Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry.

PURPOSE: Epidemiological studies on neuroendocrine tumours (NETs) generally show a major increase in incidence. To investigate this increase, epidemiological data from the Netherlands were evaluated according to histological grade. METHODS: All 47,800 patients with NET (diagnosed 1990-2010) from the population-based Netherlands Cancer Registry were stratified according to the latest World Health Organization (WHO) classification for the digestive system: well-differentiated NET grade 1 and 2 (G1NET and G2NET), and poorly differentiated (grade 3) neuroendocrine carcinoma, subdivided into large cell (G3-LCNEC) and small cell (G3-SCNEC). RESULTS: The age-standardised incidence rate (excluding G3-SCNEC) increased from 2.1/100,000 in 1990 to 4.9/100,000 in 2010. The incidence of G1NET increased from 2.0 to 3.0; there was a large increase in G2NET from 0.01 in 1990 to 0.2 in 2010, and of the G3-LCNEC from 0.01 to 1.8, respectively. In G3-SCNEC incidence in men decreased from 21.3 to 10.1, whereas in women it increased from 4.5 to 7.7. The 5-year survival improved in G1NET, particularly for metastatic disease, from 30% in 1990-2000 to 47% in 2001-2010. CONCLUSION: The increasing incidence of NET (without G3-SCNEC) was mainly due to the increase of G3-LCNEC. This increase is related to improved diagnostic procedures and to shifting in pathology from other entities (such as undifferentiated carcinoma) to NET. Improved survival was seen in all sites and stages, especially in patients with metastatic G1NET. Because of its influence on incidence and survival, we recommend to present epidemiological studies on NET according to histological classification.

Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments.

BACKGROUND: Chromogranin A (CgA) is the most important tumour marker for well-differentiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differentiated neuroendocrine carcinoma (NEC). This study investigated whether the markers progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and CK19 (MonoTotal) can be of additional value to the histological classification and help predict survival in these patients. METHODS: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET (G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteristics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox regression analyses. RESULTS: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively) when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivariate survival analysis, only CKfr was associated with survival (P<0.0001) for patients with well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC, both CKfr and NSE were associated with survival (P<0.0001 and P=0.003, respectively). CONCLUSION: Within all histological groups a combination of tumour markers proved to be more informative as diagnostic and prognostic marker than each marker alone. In patients with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in patients with SCNEC, proGRP and CKfr are preferred.

Somatostatin receptor scintigraphy and chromogranin A assay in staging and follow-up of patients with well-differentiated neuroendocrine tumors.

INTRODUCTION: Chromogranin A (CgA) assay and somatostatin receptor scintigraphy (SRS) are implemented in the standard workup of neuroendocrine tumors (NETs). The aim of this study was to assess the value of SRS and CgA in staging and follow-up patients with well-differentiated NETs. MATERIALS AND METHODS: A total of 88 consecutive patients with histologically confirmed well-differentiated NETs were included. General data such as sex, age, site of primary tumor and metastases, medication, and follow-up results, including CgA values, were gathered. The number of lesions on SRS were scored and categorized from 0 to 3 and the uptake was scored from 0 to 4. RESULTS: CgA values differed significantly between patients with and without clinical symptoms (P=0.028), a positive and negative SRS (P=0.005), the different SRS scores (P=0.002), the number of lesions (P=0.001), and the presence or absence of liver metastasis (P=0.003). The sensitivity, specificity, positive predictive value, and negative predictive value were 78, 93, 98, and 47% for SRS and 62, 100, 100, and 35% for CgA; however, by combining the test, all results improved. All patients (n=11) referred for routine follow-up had stable CgA values, whereas in one patient only the SRS score increased. In the group of patients with a suspicion on tumor progression during follow-up (n=14), CgA values increased in nine patients. In this group, the SRS score increased in two patients. CONCLUSION: Despite the higher sensitivity of SRS than of CgA in staging and restaging well-differentiated NETs, both tests are required at the initial stage. Disease extent, symptoms, and liver metastasis have an impact on both SRS results and CgA values. CgA has an important value in the assessment of tumor progression during follow-up, whereas the role of SRS in the routine follow-up of well-differentiated NETs is limited.

Increase of angiogenic growth factors after hepatic artery embolization in patients with neuroendocrine tumours.

In the event of diffuse hepatic metastases, hepatic artery embolization (HAE) can be a successful treatment option in patients with well-differentiated neuroendocrine tumours (NET). However, embolization causes hypoxia which stimulates angiogenesis and therefore tumour growth. This study investigates angiogenesis activity following HAE by measuring vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and C-terminal proendothelin-1 (proET-1) in blood. Twelve patients with well-differentiated NET and liver metastases underwent HAE. VEGF, ET-1 and proET-1 were measured before embolization and the days following treatment during hospitalization. Mean levels during treatment were compared with those at baseline. From 12 patients, 90 blood samples were obtained before and daily for 8 days following HAE. Mean (± SE) VEGF level at baseline was 116 (± 33)ng/l which increased after HAE to 313 (± 46)ng/l at day 6, followed by a gradual decrease. ProET-1 showed a similar pattern, with a mean baseline level of 9.2 (± 2.0)pmol/l and the highest level of 40.8 (± 5.7)pmol/l at day 6. Some fluctuations were observed for ET-1, with maximum levels at day 3 compared to baseline levels. In patients with well-differentiated NET who underwent hepatic arterial embolization, angiogenic growth factors increase temporarily. This implies a need to investigate the effect of anti-angiogenic drugs as an adjuvant therapy to embolization.

Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor.

PURPOSE: For the last decade chromogranin-A (CgA) has been a well-established marker for neuroendocrine tumor (NET), and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been a useful marker for left ventricular dysfunction. This study examined the diagnostic value of CgA and NT-proBNP for carcinoid heart disease (CHD), and their prognostic value for overall survival in NET patients. PATIENTS AND METHODS: Serum samples were obtained and cardiac ultrasound studies performed in 102 NET patients. The criterion for mild and severe CHD was tricuspid regurgitation stage I/II and III/IV, respectively. Proportional odds and Cox proportional hazards models were constructed respectively to identify the association between CHD and overall survival with patient characteristics and the two markers. RESULTS: Severe CHD was found in 15 (15%) of 102 patients, 13 of whom had elevated NT-proBNP levels. In the univariate proportional odds model CHD was correlated with age (P = .007), CgA (P = .002), and NT-proBNP (P < .001), whereas in the multivariate model NT-proBNP and CgA were significantly associated with CHD (P < .001 and P = .01). In the univariate Cox models, age (P = .04), sex (P = .03), CgA (P = .003), and NT-proBNP (P = .04) were related to overall survival, and in the multivariate model CgA and NT-proBNP remained significantly related to overall survival (P = .002 and P = .04, respectively). CONCLUSION: NT-proBNP and CgA are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.

Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors.

BACKGROUND: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumors (NETs), but it has a low sensitivity and the 24-hour collection is inconvenient for patients. Chromogranin A (CgA) is a promising marker, but a thorough evaluation during follow-up is still lacking. METHODS: 39 patients with metastatic gastrointestinal NETs were monitored during treatment with the long-acting octreotide SandostatinLAR. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. RESULTS: Correlations were found between CgA and physical functioning (p = 0.01) and quality of life (p = 0.03), while no significant correlations were observed between 5-HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p = 0.02), while no significant association was observed between 5-HIAA levels and survival time. CONCLUSION: Stronger correlations of CgA compared to 5-HIAA with physical functioning and wellbeing, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NETs.

Dynamic Bayesian networks as prognostic models for clinical patient management.

Prognostic models in medicine are usually been built using simple decision rules, proportional hazards models, or Markov models. Dynamic Bayesian networks (DBNs) offer an approach that allows for the incorporation of the causal and temporal nature of medical domain knowledge as elicited from domain experts, thereby allowing for detailed prognostic predictions. The aim of this paper is to describe the considerations that must be taken into account when constructing a DBN for complex medical domains and to demonstrate their usefulness in practice. To this end, we focus on the construction of a DBN for prognosis of carcinoid patients, compare performance with that of a proportional hazards model, and describe predictions for three individual patients. We show that the DBN can make detailed predictions, about not only patient survival, but also other variables of interest, such as disease progression, the effect of treatment, and the development of complications. Strengths and limitations of our approach are discussed and compared with those offered by traditional methods.

Selecting treatment strategies with dynamic limited-memory influence diagrams.

OBJECTIVE: The development of dynamic limited-memory influence diagrams as a framework for representing factorized infinite-horizon partially observable Markov decision processes (POMDPs), the introduction of algorithms for their (approximate) solution, and the application to a dynamic decision problem in clinical oncology. MATERIALS AND METHODS: A dynamic limited-memory influence diagram for high-grade carcinoid tumor pathophysiology was developed in collaboration with an expert physician. Three algorithms, known as single policy updating, single rule updating, and simulated annealing have been examined for approximating the optimal treatment strategy from a space of 10(19) possible strategies. RESULTS: Single policy updating proved intractable for finding a treatment strategy for carcinoid tumors. Single rule updating and simulated annealing both found the treatment strategy that is applied by physicians in practice. CONCLUSIONS: Dynamic limited-memory influence diagrams are a suitable framework for the representation of factorized infinite-horizon POMDPs, and the developed algorithms find acceptable solutions under the assumption of limited memory about past observations. The framework allows for finding reasonable treatment strategies for complex dynamic decision problems in medicine.

Predicting carcinoid heart disease with the noisy-threshold classifier.

OBJECTIVE: To predict the development of carcinoid heart disease (CHD), which is a life-threatening complication of certain neuroendocrine tumors. To this end, a novel type of Bayesian classifier, known as the noisy-threshold classifier, is applied. MATERIALS AND METHODS: Fifty-four cases of patients that suffered from a low-grade midgut carcinoid tumor, of which 22 patients developed CHD, were obtained from the Netherlands Cancer Institute (NKI). Eleven attributes that are known at admission have been used to classify whether the patient develops CHD. Classification accuracy and area under the receiver operating characteristics (ROC) curve of the noisy-threshold classifier are compared with those of the naive-Bayes classifier, logistic regression, the decision-tree learning algorithm C4.5, and a decision rule, as formulated by an expert physician. RESULTS: The noisy-threshold classifier showed the best classification accuracy of 72% correctly classified cases, although differences were significant only for logistic regression and C4.5. An area under the ROC curve of 0.66 was attained for the noisy-threshold classifier, and equaled that of the physician's decision-rule. CONCLUSIONS: The noisy-threshold classifier performed favorably to other state-of-the-art classification algorithms, and equally well as a decision-rule that was formulated by the physician. Furthermore, the semantics of the noisy-threshold classifier make it a useful machine learning technique in domains where multiple causes influence a common effect.

Colorectal cancer in the family: psychosocial distress and social issues in the years following genetic counselling.

BACKGROUND: This study examined: (1) levels of cancer-specific distress more than one year after genetic counselling for hereditary nonpolyposis colorectal cancer (HNPCC); (2) associations between sociodemographic, clinical and psychosocial factors and levels of distress; (3) the impact of genetic counselling on family relationships, and (4) social consequences of genetic counselling. METHODS: In this cross-sectional study, individuals who had received genetic counselling for HNPCC during 1986-1998 completed a self-report questionnaire by mail. RESULTS: 116 individuals (81% response rate) completed the questionnaire, on average 4 years after the last counselling session. Of all respondents, 6% had clinically significant levels of cancer-specific distress (Impact of Event Scale, IES). Having had contact with a professional psychosocial worker for cancer risk in the past 10 years was significantly associated with higher levels of current cancer specific distress. Only a minority of the counselees reported any adverse effects of genetic counselling on: communication about genetic counselling with their children (9%), family relationships (5%), obtaining life insurance (8%), choice or change of jobs (2%), and obtaining a mortgage (2%). CONCLUSION: On average, four years after genetic counselling for HNPCC, only a small minority of counselled individuals reports clinically significant levels of distress, or significant family or social problems.

Detection of small-bowel neuroendocrine tumors by video capsule endoscopy.

OBJECTIVES: Carcinoid tumors are the most common GI neuroendocrine tumors (NET). They often originate in the small intestine. The primary tumor is often difficult to locate, and resection in an early phase is recommended to prevent complications. This study evaluated the value of videocapsule endoscopy (VCE) in the detection of small-intestinal primary carcinoid tumor. DESIGN: Prospective descriptive study. SETTING: Tertiary referral center. PATIENTS: Twenty consecutive patients (13 men, 7 women; 60.5 +/- 9.3 years) with metastatic NET of unknown primary tumor. INTERVENTIONS: All patients underwent CT, enteroclysis, nuclear imaging, and VCE of the small bowel. RESULTS: CTs and enteroclysis did not detect a primary small-intestinal carcinoid tumor. Nuclear imaging demonstrated abnormalities in the abdominal area in 13 patients but was unable to relate this to an intestinal localization in any patient. VCE revealed a small-intestinal tumor in 9 patients. Three other patients showed external compression and erosions. At surgery, 5 patients had a small-intestinal carcinoid tumor, and, in 2 patients, a small-intestinal ischemic segment was present. LIMITATIONS: The number of false-positive VCE findings was not clear, because not all patients underwent surgery. The absence of abnormalities at VCE in patients with abnormalities at nuclear imaging might be related to the presence of carcinoid tumor restricted to the mesenterium or to a false-negative VCE. CONCLUSIONS: VCE had a high diagnostic yield of 45% for identification of primary small-intestinal carcinoid tumors. Although nuclear imaging had a comparable diagnostic yield, it could not differentiate between intestinal and mesenterial localization of the carcinoid.

Local treatment in unresectable hepatic metastases of carcinoid tumors: Experiences with hepatic artery embolization and radiofrequency ablation.

BACKGROUND: Hepatic metastases of carcinoid tumors cause incapacitating symptoms, but are usually diffuse and therefore unresectable. In this article we evaluate our experiences with local treatment techniques in the management of carcinoid patients with hepatic metastases and failing systemic treatment. METHODS: Fifteen consecutive carcinoid patients (11 men and 4 women; median age 60 years; range 45-71 years) were treated with either hepatic artery embolization (HAE) with Ivalon particles or radiofrequency ablation (RFA) (percutaneously or intra-operatively). Follow-up evaluation was performed by CT scan and 24-hours urinary 5-HIAA excretions. RESULTS: A total of 18 HAE's was performed in 13 patients, while 10 lesions in 3 patients were treated with RFA. Median follow-up was 12.5 months (2 - 25 months). Median duration of symptoms was 22 months (8 - 193 months). Median overall decrease of 5-HIAA excretion 2 months after HAE was 32% with tumor regression on CT-scan in 4 patients (30%) and improvement of symptoms with a median duration of 15 months in 3 of them (23%). Embolization led to fatal hepatic failure in one patient. The 3 patients treated with RFA showed a decrease of urinary 5-HIAA values of 34, 81 and 93% respectively, with tumor regression in all of them. Improvement of symptoms was reported in 2 patients up to 25 months. CONCLUSION: Liver embolization performed late in the clinical course had limited effect on symptoms and biochemical and radiological parameters. First experiences with RFA are favorable and might encourage to apply RFA more widely in metastatic carcinoid.

Metastatic carcinoid tumors: a clinical review.

Carcinoid tumors are neuroendocrine tumors derived from enterochromaffin cells, which are widely distributed in the body. They can originate from any location in the body, but they are traditionally described as originating from the foregut, midgut, and hindgut. Although the overall incidence of carcinoid tumors appears to have increased in the past decades, the prognosis for patients with metastatic carcinoid tumors has improved during the last decade. Due to longer survival times, complications, such as carcinoid heart disease, and new metastatic patterns, like skin and bone metastases, may become more important features of carcinoid disease. Therapy focused on these complications should be part of the management. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in better quality of life and longer survival times. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach, with decisions made in multidisciplinary meetings focused on "tailor-made" therapy based on patients' specific conditions. Because carcinoid tumors are uncommon, effort should be made to treat these patients in specialized centers and for these centers to join together in multicenter studies.

Screening behavior of individuals at high risk for colorectal cancer.

BACKGROUND AND AIMS: Periodic colonoscopy is an effective means of reducing the incidence and mortality of colorectal cancer in individuals with a family history of the disease. The aims of this study were to determine the degree of compliance and to identify the factors related significantly to noncompliance with periodic screening in this high-risk population. METHODS: A total of 178 individuals who had undergone genetic counseling for colorectal cancer between 1986 and 1998 and who had been advised to undergo periodic screening because of familial colorectal cancer (FCRC) or hereditary nonpolyposis colorectal cancer (HNPCC) were invited to complete a self-report questionnaire on psychosocial issues and screening experiences. Compliance data were derived from medical records and via self-report. RESULTS: A total of 149 individuals (84%) participated in the study. Noncompliance with screening advice was rare (in 3% of cases), but significant delays (more than 1 year) in undergoing screening were observed in approximately 25% of the cases. The number of perceived barriers to screening (eg, discomfort, embarrassment) was the only variable related significantly to noncompliance/screening delay (odds ratio, 1.2; 95% confidence interval, 1.1-1.3). Use of sedatives during the procedure and receipt of a reminder letter seemed to facilitate better compliance. CONCLUSIONS: Although few high-risk individuals abstain from screening entirely, approximately one in 4 deviates significantly from the recommended frequency of screening. Increased compliance may be achieved by reducing the discomfort and embarrassment associated with the procedure and by the use of reminder letters.

Daily cyclic changes in the urinary excretion of 5-hydroxyindoleacetic acid in patients with carcinoid tumors.

BACKGROUND: Vasoactive peptides produced by neuroendocrine tumors can induce characteristic symptoms of the carcinoid syndrome (flushing, diarrhea, and wheezing). To what extent external factors provoke these symptoms and how excretion of 5-hydroxyindoleacetic acid (5-HIAA), the degradation product of serotonin, varies throughout the day remain unknown. In this study, we investigated whether symptoms and daily activity are related to 5-HIAA excretion and whether 24-h urine collection is needed. METHODS: In 26 patients with metastatic carcinoid (14 men and 12 women; median age, 60 years) urine was collected in portions of 4 or 8 h during 2 days. Patients were asked to keep a diary in which they noted symptoms of flushes, consistency of stools, activities, and food intake. RESULTS: Excretion of 5-HIAA in 24-h urine was increased in 88% of the patients (median, 515 micromol/24 h). Overnight-collected urine appeared the most representative for 24-h collection concentrations (correlation coefficient = 0.81). We found no clear correlation between symptoms of the carcinoid syndrome and degree of activity. Watery diarrhea was reported only by patients with strong variations in 5-HIAA excretion. One-half of the patients (n = 16) exhibited a high variability in urinary 5-HIAA excretion throughout the day, with increased concentrations most prominent in morning collections (P = 0.0074) and lower concentrations in the evening (P = 0.0034). In the other patients these curves were flat. CONCLUSIONS: Cyclic changes in patients relate to high variability in 5-HIAA excretion. Overnight-collected urine can replace the 24-h urine collection, and marked variations in 5-HIAA excretion seem to be associated with severity of diarrhea.

On the use of vignettes for eliciting test-selection strategies.

Decision-support systems often include a strategy for selecting tests in their field of application. This strategy in essence captures procedural knowledge and serves to provide support for the reasoning processes involved. Generally, a test-selection strategy is offered in which tests are selected sequentially. For our field of application, we noticed that such a strategy would be an oversimplification, and decided to acquire knowledge about the actual strategy used by the experts. To this end, we composed a method that comprised an unstructured interview to gain general insight in the test-selection strategy used, and a subsequent structured interview, simulating daily practice through vignettes, to acquire full details. We used the method with two experts in our field of application and found that it closely fitted in with their daily practice and resulted in a large amount of detailed knowledge.