Talk:Neuroendocrine tumor/achive 1

Initial Citations
For this first version of this article on Neuroendocrine Tumors, here are my citations, in order roughly corresponding to the article:

The Neuroendocrine System
Neuroendocrinology: "The study of the interaction between the nervous system and the endocrine glands and their secretions". - answers.com

"Neuroendocrinology is the study of the interactions between the nervous system and the endocrine system". - Wikipedia Neuroendocrinology

"The neuroendocrine system is a network of glands that produce and secrete hormones into the bloodstream" - http://info.cancer.ca/e/glossary/N/Neuroendocrine_System.htm

"The endocrine system is a network of glands consisting of endocrine cells that produce hormones in the body. The neuroendocrine system cells are specialized endocrine cells of the nervous system and produce neurohormones. Neuroendocrine cells do not form a specific gland; instead, they are found distributed in a wide variety of body organs where they help regulate body function." - http://www.answers.com/topic/neuroendocrine-tumors

"The diffuse neuroendocrine system consists of cells that are like nerve cells in certain ways and like gland (endocrine - hormone-producing) cells in other ways. These cells do not form an actual organ like the parathyroid, adrenal, or thyroid glands. Instead, they are scattered throughout other organs like the esophagus, stomach, intestines, and lungs" - http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_gastrointestinal_carcinoid_tumors_14.asp

"Hormones are biochemical messengers that regulate physiological events in living organisms". - healthline.com

"Some hormones, called ectohormones, aren't secreted into the blood stream". - Wikipedia Hormone

Hormones are "chemical substances that regulate such specific body functions as metabolism, growth, and reproduction". - http://info.cancer.ca/e/glossary/N/Neuroendocrine_System.htm

hormone: "a product of living cells that circulates in body fluids (as blood) or sap and produces a specific often stimulatory effect on the activity of cells usually remote from its point of origin; also : a synthetic substance that acts like a hormone" - Merriam-Webster online dictionary

Hormone: "1. A substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to effect physiological activity, such as growth or metabolism. 2. A synthetic compound that acts like a hormone in the body". - answers.com

"A hormone (from Greek horman - "to set in motion") is a chemical messenger from one cell (or group of cells) to another. All multicellular organisms produce hormones (including plants - see article phytohormone)". - Wikipedia Hormone

"Hormone secretion can be stimulated and inhibited by:


 * Other hormones (stimulating- or releasing-hormones)
 * Plasma concentrations of ions or nutrients, as well as binding globulins
 * Neurons and mental activity
 * Environmental changes, e.g., of light or temperature"

- Wikipedia Hormone

peptide: "any of various amides that are derived from two or more amino acids by combination of the amino group of one acid with the carboxyl group of another and are usually obtained by partial hydrolysis of proteins" - Merriam-Webster online dictionary

"Neuroactive peptides are sequences of amino acids, usually longer than amino acid neurotransmitters yet shorter than hormones or proteins". - britannica.com

"The class of peptide includes many hormones". - britannica.com

Some peptides, "like hormones, act on certain target organs". - britannica.com

Peptides tend to be short, proteins long -- "the same molecule can be either a peptide or a protein depending on its environment". - Wikipedia Peptide

Classification by Site of Origin
"NETs ... originate from pancreatic islet cells, gastroenteric tissue (from diffuse neuroendocrine cells distributed throughout the gut), neuroendocrine cells within the respiratory epithelium, and parafollicullar cells distributed within the thyroid (the tumours being referred to as medullary carcinomas of the thyroid). Pituitary, parathyroid, and adrenomedullary neoplasms have certain common characteristics with these tumours but are considered separately". - "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours" by Ramage JK et alia, http://gut.bmjjournals.com/cgi/content/full/54/suppl_4/iv1.

"The term 'carcinoid' was introduced by S[iegfried] Oberndorfer in 1907 to distinguish carcinoids as less rapidly growing and well-differentiated epithelial tumors of the small intestine from the more aggressively growing adenocarcinoma of the gut. . . . Strictly speaking . . . the term 'carcinoid' [is] reserved for endocrine tumors of the gastrointestinal tract . . . and not for those of the pancreas. . . . The blurredness of the term 'carcinoid' results from its histological features which are almost identical with those of endocrine pancreatic tumors" - Arnold R., R. Göke, M. Wied, Th. Behr, "Neuroendocrine Gastro-Entero-Pancreatic (GEP) Tumors", Chapter 15 of Gastrointestinal and Liver Tumors by Scheppach, W.; Bresalier, R.S.; Tytgat, G.N.J. (Eds.), 2004, Springer, ISBN: 3-540-43462-3.

"During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them 'karzinoide' ('carcinoma-like'), emphasizing in particular their benign features. In 1929 he amended his classification to include the possibility that these small bowel tumors could be malignant and also metastasize" - "Siegfried Oberndorfer: origins and perspectives of carcinoid tumors" by Modlin IM, Shapiro MD, Kidd M. -.

Citation for statement that "many physicians, including oncologists, persist in calling all GEP-NETs 'carcinoid'": on a PET news forum, a patient says: "For over 4 yrs I was referred to as carcinoid. In fact even when it was discovered I was actually islet cell and the pathologist was questioned by my doctor (specialist in NET) about this the pathology said we classify all islet cell as carcinoid. Since then no matter how many times I say islet cell to a local doctor - oncologist, gastroendocrineologist, radiologist - you get the idea - they ALL continue to refer to me as carcinoid" - http://health.groups.yahoo.com/group/NET_ISLETCELL/message/402.

"Although endocrine pancreatic tumors are also called 'islet cell tumors' it is unproven that pancreatic insulinomas, gastrinomas, VIPomas etc. originate from the islets of Langerhans. . . . Therefore, it is conceivable to assume that islet tumors originate from endocrine pancreatic multipotent precursor cells which are constituants of the pancreatic duct epithelium" - Arnold.

List of secreting subtypes and list of minor subtypes such as neuroblastoma, GRFoma: mostly from Warner, Richard R. P., "Enteroendocrine Tumors Other Than Carcinoid: A Review of Clinically Significant Advances".

"There are four main types of neuroendocrine lung tumors

- http://www.answers.com/topic/neuroendocrine-tumors.
 * Small-cell lung cancer (SCLC). SCLC represents one of the most rapidly growing types of cancer.
 * Large-cell neuroendocrine carcinoma. A rare form of cancer, similar to SCLC in prognosis and treatment, except that the cancer cells are unusually large.
 * Typical carcinoid tumors. These types of neuroendocrine lung tumors grow slowly and do not often spread beyond the lungs.
 * Atypical carcinoid tumors. Atypical lung carcinoids tumors grow faster than the typical tumors and are more likely to metastasize to other organs"

"The main two groups of neuroendocrine GEP tumours are so-called carcinoid tumours and endocrine pancreatic tumours" - "Neuroendocrine GEP Tumours -- Current Views on Diagnosis and Treatment" by Dr. Kjell Öberg.

"Less than 1% of carcinoids arise in the pancreas". - Warner. Arnold in effect defines carcinoids as "extra-pancreatic endocrine gastronintestinal tumors".

Not all doctors agree that there is virtually no overlap between PETs and carcinoids. For example, endocrine surgeon Rodney Pommier says that "there are pancreatic carcinoids" . However, Pommier made his statement in a talk at a conference on carcinoids, not in a peer-reviewed journal; and in his talk he did not defined the word carcinoid.

"It also must be borne in mind that almost all of the PETs can be multiple and also can arise outside of the pancreas, particularly gastrinomas (<=77%), carcinoids (99%), and somatostatinomas (>40%)" - Warner.

"In the past, pathologists called all GEP NETs carcinoids because their histology is quite similar without special staining. This practice still is continued sometimes. However, clinicians in general understand the designation carcinoid to mean a serotonin-producing tumor, functioning or nonfunctioning" - Warner.

To confirm that "endocrine pancreatic tumor" is used synonymously with "islet cell tumor": google "endocrine pancreatic" "islet cell" tumor.

"The key event occurring in functionally active endocrine GEP tumor cells is the loss of capacity to store their hormonal product as insulin in insulinomas, gastrin in gastrinomas etc. within the tumor cell" - Arnold.

According to http://www.med.umich.edu/lrc/presentation/endo/islet.htm, islet cell tumors also produce these hormones normally not produced in islets:


 * Parathyroid hormone-like peptide
 * Adrenocorticotropin
 * Neurotensin
 * Gastric inhibitory polypeptide
 * Cholecystokinin
 * Growth hormone-releasing hormone
 * Calcitonin
 * (Prostaglandins ?)

Subtypes MEN-2, Carney's complex - Ramage.

Larry Kvols MD of Moffitt Cancer Center and Research Institute in Tampa, in "Carcinoid Tumors and the Carcinoid Syndrome: What's New in the Therapeutic Pipeline", presented at the Carcinoid Cancer Foundation's Carcinoid Symposium 2002, stresses flushing, diarrhea, CHF, and asthma as the four critical characteristics of carcinoid syndrome.

"Excessive amounts of these hormones cause a condition called carcinoid syndrome in approximately 10% of patients with carcinoid tumors" - http://www.oncologychannel.com/cancermalignancy.

"Neuroendocrine tumors (NETs) are rare neoplasms, which are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. . . . Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms originating from endocrine cells, which are characterized by the presence of secretory granules as well as the ability to produce biogenic amines and polypeptide hormones. These tumors originate from endocrine glands such as the adrenal medulla, the pituitary, and the parathyroids, as well as endocrine islets within the thyroid or the pancreas and dispersed endocrine cells in the respiratory and gastrointestinal tract. The clinical behavior of NETs is extremely variable; they may be functioning or not functioning, ranging from very slow-growing tumors (welldifferentiated NETs), which are the majority, to highly aggressive and very malignant tumors (poorly differentiated NETs). Neuroamine uptake mechanisms as well as the presence of peptide receptors and transporters at the cell membrane of several NETs constitutes the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. . . . Classically, NETs of the gastrointestinal tract are classified into 2 main groups: (1) carcinoids, which are the most common and have been traditionally divided on the basis of their site of origin into foregut (lung, thymus, stomach and duodenum), midgut (distal ileum and proximal colon), and hindgut (distal colon and rectum) and (2) endocrine pancreatic tumors (EPTs), which are divided on the basis of hormone secretion and related clinical syndromes in[to] functioning (i.e. insulinomas, gastrinomas, VIPomas, glucagonomas, somatostatinomas) and nonfunctioning tumors, the latter representing approximately 15% to 30% of all EPTs. Gastrinoma is the prevalent type of EPT" - "Imaging of Neuroendocrine Tumors" by Rufini, Vittoria MD, Maria Lucia Calcagni MD, and Richard P. Baum MD.

Incidence
"The incidence of all noncarcinoid NETs is approximately one half that of all carcinoids. Noncarcinoid NETs have been reported to occur in .4 to 1.5/100,000 of the population." - Warner.

((I assume he means clinically significant cases. The quote below indicates that he is talking about incidence (new cases), not prevalence (living cases). Let's average 0.4 and 1.5 to get 1 per 100k per year. That is 3000 new GEP-NET cases per 300 million ( = US population).))

"Clinically significant PETs have been reported to occur in approximately 1 per 100,000 people per year and account for only 1% - 2% of all pancreatic tumors. Autopsy studies indicate that there is a much greater occurrence of unrecognized clinically insignificant PETs. Kimura et alia, in a meticulous study of the pancreas of patients dying from unrelated disease, discovered a remarkably high incidence of tiny asymptomatic NETs. A total of 1.6% were found on routine microscopic study of 3 random sections of the pancreas but 10% were found on histologic study of multiple sections taken from all portions of the pancreas. These observations are clinically relevant because the high diagnostic imaging sensitivity of currently available endoscopic ultrasonography may allow the discovery of very small clinically insignificant PETs that might be coincidental, unrelated to a patient's symptoms, and hence not require surgical excision. Insulinomas are the most common functioning PETs with a 17% incidence, followed by gastrinoma (15%), PPoma (9%), VIPoma (2%), glucagonoma (1%), carcinoid (1%), somatostatinoma (1%), and the remainder are comprised of neurotensinomas, adrenocorticotropic hormeoma (ACTHoma), GRFomas, calcitonin-producing tumors, parathyroid hormonerelated peptide tumors, and other exceedingly rare neoplasms. This whole group of very rare PETs accounts for no more than 1% - 2%. . . . Nonfunctioning PETs comprise the largest group of these tumors, 15% - 30%" - Warner.

((If nonfunctioning are 15%, and insulinomas are 17% of the remainder, then insulinomas are 14% of the total. If nonfunctioning are 30%, and insulinomas are 17% of the remainder, then insulinomas are 12% of the total. Let's average that to 15%.

Hmm, but 17 + 15 + 9 + 2 + 1 + 1 + 1 + 2 is only 48 percent -- it should add to 100 percent -- or more if multiples are considered.))

Rufini agrees with the 15 to 30% for nonfunctioning PETs, and states that "gastrinoma is the prevalent type", without giving any numbers. Cancer.gov also puts gastrinoma as the most common.

"The incidence of insulinoma among residents of Olmsted County increased during the study period to a stable level during the last 2 decades of 4 cases per 1 million person-years". - "Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study" by Service FJ, et alia.

((Warner implies (3000 * 0.15 = ) 450 new insulinoma cases per 300 million. Service's 4 new insulinoma cases per million at the Mayo Clinic implies (4 * 300 = ) 1200 new PET cases in 300 million per year. Well, 450 is pretty close to 1200 in this domain.))

Klöppel et alia: "The Gastroentropancreatic Neuroendocrine Cell System and Its Tumors: The WHO Classification" by Klöppel, Günter, Aurel Perren, and Philipp U. Heitz.

Cancer.gov on "pancreatic endocrine" says that such tumors "are uncommon cancers with 200 to 1,000 new cases per year". - http://www.cancer.gov/cancertopics/pdq/treatment/isletcell/HealthProfessional/page1.

((Well, 200 to 1,000 is 0.06 to 0.3 per 100,000. And 200 to 1,000 new PETs sounds low compared with 450 to 1200 new insulinomas, and correspondingly 0.06 to 0.3 sounds low compared with 1 per 100,000.))

According to http://www.pancreaticcancer.org.uk/PCTypes.htm, "Insulinoma is the most common and well-known islet cell tumor of the pancreas, accounting for more than 75-80% of sporadic functioning pancreatic islet cell tumor" -- much higher than the 17% estimated by Warner (see above) (but perhaps "sporadic" changes the numbers -- sporadic seems to mean not-MEN). For now I will stick with Warner, a more primary and documented source than pancreaticcancer.org.uk.

"Around 40% of endocrine pancreatic tumors are insulinomas" - Arnold. According to Arnold's table of "Epidemiological data of endocrine GEP tumors", "Incidence cases per 100,000 people" are


 * all 0.01 – 0.3
 * Insulinoma 0.1–0.2
 * Gastrinoma 0.05–0.15
 * VIPoma 0.005–0.02
 * Glucagonoma 0.001–0.01

According to http://www.med.umich.edu/lrc/presentation/endo/islet.htm, incidence per million per year is


 * Insulinoma: 0.9
 * Gastrinoma: 0.4
 * Glucagonoma: <0.2
 * VIPoma: <0.2
 * Somatostatinoma: <0.2
 * PPoma: <0.2
 * Other types: <0.2

which adds up to less than 2.3, yet "pancreatic islet tumors are rare: Prevalence 1 per 100,000 in the general population", which is 10 per million per year. That web site also has a table of "Malignancy Rates" that, by the way, gives incidence estimates that seem to contradict the rates in the table above.

Perhaps it's important whether a researcher counts carcinoids or PETs or both, and whether the researcher counts all excessive secretions or just the most excessive secretion. Arnold discusses differentials (including malignancy differentials) extensively.

"MEN-I syndrome is present in 20% of patients with gastrinoma, 4% of patients with insulinoma and 13–17% of patients with glucagonoma. However, in MEN-I syndrome most endocrine pancreatic tumors are non-functional containing mostly pancreatic polypeptide or glucagon" - Arnold.

According to http://www.wrongdiagnosis.com/m/multiple_endocrine_neoplasia_type_1/prevalence.htm, prevalence of MEN-1 is "about 3 to 20 persons out of 100,000". That page makes it clear that most people with MEN do not have tumors.

Because of the wide variation in incidence estimates, I took out all statistical assertions at the "oma" level.

Classification by Cell Characteristics
Was the term neuroendocrine tumor "previously and widely used . . . for the superclass", as the article claims? To confirm, google other.than.carcinoid and note the terms used in technical papers for the larger class.

"The APUD concept led to the belief that these cells arise from the embryologic neural crest. This hypothesis eventually was found to be incorrect" - Warner.

"The APUD-concept is currently abandoned" - "Carcinoid Tumors: Current Concepts in Diagnosis and Treatment" by Kjell Öberg (1998).

Metastases and Malignancy
"A cumulative analysis of all types of carcinoid tumors in the SEER group indicates that in 45.3% metastases are already evident at the time of diagnosis" - pubmed.org (1997). It is unclear from the abstract whether the authors are discussing carcinoids strictly, or all GEP-NETs.

According to http://www.pancreaticcancer.org.uk/PCTypes.htm, "Insulinomas . . . are nearly always benign", and most of the others are malignant.

Malignancy percentages, according to Arnold's table "Classification and leading symptoms of the most frequent endocrine tumors of the gastrointestinal tract", are


 * insulinoma 5–10
 * gastrinoma >90
 * carcinoid syndrome 100
 * VIPoma 75
 * glucagonoma 50
 * somatostatinoma 50
 * GHRHoma 100
 * CRHoma, ACTHoma >90

Of noncarcinoid PETs, "percent malignant", according to Warner, is


 * insulinoma: 10
 * gastrinoma: 60-90
 * VIPoma: 50
 * glucagonoma: 50
 * somatostatinoma: 70-80
 * ACTHoma: 99
 * PTHrPoma: 99
 * neurotensinoma: ?
 * calcitoninoma: 80
 * GFRoma: 30

Representing "Malignanacy Rates", Percent of "Islet Tumors . . . With Metastases at Diagnosis" is


 * insulinoma: 31
 * gastrinoma: 50-80
 * glucagonoma: >50
 * VIPoma: 50
 * somatostatinoma: 75
 * PPoma: 100

according to http://www.med.umich.edu/lrc/presentation/endo/islet.htm.

Diagnosis
CT-scans with contrast detect 95 percent of tumors over 3 cm, 30 percent of tumors from 1 to 3 cm, and 0 percent of tumors under 1 cm, according to http://www.med.umich.edu/lrc/presentation/endo/islet.htm.

"Somatostatin is a hormone comprising two peptides, one built of 14 amino acids, the other of 28 amino acids". - Wikipedia Somatostatin

FDG-PET is not useful: http://www.emedicine.com/radio/topic363.htm

According to "CIS Chromagranin [sic] Monography: Chromogranin: A circulating neuroendocrine marker: biology, pathology, assay technology and clinical applications" by Luca C. Giovanella, at http://www.eoc.ch/allegati/mednuc_cromogranina%20A.pdf, markers include


 * Cytoplasmic markers
 * Neuron-specific enolase (NSE, gamma-gamma dimer)
 * Synaptophysin (P38)
 * Synaptobrevin (VAMP-1)
 * Synapsin (1A, 1B, 2A, 2B)
 * SV2
 * Protein P65
 * Protein S-100
 * Protein gene product (PGP 9.5)
 * Intermediate filaments (cytokeratins, vimentin, neurofilaments)
 * Protein 7B2
 * Granular markers
 * Chromogranin A (protein secretory I)
 * Chromogranin B (secretogranin I)
 * Chromogranin C (secretogranin II)
 * Pancreastatin
 * Vasostatin
 * Cytochrome b561
 * Leu-7 (HNK-1)

According to "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours" by Ramage JK et al., markers include


 * chromogranin A (CgA)
 * serum pancreatic polypeptide
 * serum calcitonin
 * and serum HCG ({alpha} and ß)
 * 5-hydroxy indole acetic acid (5-HIAA) (grade C)
 * thyroid function tests (TFTs)
 * parathyroid hormone (PTH)
 * calcium
 * calcitonin
 * prolactin
 * {alpha}-fetoprotein
 * carcinoembryonic antigen (CEA)
 * ß-human chorionic gonadotrophin (ß-HCG) (grade D)

According to http://www.med.umich.edu/lrc/presentation/endo/islet.htm, markers include


 * Pancreatic polypeptide
 * Human chorionic gonadotropin-alpha
 * Human chorionic gonadotropin-beta

According to Warner, markers include


 * serotonin
 * neurotensin
 * motilin
 * substance P
 * histamine
 * catecholamines
 * dopa
 * various rarer peptide hormones

According to Öberg, at http://pubmed.org, new markers include


 * N-terminally truncated variant of heat shock protein 70 (Hsp70)
 * CDX-2, a homeobox gene product
 * neuroendocrine secretory protein-55

http://www.medscape.com/viewarticle/420088?src=search:


 * protein gene product 9.5
 * synaptophysin, synapsin, and synaptotagmin
 * chromogranin A and HISL-19

Therapy
"There is no established standard therapy for the liver metastasis of pancreatic endocrine tumors". - http://pubmed.org.

"Importantly, streptozotocin combinations and dacarbacine are only effective in tumors of pancreatic origin. There is no established chemotherapy for malignant carcinoids of the stomach, small and large intestine" - Arnold.

For 125 patients with histologically proven unresectable islet-cell carcinomas, "median duration of regression was 18 months for the doxorubicin combination and 14 months for the 5-FU combination" - Arnold

Even for “the poorly differentiated and anaplastic NETs. . . responses may be relatively short lasting in the order of only 8–10 months” - Ramage.

Citation for statement that chelators can affect uptake: "Replacement of phenylalanine at the 3-position of octreotide by tyrosine has been shown to even increase the affinity of this compound for the sst2 receptors" - Arnold.

Citation for statement that strong uptake is a negative indication for chemo: "Response to chemotherapy in patients with strongly positive carcinoid tumours was of the order of only 10% whereas patients with SSRS negative tumours had a response rate in excess of 70%" - Ramage.

Citation for statement that iodine-131 has been used against thyroid cancer since 1943: .

Citation for statement that "MIBG therapy was developed in the 1980s and PRRT in the 1990s": "Professor Baum began 1984 already with his Frankfurt working group to use the radio receptor therapy with Iod-131 MIBG for the treatment of certain tumors (e.g. malignant Phäochromozytome or Neuroblastome as well as Paragangliome). The first radio immune therapy in Germany was already accomplished by it and its working group 1985, the first radio receptor therapy with Yttrium-90 DOTATOC for the treatment of a neuroendocrine tumor already 1997" - google.com translation of http://www.net-shg.de/Beirat/Baum.htm. "The discovery that certain tumor types overexpress receptors for peptide hormones dates back to the mid-1980s" - Krenning EP, Kwekkeboom DJ, Valkema R, Pauwels S, Kvols LK, De Jong M., "Peptide receptor radionuclide therapy", Annals of the New York Academy of Science 1014:234-245 (2004), p. 238; abstract at http://pubmed.org. "Another potential development is the use of beta-emitting isotopes coupled to somatostatin analogues for therapeutic irradiation" - Lamberts SW, Krenning EP, Klijn JG, Reubi JC, "The clinical use of somatostatin analogues in the treatment of cancer", Baillieres Clin Endocrinol Metab. 1990 Mar;4(1):29-49; abstract at http://pubmed.org.

"The approximate range of the beta-particles [emitted by 177-Lutetium] is 20 cell diameters, wherease the range of those emitted by 90-Yttrium is 150 cell diameters" - Krenning.

"Although generally regarded as mainly diagnostic, 111-Indium emits Auger and conversion electrons, which display a tissue penetration of 0.02-10 [micrometers] and 200-500 [micrometers] respectively, and which can be used therapeutically. More therapeutic experience has been gained with 90-Yttrium, which is a classical β-particle emitter. To avoid dissociation of 90-Yttrium with a maximum path length of 9 mm from the chelated somatostatin analog, a stable [DOTA0, Tyr3]-octreotide complex has been developed. . . . Whether or not [177-Lu-DOTA, Typ3]-Octreotate with a tissue penetration of 2 mm is superior to 111-Indium and 90-Yttrium labelled octreotide in the treatment of endocrine GEP tumors is currently under investigation" - Arnold. "Typ3" appears to be a misprint for "tyr3". Square brackets in phrases such as "[DOTA0, Tyr3]" represent scientific notation, not editorial insertions.

"Carrier molecules that target the cell surface, such as SSRs, require a longer particle path length [than mIBG] to achieve nuclear damage. . . . The particle range of 90-Y, for example, extends across 50 to 70 cell diameters. . . . Pancreatic NETs are rarely mIBG avid" - Lewington VJ, "Targeted radionuclide therapy for neuroendocrine tumours" (2003), at http://www.carcinoid.org/medpro/docs/ENET2003Y90Lewington.pdf. Lewington also provides the following data:


 * half life 6.7 days, beta energy (mean) 0.15 MeV, mean particle range 0.27 mm for Lu-177
 * half life 8.0 days, beta energy (mean) 0.20 MeV, mean particle range 0.45 mm for I-131
 * half life 2.7 days, beta energy (mean) 0.94 MeV, mean particle range 4.20 mm for Y-90

The twelve institutions are in Belgium (Brussels), Chile (German Hospital), Germany (Bad Berka, Berlin, Hannover, Marburg), Italy (Milan), Sweden (Uppsala), Switzerland (Basel, Geneva), The Netherlands (Rotterdam), UK (London), and USA (Houston). OK, that's 13 -- I don't claim that this list is accurate.

"If you look back at the liver, although it has two separate blood supplies, the portal vein and the hepatic artery, the liver gets 80% of its blood from the portal vein and 20% from that little hepatic artery. But tumors get 100% of their blood off the hepatic artery, and this has been shown by multiple lines of evidence" - http://www.carcinoid.org/pcf/lectures/docs/Pommier.htm.

"The normal liver gets its blood supply from two sources; the portal vein (about 70%) and the hepatic artery (30%)" - Fong, Tse-Ling, Leslie J. Schoenfield, http://www.medicinenet.com/chemo_infusion_and_chemoembolization_of_liver/article.htm.

--- End of initial citations ---

TH 22:24, 28 July 2006 (UTC)

Footnotes and citations
I have read up on footnote and citation systems, in and out of Wikipedia. None of them quite suits the purposes of this article. So I have made a hybrid out of the best of three systems: footnoting, the author-date system, and the standards used at PubMed.

Below I give the reasons why I did what I did. In effect, these are the pros and cons of the hybrid system.

Some of this system derives from the fact that this is a medical article, depending heavily on PubMed. But I think that much of the reasoning below applies to non-medical articles as well.

One problem with most footnoting systems is that a footnote number may lead merely to a pointer to a book or article, or may lead to a detailed discussion of the issues or a longer and possibly interesting quote from a book or article. I call the first a pointer note and the second a discursive note.


 * 1) I use the author-date system for pointer notes (example of citation: Rufini 2006) and I use footnotes for discursive notes. Well, that's what most people who use author-date do. But most discussions of author-date fail to point out this advantage: every footnote is now discursive -- the reader who follows any note will find a discussion or a longer quote.
 * 2) Meanwhile, the other main advantage of author-date applies to pointer notes -- namely, quick recognition, either (a) by an expert reader, who may recognize the author's name and the publication year in the first citation, and (b) by any reader, who may recognize the author's name and the publication year anywhere after the first citation. If I used footnotes for pointer notes (as in the documentary-note system), the reader would have to dig deep to find out, for example, that notes 12, 19, and 22 all refer to the same work.
 * 3) PubMed follows the standard of presenting author names as, for example, Rufini V, Calcagni MLC, Baum RP. The use of initials prevents the reader from pre-judging authors on the basis of sex. Some other systems invert the names after the first name, for example, Rufini V, MLC Calcagni, RP Baum, but I don't see any good reason for that, and it requires retyping rather than cut-and-paste from PubMed, so I follow the PubMed format.
 * 4) Chicago-style author-date uses et alia or et al. when there are four or more authors. PubMed does not. We are not strapped for space at Wikipedia. And it's easier to cut and paste the whole list from PubMed than to change it to the et alia convention. So I follow the PubMed standard. Also, sometimes the last author is a sort of supervising editor, a top expert of the institution, and therefore not an unimportant author.
 * 5) PubMed heavily abbreviates the journal names -- for example, Hum Pathol. -- and I don't want to go digging to find the full name of the journal, so I just take the name from PubMed as is.
 * 6) Even if a medical journal article is not available online, there is usually an abstract at PubMed. If so, my reference always says (a) "Abstract." immediately after the year and for example, PMID 15619202 at the end of the reference, if all my citations are entirely from the abstract; and (b) Abstract at PMID 15619202 at the end, if at least one of my citations is not entirely from the abstract. Wikipedia handles such PubMed IDs automatically. It's good to let readers see the abstract, even if they can't see my quote.
 * 7) The article is unusually full of discursive notes (footnotes) and pointer notes (author-date citations and references). So many notes threaten to clutter up the text, so I just put one note at the end of each paragraph. The reader will soon figure out that all the discursions related to a paragraph are accessible from the single note at the end. The text looks clean, the Notes look clean (all discursion and citations, no references), and the References look clean.
 * 8) The only addition I make to general author-date citation rules is to add a bare link (e.g.  ) if what I cited is available online. This is in keeping with the general author-date goal of "the most for the least" in citations. When I do this, I do not changed the reference from what it would otherwise be.
 * 9) Other than the citation link, I use no special Wikipedia tools except &lt;ref>...&lt;/ref> to embed each footnote into the text. I have a Notes section, a References section, and maybe a Further reading section for works that are useful but not cited in the article. Slightly strange: since I embed the notes in the text, but Wikipedia calls them references, the Notes section contains only this text: &lt;references />.
 * 10) Wikipedia does not hyperlink a author-date citation to the reference itself. Well, that's the way it goes.
 * 11) Putting a period or comma inside quotation marks is an illogical custom that was started, I once read, by sloppy American printers during the colonial period. In very technical writing it can lead to problems -- did the quoted phrase contain the punctuation or not? I follow the more logical convention used in the UK: periods and commas go outside the quotes.


 * If you can convince the Wikipedia community to do it your way we'll do it your way. Until then we'll do it our way. --Nbauman (talk) 14:33, 22 May 2011 (UTC)

Proposed merge of Neuroendocrine tumors and Carcinoid
The World Health Organisation has suggested the use of the follow (instead of "carcinoid"):
 * neuroendocrine tumo(u)r


 * -- or --


 * neuroendocrine carcinoma
 * See: Can J Gastroenterol. 2008 Apr;22(4):357-8., Ann N Y Acad Sci. 2004 Apr;1014:13-27. , Pathologe. 2003 Jul;24(4):287-96. )

As per above, I think it makes sense to merge carcinoid into neuroendocrine tumor (or move both to neuroendocrine carcinoma. Nephron T|C 06:18, 12 August 2008 (UTC)


 * Support as per above Nephron T|C 06:18, 12 August 2008 (UTC) (proposant)
 * Oppose. Carcinoid is a distinct disease. JFW | T@lk  14:21, 11 November 2008 (UTC)


 * Support as per above. It's a subclass, it's absolutely not distinct.  It's certainly murky, the difference, and there should not be 2 different articles.  —Preceding unsigned comment added by Danielbirns (talk • contribs) 00:35, 12 October 2010 (UTC)


 * Oppose. Carcinoid is a subgroup of neuroendocrine tumours, other NET should not be discussed on the same page as carcinoid as it creates confusion.

Review
pancreatic neuroendocrine tumours. JFW | T@lk  14:21, 11 November 2008 (UTC)
 * DOI now broken and says "Please remove all references to this resource."
 * I guess this is the article Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors. Metz and Jensen. Gastroenterology. Volume 135, Issue 5, Pages 1469-1492, November 2008
 * Says "Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. " Rod57 (talk) 03:37, 8 March 2011 (UTC)

Should we split the article
It seems too large, and some sections are large and with few subsections making it hard to find specific content. Should we split out the Diagnosis &/or Treatment sections ? Rod57 (talk) 03:29, 8 March 2011 (UTC)
 * A good editor could cut this article into half the size or less merely by deleting meaningless generic boilerplate like this:
 * According to Warner, the best care, at least for noncarcinoid GEP-NETs, is provided by "an active [as opposed to wait-and-see] approach using sequential multimodality treatment" delivered by a "multidisciplinary team, which also may include a surgeon, endocrinologist, oncologist, interventional radiologist, and other specialists".
 * What cancers are not best treated by a multidisciplinary approach? --Nbauman (talk) 14:22, 22 May 2011 (UTC)

NYT article
This NYT article contains the claim from a doctor that neuroendocrine tumors can be "cured" if they're caught early enough. It may be worth putting into the article somewhere. --Nbauman (talk) 14:16, 22 May 2011 (UTC)

NEJM article on sunitinib
This article should have a reference to sunitinib, with a cite to the NEJM article 364:503 and editorial 364:564 (and so should the Sunitinib article http://en.wikipedia.org/wiki/Sunitinib#Pancreatic_neuroendocrine_tumors). I'm too overwhelmed by the confusion of this article to do it right now. --Nbauman (talk) 14:31, 22 May 2011 (UTC)
 * Right, both "new" medicines should receive brief mention. But.... do I dare go into this article for what will end up being a major series of edits?FeatherPluma (talk) 02:40, 25 May 2011 (UTC)


 * I have made a start but there is still a huge amount of work to be done. The categories are a bit clearer but not quite there yet. The references need to be formatted. Making them conform to the usual WP style will be necessary, not because that is "an arbitrary standard", but because 1) much of the complexity and confusion arises from how the material currently reverbates inconclusively and irritatingly between citation and encyclopedic content and 2) open standards for editing paradoxically need some type of framework so that future editirs can interactively contribute. I hope to get to the medications eventually, but it will be necessary to have a clear concept of what category they are applicable.FeatherPluma (talk) 21:08, 27 May 2011 (UTC)


 * Some work has been done. 1. The citations are now in inline style. 2. I intend to edit citations to standard format, with footnotes if needed. 3. There is still a depressing amount of needed upgrading to do. The article rating has been downgraded to a C, until this is much further along.FeatherPluma (talk) 04:08, 31 May 2011 (UTC)