FOCUS ON ENDOCRINE NEOPLASIA
Neuroendocrine Tumors
FAUSTO BOGAZZI
University of Pisa
Department of Endocrinology and Metab...
Neuroendocrine Tumors
The origins
1897
Identification of enterochromaffin cells
Kulchitsky 1856-1925
1948
Isolation of ser...
Neuroendocrine Tumors
Epidemiology
Lung Appendix Stomach Colon
Small Bowel Recto Cieco Pancreas
0,6
0
1,4
1,0
0,2
Incidenc...
100.000
Cases(n)
0
1.000.000
Prevalence (database SEER)
1.200.000
NET Stomach Pancreas EsophagusColon - recto Liver
Yao JC...
1.Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153.
2.Modified from Vierimaa et al. Eur J Endocrino...
Modlin IM et al. Lancet 2008.
Mortality
at the moment is nearly stable
Neuroendocrine Tumors
Epidemiology
Hauso et al. Cancer 2008; 113: 2655-64
Panzuto et al. Endocrine-Related Cancer 2005;12:
1083-92.
Mortality depends on:
Ne...
Manifestation depends on:
Site of primary tumor
Functioning of the tumor
Non functioning NET: symptoms due to “mass effect...
Neuroendocrine Tumors
Diagnosis
1. Kloppel et al. ENETS Guidelines . Neuroendocrinology 2009: 90-162-169
Need of a documen...
Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153;
Kloppel et al. ENETS Guidelines . Neuroendocrinol...
11
Neuroendocrine Tumors
Pathology and Staging predicts Prognosis
12
Neuroendocrine Tumors
Grading Predicts Prognosis
Clinical Syndrome Tumor Location
Secretory Products Causing the
Syndrome
Carcinoid Syndrome
Lung, Stomach and Pancreas
(Fo...
Neuroendocrine Tumors
Carcinoid Syndrome
Histopathology Argyrophil/argentaffin staining CgA, Serotonin
Tumour Markers CgA, u-5-HIAA, p-NPK, p-Subst-P
P-ACTH, pCRF,...
Tumour Location Pancreas 50-60%
Duodenum 40-50%
(sometimes both, MEN-I)
20-25% Related to MEN-1
50-70% Malignant (lymphnod...
Tumour Location Pancreas
>90% malignant
Symptoms Necrolytic migratory erythema
Weight loss
Anemia
Trombosis
Impaired gluco...
Neuroendocrine Tumors
Glucagonoma Syndrome
Tumour Location Pancreas
Lung
Ganglioneuromas
>80% Malignant
(Pancreatic “nesidioblastosis”)
Symptoms Watery diarrhea (sec...
Tumour Location Duodenum
Pancreas
Colon/Rectum
>80% mixed tumours
Symptoms Gallstones
Steatorrhea
Impaired glucose toleran...
Neuroendocrine Tumors
Diagnosis
O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202
Biochemical Markers:...
Neuroendocrine Tumors
Diagnosis
O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202
Biochemical Markers:...
Neuroendocrine Tumors
Diagnosis
O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202
Biochemical Markers:...
Neuroendocrine Tumors
Diagnosis
O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202
Biochemical Markers:...
Total Body
Screening and Staging
Octreoscan (111Ind-DTPA-octreotide) (SRI)
Sensitivity <10 mm 40%
>10 mm 90%
Liver metasta...
Neuroendocrine Tumors
Diagnosis - Imaging
Table 5: Ramage JK, et al. Gut 2005; 54: 1-16.
Imaging
Scan speed
multidector TC Contrastographic study with
acquisition in different phases
Precocious
Arterial (20’’)
Pancreati...
Multidetector TC : gastrointestinal lesions
Neuroendocrine Tumors
Diagnosis -Imaging
Octreoscan
Neuroendocrine Tumors
Diagnosis -Imaging
Ecography
Neuroendocrine Tumors
Diagnosis -Imaging
Neuroendocrine Tumors
The Ultimate Goals for the Treatment of
Neuorendocrine Tumours
•Total eradication by surgery (not po...
Neuroendocrine Tumors
Therapy of Neuroendocrine Gut and
Pancreatic Tumours
Surgery
Embolisation ± Chemotherapy
Irradiation...
Kaltsas et al. Endocrine Reviews 2004, 25(3): 458-511
first line therapy in localized NET
Neuroendocrine Tumors
Surgical ...
Important role in hepatic metastatic disease
Neuroendocrine Tumors
Surgical Therapy
Neuroendocrine Tumors
Embolisation of Liver Metastases
Biochemical Response Tumour Response
Embolisation
(Spongostan®, Gel...
PROLIFERATION
DIFFERENTIATION
Biotherapy
 SSA
 IFN-α
Chemotherapy
Neuroendocrine Tumors
Proposed TNM classification and ...
Neuroendocrine Tumors
INF-α Treatment
Subjective Response 50-70%
Biochemical Response 30-70%
Tumor Response 10-15%
Neuroendocrine Tumors
Somatostatine Receptors
•Five subtypes cloned: SSTR 1-5
•SOM.14 and 28 bind to all receptor subtypes...
Neuroendocrine Tumors
Octreotide Treatment
Subjective Response 30-75% (dose dependent)
Biochemical Response 30-60% (dose d...
Tachifilaxis: Hormone secretion
Hofland, Endocrine Review 2003
Somatostatine Analogs
Neuroendocrine Tumors
Medical Therapy...
Neuroendocrine Tumors
Chemotherapy of Neuro-Endocrine Gut and
Pancreatic Tumours
Response
Rate
Endocrine pancreatic Tumor ...
Neuroendocrine Tumors
PRRT:
Effects depending on:
 Radiosensibility:
 Growth pattern of the tumor
 DNA repair
 Concent...
Neuroendocrine Tumors
PRRT:
Response: predictive factors
Elevated uptake
Presence of liver metastasis
Progression: predi...
New prospective will be available..
New Therapies
Neuroendocrine Tumors
Medical Therapy:
At the moment drugs used only in ...
Neuroendocrine Tumors
Conclusions
 NET are rare neoplasms and they still remain orphan tumors with a survival that is
sta...
Vasily Kandinsky Several Circles 1926 oil on canvas; Solomon R. Guggenheim Museum, New York
Thanks for your attention
Acknowledgments
Enio Martino
Luca Manetti
Sandra Brogioni
Chiara Sardella
Isabella Lupi
Chiara Cosci
Luca Tomisti
...
Diapositiva 1
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Diapositiva 1

  1. 1. FOCUS ON ENDOCRINE NEOPLASIA Neuroendocrine Tumors FAUSTO BOGAZZI University of Pisa Department of Endocrinology and Metabolic DiseaseRome, 10 July 2010
  2. 2. Neuroendocrine Tumors The origins 1897 Identification of enterochromaffin cells Kulchitsky 1856-1925 1948 Isolation of serotonin (5-HT) Rapport M. Foregut Midgut Hindgut 1953 Evidence of 5-HT in carcinoid tumors Lembeck F. 1963 Introduction of carcinoid tumors embryologic classification (foregut, midgut o hindgut) Williams E.D. e Sandler M. Siegfried Oberndorfer 1876-1944 1907 Introduction “karzinoide” concept (benign features) 1929 Identification of malignant and metastatizing neuroendocrine tumors
  3. 3. Neuroendocrine Tumors Epidemiology Lung Appendix Stomach Colon Small Bowel Recto Cieco Pancreas 0,6 0 1,4 1,0 0,2 Incidenceevery100.000 subjects 1980 1990 2000 1,2 0,8 0,4 1 Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153 2 Newton JN et al. Br J Cancer 1994; 70: 939-42 3 Yao JC, et al. J Clin Oncol 2008; 26(18): 3063-3072. Rare tumors: incidence 2.5-5/100,000/year in USA1 (largest group: small intestinal neuroendocrine tumors → 2.4/100000/y) 1 incidence 0.7/100000/year in Europe2 Higher incidence at autopsy: 8.4/100000/year1 Increasing incidence in the epidemiologic registry of USA3
  4. 4. 100.000 Cases(n) 0 1.000.000 Prevalence (database SEER) 1.200.000 NET Stomach Pancreas EsophagusColon - recto Liver Yao JC, et al. J Clin Oncol 2008; 26(18): 3063-3072. NET are the second most common tumors of gastrointestinal tract Neuroendocrine Tumors Epidemiology
  5. 5. 1.Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153. 2.Modified from Vierimaa et al. Eur J Endocrinol 2007; 157: 285-294 NET can appear at all age Higher incidence from the fifth decade Appendix carcinoid higher incidence at <30 years Patients with MEN1 or vHL: clinical onset 15 years earlier than sporadic forms Neuroendocrine Tumors Epidemiology
  6. 6. Modlin IM et al. Lancet 2008. Mortality at the moment is nearly stable Neuroendocrine Tumors Epidemiology
  7. 7. Hauso et al. Cancer 2008; 113: 2655-64 Panzuto et al. Endocrine-Related Cancer 2005;12: 1083-92. Mortality depends on: Neuroendocrine Tumors Epidemiology  Site of NET  Age at diagnosis  Primary tumor dimension  Tumor degree differentiation (ki67)  Disease stage
  8. 8. Manifestation depends on: Site of primary tumor Functioning of the tumor Non functioning NET: symptoms due to “mass effect” or distant metastases Functioning NET Paraneoplastic Syndrome: Cushing Syndrome, Acromegaly Neuroendocrine Tumors Clinical Manifestation Tumor Syndrome Hormones Site Carcinoid tumor Carcinoid Syndrome Serotonin, tachichinin, bradichinine, histamine Midgut Foregut Insulinoma Hypoglycemia Insulin Pancreas Glucagonoma Becker Syndrome (hyperglicemia, migrating necrolitic eritema) Glucagone Pancreas Duodenum Gastrinoma Zollinger-Ellison Syndrome Gastrin Pancreas Duodenum VIPoma Diarrea ipokaliemia-achloridria VIP Pancreas Lung
  9. 9. Neuroendocrine Tumors Diagnosis 1. Kloppel et al. ENETS Guidelines . Neuroendocrinology 2009: 90-162-169 Need of a documented hystopathological diagnosis Biopsy Resection Specimen TNM classification
  10. 10. Oberg et al. ESMO Guidelines Working group. Ann Oncol 2009; S4: 150-153; Kloppel et al. ENETS Guidelines . Neuroendocrinology 2009: 90-162-169 Neuroendocrine Tumors Diagnosis TNM classification specific for different sites Gastric Duodenum/ampulla/proximal jejunum Pancreas Lower jejunum/ ileum Grading Proposal for foregut (neuro)endocrine tumors Grade Mitotic count (10HPF)a Ki-67 index (%)b G1 <2 ≤ 2 G2 2-20 3-30 G3 >20 >20 a 10 HPF: high power field= 2mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic density b MIBI antibody: % of 2.000 tumor cells in areas of highest nuclear labeling
  11. 11. 11 Neuroendocrine Tumors Pathology and Staging predicts Prognosis
  12. 12. 12 Neuroendocrine Tumors Grading Predicts Prognosis
  13. 13. Clinical Syndrome Tumor Location Secretory Products Causing the Syndrome Carcinoid Syndrome Lung, Stomach and Pancreas (Foregut ) Ileum and Jejunum (Midgut) Serotonin, Histamine, Tachykinins, Bradykinin Serotonin, Tachykinins Bradykinin Zollonger Ellison Syndrome Pancreas Duodenum Gastrin Hypoglycemic (insulinoma) Pancreas (Sareomas) Insulin, proinsulin IGF-I/II, VIP, PHM Verner-Morrison Syndrome Pancreas, Ganglioneuro-mas, Paraganglioma, Lung VIP, PHM Glucagonoma Syndrome Pancreas Glucagon, (Glicentin) Somatostatinoma Syndrome Pancreas, Duodenum Somatostatin “Non functioning” Tumours Pancreas, Colon CgA, HCG-α/β, PP, PYY (no endocrine related symptoms) Neuroendocrine Tumors Diagnosis
  14. 14. Neuroendocrine Tumors Carcinoid Syndrome
  15. 15. Histopathology Argyrophil/argentaffin staining CgA, Serotonin Tumour Markers CgA, u-5-HIAA, p-NPK, p-Subst-P P-ACTH, pCRF, PGHRH, s-calcito- nin, p-ADH, s-PP, s-HCGα/β, u- Histamine Other Markers Stimulatory Tests Flush provocation: Pentagastrin 0,6 ug/kg bw i.v., measuring p-NKP every 5 min for 30 min Radiology Octreoscan ( 111 Ind-DTPA-octreotide) CT, US, MRI, (CT-angiography) Other Investigations Endoscopy (endoscopic ultrasound) Neuroendocrine Tumors Carcinoid Tumour Diagnosis
  16. 16. Tumour Location Pancreas 50-60% Duodenum 40-50% (sometimes both, MEN-I) 20-25% Related to MEN-1 50-70% Malignant (lymphnode metastases) Gastrinoma Triangle 80% Symptoms Gastritis Recurrent ulcers Diarrhea (malabsorption) Neuroendocrine Tumors Zollinger Ellison Syndrome
  17. 17. Tumour Location Pancreas >90% malignant Symptoms Necrolytic migratory erythema Weight loss Anemia Trombosis Impaired glucose tolerance Diarrhoea Neuroendocrine Tumors Glucagonoma Syndrome
  18. 18. Neuroendocrine Tumors Glucagonoma Syndrome
  19. 19. Tumour Location Pancreas Lung Ganglioneuromas >80% Malignant (Pancreatic “nesidioblastosis”) Symptoms Watery diarrhea (secretory) 3-20 litres/day Hypokalemia, Hypomagnesemia, Hypercalcemia Acidosis Flushing Flaccid distended gallbladder Ileus/subileus Neuroendocrine Tumors Verner-Morrison Syndrome (WDHA:s)
  20. 20. Tumour Location Duodenum Pancreas Colon/Rectum >80% mixed tumours Symptoms Gallstones Steatorrhea Impaired glucose tolerance Often “non-functioning” tumours! Neuroendocrine Tumors Somatostatinoma Syndrome
  21. 21. Neuroendocrine Tumors Diagnosis O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202 Biochemical Markers: Chromogranin A Recognized general serum marker →co-secreted in tumors with amines and peptides present in neurosecretory granules Can be elevated in functional and non-functional NET More often high in midgut NET and non-functioning pancreatic NET Levels depending on: tumor cell type, differentiation, tumor volume
  22. 22. Neuroendocrine Tumors Diagnosis O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202 Biochemical Markers: Urinary 5-HIAA In carcinoid syndrome sensitivity 70%, specificity 90% Most frequently high in midguts carcinoid than fore- and hindgut tumors Depends on tumor volume, often normal in non metstatic carcinoids At the moment can’t be considered a reliable prognositc factor Use of HPLC has to be preferred Falsely low: Renal impairment Falsely high: Malabsorption (coelic disease, intetsinal stasis, cystic fibrosis); DRUGS (FANS); FOOD (TRIPTOFAN-RICH)
  23. 23. Neuroendocrine Tumors Diagnosis O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202 Biochemical Markers: Gastrin Useful to diagnose Zollinger-Ellison Syndrome Elevated fasting serum gastrin Low gastric pH Secretin test: ∆ gastrin increase ≥110 pg/ml (sensitivity 93%) ∆ gastrin increase ≥200 pg/ml (sensitivity 85%) ∆ gastrin increase ≥ 120 pg/ml (sensitivity 94%;specificity 100%)
  24. 24. Neuroendocrine Tumors Diagnosis O’Toole et al. ENETS Guidelines. Neuroendocrinology 2009; 90: 194-202 Biochemical Markers: Insulin Useful to diagnose Insulinomas I. Symptoms of hypoglicemia II. Glucose < 40-50 mg/dl III. Relief of sympoms with glucose administration Whipple’s Triad 72h fast→ gold standard for diagnosing insulinoma To attest: Failure of appropriate insulin suppression Autonomus insulin secretion Test endpoint: document hypoglycaemia  blood glucose ≤ 2.2 mmol/L (≤ 40 mg/dL) [or <3 nmol/L, 50 mg/dL] concomitant insulin levels > 6 μU/L (≥ 36 pmol/L) A β-hydroxybutyrate level ≤ 2.7 mmol/L ( confirm test validity and inappropriate insulin suppression) A glucagon test immediately after 72-hour fasting in patients without definitive results  recommended Use of a ratio insulin to glucose is not recommended to aid diagnosis Exercise test immediately after 72 hours fasting in patients without definitive results only in supervised setting
  25. 25. Total Body Screening and Staging Octreoscan (111Ind-DTPA-octreotide) (SRI) Sensitivity <10 mm 40% >10 mm 90% Liver metastases = 90% Disclosure of Endocrine Pancreatic Tumours Endoscopic ultrasonography (EUS); sensitivity <10 mm ≈ 50% SRI + EUS sensitivity <10 mm ≈ 90% Newer Techniques Positron emission tomography with C11-5 HTP or C11-L-dopa (PET) Traditional Techniques (always a complement) CT (+ angiography), MRI US; sensitivity small tumours 10-30% Liver metastases 90% Neuroendocrine Tumors Radiology of Neuroendocrine Tumours
  26. 26. Neuroendocrine Tumors Diagnosis - Imaging Table 5: Ramage JK, et al. Gut 2005; 54: 1-16. Imaging
  27. 27. Scan speed multidector TC Contrastographic study with acquisition in different phases Precocious Arterial (20’’) Pancreatic (35’’) Venous (70’’) Fenchel S et al Eur J Radiol 2003 Horton, Radiographics 2006 Rha, Eur J Radiol 2007 Neuroendocrine Tumors Diagnosis - Imaging
  28. 28. Multidetector TC : gastrointestinal lesions Neuroendocrine Tumors Diagnosis -Imaging
  29. 29. Octreoscan Neuroendocrine Tumors Diagnosis -Imaging
  30. 30. Ecography Neuroendocrine Tumors Diagnosis -Imaging
  31. 31. Neuroendocrine Tumors The Ultimate Goals for the Treatment of Neuorendocrine Tumours •Total eradication by surgery (not possible in most cases) •Abrogation of tumor growth and/or amelioration of clinical symptoms •Improving and maintaining a good quality of life
  32. 32. Neuroendocrine Tumors Therapy of Neuroendocrine Gut and Pancreatic Tumours Surgery Embolisation ± Chemotherapy Irradiation Medical Treatment conventional for bone metastases experimental (local) Somatostatin Analogues α-Interferon Chemotherapy even palliative and tumors reduction 111Ind-DTPA-octreotide 45-60 Gy 90 Y-DOTA-octreotide
  33. 33. Kaltsas et al. Endocrine Reviews 2004, 25(3): 458-511 first line therapy in localized NET Neuroendocrine Tumors Surgical Therapy
  34. 34. Important role in hepatic metastatic disease Neuroendocrine Tumors Surgical Therapy
  35. 35. Neuroendocrine Tumors Embolisation of Liver Metastases Biochemical Response Tumour Response Embolisation (Spongostan®, Gel-Foam) 30-50% Median duration 20-30% 7-10 months Chemoembolisation (Doxorubicin) 50-80% Median duration 40-50% 10-20 months
  36. 36. PROLIFERATION DIFFERENTIATION Biotherapy  SSA  IFN-α Chemotherapy Neuroendocrine Tumors Proposed TNM classification and NET therapy Grading Proposal for foregut (neuro)endocrine tumors Grade Mitotic count (10HPF)a Ki-67 index (%)b G1 <2 ≤ 2 G2 2-20 3-30 G3 >20 >20 a 10 HPF: high power field= 2mm2, at least 40 fields (at 40x magnification) evaluated in areas of highest mitotic density b MIBI antibody: % of 2.000 tumor cells in areas of highest nuclear labeling
  37. 37. Neuroendocrine Tumors INF-α Treatment Subjective Response 50-70% Biochemical Response 30-70% Tumor Response 10-15%
  38. 38. Neuroendocrine Tumors Somatostatine Receptors •Five subtypes cloned: SSTR 1-5 •SOM.14 and 28 bind to all receptor subtypes •All receptor subtypes are 7 TM receptors and G-Protein coupled •Effector mediators are C-AMP, CA2+ /K+ FLUX, TYROSINPHOSPHATASES •Octreotide binds to SSTR2 and SSTR5 •SSTR2 mediates biochemical and tumour responses •SSTR3 mediates apoptosis •SSTR5 mediates anti-tumour response different from SSTR2 (NOT VIA PTPI-C BUT CA 2+ /K +FLUX?)
  39. 39. Neuroendocrine Tumors Octreotide Treatment Subjective Response 30-75% (dose dependent) Biochemical Response 30-60% (dose dependent) Tumor Response 0-15% (not dose dependent) Time (months) Proportionwithout progression 0 0. 25 0. 5 0. 75 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 7 2 7 8 0 0. 25 0. 5 0. 75 1 0 6 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6 7 2 7 8 8 4 Proportionwithout progression Time (monhs )
  40. 40. Tachifilaxis: Hormone secretion Hofland, Endocrine Review 2003 Somatostatine Analogs Neuroendocrine Tumors Medical Therapy Tachifilaxis: antiproliferative effect Wynick D, Clin Endocrinol (Oxf). 1989 Resistance of metastatic pancreatic endocrine tumours after long-term treatment with the somatostatin analogue octreotide. Lamberts SW, Acta Endocrinol (Copenh).,1988 Development of resistance to a long-acting somatostatin analogue during treatment of two patients with metastatic endocrine pancreatic tumours. Koelz A Gastroenterology. 1987 Escape of the response to a long-acting somatostatin analogue (SMS 201-995) in patients with VIPoma.
  41. 41. Neuroendocrine Tumors Chemotherapy of Neuro-Endocrine Gut and Pancreatic Tumours Response Rate Endocrine pancreatic Tumor Streptozocin + 5 FU 40-60% Streptozocin + doxorubicin ≈ 60% Cisplatinum + Etoposide (low differentiated tumors) ≈ 50% Taxol + doxorubicin ≈ 40-50% Midgut Carcinoid Tumours Streptozocin + 5 FU 10-30% Cisplatinum + Etoposide 10-15%
  42. 42. Neuroendocrine Tumors PRRT: Effects depending on:  Radiosensibility:  Growth pattern of the tumor  DNA repair  Concentration of radioactivity on the tumor (adsorbed dose) Reubi JC et al. Eur J Nucl Med 2000  Receptorial affinity of radiopeptides  Receptorial density on the tumors and other organs Mts linfonodali node mets from paraganglioma < liver Mts linfonodali da NET GHRH-sec. > liver » kidney & spleen VIP-secr. pancreatic NET  Pharmacokinetic: fast plasmatic clearance and renal excretion
  43. 43. Neuroendocrine Tumors PRRT: Response: predictive factors Elevated uptake Presence of liver metastasis Progression: predictive factors Elevated Ki-67 Higher tumor mass
  44. 44. New prospective will be available.. New Therapies Neuroendocrine Tumors Medical Therapy: At the moment drugs used only in clinical trials Modlin et al. Lancet Oncology 2008; 9: 61-72
  45. 45. Neuroendocrine Tumors Conclusions  NET are rare neoplasms and they still remain orphan tumors with a survival that is stable over the past three decades  Many physicians are involved in the management of NET having to cooperate daily  Therapeutic strategies must be individualized depending on tumor type, site, spread, symptoms and general condition of the patient  We still need.. • More reliable markers • Better tumor localization • Cell lines and models to define biology, behavior and genetics • More numerous and randomized trials • To develop molecularly targeted therapies • Centres of excellence and NET clinical teams to coordinate multicentre studies, extend clinical and tissue databases
  46. 46. Vasily Kandinsky Several Circles 1926 oil on canvas; Solomon R. Guggenheim Museum, New York Thanks for your attention
  47. 47. Acknowledgments Enio Martino Luca Manetti Sandra Brogioni Chiara Sardella Isabella Lupi Chiara Cosci Luca Tomisti Enrica Dell’Unto Martina Lombardi Claudio Urbani Ilaria Scattina Valentina Raffaelli Francesco Raggi Dania Russo

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