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Open access

Gaëtan Prévost, Marie Picot, Marie-Anne Le Solliec, Arnaud Arabo, Hind Berrahmoune, Mouna El Mehdi, Saloua Cherifi, Alexandre Benani, Emmanuelle Nédélec, Françoise Gobet, Valéry Brunel, Jérôme Leprince, Hervé Lefebvre, Youssef Anouar, and Nicolas Chartrel

Objective

Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients.

Design and methods

Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test.

Results

26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance.

Conclusion

The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

Open access

Guillem Cuatrecasas, Hatice Kumru, M Josep Coves, and Joan Vidal

Objective

Growth hormone (GH) was shown to stimulate proliferation, migration and survival of neural cells in animal models. GH deficiency (GHD) was reported following traumatic brain lesions; however, there are not available data in spinal cord injury (SCI) patients. The aim of the study was to evaluate (1) the frequency of GHD in chronic SCI population; (2) the efficacy/safety of GH replacement in patients with SCI and suboptimal GH secretion.

Design and methods

Nineteen consecutive patients with chronic thoracic complete SCI (AIS-A) were studied. Patients with low GH secretion were randomized in a double-blind, placebo-controlled study to receive either subcutaneous placebo injections or GH combined with physical therapy, for 6 months. Baseline cranial MRI, AIS motor and sensory scale, quality of life (spinal cord impact measurement) and modified Ashworth spasticity scale, quantitative sensory testing and neurophysiological exploration were assessed at baseline, 1, 3 and 6 months following treatment.

Results

Thirteen had GH deficiency. Seven received GH, five placebo and one dropped out. Both groups were similar according to clinical and demographical data at baseline, except for greater GH deficiency in the GH treatment group. At 6th month, patients treated with GH showed a significant improvement in SCIM-III score and in electrical perception threshold up to the 5th level below SCI, on both sides compared to baseline.

Conclusions

GHD seems to be frequent in traumatic SCI and GH replacement is safe without side effects. GH combined with physical therapy can improve quality of life of SCI patients and, strikingly, the sensory perception below lesion level.

Open access

E T Aristizabal Prada and C J Auernhammer

Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras–Raf–MEK–ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

Open access

Ruth Therese Casey, Deborah Saunders, Benjamin George Challis, Deborah Pitfield, Heok Cheow, Ashley Shaw, and Helen Lisa Simpson

Context

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary condition characterised by the predisposition to hyperplasia/tumours of endocrine glands. MEN1-related disease, moreover, malignancy related to MEN1, is increasingly responsible for death in up to two-thirds of patients. Although patients undergo radiological and biochemical surveillance, current recommendations for radiological monitoring are based on non-prospective data with little consensus or evidence demonstrating improved outcome from this approach. Here, we sought to determine whether cumulative radiation exposure as part of the recommended radiological screening programme posed a distinct risk in a cohort of patients with MEN1.

Patients and study design

A retrospective review of 43 patients with MEN1 attending our institution between 2007 and 2015 was performed. Demographic and clinical information including phenotype was obtained for all patients. We also obtained details regarding all radiological procedures performed as part of MEN1 surveillance or disease localisation. An estimated effective radiation dose (ED) for each individual patient was calculated.

Results

The mean ED for the total patient cohort was 121 mSv, and the estimated mean lifetime risk of cancer secondary to radiation exposure was 0.49%. Patients with malignant neuroendocrine tumours (NETS) had significantly higher ED levels compared to patients without metastatic disease (P < 0.0022).

Conclusions

In MEN1, radiological surveillance is associated with clinically significant exposure to ionising radiation. In patients with MEN1, multi-modality imaging strategies designed to minimise this exposure should be considered.

Open access

Shan Wu, Jianjun Zhou, Jing Guo, Zhan Hua, Jianchen Li, and Zai Wang

Angiogenesis has a pivotal role in the growth and metastasis of pancreatic neuroendocrine tumors (PNETs). Apatinib inhibits angiogenesis as a highly selective KDR inhibitor and has been used to treat advanced gastric cancer and malignancies in clinical settings. However, the efficacy of apatinib in PNETs remains unclear. The aim of this study was to compare the antitumor efficacy of apatinib with that of the standard PNET drug sunitinib in our subcutaneous and liver metastasis models of insulinoma and non-functional PNET. Our results revealed that apatinib had a generally comparable or even superior antitumor effect to that of sunitinib on primary PNET, and it inhibited angiogenesis without directly causing tumor cell cytotoxicity. Apatinib inhibited the tumor in a dose-dependent manner, and the high dose was well tolerated in mice. We also found that the apatinib efficacy in liver metastasis models was cell-type (disease) selective. Although apatinib efficiently inhibited INR1G9-represented non-functional PNET liver metastasis, it led to the emergence of a hypoxic area in the INS-1-represented insulinoma and promoted liver metastasis. Our study demonstrated that apatinib has promise for clinical applications in certain malignant PNETs, and the application of anti-angiogenesis drugs to benign insulinomas may require careful consideration.

Open access

Thomas Couronne, Paul Girot, Julien Hadoux, Thierry Lecomte, Alice Durand, Caroline Fine, Katia Vandevoorde, Catherine Lombard-Bohas, and Thomas Walter

Objective

First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment.

Material and methods

This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS).

Results

Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments.

Conclusion

LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

Open access

Kyoungjune Pak, Seongho Seo, Myung Jun Lee, Keunyoung Kim, Sunghwan Suh, Hyung-Jun Im, and In Joo Kim

Brain dopamine neurotransmission is regulated by the dopamine transporter (DAT), which drives reuptake of extracellular dopamine into the presynaptic neurons. We hypothesized that the glucose loading dose would affect the striatal DAT availability. An i.v. bolus injection of 18F-FP-CIT was administered after infusion of low-dose glucose (300 mg/kg), high-dose glucose (600 mg/kg) or placebo (normal saline). The emission data were acquired over 90 min in 23 healthy male subjects. Substantial increases of binding potential (BPNDs) from ventral striatum (VST), caudate nucleus, and putamen were observed after low-dose glucose loading (+26.0, +87.0, and +37.8%) and after high-dose glucose loading (+10.4, +51.9, and +22.0%). BPNDs of the caudate nucleus and putamen showed significant differences (P = 0.0472 and 0.0221) after placebo, low-dose glucose, and high-dose glucose loading. BPNDs in the caudate nucleus and putamen after placebo, low-dose glucose, and high-dose glucose loading were positively intercorrelated with each other. In conclusion, striatal DAT changes after physiological glucose loading, but not after supraphysiological glucose loading in humans. DAT availabilities after placebo, low-dose glucose, high-dose glucose loading were correlated to each other in the caudate nucleus and putamen, but not in the VST. Therefore, sub-regional variability in DAT regulatory mechanisms mediated by insulin may exist in humans.

Open access

Serena Martinelli, Mario Maggi, and Elena Rapizzi

Pheochromocytomas/paragangliomas (PPGLs) are rare neuroendocrine tumours linked to more than 15 susceptibility genes. PPGLs present with very different genotype/phenotype correlations. Certainly, depending on the mutated gene, and the activated intracellular signalling pathways, as well as their metastatic potential, each tumour is immensely different. One of the major challenges in in vitro research, whatever the study field, is to choose the best cellular model for that study. Unfortunately, most of the time there is not ‘a best’ cell model. Thus, in order to avoid observations that could be related to and/or dependent on a specific cell line, researchers often perform the same experiments using different cell lines simultaneously. The situation is even more complicated when there are only very few cell models obtained in different species for a disease. This is the case for PPGLs. In this review, we will describe the characteristics of the different cell lines and of mouse models, trying to understand if there is one that is more appropriate to use, depending on which aspect of the tumours one is trying to investigate.

Open access

Sandeep Kumar, Anurag Ranjan Lila, Saba Samad Memon, Vijaya Sarathi, Virendra A Patil, Santosh Menon, Neha Mittal, Gagan Prakash, Gaurav Malhotra, Nalini S Shah, and Tushar R Bandgar

Risk of metastatic disease in the cluster 2-related pheochromocytoma/paraganglioma (PPGL) is low. In MEN2 patients, identification of origin of metastases from pheochromocytoma (PCC) or medullary thyroid carcinoma (MTC) is challenging as both are of neuroendocrine origin. We aim to describe our experience and perform a systematic review to assess prevalence, demographics, biochemistry, diagnostic evaluation, management, and predictors of cluster 2-related metastatic PPGL. Retrospective analysis of 3 cases from our cohort and 43 cases from world literature was done. For calculation of prevalence, all reported patients (n = 3063) of cluster 2 were included. We found that the risk of metastasis in cluster 2-related PPGL was 2.6% (2% in RET, 5% in NF1, 4.8% in TMEM127 and 16.7% in MAX variation). In metastatic PCC in MEN2, median age was 39 years, bilateral tumors were present in 71% and median tumor size was 9.7 cm (range 4–19) with 43.5% mortality. All patients had a primary tumor size ≥4 cm. Origin of primary tumor was diagnosed by histopathology of metastatic lesion in 11 (57.9%), 131I-MIBG scan in 6 (31.6%), and selective venous sampling and CT in 1 (5.3%) patient each. In subgroup of neurofibromatosis 1 (NF1), median age was 46 years (range 14–59) with median tumor size 6 cm and 57% mortality. To conclude, the risk of metastatic disease in cluster 2-related PPGL is low, being especially high in tumors with size ≥4 cm and associated with high mortality. One-third patients of NF1 with metastatic PPGL had presented in second decade of life. Long-term studies are needed to formulate management recommendations.

Open access

K G Samsom, L M van Veenendaal, G D Valk, M R Vriens, M E T Tesselaar, and J G van den Berg

Background

Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis.

Aim

We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs.

Method

A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019.

Results

The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44–100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs.

Conclusion

SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.