A rapid rise in circulating pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours

This version was published on 1 November 2008

Ann Clin Biochem 2008;45:560-566
doi:10.1258/acb.2008.008033
© 2008 Association for Clinical Biochemistry

 

This Article
Right arrow
Abstract

Freely available
Right arrow
Figures Only
Right arrow

Full Text (PDF)

Right arrow
All Versions of this Article:

acb.2008.008033v1

45/6/560

most recent

Right arrow
Alert me when this article is cited
Right arrow
Alert me if a correction is posted
Services
Right arrow
Email this article to a friend
Right arrow

Similar articles in this journal

Right arrow
Similar articles in PubMed
Right arrow
Alert me to new issues of the journal
Right arrow
Download to citation manager
Right arrow
Citing Articles
Right arrow

Citing Articles via Web of Science (1)

Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow
Articles by Stronge, R L
Right arrow
Articles by Ardill, J E S
Right arrow Search for Related Content
PubMed
Right arrow
PubMed Citation
Social Bookmarking

What’s this?

Original Articles


R L Stronge1,
G B Turner2,
B T Johnston3,
D R McCance3,
A McGinty4,
C C Patterson5 and
J E S Ardill3


1 St George’s Hospital Medical School, University of London;
2 Altnagelvin Hospital, Londonderry;
3 Neuroendocrine Tumour Group, Royal Victoria Hospital;
4 School of Medicine;
5 Medical Statistics, Queen’s University, Belfast, UK


Corresponding author: Professor Joy Ardill. Email: joyardill{at}belfasttrust.hscni.net




Abstract

Go to previous sectionTop

 Abstract
Go to next sectionIntroduction

Go to next sectionSubjects and methods

Go to next sectionResults

Go to next sectionDiscussion

Go to next sectionACKNOWLEDGEMENTS

Go to next sectionREFERENCES

Aim: To assess the value of pancreastatin as a predictive factorfor identifying patients with neuroendocrine tumours (NETs)who respond poorly to somatostatin analogues.

Methods: A retrospective study of patients with NETs. Patient recordsfrom the Northern Ireland Neuroendocrine Tumour Register wereinterrogated. Those who had pancreastatin concentrations measuredon two or more occasions, before and during somatostatin analoguetherapy (within the set time-limits) were selected. Data relatingto diagnosis, surgery, somatostatin analogue therapy and survivaloutcome were noted. Data were subjected to univariate and multivariateanalysis using Cox proportional hazard model.

Results: Fifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical prognostic indicators were: tumour location (P < 0.001), pre-treatment pancreastatin (P < 0.001) and pancreastatin change (P < 0.001).

Conclusions: This study endorses the finding that pancreastatin is a usefulprognostic indicator of neuroendocrine disease. On commencementof treatment, one-third of the subjects showed an immediatenegative pancreastatin response to somatostatin analogues, whichwas associated with poor survival. This is the first study todocument such an association. These findings have significanttherapeutic consequences. In the presence of a rapidly risingpancreastatin alternative, treatment modalities should be sought.





Introduction

Go to previous sectionTop

Go to previous sectionAbstract

 Introduction
Go to next sectionSubjects and methods

Go to next sectionResults

Go to next sectionDiscussion

Go to next sectionACKNOWLEDGEMENTS

Go to next sectionREFERENCES

 

Neuroendocrine tumours (NETs) are a heterogeneous family of uncommon, generally slow-growing tumours derived from enterochromaffin cells. Depending on their primary site, NETs produce peptides and/or biogenic amines.1 Hypersecretion of these products may result in characteristic NET syndromes. In addition, NETs release a family of proteins known as the granins, the most important of which is chromogranin A (CgA).2 The granins and particularly CgA are found in increased quantities in endocrine tumour cells. The identification of CgA has been exploited both for diagnostic purposes and to assess response to treatment in patients with NETs.3 Circulating CgA concentrations are elevated in patients with various peptide-secreting NETs, with the highest concentrations in metastatic serotonin-secreting endocrine tumours of the ileum and colon (midgut carcinoid tumours). Elevated concentrations are also observed in functioning pancreatic tumours and in non-functioning tumours, and other NETs throughout the body.4,5 As well as beingraised in the circulation of patients with NETs, CgA is raisedin all conditions where there is an absence or suppression ofgastric acid secretion in the stomach. In normal healthy subjectsenterochromaffin-like (ECL) cells in the stomach are the maincontributors to CgA in the circulation. Where the acid negativefeed-back to gastrin is absent, because of autoimmune atrophicgastritis, H2 antagonist or proton-pump inhibitor therapy, gastrinrises and further stimulates the ECL cells to secrete increasedconcentrations of CgA.

Pancreastatin is a 49 amino acid, post-translational processing product of CgA (CgA 240–288). Before the complete sequence of CgA had been elucidated and CgA whole molecule assays were not available, pancreastatin was used as a surrogate marker for CgA in cells and in the circulation.6 Circulating pancreastatin concentrations are elevated in patients with NET when the tumour has metastasized to the liver and concentrations are proportional to hepatic tumour burden.7,8 Some pancreastatin assays thatare mid-molecule-specific cross-react strongly with CgA. However,assays that are specific to the N- or C- terminus of pancreastatinmeasure only the post-translational product of CgA, pancreastatin.Therefore, assays that are specific to pancreastatin may beused for the advantage of patients with NETs. Pancreastatindoes not show a rise in patients who are hypo- or achlorhydriac.Pancreastatin assay is used routinely along with whole moleculeCgA assay in both the referral laboratories in the UK (SAS Laboratory,Department of Endocrinology and Diabetes, Hammersmith Hospital,DuCane Road, London and Regional Regulatory peptide Laboratory,Kelvin Building, Royal Victoria Hospital, Belfast, UK). In Belfast,pancreastatin assay is used to assess the extent of liver diseasein NET patients.

Somatostatin analogues provide symptomatic relief from NET syndromes in more than 60% of patients and form the mainstay of palliative management. Somatostatin analogues act by binding with specific somatostatin receptors (SSTs) located in target tissues. SST receptors are usually found in high density in NETs, which possess up to 100 times more SST receptors than normal tissue.9 The inhibitory effects of somatostatin, mediated by SSTs, are a result of several mechanisms including: inhibition of adenyl cyclase leading to a reduction of intracellular cyclic AMP concentrations; a reduction of intracellular concentrations of Ca2+ because of decreased influx of Ca2+; and stimulation of tyrosine phosphatase activity.10 SST analogues may also inhibit cell growth11 where the antiproliferative action of SST analogues is mediated by the arrest of G1 cell cycle, which activates different signaltransduction pathways depending on the receptor subtype.

The hypothesis of this study was that pancreastatin would bea useful predictive factor identifying patients who respondpoorly to SST analogues.





Subjects and methods

Go to previous sectionTop

Go to previous sectionAbstract

Go to previous sectionIntroduction

 Subjects and methods
Go to next sectionResults

Go to next sectionDiscussion

Go to next sectionACKNOWLEDGEMENTS

Go to next sectionREFERENCES

 

Approval was obtained for this research from the Research EthicsCommittee of Queen’s University, Belfast.


Data collection

Any patient diagnosed as having two or more pancreastatin measurementsrecorded on the NET register at the Regional Regulatory PeptideLaboratory, Belfast and who had been treated with an SST analoguefor relief of symptoms, was considered for inclusion. Both pre-and during treatment circulating pancreastatin measurementswere required for inclusion and patients were excluded if thetime between pre-treatment pancreastatin measurement and treatmentcommencement exceeded six months. Pancreastatin measurementsduring treatment were recorded for one year after the commencementof SST analogues. To provide adequate survival data subjectsmust have commenced SST analogue treatment at least two yearsbefore the completion of the study. Patients were followed uptill death or till the end date of the study, whichever camefirst.

Subjects were restricted to those with NETs of the pancreas, foregut (including those of the broncho-pulmonary tract) and ileum or colon. Patients with multiple endocrine neoplasia type 1 (MEN1) or NETs of the appendix were excluded because of the very different disease courses expected in these patients. Only patients with clinical manifestations were included, as all patients were treated with SST analogues for symptom control. All patients had metastatic disease and tumour burden was recorded (number of liver metastases and lymph node metastases). Patients who had previous medical anti-proliferative treatment (including alpha-interferon, radio nucleotide targeted therapy, hepatic artery embolization or liver de-bulking) were excluded. Previous surgical reduction of a NET primary did not exclude patients from the study and this information was recorded. All pathology reports from tumour biopsies were assessed and only those with highly differentiated metastatic endocrine tumours were included. This was recorded where Ki67 had been measured. Ki67 is a measure of proliferative index in tumour cells. Highly differentiated NET cells typically have a very low Ki67, <3%, and this is associated with much better survival than those with Ki67 >3%. All subjects were treated with either Octreotide (Sandostatin® or Sandostatin LAR) or Lanreotide (Somatuline LA® or Somatuline Autogel®). All patients received only one analogue betweenthe pre- and during treatment pancreastatin measurements. Timelapse between diagnosis and treatment with SST analogues werealso recorded.


Pancreastatin assay

Circulating pancreastatin was measured in extracts of plasma using an in-house radioimmunoassay. Antibodies were raised in rabbit to synthetic human pancreastatin 39–49 coupled to albumin. Antibodies were specific to the C-terminal region of pancreastatin and cross-reaction with total intact CgA was minimal (<7%). Radiolabelled pancreastatin was prepared using the chloramine-T method. 125I was incorporated into tyr-0 pancreastatin 39–49 (Queen’s University, Belfast) and products were purified using high-performance liquid chromatography (HPLC). Standard pancreastatin preparations were prepared from synthetic porcine pancreastatin (33–49) (Bachem UK Ltd, Delphi Court, Sullivan Way, St Helens, UK). Separation of antibody-bound and unbound pancreastatin was made using dextran-coated charcoal.12 Internal quality control was maintained by including three sample pools with pancreastatin concentrations within the reference range and three pooled patient samples in the pathological range. In addition, there has also been a sample exchange between the Belfast and Hammersmith Laboratories (Proceedings of the UKINETS National Scientific Meeting December 2006). There is no external quality assurance scheme for pancreastatin. Co-efficient of inter-assay variation was quoted as 3.5–13.5% over the range 12–80 pmol/L and intra-assay variation as 8.5–14.0% over the same range. The reference range for pancreastatin assay was 0–25 pmol/L, established in a group of 100 normal healthy subjects (male 50, female 50) in the age range of 20–70 years. This laboratory has shown no change in pancreastatin concentrations with age. Pancreastatin is elevated in patients with NETs who have liver metastases, median 78 pmol/L (range 25–1850 pmol/L, n = 35) and is 12 pmol/L (range 2–22 pmol/L, n = 35) in patients with NETs and lymph node metastases.


Statistical methods

Data were collected on an Excel 2000 spreadsheet and several initial calculations were performed in Excel: age at diagnosis, time between initial pancreastatin measurement and commencement of somatostatin analogue therapy, time between somatostatin analogue therapy and follow-up pancreastatin measurement and survival (measured from the start of therapy). Patients were followed up to a fixed date a minimum of two years post-treatment or death. Data were transferred to SPSS version 11 for Windows (SPSS Inc., Chicago, IL, USA) for further statistical analysis. Univariate survival analysis was performed using Kaplan-Meier survival plots. The following data were analysed: pre-treatment pancreastatin concentration, change in pancreastatin concentration following treatment (during to pre-treatment pancreastatin ratio), age, primary tumour site and surgical resection of the primary tumour. As pancreastatin concentration showed a positive skew, a logarithmic transformation was applied prior to analysis. Comparison of survival between groups was made using a log-rank test. Covariates identified as either having an influence, or being expected to have an influence on survival by univariate analysis was analysed using Cox proportional hazards model. These included age at commencement of treatment, pre-treatment pancreastatin, post- to pre-treatment pancreastatin ratio, site of primary tumour and resection of the primary tumour. P value<0.05 was regarded as significant.





Results

Go to previous sectionTop

Go to previous sectionAbstract

Go to previous sectionIntroduction

Go to previous sectionSubjects and methods

 Results
Go to next sectionDiscussion

Go to next sectionACKNOWLEDGEMENTS

Go to next sectionREFERENCES

 

Fifty-nine patients (33 men and 26 women) registered with the Northern Ireland Neuroendocrine Tumour Register fulfilled the criteria and were included in the study. In 57 patients, the diagnosis of NET was confirmed histologically and in two diagnosis was made from positive somatostatin analogue scintigraphy, increased urinary 5-hydroxy indole acetic acid (5HIAA), CgA and neurokinin A with classical carcinoid features of diarrhoea and flushing. All patients who were included had positive somatostatin receptor scintigraphy. All those included had metastatic disease and all histologically proven tumours were highly differentiated endocrine tumours. The characteristics of the study group are recorded in Table 1. All patients were treated with somatostatinanalogues for the relief of symptoms. Delay between diagnosisand treatment varied greatly. In 14 of the 29 patients withtumours of the ileum or proximal colon, there was a delay of1–24 years between tumour resection and commencement ofsomatostatin analogue therapy during which time the patientswere symptom-free.



View this table:
[in this window]
[in a new window]
Table 1 Characteristics of study group

 

Median pancreastatin concentration prior to treatment was 90pmol/L (range 5–8640 pmol/L). In 16 patients (27%), pancreastatinconcentration was within reference range before treatment (<25pmol/L). There was a strong correlation between tumour burdenand pre-treatment circulating pancreastatin. Median during-treatmentpancreastatin concentration was 75 pmol/L (range 5–13,500pmol/L). Median survival was 3.7 years from the start of somatostatintherapy.

Of the 59 subjects, 39 (66%) showed a favourable response tosomatostatin analogue therapy with respect to circulating pancreastatinconcentrations. Median pre-treatment circulating pancreastatinwas 130 pmol/L (range 95–8,640 pmol/L). In nine patients(15%), pre-treatment concentrations were within the referencerange. Median during-treatment pancreastatin was 35 pmol/L (range5–3670 pmol/L). Of these, 29 patients had tumours of theileum or proximal colon, of the lung (4), pancreas (3), gastrinoma(2), gastric (1), thymic (1), mesenteric (1) and of unknownorigin (2). Clinical symptoms were initially alleviated in 31of 39 patients. Median survival was 5.7 years.

In 11 of the 59 subjects (19%), a significant rise in pancreastatinconcentration during treatment was observed (between 1.5 and5 times pre-treatment concentrations). Within this sub-group,median pre-treatment pancreastatin concentration was 50 pmol/L(range 10–920 pmol/L) and three of the 11 (27%) were withinthe reference range. Median during treatment pancreastatin concentrationwas 112 pmol/L (range 20–1,620 pmol/L). Eight of thesepatients had a primary tumour in the ileum or proximal colonand three in the pancreas (one each of insulinoma, Vipoma andglucagonoma). Clinical symptoms were initially alleviated innine of 11 patients. Median survival was 1.7 years.

Nine patients (15%) who had a tumour of the ileum or proximalcolon (7), lung (1) and pancreas (1 gastrinoma) showed a dramaticrise in pancreastatin concentrations following treatment (greaterthan five-fold increase). Median pre-treatment and during-treatmentconcentrations were 30 pmol/L (range 10–1190 pmol/L) and1295 pmol/L (range 145–13,500 pmol/L), respectively. Four(44.4%) of the nine had a pre-treatment measurement within thereference range. Clinical symptoms were initially alleviatedin six of nine patients. Median survival in this group was 0.3years.

Circulating pancreastatin concentrations, pre- and during-treatment, in the three groups described above are shown in Figure 1.Pancreastatin concentrations are shown on a logarithmic scale.



View larger version (15K):
[in this window]
[in a new window]
Figure 1 Change in circulating pancreastatin pre- to during-treatment with somatostatin analogues (SST)


Univariate analysis

For initial assessment of the association between pre-treatmentpancreastatin concentration and survival, the patients weredivided into three groups of approximately equal size; pancreastatin<50, 50–499 or >500 pmol/L. Change in pancreastatinconcentration with somatostatin analogue treatment was alsodivided into three groups: those whose pancreastatin fell orshowed no significant change, those with a significant risebut whose during-treatment to pre-treatment ratio was less thanfive-fold and those with a very significant rise (five-foldor greater). The prognostic value of the following variableswas then assessed using log-rank tests supplemented by Kaplan-Meiersurvival plots: age group, primary tumour location, previoussurgical resection of the primary tumour, pre-treatment pancreastatinconcentration, ratio of during- to pre-treatment pancreastatinconcentration and surgical resection. Type of treatment (Octreotideversus Lanreotide), could not be analysed as there was considerablecross-over of treatment between the during-treatment pancreastatinmeasurement and eventual outcome.

Pre-treatment pancreastatin concentration did not demonstrate significant differences in outcome ({chi}2 = 2.088, P = 0.352). Age,resection of the primary tumour, change in pancreastatin concentrationpost-treatment and tumour site all made a significant impacton outcome. Resection of the primary tumour is frequently associatedwith less advanced, therefore operable disease.

During- to pre-treatment pancreastatin ratio {chi}2 was 24.364, P < 0.001 and tumour site {chi}2 was 10.36, P = 0.006. Kaplan-Meier plots showing survival differences by change in pancreastatin concentration during treatment and primary tumour are shown in Figures 2 and 3, respectively.



View larger version (10K):
[in this window]
[in a new window]
Figure 2 Kaplan-Meier plot of cumulative survival against the change in pancreastatin (during-treatment:pre-treatment pancreastatin ratio). Solid line denotes reduced or no change; dashed line denotes 1.5-fold to five-fold increase; dotted line denotes >five-fold increase: (blot denotes censored). {chi}2 = 24.364 (P < 0.001)



View larger version (10K):
[in this window]
[in a new window]
Figure 3 Kaplan-Meier plot of cumulative survival against primary tumour site. Solid line denotes midgut carcinoid tumours; dashed line denotes broncho-pulmonary tumours and dotted line denotes pancreatic tumours (blot = censored). {chi}2 = 10.36 (P = 0.006)


Multivariate analysis

Primary tumour site, resection of the primary tumour and changein pancreastatin concentration following treatment were selectedfor multivariate analysis and were entered into a Cox proportionalhazards model. In addition, age and pre-treatment pancreastatinconcentration, although not significant in univariate analysisin this data-set, have been found to be indicators of poor prognosisin other studies and were therefore also included in the model.

There was a highly significant difference in survival outcome between the three tumour locations (P = 0.001) (Table 2). Tumours of the ileum and colon had the most favourable outcome followed by broncho-pulmonary and then by pancreatic tumours. The effect of pre-treatment pancreastatin concentration on survival was also significant (P = 0.04) with higher concentrations being associated with a poorer outcome. Change in pancreastatin following treatment was a highly significant prognostic indicator in the group (P < 0.001). An up to five-fold rise in pancreastatinduring treatment indicated a significantly poorer outcome (hazardratio [HR] 3.5) and a rise of greater than five times indicatedan even poorer prognosis (HR of 17.3). The negative survivaleffects of increasing age or lack of surgical resection didnot reach statistical significance.



View this table:
[in this window]
[in a new window]
Table 2 Cox model results in 59 patients with neuroendocrine tumours

 

In a further analysis, the sub-grouping of pancreastatin concentrations was removed and pre-treatment concentrations and during-treatment to pre-treatment ratios were included in the Cox regression model after both had been logarithmically transformed to render them less heavily skewed. Although pre-treatment concentrations and during-treatment to pre-treatment ratios were correlated, each made a highly significant contribution to the model independent of the other (P < 0.001). A 10-fold increase in pre-treatmentpancreastatin concentration was associated with a HR of 3.6(95% confidence interval [CI] 1.8, 7.3) while a 10-fold increasein during-treatment to pre-treatment ratio was associated witha HR of 5.5 (95% CI 3.0, 10.2).

Analysis of patients with tumours of the ileum and colon aloneshowed similar results for pre-somatostatin analogue pancreastatin,but the overall comparison of the three groups was no longersignificant. For during- to pre-ratio ‘significant’and ‘very significant’ rises were associated withlower HRs than before and only the latter was significant. Whenanalysed as continuous variables on log scale, both pre-therapypancreastatin and during- to pre-pancreastatin ratios remainedsignificant (HRs 3.5 and 4.3, respectively, compared with 3.6and 5.5 in the full data set). Age and surgical resection werenot associated with a significant effect on survival in thissubgroup.





Discussion

Go to previous sectionTop

Go to previous sectionAbstract

Go to previous sectionIntroduction

Go to previous sectionSubjects and methods

Go to previous sectionResults

 Discussion
Go to next sectionACKNOWLEDGEMENTS

Go to next sectionREFERENCES

 

In this study, an elevated pre-treatment plasma pancreastatin concentration was found to be a significant indicator of poor outcome. When pancreastatin is >500 pmol/L at presentation, this is an independent indicator of poor outcome. This finding is in agreement with data from other groups both for pancreastatin and whole molecule CgA.7,8,13 As pancreastatin is known to correlatewith the number of liver metastases, it may be used as an indicatorof the progression of metastatic disease in patients with NETs.

Although reports have indicated that the majority of patients with carcinoid syndrome and pancreatic NETs show a clinical response to somatostatin analogues,14 no study to date has demonstrateda negative response to treatment. This is the first study toshow a paradoxical rise in a biochemical tumour marker in responseto treatment with somatostatin analogues in a group of patientswith highly differentiated NETs. In the present study, 20 (40%)of the 59 patients showed a significant rise in pancreastatinwithin one year (1–42 weeks) of commencing somatostatinanalogue treatment. This rise in circulating pancreastatin duringtherapy was associated with a worse survival when compared withthose patients who showed positive or neutral biochemical response.This finding was substantiated by a graded response that wasillustrated by the sub-groups imposed on the data, which showedthat those patients with higher during- to pre-pancreastatinratio showed poorer survival. The reasons for these findingsare unclear. Some patients who showed a negative response totreatment with respect to pancreastatin had advanced disease,but likewise some who responded well also had advanced disease.Also some patients in all groups had a small amount of diseaseduring the commencement of treatment and their response to treatmentwas not predictable from the tumour bulk according to radiologyfindings or pre-treatment pancreastatin concentrations. Nine(15%) of 59 patients who showed a fall or steady pancreastatinduring treatment had pre-treatment concentrations within thereference range (survival 5.7 years in this group), three (27%)of 11 who showed a significant rise had pre-treatment concentrationswithin the reference range (survival 1.7 years) and four ofnine patients who showed a highly significant rise had pre-treatmentconcentrations within the reference range (survival 0.3 years).The association between a rapidly rising circulating pancreastatinin response to somatostatin analogue treatment and poor outcomewas more highly significant than the association between elevatedpre-treatment pancreastatin and poor outcome. This may suggestthat patients with a rapidly rising pancreastatin were in, orentered a tumour phase with rapid tumour progression. Whetherthis was spontaneous or in response to treatment is not clear.

It has been reported that an elevated proliferative index assessed by Ki67 indicated poor prognosis in NETs.15 Patients with high Ki67 are expected to show a poor response to somatostatin analogues and guidelines recommend the use of other treatment modalities.16 However, a single report of high-dose treatment with somatostatin analogues in patients with advanced midgut carcinoid tumours has shown tumour stabilization in 75% of patients with a reduction of Ki67 in 25%.17 At the time of referral, patients frequentlyconsent for liver biopsy. For these and for those who undergosurgery, Ki67 was assessed. However, it is uncommon if not unethicalfor patients to undergo repeated biopsy; therefore, Ki67 isnot readily accessible for assessment of tumour change and mostunits rely on radiology along with tumour markers and peptidebiochemistry to assess tumour progression. Ki67 had been measuredin only a small number of the subjects in this study (18 of59) within the time limits, and was raised (>3%) in onlyone pancreatic tumour.

Another potential mechanism for poor response to somatostatin analogue therapy is that somatostatin analogues may be implicated in the regulation of oncogenes or tumour-suppressor genes.17 The tumour suppressor gene, Zac1, is essential for the anti-proliferative action of somatostatin. It has been shown that knocking-out Zac1 abolishes the inhibitory action of somatostatin analogues.

NETs express a high density of somatostatin receptors for whichsomatostatin analogues have high affinity, particularly receptorSST2. Altered regulation of receptors or the expression of differentreceptor subtypes in this sub-group of patients may contributeto the unexpected negative response to somatostatin analoguesin some patients. All patients however had positive somatostatinreceptor scintigraphy, which relies on the same receptor sub-types.

In summary, this study supports the finding that pancreastatinis a useful prognostic indicator of neuroendocrine disease.Further, in more than one-third of subjects a negative biochemicalresponse to somatostatin analogues therapy was observed andwas associated with poor survival outcome. This is the firststudy to identify such a correlation and should be followedup with a prospective study in order to substantiate these findings.Given that the described biochemical response can be identifiedat an early stage of treatment, these findings have significanttherapeutic consequences and may be used to identify patientswho are not responding to somatostatin analogue therapy evenwhen symptoms are relieved. In the presence of a rapidly risingpancreastatin other treatment modalities should be sought withurgency.

 

 

 

 

 




ACKNOWLEDGEMENTS

Go to previous sectionTop

Go to previous sectionAbstract

Go to previous sectionIntroduction

Go to previous sectionSubjects and methods

Go to previous sectionResults

Go to previous sectionDiscussion

 ACKNOWLEDGEMENTS
Go to next sectionREFERENCES

 

This project was supported by a Wellcome Foundation ElectivePrize and a studentship with The School of Medicine, Queen’sUniversity, Belfast.

(Accepted March 3, 2008)



REFERENCES

Go to previous sectionTop

Go to previous sectionAbstract

Go to previous sectionIntroduction

Go to previous sectionSubjects and methods

Go to previous sectionResults

Go to previous sectionDiscussion

Go to previous sectionACKNOWLEDGEMENTS

 REFERENCES


  1. Warner RRP. Enterendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology 2005;128:1668–84[Medline]
  2. Portela-Gomes GM, Stridsberg M, Johansson H, Wilander E, Grimelius L. Chromogranin A in human neuroendocrine tumors: an immunohistochemical study with region-specific antibodies. Am J Surg Pathol 2001;25:1261–7[Medline]
  3. O’Connor DT, Deftos LJ. Secretion of chromogranin A by peptide-producing endocrine neoplasms. N Engl J Med 1986;314:1145–51[Abstract]
  4. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors. Analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997;8:685–90[Abstract/Free Full Text]
  5. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion 2000;62:33–8[Medline]
  6. Ardill J. Gut hormone peptide markers for endocrine tumours (NETs) of the gastroenteropancreatic (GEP) tract. Ann Clin Biochem 2008, in press.
  7. Turner GB, Johnston BT, McCance DR, et al. Circulating markers of prognosis and response to treatment in patients with midgut carcinoid tumours. Gut 2006;55:1586–91[Abstract/Free Full Text]
  8. Calhoun K, Toth-Fejel S, Cheek , Pommier RI. Serum peptide profiles in patients with carcinoid tumours. Am J Surg 2003;186:28–31[Medline]
  9. Delle Fave G, Corleto VD. Oncogenes, growth factors, receptor expression and proliferation markers in digestive neuroendocrine tumours. A critical reappraisal. Ann Oncol 2001;12(Suppl. 2):S13–7[Abstract/Free Full Text]
  10. De Herder WW, Lamberts SWJ. Somatostatin and somatostatin analogues: diagnostic and therapeutic uses. Curr Opin Oncol 2002;14:53–7[Medline]
  11. Froidevaux S, Eberle AN. Somatostatin analogs and radiopeptides in cancer therapy. Biopolymers 2002;66:161–83[Medline]
  12. McGrath-Linden SJ, Johnston CF, O’Connor DT, Shaw C, Buchanan KD. Pancreastatin-like immunoreactivity in human carcinoid disease. Regul Pept 1991;33:55–70[Medline]
  13. Tateishi K, Kitayama N, Matsuoka Eunakoski A. Comparison of chromogranin A and pancreastatin levels in plasma of patients with pancreatic islet cell tumor. Life Sci 1995;57:889–95[Medline]
  14. Faiss S, Pape UF, Boehmig M, et al. Prospective, randomised, multicenter trial on the antiproliferative of lanreotide, interferon alfa and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors – the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003;21:2689–96[Abstract/Free Full Text]
  15. Chaudhry A, Oberg K, Wilander E. A study of biological behaviour based on the expression of a proliferating antigen in neuroendocrine tumours of the digestive system. Tumor Biol 1992;13:27–35
  16. Falconi M, Plockinger U, Kwekkeboom DJ, et al. Well differentiated pancreatic non-functioning tumours/carcinoma. Neuroendocrinol 2006;84:196–211[Medline]
  17. Lubomiershi N, Kersting M, Bert T, et al. Suppressor genes in the 9p21 Gene Cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumours. Cancer Res 2001;61:5905–10[Abstract/Free Full Text]


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What’s this?






This Article
Right arrow
Abstract

Freely available
Right arrow
Figures Only
Right arrow

Full Text (PDF)

Right arrow
All Versions of this Article:

acb.2008.008033v1

45/6/560

most recent

Right arrow
Alert me when this article is cited
Right arrow
Alert me if a correction is posted
Services
Right arrow
Email this article to a friend
Right arrow

Similar articles in this journal

Right arrow
Similar articles in PubMed
Right arrow
Alert me to new issues of the journal
Right arrow
Download to citation manager
Right arrow
Citing Articles
Right arrow

Citing Articles via Web of Science (1)

Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow
Articles by Stronge, R L
Right arrow
Articles by Ardill, J E S
Right arrow Search for Related Content
PubMed
Right arrow
PubMed Citation
Social Bookmarking

What’s this?