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An Update in the Diagnosis and
Management of Carcinoid (NET)
Aaron Vinik MD, PhD, FCP, MACP, FACE
Murray Waitzer Endowed Chair for Diabetes Research,
Professor, Medicine, Neurobiology and Pathology,
Director Neuroendocrine Unit and Scientific Director
The Leonard Strelitz, Diabetes and Metabolic Center,
Norfolk VA 23510
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Learning Objectives
Recognize the clinical syndromes and different types of
Neuroendocrine tumors responsible for the constellation
of these features
Provide aids to differentiate NETS from masquerading
diseases
Understand the choices of management and the use of an
algorithm for clinical, biochemical and radiological
diagnosis
Understand and make informed choices based upon a
"decision tree" for management of NETS
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10 years ago the USA had Steve Jobs, Bob Hope and
Johnny Cash ....
Now they have no Jobs, no Hope and no Cash.
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NETS The Neglected Side of Cancer
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Neuroendocrine Tumor Distribution
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Evolution of Neuroendocrinology
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It Ain’t What you Don’t Know
It ain’t what you don’t know that gets you
into trouble
It’s what you know for sure that just ain’t
so!
Mark Twain
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NET
Functioning Non-functioning
Morbidity and mortality
resulting from:
•Hormonal or hormone-related
symptoms/syndromes
Functioning versus
Non-functioning NET
Morbidity and mortality
resulting from:
•Tumor expansion
Marianne Pavel, Vinik et al 2017
Morbidity and mortality resulting
from Tumor expansion
Secretory but non-functioning
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The Ubiquitous Neuroendocrine Cell
5-HIAA
5-HIAA
5-HT
5-HT into gut lumen
5-HT
RER
Tryptophan
Tryptophan
5-HTP
5-HT
MAO
Prosecretory
granules
(processing of
prohormones
and CgA
Golgi
5-HT
Into portal circulation
Packaging of
prohormones
and CgA
Secretory granules
(e.g. pancreastatin,
chromostatin and
CgA)
Formation of
prohormones
and CgA VMAT
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The Multipotency of the EC Cell
Protodifferentiated Adult Stem Cell
Alpha Beta Delta EC G/CCK Cell PP Glucagonoma Insulinoma Somatostatinoma Gastrinoma/CCKoma PPoma
•EC Cell Carcinoid
•Gastrin Gastrinoma
•ACTH Cushing’s
•GHRH Acromegaly
•Calcitonin Diarrhea/Flushing
•VIP WDHHA
•CGRP Diarrhea/Flushing
•Substance P Diarrhea/Flushing
•HHM Hypercalcemia
•IGF 11
•GLP-1 Hypoglycemia
•INGAP Nesidioblastosis
•Ghrelin Ghrelinoma
Vinik and Perry
Degroot 2017
Vinik et al,
Pancreas 39(6):
713-733, 2010
Vinik et al,
Pancreas 39(6):
801-818, 2010
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Pathology of NETs
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Genetics of NETS
MEN-1 gene in > 44% ,
DAXX 25%
ATRX 17.6%
MTOR pathway >14%
Mutations survive 10y
No mutations >60% died in 5y
WREN 51 mRNA markers Jiao et al Science331, 1199-1203 , 2011
Duque M et al. J Pancreas 2013 July 10; 14(4):372-376
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Biomarkers in Neuroendocrine Tumors
Primary Tumor Growth
Metastases
Flushing
Diarrhea
Death
0 2 4 6 8 10 12 14
16 18 20 Years
Vague abdominal symptoms
Diagnosis
Irritable Bowel Correct
Diagnosis
Vinik, Woltering, Go Caplyn and Warner. Pancreas , 2016
Chromogranin
Pancreastatin
Neurokinin A
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Improvement of NET Grading System using
Mitoses and Ki-67
Grading proposal for foregut NET
Grade Mitotic count (10
HPF)
Ki-67 index
(%)
G1 < 2 ≤ 2
G2 2–20 3–20
G3 > 20 > 20
Rindi G, et al. Virchows Arch. 2006;449:395-401. Pape UF, et al. Cancer. 2008;113:256-65.
Cu
mu
lati
ve s
urv
ival
0 50 100 150 200 250 300
Time
0
0.2
0.4
0.6
0.8
1.0
Grading using Ki67
G1
G2
G3 Univariate analysis:
G1 vs. G2: p = 0.040
G1 vs. G3: p < 0.0001
G2 vs. G3: p < 0.0001
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Tumor cells display a neuroendocrine phenotype
Balanced amounts of neuroendocrine and exocrine tumor cells
1. NET G1
2. NET G2
3. NET G3
4. NEC (small cell &
large cell carcinoma)
5. Mixed
neuroendocrine-non
neuroendocrine
neoplasm
NEUROENDOCRINE NEOPLASMS WHO 2017 GENERAL CATEGORIES
panNEN
Lloyd RV, Osamura RY, Klöppel G, Rosai J WHO Classification of Tumours of Endocrine Organs, 2017
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Diagnosis of GEP NETS
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Clinical Presentation sof
Neuroendocrine Tumors Major Clinical
manifestations – Flushing 84%
– Diarrhea 79%
– Heart Disease 37%
– Bronchoconstriction 17%
Seldom Discussed
– Diabetes, Metabolic Syndrome, NASH 37%
– Hypertension 50%
– NeuroMyopathy 7%
– Pigmentation, arthropathy 5%
– Hyper-hypoglycemia, ( NIHHPS) <1%
– Ulcer disease, Skin rashes <1%
– Psychological Disturbances <1%
Tumor production of cytokines (TNF a. IL6, NFb)
– Fever, fatigue, weight loss, cachexia
Tumor stimulation of antibody formation ( Ca Channels )P,Q) Ach receptor, CANCA, PANCA, Hu
– Neurological syndromes, Peripheral Neuropathy, Autonomic Neuropathy, Cerebellar Ataxia, Eaton Lambert, Myaesthenia, CIDP
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Flushing
Dry
Neurendocrine
Tumor
Wet
Other
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Features Associated with Flushing FLUSHING SYNDROME ASSOCIATED FEATURES
Carcinoid Diarrhea, wheezing
Medullary Carcinoma Thyroid Mass in neck, Family history
Pheochromocytoma Paroxysmal hypertension, pallor,
tachycardia
Diabetes Autonomic neuropathy/Chlorpropamide
Menopause Cessation of Menses
Autonomic Epilepsy Diencephalic seizures
Panic Syndrome Phobias, anxiety
Mastocytosis Dyspepsia, peptic ulcer, dermatographia
Polycythemia, renal cell Ca Plethora
Food Alcohol, MSG, Nitrites, Cheese, Tyramine
containing foods
Drugs Niacin, Phosphodiesterase 5 Inhibitors
Idiopathic Destitute
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Tests to Identify Cause of Flushing CLINICAL
CONDITION
TESTS
Carcinoid 5HIAA, 5 HTP,SP, CGA,
Pancreastatin, NKA, Pro BNP
Medullary Carcinoma Thyroid/ C
cell hyperplasia
Calcitonin, Calcium Infusion, CEA,
Ret Proto-oncogene
Pheochromocytoma,
paraganglioma
Fractionated Metanephrines in
plasma, Methoxytyramine, SHDB(C)
Diabetic AN HRV, 2h PP glucose
Menopause FSH
Epilepsy EEG
Panic Pentagastrin/ACTH
Mastocytosis Plasma histamine, urine tryptase
Hypomastia, Mitral prolapse, Cardiac Echo
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Diarrhea
Secretory
persists with fasting
Endocrine
Non-secretory
Improves with fasting
Gastroenterological
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Character of Secretory and Osmotic
Diarrhea
Secretory
– Large volume stools
– Persists during fasting
– 2X [Na + + K+ ] = stool osmolality
Osmotic
– Small volume <1L/d
– Disappears with fasting
– 2X [Na + + K+ ] < stool osmolality i.e. osmotic gap,
search for idiogenic osmoles
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Causes of Secretory Diarrhea
Watery diarrhea, hypokalemia, hyperchlorhydria,acidosis syndrome
Zollinger Ellison syndrome
Carcinoid
Medullary carcinoma of thyroid
Secreting villous adenoma of rectum
Surreptitious laxative abuse
Idiopathic
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Pathogenesis of Endocrine
Diarrhea
Stomach
Small
Intestine
Colon
Gastrin/
CCK VIP, PP,
SP,CGRP, TCT Increased
Acid secretion
Decreased absorption
And impaired
digestion
Exceeds absorptive
capacity Increased
Fecal Volume
Increased net secretion
of fluid and ions
Exceeds absorptive
capacity
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Metastatic Neuroendocrine Tumors:
What are the Systemic Treatment
Options?
• Somatostatin analogs
• Cytotoxic Chemotherapy
• “Targeted” Therapies
• PRRT
Metastatic Neuroendocrine Tumors:
What are the Endpoint Options?
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Diagnosis of NETS
Localization Procedures
– Ultrasound
– CAT
– MRI
– PET
– Octreoscan
– Gallium DOTA TOC(NOC)
– MIBG
– Angiography
– Venous sampling
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TEST
Sensitivity
Specificity
PPV
NPP
CT
83%
76%
MRI
93%
88%
US
50-85%
76-97%
OctreoScan
52-78%
93%
98%
47%
PET/CT 68Ga-DOTATOC
97%
92%
PET/CT 68Ga-DOTANOC
78%
93%
92%
Sensitivity, Specificity, Positive and Negative
Predictive Values for Diagnosis of NETS
PET/CT 18F-FDG-PET
(NETs with
proliferation index >15%)
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PET with 68Ga-DOTA-
Octreotide Facts and Fallacies
Advantages:
no cyclotron required
more sensitive than Octreoscan 40-100 fold
possible to use for radioactive or tumor-targeted
treatment
may be possible to quantify somatostatin receptors -
tumor-targeted therapy
If you find Mets Gallium Scanning finds more
If you cannot find the tumor Gallium scanning may not
find it for you
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68Ga-DOTA-Octreotide Scanning
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Octreoscan vs.
PET/CT with 68Ga-DOTA-Octreotide
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•Breast & lung
•Bone destruction
mediated by OCL
•Prostate & breast
•Bone formation
mediated by OB
Osteolytic
Osteoblastic
Solid Tumor Metastases
What Makes Bone a Favorable Site?
NETS: Osteoblastic, osteolytic
Bone Alk Phos and NTX
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Evaluation of Neuroendocrine Tumors
Clinical Syndrome
Flushing , Diarrhea,hypertension
Hypoglycemia, ulcer, rash
Biochemical and
Tissue Diagnosis
Pancreastatin, CGA, NKA, NSE, insulin, gastrin, glucagon IGF2, PThrp,Tryptase, histamine, Alk Phos, NTx,fractionated Metanephrines, Calcitonin PNET
Negative Symptomatic
Treatment
Tissue: CGA/Ki-67, Synaptophysin, Specific hormone
Exclude other causes
Flushing wet or dry Secretory vs. non secretory
Carcinoma, thyrotox, Cushing’s
MCT, Pheo, factitious
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Management of Neuroendocrine
Tumors
Localizaton and Resection
– Ultrasound
– CAT
– MRI
– PET
– Octreoscan/Gallium 68 scan
– Angiography
Localized Surgery
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Management of Neuroendocrine
Tumors
Localizaton and Resection
– Ultrasound
– CAT
– MRI
– PET
– Octreoscan
– Angiography
Liver Involvement Surgery
<50%
RFA, Resection
>50%
Consider Partial
RFA, Resection
Therapeutic Trial
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Management of Neuroendocrine
Tumors
Localizaton and Resection
– Ultrasound
– CAT
– MRI
– PET
– Octreoscan/68Ga-DOTA-Octreotide
– Angiography
Extrahepatic Mets Surgery
Debulking
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Management of Neuroendocrine
Tumors
Metastatic
– OctreoScan
– Galliium DOTATOC
Positive
Angiography
Sandostatin
LAR
Lanreotide
Neg
ati
ve
H.A.C.E.
Hep Art Chemo Embo
SIR Spheres Therapy
Conventional Chemo
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Management of Metastatic
Tumors
LAR for 3months
+Octreotide for escape
Arrest or Reversal
Continue LAR+
Octreotide
Progression
>10,000 pg/ml Interferon
Indium Pentreotide(<2cm),
Lutecium 177 DOTATOC(2-4cm),
Ytrium 90 DOTATOC (>4cm)
Infarction
Pamidronate for
Bone metastases
< 10,000pg/ml
Increase LAR+
Lanreotide
Check Octreotide or
Lanreo Level
10432821N =
LAR(mg/month)
60302010
Octr
eo
tid
e:P
lasm
a
15000
12500
10000
7500
5000
2500
0
93
24
62
47
Woltering, Vinik, Odorisio, et al
Pancreas 31; 392-400, 2005. Pancreas:33;250-254, 2006
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Management of Metastatic
Tumors
LAR/Somatuline for 3months
+Octreotide for escape
Arrest or Reversal
Continue LAR+
Octreotide
Progression
>10,000 pg/ml
Chemo/Interferon
Radiation
Infarction
Pamidronate for
Bone metastases
< 10,000pg/ml
Increase LAR+
Octreotide
Check Octreotide/
Lanreotide Level
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ala
thr
trp
gly cys lys asn phe phe
lys
phe thr cys ser
Human somatostatin
Amino acids essential
for receptor binding
Somatostatin Analogs
• inhibit multitude of hormones
• T ½ 3 minutes
•binds all 5 receptor sub-types
val
D trp
D bnal cys tyr
lys
cys Thr ol
Lanreotide
thr
D trp
D phe cys phe
lys
cys Thr ol
Octreotide
• more specific
• T½ 100 min
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Octreotide LAR Lanreotide Depot
Requires reconstitution
Ready to use, prefilled syringe
10, 20, 30 mg 60, 90, 120 mg
IM q 4 wks (~1.5 inch needle)
Deep SC q 4 wks (~3/4 inch needle)
Volume; 2-2.5 mL Volume; 0.3-0.5 mL
Healthcare professional
administration
Self or partner administration
possible Product Information Somatuline® Depot, 2007. Bevan JS, et al. Clin Endocrinol (Oxf). 2008;68(3):343-349.
Product Information Sandostatin LAR® Depot, 2006. 48
Lanreotide
depot
Long-acting
octreotide
Comparison of Approved
Somatostatin Analogs
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PROMID: Rinke A et al, J Clin
Oncol 2009; 27: 4656-63 CLARINET: Caplin ME et al. N Engl J Med
2014;371:224-233.
Octreotide and Lanreotide for the Treatment
of Advanced NET
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ELECT: Exploratory Endpoint
(Supportive Analyses)
.
1. Gomez-Panzani E, et al. Poster presented at ENETS. March 5-7, 2014; Barcelona, Spain.
2. Vinik A, et al. Abstract presented at ASCO GI. January 16-18, 2014; San Francisco, CA.
40.7%
6.8%
52.5
23.2%
5.4%
71.4
0
10
20
30
40
50
60
70
80
Complete Success Partial Success Failure
Lanreotide 120 mg
Placebo
Per
cen
tag
e o
f
pa
tien
ts (
%)
(≤3 days
Greater Chance of Complete/Partial
Success With Lanreotide
P=0.04 OR 2.4 [95% CI: 1.1, 5.3]
Treatment Response (Number of Days of Octreotide SC Use) In the
4 Weeks Following Final Injection
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51
Somatostatin in NETS
Somatostatin analogs are safe and effective
Long-term administration of somatostatin analog is
safe and effective
In NETs, these analogs control symptoms and some
tumor markers, and are effective in controlling tumor
growth; symptomatic escape may require short-acting
analogs
Radioactive analogs “Lutathera” are promising but
not available for all
New and better drugs are still needed
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mTOR
Inherited syndromes
Associated with NET
Therapeutic Agents
in NET Growth Factors:
Growth Factor Receptors:
AKT
PI3-K
Cell Growth & Survival
Sunitinib
Sorafenib
Pazopanib
Bevacizumab
Everolimus,
Temsirolimus
TSC 1/2
VEGF VEGF
VEGFR
RET
mTOR
VEGFR
PDGFR PDGFR
MEN2 RET
The RTK/PI3-K/AKT/mTOR Pathway in Neuroendocrine Tumors
RET
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Telotristat Etiprate
A Tryptophan Hydroxylase (TPH) Inhibitor
• Telotristat etiprate is a novel oral
inhibitor of TPH, the rate-limiting
enzyme in serotonin biosynthesis1
• Two early-stage clinical studies
demonstrated the safety and evidence
of clinical activity in carcinoid
syndrome2,3
• Both preclinical and clinical studies
suggested that telotristat etiprate is
associated with minimal CNS activity1-3
• Granted Fast Track Status and
Orphan Drug Designation4
54
5-HT
secretion
Tryptophan
5-HTP
5-HT
5-HT in blood
5-HIAA
5-HIAA filtered by kidney
5-HIAA in urine
Monoamine oxidase
Aldehyde dehydrogenase
TPH Telotristat
Etiprate
Adapted from ref. 5, Figure 44-3
5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, serotonin; 5-HTP, hydroxytryptophan; CNS, central nervous system; TPH, tryptophan hydroxylase.
1.Liu Q, Yang Q, Sun W, et al. J Pharmacol Exp Ther 2008; 325:47–55. 2. Kulke MH, O'Dorisio T, Phan A, et al. Endocr Relat Cancer 2014;21:705–714. 3. Pavel
M, Horsch D, Caplin M, et al. J Clin Endocrinol Metab 2015;100:1511–1519. 4. FDA Orphan Drug Designations. Available at:
http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index. Accessed September 2015. 5. Kronenberg HM, Melmed S, Polonsky KS, et al. Williams Textbook of
Endocrinology, 11th edn. 2008:1823–1824.
Serotonin Synthesis in Carcinoid Tumor Cells
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• Hodges–Lehmann estimator of treatment differences showed a median reduction versus placebo of
– –0.81 BMs daily for telotristat etiprate 250 mg dose (P<0.001)
– –0.69 for telotristat etiprate 500 mg dose (P<0.001)
TELESTAR: Reduction in Daily Bowel Movement
Frequency Averaged Over Double-Blind Treatment
Phase
55
BM, bowel movement.
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From: Oberg, Theranostics 2012; 2: 448-58
Peptide Receptor Radionuclide Therapy
(PRRT)
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Phase 3 Trial of 177Lu-Dotatate
for Midgut
Neuroendocrine Tumors
J. Strosberg, G. El-Haddad, E. Wolin, A. Hendifar, J. Yao, B. Chasen, E. Mittra,
P.L. Kunz, M.H. Kulke, H. Jacene, D. Bushnell, T.M. O’Dorisio, R.P. Baum,
H.R. Kulkarni, M. Caplin, R. Lebtahi, T. Hobday, E. Delpassand, E. Van Cutsem,
A. Benson, R. Srirajaskanthan, M. Pavel, J. Mora, J. Berlin, E. Grande, N. Reed,
E. Seregni, K. Öberg, M. Lopera Sierra, P. Santoro, T. Thevenet, J.L. Erion,
P. Ruszniewski, D. Kwekkeboom, and E. Krenning, for the NETTER-1 Trial Investigators*
N engl j med 376;2 nejm.org January 12, 2017
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Progression-free survival and overall survival in
LUTATHERA TRIAl
Strosberg J et al. NEJM 2017; 376:125-35.
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Practical points for LUTATHERA : • Outpatient
administration in U.S.
• Relatively low-risk to
family members and
general public: avoid
sharing bed and limit
contact with children x 1
week after each
treatment
• Amino acid infusion:
commercial formulation
vs. compounded
arginine/lysine
• Duration of time off
long-acting SSA: 4
weeks vs. 6 weeks
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Where does PRRT
fit in?
60
Phase 3 randomized data only in midgut
NETs.
Early phase data suggesting higher response
rates in non-midgut NETs (esp. pancreatic).
Approved both by EMA and FDA for
advanced GEP-NETs
Somatostatin-receptor (SSTR) expression is
strong predictive marker.
Consider as 2nd line therapy in patients with
strong SSTR expression.
Advantages: Limited treatment course (4x),
long PFS, relatively low toxicity
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“Do not go where the
path may lead, go
instead where there is
no path and leave a
trail"
-Ralph Waldo Emerson
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Health Related Quality of Life (HQOL)
Requires a Multidimensional Assessment of:
Quality of Life Generic Tools PROMIS and SF 36
Disease Specific Tools
Norfolk QOL-NET
QLQ-GINET-21
QLQ-C30
Physical
Cognitive
Emotional
Depression
Anxiety
Social
Disease
ADLs Insomnia
Fatigue
Consti-
pation
Diarrhea
Pain
Appetite
loss
Dyspnea
Flushing
Nausea
Vomiting
Hand Foot
Syndrome
Ulcer,
rash,
Hypo
glycemia
Symptoms
Therapies
Traditional QOL
Features
Injections
Vinik EJ, Vinik AI 2009
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Quality of Life in 265 Patients with Gastroenteropancreatic
or Bronchial Neuroendocrine Tumors Treated with
[177Lu-DOTA0,Tyr3]Octreotate
• QOL symptoms after [177Lu-DOTA0,Tyr3]octreotate
(177Lu-octreotate) therapy in patient with inoperable or
metastasized gastroenteropancreatic or bronchial
neuroendocrine tumors (NET)
• Two hundr sixty-five Dutch patients completed the QOL
questionnaire of
• Significan differences of at least 10 points in global health
status (GHS)/QOL scores, symptom scores, and Karnofsky
performance Saima Khan, Eric P. Krenning, Martijn van Essen, Boen L. Kam, Jaap J. Teunissen, and
Dik J. Kwekkeboom J Nucl Med 2011; 52:1361–1368
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QOL Results • Regardless of the treatment outcome,
• QOL, insomnia, appetite loss, and diarrhea improved
significantly in the total group. And in patients with bone
metastases or a decrease of 50% or more in Chromogranin A.
• QOL or symptoms at the start of therapy quality of life
improved with therapy in 36%
– 49%, fatigue;
– 70% , nausea plus vomiting;
– 53%, pain;
– 44%, dyspnea;
– 59%, insomnia;
– 63%, appetite loss;
– 60%, constipation;
– 67%, diarrhea.
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Tryptophan
Why Patients with a Carcinoid Tumor are Depressed
5-Hydroxylation
5 – Hydroxytryptophan (5HTP)
Serotonin
5HTP
SEROTONIN
TRP
5HTP
SEROTONIN
In the Presence
of a Tumor
5HT
Typical
Route
Will enter blood
stream,
but cannot pass
blood
brain barrier.
Decarboxylase
(Liver, Platelets
Intestinal Cells)
Decarboxylation
BLOOD BRAIN
Serotonin Levels
Copyright 2009 Aaron and Etta Vinik VinikEJ, Vinik AI, Diebold A, Woltering E. in Raymond et al
Management of Tumors of the Pancreas and Digestive Tract 2014 p213 Springer Verlag.
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The Changing Face of Management of
Neuroendocrine Tumors
1900 2000 2007
Surgery
Chemotherapy
Embolization
Interferon
Octreotide/Lanreotide
GF and Angiogenesis
(MTOR and TKI) Inhibitors
PRRT ,immunotherapy ,
Serotonin synthesis
inhibitors etc
2015 2018
Exenteration
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Clinical Syndrome
Biochemical and
Tissue Diagnosis
Negative
Symptomatic
Treatment
Urine: 5HT, 5HTP,
Metanephrines, tryptase
Blood: serotonin, CGRP,
5HIAA, NKA Fractionated
Meta/Normetanephrines,
Calcitonin, Histamine,
Pancreastatin,
Chromogranin A
Ultrasound
CAT
MRI
PET
Octreoscan or
Gallium 68 scan
MIBG
Angiography
Scintigraphy
• Chromogranin A
• Synaptophysin
• Neuron Specific Enolase
• Ki-67, Mitotic Index
• Individual hormones –
insulin, glucagon, PP
somatostatin, INGAP,
etc.
Immunohistochemistry +
v
e
+
v
e
TUMOR
Management
+ve +ve
Surgery
Chemotherapy
Embolization
CLINICAL
TRIALS
Octreotide or
Lanreotide
GF and Angiogenesis
Inhibitors and TKIs,
MTOR Inhibitors
Norfolk Algorithm for NET Management
PRRT
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Summary and Conclusions
– NETs on the increase, require high level of suspicion – Monitor
• Tumor burden
• Clinical responses
• Biomarkers, – pancreastatin,
– Neurokinin A
– Cga
– Be aggressive. Use tumor debulking procedures judiciously
– Tumor growth can be arrested • Carcinoids, Vipomas, Ppomas
• ACTH, Calcitonin and Gastrin may be resistant
• May require ancillary measures
– Octreotide/Lanreotide controls symptoms and may cause biochemical and tumor burden improvement, Must treat to target plasma Octreotide/Lanreotide Plasma Levels
– Gallium Scanning now a reality and will replace Octreoscan
– New therapies with agents acting on the RTK/PI3-K/AKT/mTOR pathway PRRT a reality in USA
(they may not be parallel)
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And the FUTURE
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ANY
QUESTIONS?
To the world you may be just
one person, but to one person
you may be the world.
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