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Wouter W de Herder and Charis Eng

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Wouter W de Herder, Erik P Krenning and Gabriel P Krestin

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Wouter T Zandee, Kimberly Kamp, Roxanne C van Adrichem, Richard A Feelders and Wouter W de Herder

The treatment of hormone hypersecretory syndromes caused by neuroendocrine tumors (NETs) can be a major challenge. NETs originating from the small intestine often secrete serotonin causing flushing, diarrhea and valve fibrosis, leading to dehydration or heart failure in severe cases. NETs from the pancreas can secrete a wider variety of hormones, like insulin, glucagon and gastrin leading to distinct clinical syndromes. Historically mortality in patients with functioning NETs was high due to the complications caused by the hypersecretion of hormones. This has been reduced with several drugs: proton-pump inhibitors decrease acid secretion caused by gastrinomas. Somatostatin analogs can inhibit the secretion of multiple hormones and these are now the cornerstone for treating patients with a gastroenteropancreatic NET. However, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs and everolimus can also decrease symptoms of hypersecretion and increase progression-free survival. Several factors affect the survival in patients with a functioning NET. Complications of hypersecretion negatively impact survival; however, secretion of hormones is also often a sign of a well-differentiated NET and due to the symptoms, functioning NETs can be detected in an earlier stage suggesting a positive effect on prognosis. The effect on survival is also dependent on the type of hormone being secreted. This review aims to study the effect of hormone secretion on the prognosis of NETs with the contemporary treatments options available today.

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Johannes Hofland, Aura D Herrera Martínez, Wouter T Zandee and Wouter W de Herder

Carcinoid syndrome (CS) is a debilitating disease caused by functional neuroendocrine tumors. Several treatment options are available to alleviate the hormonal symptoms, but their relative efficacy is unknown. Online databases were searched for publications on the treatment of CS symptoms. Independent reviewers assessed relevant publications for study quality and outcome. Meta-analysis of the outcomes of the intervention on CS-related symptoms was stratified by type of treatment. We found 3682 therapeutic interventions on CS-specific outcomes collected from 93 studies. Overall, the study qualities were poor with only six randomized controlled clinical trials. The somatostatin analogs octreotide and lanreotide induced symptomatic improvement in 65-72% and biochemical response in 45-46% of patients. An increase in dose or frequency or interclass switch led to a reduction of flushes and/or diarrhea in 72-84% of cases. Retrospective, institutional series showed that liver-directed therapy can improve symptoms in 82% of CS patients with liver-dominant disease. The serotonin synthesis inhibitor telotristat ethyl reduced bowel movements in 40% of patients with diarrhea refractory to somatostatin analogs. Interferon-alpha controlled CS symptoms in 45-63% of cases. Favorable response has been noted after radionuclide therapy in subgroup analyses of studies not specifically involving CS patients. Chemotherapy and everolimus did not induce significant response in the CS. We conclude that several treatment lines can be offered to patients suffering from the carcinoid syndrome. Initiation of randomized controlled trials with a primary outcome on carcinoid syndrome symptoms is strongly recommended.

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Gregory Kaltsas, Ioannis I Androulakis, Wouter W de Herder and Ashley B Grossman

Neuroendocrine tumours may be either benign or malignant tumours, and have the ability to synthesise and secrete biologically active substances characteristic of the cell of origin that can cause distinct clinical syndromes. The term ‘paraneoplastic syndromes’ (PNSs) is used to denote syndromes secondary to substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells; such syndromes are mainly associated with hormonal and neurological symptoms. Appreciation of the presence of such syndromes is important as clinical presentation, if not identified, may delay the diagnosis of the underlying neoplasia. Conversely, early recognition can allow for more rapid diagnosis, particularly as the coexistence of a neoplasm with a clinical or biochemical marker offers an additional determinant of tumour status/progression. PNSs can complicate the patient's clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. Their diagnosis involves a multidisciplinary approach, and detailed endocrinological, neurological, radiological and histological studies are required. Correct diagnosis is essential as the treatment of choice will be different for each disorder, particularly in the case of malignant tumours; it is therefore important to develop appropriate means to correctly identify and localise these tumours. Clinical awareness and the incorporation into clinical practise of 111In-octreotide scintigraphy, chromogranin A and other evolving biochemical marker measurement techniques have substantially contributed to the identification of patients harbouring such syndromes. Disease-specific medical therapies are mandatory in order to prevent recurrence and/or further tumour growth. Owing to their rarity, central registration of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.

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Anela Blažević, Johannes Hofland, Leo J Hofland, Richard A Feelders and Wouter W de Herder

Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.

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Kimberly Kamp, Ronald A M Damhuis, Richard A Feelders and Wouter W de Herder

An increased association between neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NET) and other second primary malignancies has been suggested. We determined whether there is indeed an increased risk for second primary malignancies in GEP-NET patients compared with an age- and sex-matched control group of patients with identical malignancies. The series comprised 243 men and 216 women, diagnosed with a GEP-NET between 2000 and 2009 in a tertiary referral center. The timeline, before-at-after diagnosis, and the type of other malignancies were studied using person-year methodology. Poisson distributions were used for testing statistical significance. All data were cross-checked with the Dutch National Cancer Registry. Out of 459 patients with GEP-NET, 67 (13.7%) had a second primary cancer diagnosis: 25 previous cancers (5.4%), 13 synchronous cancers (2.8%), and 29 metachronous cancers (6.3%). The most common types of second primary cancer were breast cancer (n=10), colorectal cancer (n=8), melanoma (n=6), and prostate cancer (n=5). The number of patients with a cancer history was lower than expected, although not significant (n=25 vs n=34.5). The diagnosis of synchronous cancers, mainly colorectal tumors, was higher than expected (n=13 vs n=6.1, P<0.05). Metachronous tumors occurred as frequent as expected (n=29 vs n=25.2, NS). In conclusion, our results are in contrast to previous studies and demonstrate that only the occurrence of synchronous second primary malignancies, mainly colorectal cancers, is increased in GEP-NET patients compared with the general population.

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Kimberly Kamp, Brenda Gumz, Richard A Feelders, Dik J Kwekkeboom, Gregory Kaltsas, Frederico P Costa and Wouter W de Herder

Although 177Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with 177Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5–21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

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Aura D Herrera Martínez, Leo Hofland, María Ángeles Gálvez Moreno, Justo P Castaño, Wouter W de Herder and R A Feelders

Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include: (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, e.g the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/ endothelial/progenitor cells or cell free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

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Anela Blažević, Wouter T Zandee, Gaston J H Franssen, Johannes Hofland, Marie-Louise F van Velthuysen, Leo J Hofland, Richard A Feelders and Wouter W de Herder

Mesenteric fibrosis (MF) surrounding a mesenteric mass is a hallmark feature of small intestinal neuroendocrine tumours (SI-NETs). Since this can induce intestinal obstruction, oedema and ischaemia, prophylactic resection of the primary tumour and mesenteric mass is often recommended. This study assessed the predictors for mesenteric metastasis and fibrosis and the effect of MF and palliative surgery on survival. A retrospective analysis of 559 patients with pathologically proven SI-NET and available CT-imaging data was performed. Clinical characteristics, presence of mesenteric mass and fibrosis on CT imaging and the effect of palliative abdominal surgery on overall survival were assessed. We found that MF was present in 41.4%. Older age, 5-HIAA excretion ≥67 μmol/24 h, serum CgA ≥121.5 μg/L and a mesenteric mass ≥27.5 mm were independent predictors of MF. In patients ≤52 years, mesenteric mass was less often found in women than in men (39% vs 64%, P = 0.002). Corrected for age, tumour grade, CgA and liver metastasis, MF was not a prognostic factor for overall survival. In patients undergoing palliative surgery, metastasectomy of mesenteric mass or prophylactic surgery did not result in survival benefit. In conclusion, we confirmed known predictors of MF and mesenteric mass and suggest a role for sex hormones as women ≤52 years have less often a mesenteric mass. Furthermore, the presence of MF has no effect on survival in a multivariate analysis, and we found no benefit of metastasectomy of mesenteric mass or prophylactic surgery on overall survival.