mTOR inhibitor
• No autoimmune disease
R
1:1
Everolimus
10 mg PO qd
• Primary Outcome Measure: OS
• Secondary Outcome Measures: PFS, ORR, duration of
objective response, duration of OS by PD-L1 status,
safety, disease-related symptom progression rate
Start Date: September 2012
Estimated Trial Completion Date: September 2016
Estimated Primary Completion Date: May 2015
Status: Ongoing but not recruiting
Trial Director: Bristol-Myers Squibb
N=822

OS in Patients With mRCC
Median OS was 25 months and 19.6 months in the nivolumab and everolimus
groups, respectively
Motzer et al. N Engl J Med. 2015;373(19):1803-1813.
Median OS,
months
(95% CI)
Nivolumab 25.0 (21.8–NE)
Everolimus 19.6 (17.6–23.1)
0 3 6 12
9 15
Months
18 21 24 27 30 33
# of patients at risk
Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0
411 366 324 287 265 241 187 115 61 20 2 0
Everolimus
0.0
0.3
0.1
0.2
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall
Survival
(Probability)
Nivolumab
Everolimus

Duration of Response (DOR) in Patients
With mRCC
Motzer et al. N Engl J Med. 2015;373(19):1803-1813.
Majority of patients showed a response at first assessment
0 16 32 64
48 80
Time (Weeks)
96 112 128
Responders
Ongoing response
First response
Off treatment
Nivolumab
Everolimus On treatment

Landmark Overall Survival Analysis in Patients Treated and Not Treated
Beyond Progression
• In a landmark analysis beginning from 4 weeks post-progression, median OS was
20.4 months (95% CI, 17.3–NE) in patients treated with nivolumab beyond progression
and 11.4 months (95% CI, 9.4–14.6) in patients not treated beyond progression
Escudier B et al. Poster presentation at ASCO 2016. 4509.
TBP
NTBP
153 153 146 142 132 123 96 65 30 17 2 0
145 131 113 101 84 69 54 29 16 3 0 0
Months
Overall
Survival
(Probability)
0.0
0 3 6 9 12 15 18 21 24 27 30 33
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
1.0
0.9
Not treated beyond progression
Treated beyond progression
Median OS, months (95% CI)
Treated beyond progression 28.1 (23.2–NE)
Not treated beyond progression 15.0 (12.1–18.2)
HR (95% CI), 0.41 (0.29–0.57)
Overall survival with nivolumab

¿En primera línea y en
combinación es superior que el
actual standard de cuidado?

RJ Motzer et al. N Engl J Med 2018;378:1277-1290.
Overall Survival and Progression-free Survival among IMDC
Intermediate- and Poor-Risk Patients.

¿Qué pasa si combinamos con
antiangiogénicos?

¿Cuál es el rol en adyuvancia y
neoadyuvancia?

Decision Point….
Immunotherapy
PD-1 alone
PD-1/CTLA-4
Combination

Time to Response and Durability of Response in Patients
Who Discontinued Due to Adverse Events
(Pooled Analysis of Checkmate 067 and 069
Minimum 18-month follow-up, median 21.3-month follow-up.
Adapted from Schadendorf D et al. J Clin Oncol. 2017;35:3807-3814.
Patients
Weeks
0 112
96
88
80
64
56
40
32
16
8 24 48 72 104
On treatment
Off treatment
First response
Ongoing response

Adjuvant Therapy With Nivolumab Versus Ipilimumab
After Complete Resection of Stage III/IV Melanoma:
Updated Results from a
Phase 3 Trial (CheckMate 238)
Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5
C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10
Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15
Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19*
1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute,
Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Charles A. Sammons
Cancer Center, Dallas, Texas, USA; 7Hospices Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology
Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France;
12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology,
University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and University of Queensland, Brisbane,
Australia; 16University Hospital Zurich, Switzerland; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust,
London, UK; 19Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study.
Abstract Number 9502

Primary Endpoint: RFS in All Patients
RFS
(%)
Months
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 27
3 9 15 21 30 33
NIVO
IPI
NIVO
IPI
NIVO IPI
Events/patients 171/453 221/453
Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR)
HR (95% CI) 0.66 (0.54, 0.81)
Log-rank P value <0.0001
63%
50%
70%
60%
453 353 311 280 205 28
394 331 291 264 7 0
453 314 251 216 149 23
363 270 230 204 5 0
66%
53%
aMedian estimate not reliable or stable due to few patients at risk.

Future Directions
• A new partner for PD-1
– Less toxic than ipi
– More effective than PD-1 alone
• Overcoming Resistance
– Making ”cold” tumors “hot”
• Patient selection
– Role of biomarkers

Making Tumors “Hot”
Responsive to Immunotherapy
Generate
T-cells:
+ Combination CPIs
+ Immune activating antibodies
or cytokines
+ TLR agonists or oncolytic
viruses
+ IDO or macrophage inhibitors
+ Targeted therapies
Bring T-cells
into tumors:
Vaccines
TCR engineered ACT
CAR engineered ACT

Biomarkers
• Approximately 50% of melanomas contain
mutations in the BRAF gene, a critical component
of the growth promoting MAP kinase pathway1
• Some melanomas have activating mutations in the
human KIT, NRAS, and other genes1-3
• Only BRAF is currently recommended to be tested
in melanoma patients except in clinical trials
• BRAF is an activating mutation that is mutually
exclusive with NRAS or c-KIT1
 All of these activate the MAP-kinase pathway
that promotes tumor growth1-3
 Younger patients are more likely to have
mutations5
45
Site of
melanoma
Frequency of genetic mutation1
BRAF GNA11 GNAQ KIT NRAS
Acral surfaces 15% 15% 15%
Mucosal
surfaces
5% 20% 15%
Skin with
chronic sun
damage
10% 2% 10%
Skin without
chronic sun
damage
50% 20%
Uvea 55% 25%
Biomarker-based stratification of patients is evolving in clinical trials.
The NCCN expert panel supports obtaining tissue samples for genetic analysis4
Sources
1. Sosman JA ASCO, 2011: Educational Book pages 367-372.
2. Curtin JA et al. J Clin Oncol. 2006;24:4340-4346.
3. Van Raamsdonk CD et al. N Engl J Med. 2010;363:2191-2199.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v2.2013.
5. Hacker E et al. J Invest Dermatol 2010;130(1):241-248.

But despite these advances, unmet needs remain
EGFR
ALK
ROS1
NSCLC
No actionable
driver mutation
BRAF
How can we improve outcomes for the majority of
NSCLC patients who have no actionable driver mutation?

Examples of Prognostic Implications
of Immune Response
Correlation with Positive Outcome:
Presence of TILs Associated with
Increased Recurrence-Free Survival1
Correlation with Negative Outcome:
Higher NSCLC-Infiltrating Tregs Associated
with Worse Recurrence-Free Survival2
Recurrence-Free
Survival
(%)
Survival Time (Months)
24 36
12 48 60
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
FoxP3+ cell <3
FoxP3+ cell ≥3
Patients with Stage I–III NSCLC
with Surgical Resection (N=100)2
Recurrence-Free
Survival
(%)
1.0
0.8
0.6
0.4
0.2
0.0
0.0 10 20 30 40 50 60
Survival Time (Months)
TIL–
TIL+
P=0.011
Patients with Stage Ia NSCLC with
Surgical Resection (N=273)1
FoxP3 cell < (≥) 3 = lower (higher) levels of FoxP3; TILs = tumor-infiltrating lymphocytes; Tregs = regulatory T cells.
1. Shimizu K, et al. J Thorac Oncol. 2010;5:585-590. 2. Horne ZD, et al. J Surg Res. 2011;171:1-5.

Respuestas a terapias Anti PD-1/PD-L1:
Papel de la Histología, expresión de PDL-1 y estado mutacional
Para los 3 anticuerpos disponibles actualmente:
 La expresión de PD-L1 está fuertemente asociada con mejores tasas
de respuesta.
 Las respuestas ocurren independientemente de la histología,
antecedente de tabaquismo y estado mutacional (EGFR/K-ras).

Tumor Mutational Burden (TMB)
Tumors with more mutations are more likely to respond to immunotherapies,
because of the increased likelihood that they will have neoantigens that can
be targeted by the immune system.
TMB is a measurement of the total number of coding somatic base
substitution and indel mutations occurring in a tumor specimen, per
megabase of coding genome assessed.

©2016 Foundation Medicine, Inc. 56
TMB IS A BIOMARKER FOR RESPONSE TO IMMUNOTHERAPY
Cancer immunology. Mutational landscape determines sensitivity to
PD-1 blockade in non-small cell lung cancer.
Rizvi et al., Science, 2015
Genetic Basis for Clinical Response to CTLA-4
Blockade in Melanoma
Snyder et al., NEJM, 2014

Conclusiones
• La caracterización molecular del Cáncer nos ha mostrado
realmente la muy compleja heterogeneidad de esta enfermedad y
gracias a esto hemos entendido las fallas anteriores en decisiones
terapéuticas. Muy probablemente, los estudios clínicos que hemos
realizado ya no tendrán, dentro de poco, una gran validez científica
pues hay que entender que “one size fits all” no aplica en esta
enfermedad.
• Es solo a través del conocimiento de las mutaciones genéticas
específicas y el desarrollo de terapias dirigidas a ellas que
lograremos cambiar la historia natural de la enfermedad.

Mensajes
• El cáncer es una enfermedad causada por alteraciones genéticas generalmente
múltiples, heterogéneas, intercambiables.
• La detección de quien conduce la enfermedad al inicio y en cada momento de la
misma seria determinante para conducir el tratamiento y a veces corregir el
rumbo.
• Las plataformas genómicas pueden detectar alteraciones potencialmente blanco
de tratamientos específicos.
• Los futuros estudios deberían incluir con mas frecuencia estas determinaciones.
• La accesibilidad y su validación en más estudios clínicos permitiría seleccionar
pacientes que podrían beneficiarse de tratamientos específicos así como
determinar quienes no tendrían beneficios de tratamientos establecidos.

Combinatorial immunotherapy
anti-CD137
anti-OX40
anti-CD40
Radiotherapy
Chemotherapy
Vaccination
Treg depletion/
inactivation
Adoptive T-cell
immunotherapy
Clinical standard
Clinical trials
Preclinical studies
anti-PD1
anti-PDL1
Anti-angiogenic
therapy
IDO inh
anti-CTLA4
Perez Gracia, et al. Curr Opinion Immunol 2014

What Is Being Tested in the Immune Checkpoint Inhibitor Perioperative trials?<br />
Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

The future of Immuno Oncology in RCC (4)
Presented By Bernard Escudier at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary
Care

Feces composition differs between responders and non responders to IO
Care

Feces modification by antibiotics may negatively impact efficacy of IO
Care

PROBLEMAS IMPORTANTES
• Necesitamos comprender los mecanismos de resistencia y desarrollar nuevas estrategias para
sortearlos.
• Los pacientes que responden son importantes pero preocupan los que no responden.
• Necesitamos mejores biomarcadores para seleccionar los pacientes que se beneficiaran.
• La toxicidad es manejable salvo la toxicidad financiera que es de grado ¾ con alto riesgo de
transformarse en grado 5 matando al sistema y limitando el acceso de los pacientes a los nuevos
tratamientos.

Presented By Ravi Madan at 2014 ASCO Annual Meeting

Conclusiones
• La inmunoterapia puede enlentecer el crecimiento de los tumores
más que alterar su progresión a corto término.
• La inmunoterapia puede ejercer su efecto por un largo periodo de
tiempo.
• Combinaciones terapéuticas diseñadas racionalmente pueden lograr
efectos sinérgicos de alto impacto.
• Hoy logramos contener la evolución de muchos tipos de tumores
• Tal vez estemos curando algunos.

Muchas Gracias
Dr. Carlos Silva
Hospital Británico de Buenos Aires-Hospital Universitario Austral
Universidad Católica Argentina

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