Neuro
`-endocrinology
`
`
`
`Neuroendocrinology 2004;80(suppl 1):94-98
`DOI: 10.1159/000080749
`
`
`
`From Basic to Clinical Research in
`Gastroenteropancreatic Neuroendocrine Tumor
`Disease — The Clinician-Scientist Perspective
`
`Bertram Wiedenmann_ Ulrich-Frank Pape
`
`Departmentof Internal Medicine, Division of Hepatology and Gastroenterology,Interdisciplinary Center of
`Metabolism and Endocrinology, Charité, Campus Virchow Hospital, University Medicine Berlin, Berlin, Germany
`
`Key Words
`Basic and clinical research - New drugs-
`Neuroendocrine tumor: Unresolved clinical issues
`
`Abstract
`
`Patients with rare tumors represent a diagnostic and
`therapeutic challenge for non-specialized physicians,
`surgeons and other medical doctors. Whereas several
`specialized centers have gathered data for an improved
`diagnosis and therapy of neuroendocrine tumor disease,
`numerous clinical issues have not been resolved on an
`
`evidence-based medicine level. Furthermore, the evalua-
`tion of new treatment options has been overshadowed
`by the low incidence of the disease.
`In this article, a
`major medical challenge for the diagnosis and therapy of
`neuroendocrine tumor disease is addressed. As well,
`new therapeutic treatment options translated from cur-
`rent findings in the fields of molecular and tumor biology
`are discussed.
`
`Copyright @ 2004 S. Karger AG,Basel
`
`Neuroendocrine tumors (NETs)originate in different
`organs and sites [1, 2]. Based on their diverse primary
`tumorlocalizations, NETs of the gastroenteropancreatic
`(GEP) system encompassa family of distinct or even indi-
`vidual tumors, which haveto be considered as distinct as
`adenocarcinomas of the stomach, rectum and pancreas
`[3]. NETcells also exhibit, in relation to their primary
`origin, distinct cell biological features, such as distinct
`secretory as well as growth and differentiation properties
`[4].
`For example, NETslocated in the rectum (also called
`rectal carcinoids) practically never secrete hormones or
`biogenic amines to cause hypersecretion-related symp-
`toms and syndromes. Theyusually grow slowly and me-
`tastasize late, i.e. only once a tumor exceeds a diameter of
`1-2 cm [5, 6].
`By contrast, NETs of the colon are usually dedifferen-
`tiated and metastasize early [7]. On the other hand, they
`are similar to NETs of the rectum in that they are non-
`functional, i.e. no secretion of hormones and biogenic
`aminesis observed which can cause hypersecretion-relat-
`ed syndromes and symptoms. Despite this, however,
`functionally inactive polypeptides such as chromogranin
`A can be detected in patients with metastatic disease in
`the bloodstream [8].
`By contrast, NETs of the pancreas often secrete hor-
`mones(e.g. insulin, gastrin, glucagon and VIP) but very
`
`KARG E R
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2004 S. Karger AG, Basel
`0028-3835/04/0807-0094$21.00/0
`
`Accessible online at:
`www. karger.com/nen
`
`Bertram Wiedenmann, Departmentof Internal Medicine, Division ofHepatology and
`Gastroenterology, Interdisciplinary Center ofMetabolism and Endocrinology
`Charité, Campus Virchow Hospital, University Medicine Berlin
`AugustenburgerPlatz 1, DE-13353 Berlin (Germany), Tel. +49 30 450 553 022
`Fax +49 30 450 553 902, E-Mail bertram.wiedenmann@charite.de
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 001
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 001
`
`

`

`rarely biogenic amines (e.g. serotonin and catechol-
`amines)[5, 9].
`This clinical and tumorbiological phenomenonis con-
`trasted by NETsofthe ileum, which often secrete biogenic
`amines but rarely hormones(the only exception being
`tachykinins). Similar for both NETsof the pancreas and
`the ileum is their usually low proliferation index as deter-
`mined by Ki67 (< 10%) [2, 5].
`Based on these tumor biological and clinical facts,
`NETshave been diagnosed and treated as separate dis-
`eases, i.e. according to their primary location,state of dif-
`ferentiation and stage [10, 11].
`NET patients often represent a difficult diagnostic
`challengeat their first doctor’s visit. This holds especially
`true for patients who only exhibit discrete functionality
`such as mild phases of impaired consciousness(e.g. insuli-
`noma), epigastric pain (e.g. gastrinoma) or intermittent,
`nocturnal diarrhea(e.g. carcinoid syndrome).
`This also holds true for patients with MEN-1, which
`are knownto be genetically affected by a menin mutation
`[12, 13]; however, in the early tumorstage, only provoca-
`tion tests can detect small or even minimal disease. Clear-
`ly, laboratory diagnosis without provocation tests will
`practically always be negative in these very early tumor
`stages. Aside from provocationtests, the bona fide tumor
`markers, chromogranin A and 5-HIAA,will only be raised
`once metastases have formed. Furthermore, these mark-
`ers have to be considered with care, since synthesis of
`these marker molecules depends on the primary tumor
`location as well as the state of tumor differentiation [14].
`Histological diagnosis, in a preoperative setting, re-
`quires the imaging of NET lesions, be they liver metas-
`tases, gastric or rectal polyps or pancreatic lesions. In
`somecases, functionality as well as a positive laboratory
`test may be present but no lesion can be detected [4, 15].
`Only during the course of the disease can the tumorlesion
`be detected. Therefore, more sensitive diagnostic proce-
`dures are required allowing the consistent earlier detec-
`tion of tumorlesions smaller than 5 or even 2 mm.This
`would also imply the hope that tumorsconsisting of less
`than, for example, 1 million tumorcells (corresponding to
`a diameter of approximately 3 mm) should be detectable
`in living tissue. Clearly, in contrast to the given limited in
`vivo conditions, immunohistology can allow the detection
`of a single tumorcell, for example in lymph nodesorin
`bone marrow. Thus, improvementof our current in vivo
`imaging standards is required to comeclose to the well-
`established in vitro imaging conditions.
`Similarly, endoscopic ultrasound, the continuously im-
`proving MRItechnology as well as somatostatin receptor
`
`scintigraphy represent moves in the right direction in
`order to comecloser to the ideal in the possible detection
`of the first and only tumorcell [16, 17].
`As far as new therapeutic options in NET disease are
`concerned, surgical methods have been improved by new
`minimally invasive procedures, for example in laparo-
`scopic ileocecal resection. However, it remainsto be deter-
`minedif this approach will substitute for the conventional
`‘open’ approach. Considering, for example, that we can
`evaluate the lymph nodestatus in ileal NETjust as well by
`laparoscopyas by ‘open surgery’ is very promising.
`Furthermore, local ablative procedures have increas-
`ingly been used by now in NETdisease. Although promis-
`ing in terms of control of symptoms, no data have been
`obtained so far in a prospective, randomized, multicen-
`tric setting demonstrating a prolonged survival in NET
`patients.
`Similarly, peptide-guided radioreceptor therapy has
`been used in several trials and shown to be quite promis-
`ing for both control of hypersecretion-related symptoms
`as well as control of tumor growth [17-19]. So far, how-
`ever, only one prospective multicenter trial with radiola-
`beled octreotate coupled to yttrium 90 via a chemical
`DOTATOCbridge (Octreother) has been performed. Fi-
`nalresults of this trial are not yet ready.
`Furthermore, chemotherapy has only partially been
`effective in two NET groups: in pancreatic as well as in
`undifferentiated NETs.In thefirst group, streptozotocin-
`based regimens combined with 5-FU or doxorubicin are
`of some value [20]. For undifferentiated, anaplastic
`NETs,cis-platinum plus VP16/etoposide can lead to
`someresponses [21]. However, these responseslast only a
`few months. Based on these limited effects of presently
`used chemotherapeutic agents, new chemotherapeutics
`may be worth testing such as oxaliplatin- or taxol-based
`regimensin anaplastic NETs[22].
`Clearly, based on the above-given limited clinical
`knowledge in the field of diagnostics, as well as therapeu-
`tics in NET disease, a substantial numberofclinical ques-
`tions have to be answered in prospective pan-European or
`even global trials.
`The major issues and questions to be answeredare:
`(1) development of a staging, grading and subsequent
`TNMclassification as an objective measure for prognosis
`in NETpatients; (2) evaluation of conventional entero-
`clysma as compared to the newly developed MR-Sellink
`procedure; (3) determination of the cost-effectiveness of
`somatostatin receptor scintigraphy in comparison to oth-
`er imaging procedures in a prospective multicentric set-
`ting; (4) performance of a randomized prospective study
`
`Basic and Clinical Research of GEP NETs
`in an International Context
`
`Neuroendocrinology 2004;80(supp! 1):94-98
`
`95
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 002
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 002
`
`

`

`Table 1. Overexpression of growth factors and their cognate recep-
`tors in GEP NETs
`
`Growth factor
`
`Receptor
`
`PDGF
`bFGF
`TGF-a
`TGFE-B
`HGF
`IGF
`VEGF
`
`PDGF-a-R
`FGF-RI, FGF-RII
`EGF-R
`TGF-B-RI, TGF-B-RII
`HGF-R
`IGF-R
`KDR,Fit-1
`
`Reference
`
`25
`26
`27, 28, 29
`24
`29
`30, 31
`23
`
`on surgical debulking vs. medical therapy in patients with
`noncuratively resectable cancer; (5) evaluation of local
`ablative procedures (radiofrequency thermalablation, la-
`ser-induced thermotherapy and others) in comparison
`with medical therapy underthe aspects of both, control of
`symptoms as well as tumor growth; (6) evaluation of
`embolization vs. chemoembolization in a prospectiveset-
`ting; (7) determination of the antiproliferative effect of
`biotherapeuticsin relation to primary localization, tumor
`differentiation and drug bioavailability; (8) evaluation of
`the antiproliferative effect of ‘cold’ vs. ‘hot’ somatostatin
`analogues; (9) evaluation of newly developed biothera-
`peutics (see below); (10) evaluation of the effect of perito-
`neal carcinosis on gastrointestinal motility; (11) evalua-
`tion of the prognostic value of micrometastasis in lymph
`nodes, liver and blood, and (12) evaluation of certain
`tumorbiological phenomenasuch as anoikis, angiogene-
`sis and cell cycle activity in differentiated and undifferen-
`tiated NETcells in vitro. In addition to new chemothera-
`peutic agents, biotherapy or targeted therapy should be
`helpful in the expansion of our current therapeutic arma-
`mentarium (see below).
`Clearly, on a cellular level, we will have to learn more
`about the key molecular players involved in the tumor
`biology of NET disease. Furthermore, as far as NETcell
`crosstalk is concerned, aside from NETcells, we have very
`little knowledge concerning the interaction of immuno-
`cytes, endothelial cells, non-NET epithelial cells and neu-
`rons with NET cells. Furthermore, we do not know if
`clonal development of NET cells varies in relation to a
`given specific cellular compartment.
`Despite this, however, new agents developed in the
`field of targeted therapy will, we hope, allow us to study
`possible interference/inhibition of various growth factor
`signalling pathways. Similarly, signalling pathways linked
`
`with G-protein-coupled receptors as well as calcium chan-
`nels represent promising therapeutic targets.
`Interference with these pathways will also include
`interference with angiogenesis andcellular crosstalk (e.g.
`via integrins). It might also allow an improved therapeutic
`control of nuclear replication and membrane transport/
`secretion. This may not only hold true for NETcells but
`may also include immunocytes and other non-NETcells.
`Among the most promising new therapeutic ap-
`proachesin targeted therapy may be the inhibition of syn-
`thesis and/or secretion, as well as receptor binding of
`growth factors such as vascular endothelial growth factors
`[23, 24]. Based on their action on endothelial cell activa-
`tion, followed by a consecutive vascular hyperpermeabili-
`ty and matrix permeation, followed in turn by the induc-
`tion of endothelial proliferation, migration, lumen forma-
`tion andstabilization ofpericytes, this growth factor fami-
`ly warrants further detailed studies in NETs. This ap-
`proachis further supported by the fact that NET diseaseis
`characterized by hypervascularization within the tumor
`tissue [25].
`Growth factor signalling in GEP NETshasso far been
`quite extensively studied [23, 24, 26-32]. Biological pa-
`rameters such as growth, glucose metabolism, survival
`and mitogenesis have mainly been studied in vitro by the
`overexpression of growth factors and their cognate recep-
`tors in GEP NETcelllines. Details and references on the
`signalling pathways of PDGF, bFGF, EGF, HGF, IGF
`and VEGFin GEP NETare shown in table 1. Aside from
`the biological functions of the various growth factors, the
`function of somatostatin including its analogues has been
`extensively studied in NET [33].
`As comprehensively discussed by Schmid et al. [34],
`somatostatin as well its analogues play an important role
`in the treatment of hypersecretion-related symptomsin
`NETs. However,in order to improvethe potencyofthese
`pharmacological agents, more detailed studies are re-
`quired analyzing the crosstalk of somatostatin analogues
`with phosphatases and calcium channels. In addition, a
`variety of mechanismsofinterferon-o action on NETcells
`has been elucidated [35, 36] and justifies this substance as
`both an antisecretory as well as an antiproliferative agent,
`although its side effects have to be considered [37, 38].
`In this context, it is of note that a recent study by
`Mergleret al. [39, 40] suggested for the first time that R-
`type Ca2* channels are expressed in NETs, which in turn
`can be used as therapeutic targets by interfering with their
`function such as with SNX-482.
`Aside from new drug targets, a number of medical
`agents are available on the market for other indications.
`
`96
`
`Neuroendocrinology 2004;80(suppl 1):94-98
`
`Wiedenmann/Pape
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 003
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 003
`
`

`

`The antiproliferative action of COX-2/NSAIDs in NET
`cells has recently been demonstrated in vitro for thefirst
`time [41]. Clearly, COX-2 inhibitors represent an inter-
`esting new therapeutic approach for NETsbased on their
`low side effects and their possible combination with other
`orally available agents(e.g. capecitabine).
`Similarly, other pharmaceutical agents, characterized
`by their signalling via growth factor receptors, G-protein-
`coupled receptors, calcium channels, integrins and nu-
`clear proteins are currently evaluated in numerousclini-
`cal, oncological trials for non-NET indications. These
`include targeted therapeutics such as gefinitib (Iressa®)
`interfering with EGFreceptor signalling; imatinib inter-
`fering with PDGFc-kit signalling; SOM 230 interfering
`with somatostatin signalling; bevacizumab (Avastin®)in-
`terfering with VEGF-A signalling; PTK/ZK interfering
`with VEGFR 1-3, PDGFR c-kit and c-Fmssignalling;
`Medi-522 andcilengitide interfering with integrin-a,B3
`signalling; flavopyridol and rapamycin interfering with
`nuclear replication and membranetransport/secretion.
`
`In summary, numerous questions remain to be an-
`swered, both at the level of diagnostics and therapeutics.
`To answer these primary questions, multicentric, pro-
`spective, randomized studies are required in orderto gen-
`erate better evidence-based medicine levels than those
`that have been obtained so far. Clearly, this also implies
`the performance ofstudies evaluating the cost-benefit of
`currently applied diagnostics and therapeutics. In addi-
`tion, new therapeutic strategies are required in order to
`improve current, rather limited treatment options espe-
`cially in metastatic NET disease. Here, new targeted ther-
`apies offer new hopeespecially in the fields of angiogene-
`sis, nuclear replication, cellular adhesion andsignal trans-
`duction.
`
`Acknowledgments
`
`The authors are indebted to M. Szott-Emusand E. Zach, Berlin,
`Germany,fortheir excellent editorial support.
`
`References
`
`Modlin IM, Lye KD, Kidd M:A 5-decadeanal-
`ysis of 13,715 carcinoid tumors. Cancer 2003;
`97:934-959,
`Rindi G, Bordi C: Highlights of the biology of
`endocrine tumours of the gut and pancreas.
`Endocr Relat Cancer 2003;10:427-436.
`Kloppel G, Perren A, Heitz PU: The gastroen-
`teropancreatic neuroendocrinecell system and
`its tumors: The WHOclassification, Ann N Y
`AcadSci 2004;1014:13-27.
`Wiedenmann B, John M, Ahnert-Hilger G,
`Riecken EO: Molecular and cell biological as-
`pects of neuroendocrine tumors of the gas-
`troenteropancreatic system. J Mol Med 1998;
`76:637-647.
`Caplin ME, Buscombe JR, Hilson AJ, Jones
`AL, Watkinson AF, Burroughs AK: Carcinoid
`tumour. Lancet 1998;352:799-805.
`Federspiel BH, Burke AP, Sobin LH, Shekitka
`KM:Rectal and colonic carcinoids. A clinico-
`pathologic study of 84 cases. Cancer 1990;65:
`135-140.
`Bernick PE, Klimstra DS, Shia J, Minsky B,
`Saltz L, Shi W, Thaler H, Guillem J, Paty P,
`Cohen AM, Wong WD: Neuroendocrinecarci-
`nomasofthe colon and rectum. Dis Colon Rec-
`tum 2004;47:163-169.
`Lamberts SW, Hofland LJ, Nobels FR: Neu-
`roendocrine tumor markers. Front Neuroendo-
`crinol 2001;22:309-339.
`
`w
`
`ws
`
`oo
`
`9
`
`10
`
`1 _
`
`12
`
`13
`
`Polak JM, Bloom SR, Adrian TE, Heitz P,
`Bryant MG, Pearse AG: Pancreatic polypep-
`tide in insulinomas,gastrinomas, vipomas, and
`glucagonomas. Lancet 1976;i:328-330.
`Pape UF, Bohmig M, Berndt U, Tiling N,
`Wiedenmann B, Plockinger U: Survival and
`clinical outcome of patients with neuroendo-
`crine tumors of the gastroenteropancreatic
`tract in a German referral center. Ann N Y
`Acad Sci 2004; 1014:222-233,
`Wiedenmann B, Jensen RT, Mignon M, Mod-
`lin CI, Skogseid B, Doherty G, Oberg K: Preop-
`erative diagnosis and surgical managementof
`tu-
`neuroendocrine
` gastroenteropancreatic
`mors: General recommendations by a consen-
`sus workshop. World J Surg 1998;22:309-318.
`LemmensI, Van de Ven WJ, Kas K, Zhang
`CX, Giraud S, Wautot V, Buisson N, De Witte
`K, Salandre J, Lenoir G, Pugeat M, Calender
`A, Parente F, Quincey D, Gaudray P, De Wit
`MJ, Lips CJ, Hoppener JW, Khodaei S, Grant
`AL, Weber G, Kytola 8S, Teh BT, Farnebo F,
`Thakker RV:Identification of the multiple en-
`docrine neoplasia type 1 (MENI1) gene. The
`European Consortium on MEN1. Hum Mol
`Genet 1997;6:1177-1183.
`Chandrasekharappa SC, Guru SC, Manickam
`P, Olufemi SE, Collins FS, Emmert-Buck MR,
`Debelenko LV, Zhuang Z, Lubensky IA, Liotta
`LA, Crabtree JS, Wang Y, Roe BA, Weisemann
`J, Boguski MS, Agarwal SK, Kester MB, Kim
`YS, Heppner C, Dong Q, Spiegel AM, Burns
`AL, Marx SJ: Positional cloning of the gene for
`multiple endocrine neoplasia type 1. Science
`1997;276:404—407.
`
`14 Brandi ML, Gagel RF, Angeli A, Bilezikian JP,
`Beck-Peccoz P, Bordi C, Conte-Devolx B,Fal-
`chetti A, Gheri RG, Libroia A, Lips CJ, Lom-
`bardi G, Mannelli M, Pacini F, Ponder BA,
`RaueF, Skogseid B, Tamburrano G, Thakker
`RV, Thompson NW, Tomassetti P, Tonelli F,
`Wells SA Jr, Marx SJ: Guidelines for diagnosis
`and therapy of MEN type | and type 2. J Clin
`Endocrinol Metab 2001;86:5658-5671.
`15 Ricke J, Klose KJ, Mignon M, Oberg K, Wie-
`denmann B: Standardisation of imaging in
`neuroendocrine tumours: Results of a Euro-
`pean delphi process. Eur J Radiol 2001;37:8-
`17.
`16 ZimmerT, Stolzel U, Bader M, Koppenhagen
`K, Hamm B, Buhr H, Riecken EO, Wieden-
`mann B: Endoscopic ultrasonography and so-
`matostatin receptor scintigraphy in the preop-
`erative localisation of insulinomas and gastri-
`nomas. Gut 1996;39:562-568.
`17 Breeman WA, de Jong M, Kwekkeboom DJ,
`Valkema R, Bakker WH, Kooij PP, Visser TJ,
`Krenning EP: Somatostatin receptor-mediated
`imaging and therapy: Basic science, current
`knowledge, limitations and future perspectives.
`Eur J Nucl Med 2001;28:1421-1429.
`18 Otte A, Mueller-Brand J, Dellas S, Nitzsche
`EU, Herrmann R, Maecke HR: Yttrium-90-
`labelled
`somatostatin-analogue
`for
`cancer
`treatment. Lancet 1998;351:417-418.
`
`Basic and Clinical Research of GEP NETs
`in an International Context
`
`Neuroendocrinology 2004;80(suppl 1):94-98
`
`97
`
`West-Ward Pharm.
`Exhibit 1052
`Page 004
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 004
`
`

`

`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`Kwekkeboom DJ, Bakker WH, Kam BL, Teu-
`Detjen KM, Welzel M, Farwig K, Brembeck
`Chaudhry A, Funa K, Oberg K: Expression of
`FH, Kaiser A, Riecken EO, Wiedenmann B,
`growth factor peptides and their receptors in
`nissen JJ, Kooij PP, de Herder WW,Feelders
`Rosewicz S: Molecular mechanism ofinterfer-
`neuroendocrine tumors ofthe digestive system.
`RA, van Eijck CH, de Jong M, Srinivasan A,
`Acta Oncol 1993;32:107-114.
`Erion JL, Krenning EP: Treatmentof patients
`on-alfa-mediated growth inhibition in human
`neuroendocrine tumorcells. Gastroenterology
`Nilsson O, Wangberg B, Kolby L, Schultz GS,
`with gastro-entero-pancreatic (GEP) tumours
`with the novel radiolabelled somatostatin ana-
`2000; 118:735-748.
`Ahlman H: Expression of transforming growth
`factor alpha and its receptor in human neu-
`logue [177Lu-DOTA(0),Tyr3]octreotate. Eur J
`Detjen KM,Kehrberger JP, Drost A, Rabien A,
`Welzel M, WiedenmannB, Rosewicz S: Inter-
`roendocrine tumours. Int J Cancer 1995;60:
`Nucl Med MolImaging 2003;30:417-422.
`645-651.
`Moertel CG, Lefkopoulo M, Lipsitz S, Hahn
`feron-gamma inhibits growth of human neu-
`roendocrine carcinoma cells via induction of
`Shimizu T, Tanaka S, HarumaK, Kitadai Y,
`RG, Klaassen D: Streptozocin-doxorubicin,
`apoptosis, Int J Oncol 2002;21:1133-1140.
`streptozocin-fluorouracil or chlorozotocin in
`Yoshihara M, Sumii K, Kajiyama G, Shima-
`moto F: Growth characteristics of rectal carci-
`the treatment of advancedislet-cell carcinoma.
`Faiss S, Pape UF, Bohmig M,Dorffel Y, Mans-
`mann U, Golder W, Riecken EO, Wiedenmann
`N Engl J Med 1992;326:519-523.
`noid tumors. Oncology 2000;59:229-237.
`B;International Lanreotide and Interferon Alfa
`Moertel CG, Kvols LK, O’Connell MJ, Rubin
`Peghini PL, Iwamoto M,Raffeld M, Chen YJ,
`J: Treatment of neuroendocrine carcinomas
`Study Group: Prospective, randomized, multi-
`Goebel SU, Serrano J, Jensen RT: Overexpres-
`center trial on the antiproliferative effect of
`sion of epidermal growth factor and hepatocyte
`with combined etoposide and cisplatin. Evi-
`lanreotide, interferon-alfa, and their combina-
`dence of major therapeutic activity in the ana-
`growth factor receptors in a proportion of gas-
`plastic variants of these neoplasms. Cancer
`tion for therapy of metastatic neuroendocrine
`trinomascorrelates with aggressive growth and
`lower curability. Clin Cancer Res 2002;8:
`1991;68:227-232.
`gastroenteropancreatic tumors. J Clin Oncol
`2273-2285.
`2003;2 1:2689-2696.
`Rougier P, Mitry E: Chemotherapyin the treat-
`Wulbrand U, Remmert G, Zofel P, Wied M,
`Pape UF, WiedenmannB: Adding interferon-
`mentof neuroendocrine malignant tumors. Di-
`alpha to octreotide slows tumour progression
`Arnold R, Fehmann HC: mRNAexpression
`gestion 2000;62(suppl 1):73-78.
`compared with octreotide alone but evidenceis
`von Marschall Z, Scholz A, Cramer T, Schafer
`patterns of insulin-like growth factor system
`lacking for improved survival in people with
`components in human neuroendocrine tu-
`G, Schirner M, Oberg K, Wiedenmann B,
`mours. Eur J Clin Invest 2000;30:729-739.
`Hocker M, Rosewicz S: Effects of interferon
`disseminated midgut carcinoid tumours. Can-
`cer Treat Rev 2003;29:565-569.
`von Wichert G, Jehle PM, Hoeflich A, Kosch-
`alpha on vascular endothelial growth factor
`nick S, Dralle H, Wolf E, Wiedenmann B,
`Mergler $8, Wiedenmann B, Prada J: R-type
`gene transcription and tumor angiogenesis. J
`Natl CancerInst 2003;95:437-448.
`Boehm EO,Adler G,Seufferlein T: Insulin-like
`Ca?* channel activity is associated with chro-
`mogranin A secretion in human neuroendo-
`Wimmel A, WiedenmannB, Rosewicz S: Auto-
`growth factor-I is an autocrine regulator of
`crine tumor BON cells. J Membr Biol 2003;
`chromogranin A secretion and growth in hu-
`crine growth inhibition by transforming growth
`194:177-186.
`man neuroendocrine tumorcells. Cancer Res
`factor beta-1 (TGFbeta-1) in human neuroen-
`2000;60:4573-4581.
`Mergler S, Drost A, Bechstein WO, NeuhausP,
`docrine tumour cells. Gut 2003:52:1308-
`1316.
`Wiedenmann B: Ca2* channel properties in
`Krenning EP, Valkema R, Kooij PP, Breeman
`neuroendocrine tumor cell cultures investi-
`Folkman J: Fundamental concepts of the an-
`WA, Bakker WH, de Herder WW,van Eijck
`gated by whole-cell patch-clamp technique.
`giogenic process. Curr Mol Med 2003;3:643-
`CH, Kwekkeboom DJ, de Jong M, Jamar F,
`651.
`Pauwels S: Therole ofradioactive somatostatin
`Ann NYAcadSci 2004;1014:137-139.
`41
`26
`Chaudhry A, Papanicolaou V, Oberg K, Heldin
`and its analogues in the control of tumor
`Detjen KM, Welzel M, WiedenmannB,Rose-
`CH, Funa K: Expression of platelet-derived
`wicz S: Nonsteroidal anti-inflammatory drugs
`growth. Recent Results Cancer Res 2000;153:
`1-13.
`growth factor and its receptors in neuroendo-
`inhibit growth of human neuroendocrine tu-
`crine tumors of the digestive system. Cancer
`Schmid HA, Schoeffter P: Functional activity
`morcells via G1 cell-cycle arrest. Int J Cancer
`2003; 107:844-853.
`Res 1992;52:1006-1012.
`of the multiligand analog SOM230 at human
`recombinant somatostatin receptor subtypes
`supports its usefulness in neuroendocrine tu-
`mors. Neuroendocrinology 2004;80(suppl1):
`47-50.
`
`36
`
`37
`
`38
`
`39
`
`40
`
`98
`
`Neuroendocrinology 2004;80(supp! 1):94-98
`
`Wiedenmann/Pape
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 005
`
`West-Ward Pharm.
`
`Exhibit 1052
`Page 005
`
`