Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery.

BACKGROUND: Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. METHODS: We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. RESULTS: The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. CONCLUSIONS: These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

A New Generation Somatostatin-Dopamine Analogue Exerts Potent Antitumoral Actions on Pituitary Neuroendocrine Tumor Cells.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed. OBJECTIVE: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes. METHODS: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065. RESULTS: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation. CONCLUSIONS: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs.

Statins Directly Regulate Pituitary Cell Function and Exert Antitumor Effects in Pituitary Tumors.

INTRODUCTION: Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostatin analogues [SSAs]/dopamine agonists), underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin (MF) or SSAs. METHODS: Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, nonfunctioning pituitary tumors, and PitNET cell-lines (AtT20/GH3-cells). RESULTS: All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GH-releasing hormone-receptor/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects. CONCLUSION: Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs.

Long-Term Impact of an Educational Antimicrobial Stewardship Program on Hospital-Acquired Candidemia and Multidrug-Resistant Bloodstream Infections: A Quasi-Experimental Study of Interrupted Time-Series Analysis.

BACKGROUND: The global crisis of bacterial resistance urges the scientific community to implement intervention programs in healthcare facilities to promote an appropriate use of antibiotics. However, the clinical benefits or the impact on resistance of these interventions has not been definitively proved. METHODS: We designed a quasi-experimental intervention study with an interrupted time-series analysis. A multidisciplinary team conducted a multifaceted educational intervention in our tertiary-care hospital over a 5-year period. The main activity of the program consisted of peer-to-peer educational interviews between counselors and prescribers from all departments to reinforce the principles of the proper use of antibiotics. We assessed antibiotic consumption, incidence density of Candida and multidrug-resistant (MDR) bacteria bloodstream infections (BSIs) and their crude death rate per 1000 occupied bed days (OBDs). RESULTS: A quick and intense reduction in antibiotic consumption occurred 6 months after the implementation of the intervention (change in level, -216.8 defined daily doses per 1000 OBDs; 95% confidence interval, -347.5 to -86.1), and was sustained during subsequent years (average reduction, -19,9%). In addition, the increasing trend observed in the preintervention period for the incidence density of candidemia and MDR BSI (+0.018 cases per 1000 OBDs per quarter; 95% confidence interval, -.003 to .039) reverted toward a decreasing trend of -0.130 per quarter (change in slope, -0.029; -.051 to -.008), and so did the mortality rate (change in slope, -0.015; -.021 to -.008). CONCLUSIONS: This education-based antimicrobial stewardship program was effective in decreasing the incidence and mortality rate of hospital-acquired candidemia and MDR BSI through sustained reduction in antibiotic use.

Is a second recombinant human thyrotropin stimulation test useful? The value of postsurgical undetectable stimulated thyroglobulin level at the time of remnant ablation on clinical outcome.

OBJECTIVE: The management of patients with differentiated thyroid cancer (DTC) has changed in recent years, and monitoring depends on the risk of persistent/recurrent disease. The objective was to assess the prognostic value of a single stimulated thyroglobulin (Tg) measured at the time of the first radioiodine therapy (Stim-Tg1), and the utility of a second stimulated Tg measurement performed 6-12 months later (Stim-Tg2). We also examined the role of neck ultrasound (US) in the early diagnosis of recurrence. DESIGN: This was a retrospective observational cohort study conducted in a tertiary referral hospital. Of 213 evaluated patients with DTC, 169 were finally included. METHODS: Measurement of Stim-Tg1, Stim-Tg2 and neck US. RESULTS: Stim-Tg1 was undetectable in 71 of 169 patients (42%). All of them (71/71) continued to have negative Stim-Tg2. Seventy of 71 had an excellent response to the first treatment. Sixty-eight of 71 had no evidence of disease after an average follow-up of 7·2 years. In patients with detectable Stim-Tg1 (98/169; 58%), Stim-Tg2 became negative in 40. The negative predictive value (NPV) of Stim-Tg1 was 0·96. The optimal Stim-Tg1 cut-off level for identifying persistence was 3·65 ng/ml. Recurrence was detected in 14 patients. Neck US was useful for identifying local recurrence (13/14; 92·85%). CONCLUSIONS: Stim-Tg1 is a reliable marker with a high NPV. A second stimulation test should be avoided in patients with negative Stim-Tg1. In patients with biochemical persistence, Stim-Tg2 is useful for confirming/ruling out final status. Neck US plays a valuable role in the early diagnosis of recurrence.

Variations in diabetes remission rates after bariatric surgery in Spanish adults according to the use of different diagnostic criteria for diabetes.

BACKGROUND: There are multiple criteria to define remission of type 2 diabetes (DM2) after bariatric surgery but there is not a specific one widely accepted. Our objectives were to compare diagnostic criteria for DM2 remission after bariatric surgery: Criteria from Spanish scientific associations (SEEN/SEEDO/SED) and from the American Diabetes Association (ADA). We also aim to analyse the degree of correlation between these sets of criteria. METHODS: Retrospective observational study in 127 patients undergoing bariatric surgery in a single centre (Hospital Universitario Reina Sofía, Córdoba, Spain) between January 2001 and December 2009. We analysed DM2 remission following bariatric surgery comparing DM2 diagnostic criteria approved by Spanish scientific associations and ADA criteria. RESULTS: In total, 62.2% of patients were women; mean age was 47.1 years. Following surgery, 52% achieved complete remission according to ADA criteria, and 63.8% following the criteria approved by Spanish associations (p = 0.001);18.9 and 8.7%, respectively, showed partial remission (p = 0.007), and 29.1 and 27.6% no remission, according to the criteria approved by each association (p = 0.003). There was good correlation between both sets of criteria (Rho 0.781; p < 0.001). CONCLUSIONS: In our series, using more stringent criteria for defining DM2 remission (ADA criteria) results in a lower rate of remission, although we found a a high degree of correlation between both sets of criteria.

Thyroid remnant ablation success and disease outcome in stage III or IV differentiated thyroid carcinoma: recombinant human thyrotropin versus thyroid hormone withdrawal.

BACKGROUND: Most publications to date compare outcomes after post-surgical thyroid remnant ablation stimulated by recombinant human thyrotropin (rhTSH) versus thyroid hormone withholding/withdrawal (THW) in low-recurrence risk differentiated thyroid carcinoma (DTC) patients. We sought to perform this comparison in high-risk patients. METHODS: We retrospectively analyzed ~9-year single-center experience in 70 consecutive adults with initial UICC (Union for International Cancer Control) stage III/IV, M0 DTC undergoing rhTSH-aided (N.=54) or THW-aided (N.=16) high-activity ablation. Endpoints included ablation success and DTC outcome. Assessed ≥1 year post-ablation, ablation success comprised a) no visible scintigraphic thyroid bed uptake or pathological extra-thyroidal uptake; b) undetectable stimulated serum thyroglobulin (Tg) without interfering autoantibodies; c) both criteria. DTC outcome, determined at the latest visit, comprised either 1) "no evidence of disease" (NED): undetectable Tg, negative Tg autoantibodies, negative most recent whole-body scan, no suspicious findings clinically, on neck ultrasonography, or on other imaging; 2) persistent disease: failure to attain NED; or 3) recurrence: loss of NED. RESULTS: After the first ablative activity, ablation success by scintigraphic plus biochemical criteria was 64.8% in rhTSH patients, 56.3% in THW patients (P=NS). After 3.5-year versus 6.2-year median follow-up (P<0.05), DTC outcomes were NED, 85.2%, persistent disease, 13.0%, recurrence, 1.9%, in the rhTSH group and NED, 87.5%, persistent or recurrent disease, 6.3% each, in the THW group (P=NS). CONCLUSION: In patients with initial stage III/IV, M0 DTC, rhTSH-aided and THW-assisted ablation were associated with comparable remnant eradication or DTC cure rates.

Flexible and scalable genotyping-by-sequencing strategies for population studies.

BACKGROUND: Many areas critical to agricultural production and research, such as the breeding and trait mapping in plants and livestock, require robust and scalable genotyping platforms. Genotyping-by-sequencing (GBS) is a one such method highly suited to non-human organisms. In the GBS protocol, genomic DNA is fractionated via restriction digest, then reduced representation is achieved through size selection. Since many restriction sites are conserved across a species, the sequenced portion of the genome is highly consistent within a population. This makes the GBS protocol highly suited for experiments that require surveying large numbers of markers within a population, such as those involving genetic mapping, breeding, and population genomics. We have modified the GBS technology in a number of ways. Custom, enzyme specific adaptors have been replaced with standard Illumina adaptors compatible with blunt-end restriction enzymes. Multiplexing is achieved through a dual barcoding system, and bead-based library preparation protocols allows for in-solution size selection and eliminates the need for columns and gels. RESULTS: A panel of eight restriction enzymes was selected for testing on B73 maize and Nipponbare rice genomic DNA. Quality of the data was demonstrated by identifying that the vast majority of reads from each enzyme aligned to restriction sites predicted in silico. The link between enzyme parameters and experimental outcome was demonstrated by showing that the sequenced portion of the genome was adaptable by selecting enzymes based on motif length, complexity, and methylation sensitivity. The utility of the new GBS protocol was demonstrated by correctly mapping several in a maize F2 population resulting from a B73×Country Gentleman test cross. CONCLUSIONS: This technology is readily adaptable to different genomes, highly amenable to multiplexing and compatible with over forty commercially available restriction enzymes. These advancements represent a major improvement in genotyping technology by providing a highly flexible and scalable GBS that is readily implemented for studies on genome-wide variation.

The Trichoplax genome and the nature of placozoans.

As arguably the simplest free-living animals, placozoans may represent a primitive metazoan form, yet their biology is poorly understood. Here we report the sequencing and analysis of the approximately 98 million base pair nuclear genome of the placozoan Trichoplax adhaerens. Whole-genome phylogenetic analysis suggests that placozoans belong to a 'eumetazoan' clade that includes cnidarians and bilaterians, with sponges as the earliest diverging animals. The compact genome shows conserved gene content, gene structure and synteny in relation to the human and other complex eumetazoan genomes. Despite the apparent cellular and organismal simplicity of Trichoplax, its genome encodes a rich array of transcription factor and signalling pathway genes that are typically associated with diverse cell types and developmental processes in eumetazoans, motivating further searches for cryptic cellular complexity and/or as yet unobserved life history stages.

Evolutionary genetics of the hydroid allodeterminant alr2.

We surveyed genetic variation in alr2, an allodeterminant of the colonial hydroid Hydractinia symbiolongicarpus. We generated cDNA from a sample of 239 Hydractinia colonies collected at Lighthouse Point, Connecticut, and identified 473 alr2 alleles, 198 of which were unique. Rarefaction analysis suggested that the sample was near saturation. Most alleles were rare, with 86% occurring at frequencies of 1% or less. Alleles were highly variable, diverging on average by 18% of the amino acids in a predicted extracellular domain of the molecule. Analysis of 152 full-length alleles confirmed the existence of two structural types, defined by exons 4-8 of the gene. Several residues of the predicted immunoglobulin superfamily-like domains display signatures of positive selection. We also identified 77 unique alr2 pseudogene sequences from 85 colonies. Twenty-seven of these sequences matched expressed alr2 sequences from other colonies. This observation is consistent with pseudogenes contributing to alr2 diversification through sequence donation. A more limited collection of animals was made from a distant, relict population of H. symbiolongicarpus. Sixty percent of the unique sequences identified in this sample were found to match sequences from the Lighthouse Point population. The large number of alr2 alleles, their degree of divergence, the predominance of rare alleles in the population, their persistence over broad spatial and temporal scales, and the signatures of positive selection in multiple residues of the putative recognition domain paint a consistent picture of negative-frequency-dependent selection operating in this system. The genetic diversity observed at alr2 is comparable to that of the most highly polymorphic genetic systems known to date.

Bariatric surgery and calcifediol treatment, Gordian knot of severe-obesity-related comorbidities treatment.

Background: Obesity (OB) is a chronic metabolic disease with important associated comorbidities and mortality. Vitamin D supplementation is frequently administered after bariatric surgery (BS), so as to reduce OB-related complications, maybe including chronic inflammation. Aim: This study aimed to explore relations between vitamin D metabolites and components of the inflammasome machinery in OB before and after BS and their relations with the improvement of metabolic comorbidities. Patients and methods: Epidemiological/clinical/anthropometric/biochemical evaluation was performed in patients with OB at baseline and 6 months after BS. Evaluation of i) vitamin-D metabolites in plasma and ii) components of the inflammasome machinery and inflammatory-associated factors [NOD-like-receptors (NLRs), inflammasome-activation-components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators] in peripheral blood mononuclear cells (PBMCs) was performed at baseline and 6 months after BS. Clinical and molecular correlations/associations were analyzed. Results: Significant correlations between vitamin D metabolites and inflammasome-machinery components were observed at baseline, and these correlations were significantly reduced 6 months after BS in parallel to a decrease in inflammation markers, fat mass, and body weight. Treatment with calcifediol remarkably increased 25OHD levels, despite 24,25(OH)2D3 remained stable after BS. Several inflammasome-machinery components were associated with improvement in metabolic comorbidities, especially hypertension and dyslipidemia. Conclusion: The beneficial effects of vitamin D on OB-related comorbidities after BS patients are associated with significant changes in the molecular expression of key inflammasome-machinery components. The expression profile of these inflammasome components can be dynamically modulated in PBMCs after BS and vitamin D supplementation, suggesting that this profile could likely serve as a sensor and early predictor of the reversal of OB-related complications after BS.

Spliceosomic dysregulation unveils NOVA1 as a candidate actionable therapeutic target in pancreatic neuroendocrine tumors.

Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n = 13) and minor spliceosome (n = 4) and associated splicing factors (n = 27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently, in vivo and in vitro models were applied to explore the pathophysiological role of NOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Using in vivo and in vitro assays, we demonstrate that one of those altered factors, NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance of NOVA1 in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.

Genetic diversity of the allodeterminant alr2 in Hydractinia symbiolongicarpus.

Hydractinia symbiolongicarpus, a colonial cnidarian (class Hydrozoa) epibiont on hermit crab shells, is well established as a model for genetic studies of allorecognition. Recently, two linked loci, allorecognition (alr) 1 and alr2, were identified by positional cloning and shown to be major determinants of histocompatibility. Both genes encode putative transmembrane proteins with hypervariable extracellular domains similar to immunoglobulin (Ig)-like domains. We sought to characterize the naturally occurring variation at the alr2 locus and to understand the origins of this molecular diversity. We examined full-length cDNA coding sequences derived from a sample of 21 field-collected colonies, including 18 chosen haphazardly and two laboratory reference strains. Of the 35 alleles recovered from the 18 unbiased samples, 34 encoded unique gene products. We identified two distinct structural classes of alleles that varied over a large central region of the gene but both possessed highly polymorphic extracellular domains I, similar to an Ig-like V-set domain. The discovery of structurally chimeric alleles provided evidence that interallelic recombination may contribute to alr2 variation. Comparisons of the genomic region encompassing alr2 from two field-derived haplotypes and one laboratory reference sequence revealed a history of structural variation at the haplotype level as well. Maintenance of large numbers of equally rare alleles in a natural population is a hallmark of negative frequency-dependent selection and is expected to produce high levels of heterozygosity. The observed alr2 allelic diversity is comparable with that found in immune recognition molecules such as human leukocyte antigens, B cell Igs, or natural killer cell Ig-like receptors.

Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST5 ) in pituitary and pancreatic neuroendocrine tumors.

Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients: the SOLID study.

BACKGROUND: At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. METHODS: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. RESULTS: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2-10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8-56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0-5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. CONCLUSIONS: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04407143.

Catecholaminergic Crisis After a Bleeding Complication of COVID-19 Infection: A Case Report.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents in some cases with hemostatic and thrombotic complications. Pheochromocytomas are unusual, though potentially lethal tumors. Herein we describe the first case of hemorrhage in a pheochromocytoma related to SARS-CoV-2 infection. A 62-year-old man consulted for syncope, fever, and palpitations. He was diagnosed with SARS-CoV-2 pneumonia and presented with a hemorrhage in a previously unknown adrenal mass, which resulted in a catecholaminergic crisis. Medical treatment and surgery were required for symptom control and stabilization. We hereby alert clinicians to watch for additional/unreported clinical manifestations in COVID-19 infection.

Dysregulation of Components of the Inflammasome Machinery After Bariatric Surgery: Novel Targets for a Chronic Disease.

BACKGROUND: Obesity is a metabolic chronic disease with important associated morbidities and mortality. Bariatric surgery is the most effective treatment for maintaining long-term weight loss in severe obesity and, consequently, for decreasing obesity-related complications, including chronic inflammation. AIM: To explore changes in components of the inflammasome machinery after bariatric surgery and their relation with clinical/biochemical parameters at baseline and 6 months after bariatric surgery. PATIENTS AND METHODS: Twenty-two patients with morbid-obesity that underwent bariatric surgery (sleeve gastrectomy and Roux-en-Y gastric bypass) were included. Epidemiological/clinical/anthropometric/biochemical evaluation was performed at baseline and 6 months after bariatric surgery. Inflammasome components and inflammatory-associated factors [nucleotide-binding oligomerization domain-like receptors (NLRs), inflammasome activation components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators) were evaluated in peripheral blood mononuclear cells (PBMCs) at baseline and 6 months after bariatric surgery. Clinical molecular correlations/associations were analyzed. Functional parameters (lipid accumulation/viability/apoptosis) were analyzed in response to specific inflammasome components silencing in liver HepG2 cells). RESULTS: A profound dysregulation of inflammasome components after bariatric surgery was found, especially in NLRs and cell-cycle and DNA damage regulators. Several components were associated with baseline metabolic comorbidities including type 2 diabetes (C-C motif chemokine ligand 2/C-X-C motif chemokine receptor 1/sirtuin 1), hypertension (absent in melanoma 2/ASC/purinergic receptor P2X 7), and dyslipidemia [C-X-C motif chemokine ligand 3 (CXCL3)/NLR family pyrin domain containing (NLRP) 7) and displayed changes in their molecular profile 6 months after bariatric surgery. The gene expression fingerprint of certain factors NLR family CARD domain containing 4 (NLRC4)/NLRP12/CXCL3)/C-C motif chemokine ligand 8/toll-like receptor 4) accurately differentiated pre- and postoperative PBMCs. Most changes were independent of the performed surgical technique. Silencing of NLRC4/NLRP12 resulted in altered lipid accumulation, apoptosis rate, and cell viability in HepG2 cells. CONCLUSION: Bariatric surgery induces a profound alteration in the gene expression pattern of components of the inflammasome machinery in PBMCs. Expression and changes of certain inflammasome components are associated to baseline metabolic comorbidities, including type 2 diabetes, and may be related to the improvement and reversion of some obesity-related comorbidities after bariatric surgery.

Neuroendocrine neoplasms: current and potential diagnostic, predictive and prognostic markers.

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, for example, 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.

Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives.

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.