Aspects on Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumours

Aspects on Diagnosis and Treatment of Gastrointestinal Neuroendocrine Tumours Background. Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) originate from endocrine cells of the intestinal mucosa and pancreas. The tumour cells contain chromogranin A (CgA) and usually have a high expression of somatostatin receptors (SSTR), which can be used for diagnosis and treatment. The treatment alternatives in patients with disseminated GEP-NETs include debulking surgery, hepatic arterial embolization (HAE), in selected cases orthotopic liver transplantation (OLT), or somatostatin receptor (SSTR)-mediated radiation therapy besides medical treatment with somatostatin analogues, interferon, or combination of cytotoxic drugs. Material & Methods. A xenograft model with a transplantable midgut carcinoid tumour (GOT 1) was used to study the correlation between tumour weight and the tumour marker chromogranin A (CgA) in plasma as well as the therapeutic effects of the somatostatin analogue octreotide. The uptake and biodistribution of the radiopharmaceuticals 177Lu-octreotide and 177Lu-octreotate in GOT 1-bearing nude mice were studied. A consecutive series of 107 patients treated with HAE was analyzed regarding biochemical response and survival. The effect of SSTR-mediated radiation therapy was analysed in a consecutive series of 26 patients with disseminated GEP-NETs as well as in 6 patients with non-resectable recurrence of tumour after OLT. The absorbed dose to the kidney as a tool for optimization of radiotherapy was evaluated. Results. In GOT 1-bearing nude mice there was a strong correlation between tumour weight and P-CgA (P<0.00001). The P-CgA/tumour weight ratio was significantly lowered by octreotide (P<0.037). The uptake of 177Lu-octreotate was twice that of 177Lu-octreotide (P=0.00061) and the reduction of tumour volume was significantly higher in animals given 177Lu-octreotate (P=0.003). The tumour volume correlated significantly with P-CgA, which served as a marker of treatment effect. A good biochemical response with decreased tumour markers correlated with prolonged survival in patients after HAE (P=0.003). There was also a significant correlation between the responses to primary and repeat HAE. SSTR-mediated radiation therapy resulted in 38% partial tumour reduction according to RECIST-criteria. By using the absorbed dose to the kidney as a limiting factor for therapy we found that 10 patients received fewer than 4 treatments but 4 patients were identified as candidates for additional treatment. There was a significant reduction of glomerular filtration rate (GFR) after radiotherapy (P=0.0013). Also in transplanted patients SSTR-mediated radiation therapy could be used to treat tumour recurrence. Conclusions. 1. P-CgA was well suited for monitoring of the tumour burden and tumour response in GOT 1-bearing nude mice. 2. 177Lu-octreotate was a more suitable radiopharmaceutical than 177Lu-octreotide and the in vivo data allowed accurate determination of absorbed dose. 3. HAE provided prolonged survival in biochemically responsive patients. Repeat HAE can be considered in patients with favourable response to the first procedure. 4. Calculation of the accumulated dose to the kidneys during SSTR-mediated radiotherapy was valuable to optimize the treatment. 5. SSTR-mediated radiotherapy was a treatment option also for patients with non-resectable recurrence of SSTR-expressing tumours, previously treated with OLT. Key words: Carcinoid, endocrine pancreatic tumour, neuroendocrine, octreotide, somatostatin receptor, peptide receptor radionuclide therapy, absorbed dose, chromogranin A, liver transplantation

Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets.

We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

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