Small intestinal neuroendocrine tumors (SI-NETs) are small, slow growing neoplasms with loss of one copy of chromosome 18 as a common event. Frequently mutated genes on chromosome 18 or elsewhere have not been found so far. The aim of this study was to investigate a possible tumor suppressor role of the transmembrane receptor type tyrosine phosphatase PTPµ (PTPRM at 18p11) in SI-NETs. Immunohistochemistry, quantitative RT-PCR, colony formation assay and quantitative CpG methylation analysis by pyrosequencing were performed. Undetectable/very low levels of PTPRM or aberrant pattern of immunostaining, with both negative and positive areas, were detected in the majority of tumors (33/40), and a significantly reduced mRNA expression in metastases compared to primary tumors was observed. Both the DNA methylation inhibitor 5-aza-2′-deoxycytidine and the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep) induced PTPRM expression in CNDT2.5 and KRJ-I SI-NET cells. CpG methylation of upstream regulatory regions, the promoter region and the exon 1/intron 1 boundary was detected by pyrosequencing analysis of the two cell lines and not in the analyzed SI-NETs. Overexpression of PTPRM in the SI-NET cell lines reduced cell growth and cell proliferation and induced apoptosis. The tyrosine phosphatase activity of PTPRM was not involved in cell growth inhibition. The results support a role for PTPRM as a dysregulated candidate tumor suppressor gene in SI-NETs and further analyses of the involved mechanisms are warranted.
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Elham Barazeghi, Per Hellman, Gunnar Westin, and Peter Stålberg
Anna Malczewska, Kjell Oberg, and Beata Kos-Kudla
The absence of a reliable, universal biomarker is a significant limitation in neuroendocrine neoplasia (NEN) management. We prospectively evaluated two CgA assays, (NEOLISA, EuroDiagnostica) and (CgA ELISA, Demeditec Diagnostics (DD)) and compared the results to the NETest.
NEN cohort (n = 258): pancreatic, n = 67; small intestine, n = 40; appendiceal, n = 10; rectal, n = 45; duodenal, n = 9; gastric, n = 44; lung, n = 43. Image-positive disease (IPD) (n = 123), image & histology- negative (IND) (n = 106), and image-negative and histology positive (n = 29). CgA metrics: NEOLISA, ULN: 108 ng/mL, DD: ULN: 99 ng/mL. Data mean ± s.e.m. NETest: qRT-PCR – multianalyte analyses, ULN: 20. All samples de-identified and assessed blinded. Statistics: Mann–Whitney U-test, Pearson correlation and McNemar-test.
CgA positive in 53/258 (NEOLISA), 32 (DD) and NETest-positive in 157/258. In image- positive disease (IPD, n = 123), NEOLISA-positive: 33% and DD: 19%. NETest-positive: 122/123 (99%; McNemar’s Chi2= 79–97, P < 0.0001). NEOLISA was more accurate than DD (P = 0.0003). In image- negative disease (IND), CgA was NEOLISA-positive (11%), DD (8%), P = NS, and NETest (33%). CgA assays could not distinguish progressive (PD) from stable disease (SD) or localized from metastatic disease (MD). NETest was significantly higher in PD (47 ± 5) than SD (29 ± 1, P = 0.0009). NETest levels in MD (35 ± 2) were elevated vs localized disease (24 ± 1.3, P = 0.008).
NETest, a multigenomic mRNA biomarker, was ~99% accurate in the identification of NEN disease. The CgA assays detected NEN disease in 19–33%. Multigenomic blood analysis using NETest is more accurate than CgA and should be considered the biomarker standard of care.
Mauricio Alvarez, Oswaldo Rincón Sierra, Ginna Saavedra, and Sergio Moreno
Vitamin B12 deficiency resulting from metformin use has been demonstrated in multiple studies. In this study, we aimed to evaluate the prevalence of vitamin B12 deficiency in patients with chronic metformin use and the relationship between vitamin B12 deficiency and diabetic neuropathy.
A cross-sectional study was conducted with 162 patients. Vitamin B12 levels were measured by chemiluminescence immunoassay. Diabetic neuropathy was evaluated by patient record, nerve conduction and Michigan test for the diagnosis of diabetic neuropathy. Additional data, including demographic characteristics were collected. A linear regression model was used to evaluate variables that correlated with vitamin B12 levels and diabetic neuropathy.
Low vitamin B12 levels were found in 7.3% (95% CI: 4.0–12%) of patients. In those with diabetic neuropathy, altered (low and borderline) vitamin B12 level was 64% (95% CI: 47–78%) compared to 17% (95% CI: 10–26%) in patients without diabetic neuropathy (coefficient: −110.8; CI 95%: −165.8, −59.7). Those taking a higher metformin dose had lower levels of vitamin B12 (coefficient: −0.061; CI 95%: −0.09, −0.024). In addition, female patients had higher levels of vitamin B12 compared to men (coefficient: 49.1; CI 95%: 2.3–95).
Vitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B12. Higher doses of metformin and male sex were factors related to lower levels of vitamin B12.
Qi Zhang, Hongshan Wang, Yanhong Xie, Suming Huang, Ke Chen, Botian Ye, Yupeng Yang, Jie Sun, Hongyong He, Fenglin Liu, Zhenbin Shen, Weidong Chen, Kuntang Shen, Yuan Ji, and Yihong Sun
A new subcategory, grade 3 neuroendocrine tumors, is incorporated into the grading system of pancreatic neuroendocrine neoplasms in the 2017 WHO classification in order to differentiate grade 3 neuroendocrine tumors from neuroendocrine carcinomas. The 2019 WHO classification extends the concept of grade 3 neuroendocrine tumors to gastrointestinal high-grade neuroendocrine neoplasms. However, there is still limited study focusing on the gastric grade 3 neuroendocrine tumors and gastric neuroendocrine carcinomas. We retrospectively enrolled 151 gastric high-grade neuroendocrine neoplasms patients, who underwent radical resection from January 2007 to December 2015. Clinicopathologic and prognostic features were studied. The Surveillance, Epidemiology, and End Results (SEER) database was used to verify the prognostic determinants found in the Zhongshan cohort. Neuroendocrine carcinomas showed a higher Ki67 index and higher mitotic count than grade 3 neuroendocrine tumors. We identified 109 (72.2%) patients with neuroendocrine carcinomas, 12 (7.9%) patients with grade 3 neuroendocrine tumors, and 30 (19.9%) patients with mixed neuroendocrine-non-neuroendocrine neoplasms. Although neuroendocrine carcinomas demonstrated higher Ki67 index (P = 0.004) and mitoses (P = 0.001) than grade 3 neuroendocrine tumors, their prognosis after radical resection did not demonstrate significant differences (P = 0.709). Tumor size, perineural invasion, and TNM stage were independent prognostic factors of gastric high-grade neuroendocrine neoplasms.
The brain hosts a vast and diverse repertoire of neuropeptides, a class of signalling molecules often described as neurotransmitters. Here I argue that this description entails a catalogue of misperceptions, misperceptions that feed into a narrative in which information processing in the brain can be understood only through mapping neuronal connectivity and by studying the transmission of electrically conducted signals through chemical synapses. I argue that neuropeptide signalling in the brain involves primarily autocrine, paracrine and neurohormonal mechanisms that do not depend on synaptic connectivity and that it is not solely dependent on electrical activity but on mechanisms analogous to secretion from classical endocrine cells. As in classical endocrine systems, to understand the role of neuropeptides in the brain, we must understand not only how their release is regulated, but also how their synthesis is regulated and how the sensitivity of their targets is regulated. We must also understand the full diversity of effects of neuropeptides on those targets, including their effects on gene expression.
Myrtille Fouché, Yves Bouffard, Mary-Charlotte Le Goff, Johanne Prothet, François Malavieille, Pierre Sagnard, Françoise Christin, Davy Hayi-Slayman, Arnaud Pasquer, Gilles Poncet, Thomas Walter, and Thomas Rimmelé
Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients (liver metastases: 59, prior carcinoid syndrome: 49, carcinoid heart disease: 7) were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol.
Guillem Cuatrecasas, Hatice Kumru, M Josep Coves, and Joan Vidal
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.
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.
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.
Catherine Cardot Bauters, Emmanuelle Leteurtre, Bruno Carnaille, Christine Do Cao, Stéphanie Espiard, Malo Penven, Evelyne Destailleur, Isabelle Szuster, Tonio Lovecchio, Julie Leclerc, Fredéric Frénois, Emmanuel Esquivel, Patricia L M Dahia, Emilie Ait-Yahya, Michel Crépin, and Pascal Pigny
We previously described a family in which predisposition to pheochromocytoma (PCC) segregates with a germline heterozygous KIF1B nucleotide variant (c.4442G>A, p.Ser1481Asn) in three generations. During the clinical follow-up, one proband’s brother, negative for the KIF1B nucleotide variant, developed a bilateral PCC at 31 years. This prompted us to reconsider the genetic analysis.
Design and methods
Germline DNA was analyzed by next-generation sequencing (NGS) using a multi-gene panel plus MLPA or by whole exome sequencing (WES). Tumor-derived DNA was analyzed by SnapShot, Sanger sequencing or NGS to identify loss-of-heterozygosity (LOH) or additional somatic mutations.
A germline heterozygous variant of unknown significance in MAX (c.145T>C, p.Ser49Pro) was identified in the proband’s brother. Loss of the wild-type MAX allele occurred in his PCCs thus demonstrating that this variant was responsible for the bilateral PCC in this patient. The proband and her affected grandfather also carried the MAX variant but no second hit could be found at the somatic level. No other pathogenic mutations were detected in 36 genes predisposing to familial PCC/PGL or familial cancers by WES of the proband germline. Germline variants detected in other genes, TFAP2E and TMEM214, may contribute to the multiple tumors of the proband.
In this family, the heritability of PCC is linked to the MAX germline variant and not to the KIF1B germline variant which, however, may have contributed to the occurrence of neuroblastoma (NB) in the proband.
Arno Téblick, Lies Langouche, and Greet Van den Berghe
Critical illness is hallmarked by major changes in all hypothalamic–pituitary–peripheral hormonal axes. Extensive animal and human studies have identified a biphasic pattern in circulating pituitary and peripheral hormone levels throughout critical illness by analogy with the fasting state. In the acute phase of critical illness, following a deleterious event, rapid neuroendocrine changes try to direct the human body toward a catabolic state to ensure provision of elementary energy sources, whereas costly anabolic processes are postponed. Thanks to new technologies and improvements in critical care, the majority of patients survive the acute insult and recover within a week. However, an important part of patients admitted to the ICU fail to recover sufficiently, and a prolonged phase of critical illness sets in. This prolonged phase of critical illness is characterized by a uniform suppression of the hypothalamic–pituitary–peripheral hormonal axes. Whereas the alterations in hormonal levels during the first hours and days after the onset of critical illness are evolutionary selected and are likely beneficial for survival, endocrine changes in prolonged critically ill patients could be harmful and may hamper recovery. Most studies investigating the substitution of peripheral hormones or strategies to overcome resistance to anabolic stimuli failed to show benefit for morbidity and mortality. Research on treatment with selected and combined hypothalamic hormones has shown promising results. Well-controlled RCTs to corroborate these findings are needed.
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.