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Open access

Fan Zhang, Jian Chen, Xinyue Lin, Shiqiao Peng, Xiaohui Yu, Zhongyan Shan and Weiping Teng

Objective

Maternal hypothyroidism during pregnancy can affect the neurodevelopment of their offspring. This study aimed to investigate the effects of maternal subclinical hypothyroidism (SCH) on spatial learning and memory, and its relationship with the apoptotic factors in cerebral cortex of the offspring.

Methods

Female adult Wistar rats were randomly divided into three groups (n = 15 per group): control (CON) group, SCH group and overt hypothyroidism (OH) group. Spatial learning and memory in the offspring were evaluated by long-term potentiation (LTP) and Morris water-maze (MWM) test. The protein expression of the p75 neurotrophin receptor (p75NTR), phospho-c-Jun N-terminal kinase (p-JNK), the pro-apoptotic protein p53 and Bax were detected by Western blotting.

Results

The Pups in the SCH and OH groups showed longer escape latencies in the MWM and decreased field-excitatory post synaptic potentials in LTP tests compared with those in the CON group. p75NTR, p-JNK, p53 and Bax expression levels in the cerebral cortex increased in pups in the SCH and OH groups compared with those in the CON group.

Conclusions

Maternal SCH during pregnancy may impair spatial learning and memory in the offspring and may be associated with the increased apoptosis in the cerebral cortex.

Open access

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.

Open access

Maria Angela D'amico, Barbara Ghinassi, Pascal Izzicupo, Lamberto Manzoli and A Di Baldassarre

Chromogranin A (CgA (CHGA)) is the major soluble protein co-stored and co-released with catecholamines and can function as a pro-hormone by giving rise to several bioactive peptides. This review summarizes the physiological functions, the pathogenic implications, and the recent use of these molecules as biomarkers in several pathological conditions. A thorough literature review of the electronic healthcare databases MEDLINE, from January 1985 to September 2013, was conducted to identify articles and studies concerned with CgA and its processing. The search strategies utilized keywords such as chromogranin A, vasostatins 1 and 2, chromofungin, chromacin, pancreastatin, catestatin, WE14, chromostatin, GE25, parastatin, and serpinin and was supplemented by the screening of references from included papers and review articles. A total of 209 English-language, peer-reviewed original articles or reviews were examined. The analysis of the retrospective literature suggested that CgA and its several bioactive fragments exert a broad spectrum of regulatory activities by influencing the endocrine, the cardiovascular, and the immune systems and by affecting the glucose or calcium homeostasis. As some peptides exert similar effects, but others elicit opposite responses, the regulation of the CgA processing is critical to maintain homeostasis, whereas an unbalanced production of peptides that exert opposing effects can have a pathogenic role in several diseases. These clinical implications entail that CgA and its derived peptides are now used as diagnostic and prognostic markers or to monitor the response to pharmacological intervention not only in endocrine tumors, but also in cardiovascular, inflammatory, and neuropsychiatric diseases.

Open access

Jean-Benoît Corcuff, Laurence Chardon, Ines El Hajji Ridah and Julie Brossaud

Context

Biogenic amines such as 5-hydroxy-indole acetic acid (5HIAA) the main metabolite of serotonin or metanephrines (catecholamines metabolites) are used as biomarkers of neuroendocrine tumours.

Objective

To re-evaluate the recommendations for urinary sampling (preservatives, diet, drugs, etc.) as many of the reported analytical interferences supporting these recommendations are related to obsolete assays.

Methods

Bibliographic analysis of old and modern assays concerning preservation, extraction, assay and interferences.

Results

5HIAA may degrade as soon as urine is excreted. Thus, acids as preservatives (hydrochloric or acetic acid) have to be immediately added. Care should be taken not to decrease the pH under 2. Urine preservative for metanephrine assays is not mandatory. Diets including serotonin-, tryptophan- and dopamine-rich foods have to be avoided depending on the biomarkers investigated (bananas, plantain, nuts, etc.). Tryptophan-rich over-the-counter formulas have to be prohibited when 5HIAA has to be assayed. Acetaminophen may interfere with electrochemical detection depending on high-pressure liquid chromatography (HPLC) parameters. No interference is known with mass spectrometric assays but with the one described for metanephrines determination. Some drugs interfere however with serotonin and catecholamines secretion and/or metabolism (monoamine oxidase inhibitors, serotonin or dopamine recapture inhibitors, etc.).

Conclusion

Revisited recommendations are provided for the diet, the drugs and the preservatives before HPLC coupled with electrochemical and mass spectrometry assays.

Open access

Fernando Aprile-Garcia, María Antunica-Noguerol, Maia Ludmila Budziñski, Ana C Liberman and Eduardo Arzt

Inflammatory responses are elicited after injury, involving release of inflammatory mediators that ultimately lead, at the molecular level, to the activation of specific transcription factors (TFs; mainly activator protein 1 and nuclear factor-κB). These TFs propagate inflammation by inducing the expression of cytokines and chemokines. The neuroendocrine system has a determinant role in the maintenance of homeostasis, to avoid exacerbated inflammatory responses. Glucocorticoids (GCs) are the key neuroendocrine regulators of the inflammatory response. In this study, we describe the molecular mechanisms involved in the interplay between inflammatory cytokines, the neuroendocrine axis and GCs necessary for the control of inflammation. Targeting and modulation of the glucocorticoid receptor (GR) and its activity is a common therapeutic strategy to reduce pathological signaling. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that catalyzes the addition of PAR on target proteins, a post-translational modification termed PARylation. PARP1 has a central role in transcriptional regulation of inflammatory mediators, both in neuroendocrine tumors and in CNS cells. It is also involved in modulation of several nuclear receptors. Therefore, PARP1 and GR share common inflammatory pathways with antagonic roles in the control of inflammatory processes, which are crucial for the effective maintenance of homeostasis.

Open access

Anna Malczewska, Magdalena Witkowska, Karolina Makulik, Agnes Bocian, Agata Walter, Joanna Pilch-Kowalczyk, Wojciech Zajęcki, Lisa Bodei, Kjell Oberg and Beata Kos-Kudła

Introduction

Current monoanalyte biomarkers are ineffective in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). NETest, a novel multianalyte signature, provides molecular information relevant to disease biology.

Aim(s)

Independently validate NETest to diagnose GEP-NETs and identify progression in a tertiary referral center.

Materials and methods

Cohorts are 67 pancreatic NETs (PNETs), 44 small intestine NETs (SINETs) and 63 controls. Well-differentiated (WD) PNETs, n = 62, SINETs, all (n = 44). Disease extent assessment at blood draw: anatomical (n = 110) CT (n = 106), MRI (n = 7) and/or functional 68Ga-SSA-PET/CT (n = 69) or 18F-FDG-PET/CT (n = 8). Image-positive disease (IPD) was defined as either CT/MRI or 68Ga-SSA-PET/CT/18F-FDG-PET/CT-positive. Both CT/MRI and 68Ga-SSA-PET/CT negative diagnosis in WD-NETs was considered image-negative disease (IND). NETest (normal: 20): PCR (spotted plates). Data: mean ± SD.

Results

Diagnosis

NETest was significantly increased in NETs (n = 111; 26 ± 21) vs controls (8 ± 4, p < 0.0001). Seventy-five (42 PNET, 33 SINET) were image positive. Eleven (8 PNET, 3 SINET; all WD) were IND. In IPD, NETest was significantly higher (36 ± 22) vs IND (8 ± 7, P < 0.0001). NETest accuracy, sensitivity and specificity are 97, 99 and 95%, respectively

Concordance with imaging

NETest was 92% (101/110) concordant with anatomical imaging, 94% (65/69) with 68Ga-SSA-PET/CT and 96% (65/68) dual modality (CT/MRI and 68Ga-SSA-PET/CT). In 70 CT/MRI positive, NETest was elevated in all (37 ± 22). In 40 CT/MRI negative, NETest was normal (11 ± 10) in 31. In 56 68Ga-SSA-PET/CT positive, NETest was elevated (36 ± 22) in 55. In 13 68Ga-SSA-PET/CT negative, NETest was normal (9 ± 8) in ten.

Disease status

NETest was significantly higher in progressive (61 ± 26; n = 11) vs stable disease (29 ± 14; n = 64; P < 0.0001) (RECIST 1.1).

Conclusion

NETest is an effective diagnostic for PNETs and SINETs. Elevated NETest is as effective as imaging in diagnosis and accurately identifies progression.

Open access

Alberto Bongiovanni, Federica Recine, Flavia Foca, Valentina Fausti, Nada Riva, Greta Fabbri, Stefano Severi, Chiara Liverani, Alessandro De Vita, Chiara Spadazzi, Giacomo Miserocchi, Laura Mercatali, Dino Amadori and Toni Ibrahim

The incidence of neuroendocrine neoplasia (NEN) is higher in individuals ≥70 years of age (elderly) who are underrepresented in clinical trials because of comorbidities and low performance status. We retrospectively analyzed the outcome of elderly patients with metastatic NEN (mNEN). Comorbidities were summarized by Charlson Comorbidity Index (CCI), Kaplan–Meier method was applied to estimate overall survival (OS) and Cox’s proportional hazard model was used to assess the impact of known prognostic factors. We retrieved data on 145 mNEN patients aged ≥70 years seen at our center from June 2007 to March 2016. Fifty-six (38.6%) were aged ≥75 years. ECOG PS was 0 in 45.7% of cases and CCI was 0 in 41.0% and 1 in 37.4%. A total of 75.4% of patients had grade (G)1/G2 NEN and 24.6%, G3. Octreoscan/Gallium PET/CT and FDG-PET/CT were positive in 94.2% and 70.3% of cases, respectively. Median follow-up was 72.3 (53.2–85.1) months. Seventy-nine patients received first-line somatostatin analogs (SSA), 23 peptide receptor radionuclide therapy (PRRT) and 36 chemotherapy (CHT). Seven did not undergo first-line therapy and 102 received more than one line. Median overall survival (mOS) was 5.1 years (95% CI: 3.4–6.6). No differences in mOS were seen according to CCI. First-line PRRT patients had a mOS of 6.5 years (95% CI: 3.3–not reached (NR)), SSA 5.7 years (95% CI: 4.2–7) and CHT 5.9 years (95% CI: 0.4–NR). mOS in CHT-treated G3 patients was 1.5 years (1.0–2.5). ECOG PS and FDG PET/CT were identified as independent prognostic factors. Results suggest that the above treatments positively impacted OS in elderly mNEN patients, including those aged ≥75 years.

Open access

Kjell Oberg, Eric Krenning, Anders Sundin, Lisa Bodei, Mark Kidd, Margot Tesselaar, Valentina Ambrosini, Richard P Baum, Matthew Kulke, Marianne Pavel, Jaroslaw Cwikla, Ignat Drozdov, Massimo Falconi, Nicola Fazio, Andrea Frilling, Robert Jensen, Klaus Koopmans, Tiny Korse, Dik Kwekkeboom, Helmut Maecke, Giovanni Paganelli, Ramon Salazar, Stefano Severi, Jonathan Strosberg, Vikas Prasad, Aldo Scarpa, Ashley Grossman, Annemeik Walenkamp, Mauro Cives, Irene Virgolini, Andreas Kjaer and Irvin M Modlin

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

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.

Open access

Irvin M Modlin, Harry Aslanian, Lisa Bodei, Ignat Drozdov and Mark Kidd

A critical requirement in neuroendocrine tumor (NET) management is a blood biomarker test that is sensitive, specific and reproducible. We evaluated a PCR-based 51-transcript signature to detect tumors, compared it with chromogranin A (CgA) and examined the confounding effect of proton pump inhibitors (PPIs), which cause falsely elevated CgA levels. The multigene signature was evaluated in two groups. Group 1: 125 prospectively collected NETs: gastroenteropancreatic NETs (n=91, including 42 pancreatic and 40 small intestinal), carcinoids of unknown primary (n=18) and other sites (n=16). Group 2: prospectively collected non-NET patients receiving PPIs (>1 month; dyspepsia, n=19; GERD, n=6; and pancreatitis, n=4) and 50 controls. All samples were analyzed by PCR (marker genes) and ELISA (DAKO–CgA). Sensitivity comparisons included χ2, non-parametric measurements, and receiver operating characteristic (ROC) curves. Group 1: 123 NETs were PCR-positive (98.4%) compared with 50 (40%) CgA-positive (χ2=97.3, P<10−26). Significant differences (P<0.001) were noted between pancreas: PCR 95% vs CgA 29.2% (P<10−9) and small intestine: 100 vs 58% (P<10−4). The multigene test was elevated in all grades (G1–G3), in both local and disseminated disease, and was not normalized by somatostatin analog therapy. It was also elevated in 97% of CgA normal NETs. Group 2: PPI administration increased CgA in 83% and CgA was elevated in 26% of controls. PCR values were not elevated in either group. PCR performance metrics were as follows: sensitivity 98.4%, specificity 100%, positive predictive value 100%, negative predictive value 97.8%, and the ROC-derived area under the curve (AUC) was 0.997. These were significantly better than CgA (all metrics <60%; AUC, 0.54; Z-statistic, 10.44, P<0.0001). A 51-panel multigene blood transcript analysis is significantly more sensitive than plasma CgA for NET detection and is unaffected by acid suppression therapy.