CXCR4: From Signaling to Clinical Applications in Neuroendocrine Neoplasms.

There are several well-described molecular mechanisms that influence cell growth and are related to the development of cancer. Chemokines constitute a fundamental element that is not only involved in local growth but also affects angiogenesis, tumor spread, and metastatic disease. Among them, the C-X-C motif chemokine ligand 12 (CXCL12) and its specific receptor the chemokine C-X-C motif receptor 4 (CXCR4) have been widely studied. The overexpression in cell membranes of CXCR4 has been shown to be associated with the development of different kinds of histological malignancies, such as adenocarcinomas, epidermoid carcinomas, mesenchymal tumors, or neuroendocrine neoplasms (NENs). The molecular synapsis between CXCL12 and CXCR4 leads to the interaction of G proteins and the activation of different intracellular signaling pathways in both gastroenteropancreatic (GEP) and bronchopulmonary (BP) NENs, conferring greater capacity for locoregional aggressiveness, the epithelial-mesenchymal transition (EMT), and the appearance of metastases. Therefore, it has been hypothesized as to how to design tools that target this receptor. The aim of this review is to focus on current knowledge of the relationship between CXCR4 and NENs, with a special emphasis on diagnostic and therapeutic molecular targets.

Same-day comparative protocol PET/CT-PET/MRI [68 Ga]Ga-DOTA-TOC in paragangliomas and pheochromocytomas: an approach to personalized medicine.

BACKGROUND: PET/MRI is an emerging imaging modality which enables the evaluation and quantification of biochemical processes in tissues, complemented with accurate anatomical information and low radiation exposure. In the framework of theragnosis, PET/MRI is of special interest due to its ability to delineate small lesions, adequately quantify them, and therefore to plan targeted therapies. The aim of this study was to validate the diagnostic performance of [68 Ga]Ga-DOTA-TOC PET/MRI compared to PET/CT in advanced disease paragangliomas and pheochromocytomas (PGGLs) to assess in which clinical settings, PET/MRI may have a greater diagnostic yield. METHODS: We performed a same-day protocol with consecutive acquisition of a PET/CT and a PET/MRI after a single [68 Ga]Ga-DOTA-TOC injection in 25 patients. Intermodality agreement, Krenning Score (KS), SUVmax (Standard Uptake Value), target-to-liver-ratio (TLR), clinical setting, location, and size were assessed. RESULTS: The diagnostic accuracy with PET/MRI increased by 14.6% compared to PET/CT especially in bone and liver locations (mean size of new lesions was 3.73 mm). PET/MRI revealed a higher overall lesion uptake than PET/CT (TLR 4.12 vs 2.44) and implied an upward elevation of the KS in up to 60% of patients. The KS changed in 30.4% of the evaluated lesions (mean size 11.89 mm), in 18.4% of the lesions it increased from KS 2 on PET/CT to a KS ≥ 3 on PET/MRI and 24.96% of the lesions per patient with multifocal disease displayed a KS ≥ 3 on PET/MR, that were not detected or showed lower KS on PET/CT. In 12% of patients, PET/MRI modified clinical management. CONCLUSIONS: PET/MRI showed minor advantages over conventional PET/CT in the detection of new lesions but increased the intensity of SSRs expression in a significant number of them, opening the door to select which patients and clinical settings can benefit from performing PET/MRI.

Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma.

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.

Impact of Diabetes Mellitus in Patients with Pancreatic Neuro-Endocrine Tumors: Causes, Consequences, and Future Perspectives.

Diabetes mellitus (DM) and pancreatic neuroendocrine tumors (pNETs) are two entities closely linked together. DM has been described as a risk factor for the development of pNETs and for the aggressiveness of the disease. On the other hand, DM due to pNETs is frequently undiagnosed or misclassified as type 2 DM when it is due to type 3 DM. In addition, metformin, a commonly prescribed drug for type 2 DM, has an antiproliferative property and is gaining increasing attention as an antitumor agent. This review article presents the findings published in the last few years on pNETs and DMs. Emphasis will be placed on DM as a risk factor, pNET as a risk factor for the development of type 3 DM, the management of type 3 DM on pNET, and DM as a prognostic factor in patients with pNET, as well as the future clinical implications of DM in these patients. The coexistence of DM and pNET is extensively presented. It is important to perform future clinical trials, which are necessary to establish the role of metformin on pNET disease. Increasing awareness among professionals managing pNET on the importance of a correct DM diagnosis and management of the disease must be a priority due to the implications on mortality and comorbidities it may have in these patients.

Response to targeted radionuclide therapy with [131I]MIBG AND [177Lu]Lu-DOTA-TATE according to adrenal vs. extra-adrenal primary location in metastatic paragangliomas and pheochromocytomas: A systematic review.

Purpose: Targeted radionuclide therapy (TRT) with [131I]MIBG and [177Lu]Lu-DOTA-TATE is an alternative treatment to the classic schemes in slow progressive metastatic/inoperable paraganglioma (PGL) and pheochromocytoma (PHEO). There is no consensus on which treatment to administer and/or the best sequence in patients who are candidates for both therapies. To clarify these questions, this systematic review assesses the prognostic value of [131I]MIBG and [177Lu]Lu-DOTA-TATE (PRRT-Lu) treatments in terms of progression-free survival (PFS) both globally and considering the primary location. Methods: This review was developed according to the PRISMA Statement with 27 final studies (608 patients). Patient characteristics, treatment procedure, and follow-up criteria were evaluated. In addition, a Bayesian linear regression model weighted according to its sample size and an alternative model, which also included an interaction between the treatment and the proportion of PHEOs, were carried out, adjusted by a Student's t distribution. Results: In linear regression models, [131I]MIBG overall PFS was, on average, 10 months lower when compared with PRRT-Lu. When considering the interaction between treatment responses and the proportion of PHEOs, PRRT-Lu showed remarkably better results in adrenal location. The PFS of PRRT-Lu was longer when the ratio of PHEOs increased, with a decrease in [131I]MIBG PFS by 1.9 months for each 10% increase in the proportion of PHEOs in the sample. Conclusion: Methodology, procedure, and PFS from the different studies are quite heterogeneous. PRRT-Lu showed better results globally and specifically in PHEOs. This fact opens the window to prospective trials comparing or sequencing [131I]MIBG and PRRT-Lu.

[177Lu]Lu-DOTA-TATE and [131I]MIBG Phenotypic Imaging-Based Therapy in Metastatic/Inoperable Pheochromocytomas and Paragangliomas: Comparative Results in a Single Center.

Purpose: The aim of the study is to assess phenotypic imaging patterns and the response to treatment with [177Lu]Lu-DOTA-TATE and/or [131I]MIBG in paragangliomas (PGLs) and pheochromocytomas (PHEOs), globally and according to the primary location. Methods: This is a 17-patient retrospective observational study, with 9 cases treated with [177Lu]Lu-DOTA-TATE and 8 with [131I]MIBG (37 total treatments). Functional imaging scans and treatment responses were studied in order to choose the best therapeutic option and to define the progression-free survival (PFS) and disease control rate (DCR) according to treatment modality and primary location. Results: All patients were studied with phenotypic nuclear medicine images. Twelve of 17 patients were tested with both [123I]MIBG and somatostatin receptor images, and 6/12 showed appropriate expression of both targets to treatment in the phenotypic images. The rest of the patients were tested with one of the image modalities or only showed suitable uptake of a single radiotracer and were treated with the corresponding therapeutic option. [177Lu]Lu-DOTA-TATE PFS was 29 months with a DCR of 88.8%. [131I]MIBG PFS was 18.5 months with a 62.5% DCR. According to the primary location, the best PFS was in PHEOs treated with [177Lu]Lu-DOTA-TATE. Although the series are small due to the low disease prevalence and do not allow to yield statistically significant differences, this first study comparing [177Lu]Lu-DOTA-TATE and [131I]MIBG displays a trend to an overall longer PFS with [177Lu]Lu-DOTA-TATE, especially in the adrenal primary location. When both radionuclide targets are expressed, the patients' comorbidity and treatment effectiveness should be valued together with the intensity uptake in the phenotypic image in order to choose the best therapeutic option. These preliminary retrospective results reinforce the need for a prospective, multicentric trial to be confirmed.

Management of incidentally discovered appendiceal neuroendocrine tumors after an appendicectomy.

Appendiceal neuroendocrine tumors (aNETs) are an uncommon neoplasm that is relatively indolent in most cases. They are typically diagnosed in younger patients than other neuroendocrine tumors and are often an incidental finding after an appendectomy. Although there are numerous clinical practice guidelines on management of aNETs, there is continues to be a dearth of evidence on optimal treatment. Management of these tumors is stratified according to risk of locoregional and distant metastasis. However, there is a lack of consensus regarding tumors that measure 1-2 cm. In these cases, some histopathological features such as size, tumor grade, presence of lymphovascular invasion, or mesoappendix infiltration must also be considered. Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease, except in the case of tumors smaller than 1 cm without additional risk factors. Somatostatin receptor scintigraphy or positron emission tomography with computed tomography should be considered in cases with suspected residual or distant disease. The main point of controversy is the indication for performing a completion right hemicolectomy after an initial appendectomy, based on the risk of lymph node metastases. The main factor considered is tumor size and 2 cm is the most common threshold for indicating a colectomy. Other factors such as mesoappendix infiltration, lymphovascular invasion, or tumor grade may also be considered. On the other hand, potential complications, and decreased quality of life after a hemicolectomy as well as the lack of evidence on benefits in terms of survival must be taken into consideration. In this review, we present data regarding the current indications, outcomes, and benefits of a colectomy.

Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.

GLP 1 receptor agonists, glycemic variability, oxidative stress and acute coronary syndrome.

Glycemic variability (GV) has been recently described as an independent cardiovascular risk factor in patients with acute coronary syndrome (ACS). Also, new findings suggest that GV plays an important role in the development of complications related to impaired glucose metabolism and oxidative stress. On the other hand, although treatment for diabetes can reduce HbA1c in a similar extent their effectiveness over GV can be radically different. Patients in the acute setting of a coronary syndrome should be strictly monitorized to maintain glucose within recommended values; avoiding values lower than 90 mg/dL (5 mmol/L) and higher than 180 mg/dL (10 mmol/L). Also, evidence suggests the importance of not only maintaining glucose within certain values but also decreasing short-term GV as it has been associated with an increase in MACE in these patients. GLP-1 receptor agonists (GLP-1 RA) have demonstrated a decrease in GV and oxidative stress; therefore, the aim of this paper is to hypothesize the beneficial effect of GLP-1 RA in short-term GV and oxidative stress during the initial period of an ACS.

Simultaneous Pancreas Kidney Transplantation Improves Cardiovascular Autonomic Neuropathy with Improved Valsalva Ratio as the Most Precocious Test.

BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation is a proven option of treatment for patients with type 1 diabetes mellitus (T1DM) and related end-stage renal disease. There is discrepancy between the results of different studies about the impact of prolonged normalization of glucose metabolism achieved by SPK on the course of diabetic complications including severe forms of diabetic neuropathy. The objective of the study was to evaluate the prevalence of cardiovascular autonomic neuropathy (CAN) in patients undergoing SPK transplantation and its evolution 10 years after transplantation. METHODS: Prospective study of 81 patients transplanted in a single center from year 2002 to 2015. Autonomic function was assessed using cardiovascular autonomic reflex tests (CARTs). CARTs were made before SPK transplantation and during the follow-up. Evolution of tests after SPK transplantation was evaluated by contrasting hypotheses (paired tests). Multiple testing was adjusted with the Benjamini-Hochberg procedure with a false discovery rate of 10%. RESULTS: 48 males and 33 females, mean age 37.4 ± 5.7 years, mean BMI 24.0 ± 3.4 kg/m2, and mean duration of diabetes 25.5 ± 6.5 years, received SPK transplantation. Ten years after SPK transplantation, 56 patients re tained the pancreatic graft (42 of them with normofunctioning pancreas and 14 with low doses of insulin therapy). These 42 patients were selected for the autonomic study. Before transplant procedure, all CART results were abnormal. After SPK transplantation, paired test analysis showed an improvement of systolic blood pressure (SBP) response to orthostasis at the 5th year after SPK (p = 0.03), as well as improvement of the Valsalva ratio at the 3rd (p < 0.001) and 5th (p = 0.001) year after SPK. After correcting for the false discovery rate, all the variables of autonomic study reached significance at different time points. CONCLUSIONS: Prevalence of CAN in patients who are candidates for SPK transplantation is high and is generally advanced. SPK transplantation improves CAN with improved Valsalva ratio as the most precocious test.

Glycemic variability in type 2 diabetes mellitus and acute coronary syndrome: liraglutide compared with insulin glargine: a pilot study.

OBJECTIVE: To explore the glucagon-like peptide-1 analogue liraglutide in the hospital setting in patients with type 2 diabetes mellitus (T2DM) and acute coronary syndrome and to evaluate the safety and efficacy and its impact on hospitalization and short-term glycemic variability (GV). METHODS: A 12-week, open-label, prospective, randomized pilot clinical study with parallel groups that compared liraglutide (group 1) with glargine (group 2) and its impact on glycemic control and GV. RESULTS: Thirteen patients were included. During hospitalization, mean glucose was 164.75 mg/dL (standard deviation [SD] 19.94) in group 1 and 166.69 mg/dL (38.22) in group 2. GV determined by CV and SD was 20.98 (7.68) vs. 25.48 (7.19) and 34.37 (13.05) vs. 43.56 (19.53) in groups 1 and 2, respectively. Group 1 prandial insulin requirements during hospitalization were lower compared with group 2. Follow-up A1c in group 1 was 6.9% (-1.51%) and 6.5% in group 2 (-1.27). GV after discharge and hypoglycemia were lower in group 1 compared with group 2. CONCLUSIONS: Liraglutide seems to reduce GV in the acute phase of acute coronary syndrome, and patients achieved optimal control with a low incidence of hypoglycemia. These results support the need to explore liraglutide in a larger multicenter trial. Trial registration: The study was approved by the National Medical Ethics Committee of Spain. The study was registered at European Clinical Trials Database (EudraCT): 2014003298-40.

Prevention and Management of Hormonal Crisis during Theragnosis with LU-DOTA-TATE in Neuroendocrine Tumors. A Systematic Review and Approach Proposal.

Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTR) on their cell surface. The first-line pharmacological treatment for inoperable metastatic functioning well-differentiated NETs are somatostatin analogs. On second line, Lu-DOTA-TATE (177Lu-DOTA0 Tyr 3 octreotate) has shown stabilization of the disease and an increase in progression free survival, as well as effectiveness in controlling symptoms and increasing quality of life. The management of functional NETs before and during LU-DOTA-TATE treatment is specially challenging, as several complications such as severe carcinoid and catecholamine crisis have been described. The aim of this review is to establish practical guidance for the management and prevention of the most common hormonal crises during radionuclide treatment with Lu-DOTA-TATE: carcinoid syndrome (CS) and catecholamine hypersecretion, as well as to provide a brief commentary on other infrequent metabolic complications. To establish a practical approach, a systematic review was performed. This systematic review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and conducted using MEDLINE (accessed from PubMed), Google Scholar and ClinicalTrials.gov. Literature searches found 449 citations, and finally nine were considered for this systematic review.

Autoimmune Diabetes Recurrence After Pancreas Transplantation: Diagnosis, Management, and Literature Review.

BACKGROUND Pancreas transplantation can be a viable treatment option for patients with type 1 diabetes mellitus (T1DM), especially for those who are candidates for kidney transplantation. T1DM may rarely recur after pancreas transplantation, causing the loss of pancreatic graft. The aim of this study was to describe the prevalence of T1DM recurrence after pancreas transplantation in our series. MATERIAL AND METHODS Eighty-one patients transplanted from 2002 to 2015 were included. Autoantibody testing (GADA and IA-2) was performed before pancreas transplantation and during the follow-up. RESULTS The series includes 48 males and 33 females, mean age 37.4±5.7 years and mean duration of diabetes 25.5±6.5 years. Patients received simultaneous pancreas kidney (SPK) transplantation. After SPK transplantation, 56 patients retained pancreatic graft, 8 patients died, and 17 patients lost their pancreatic graft. T1DM recurrence occurred in 2 of the 81 transplanted patients, yielding a prevalence of 2.5%, with an average time of appearance of 3.3 years after transplant. Pancreatic enzymes were normal in the 2 patients, ruling out pancreatic rejection. T1DM recurrence was confirmed histologically, showing selective lymphoid infiltration of the pancreatic islets. CONCLUSIONS T1DM recurrence after pancreas transplantation is infrequent; however, it is one of the causes of pancreatic graft loss that should always be ruled out. Negative autoimmunity prior to transplantation does not ensure that T1DM does not recur.

GLP-1 Receptor Agonists and Cardiovascular Disease in Patients with Type 2 Diabetes.

Diabetes mellitus is a chronic disease prevalence of which is high and continually growing. Cardiovascular disease continues to be the leading cause of death in patients with T2DM. The prevention of cardiovascular complications and the cardiovascular safety of treatments should be a primary objective when selecting treatment. Among all the drugs available, the compounds known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) appear to be not just innocuous in terms of CVD but indeed to be beneficial. GLP-1 RA actions not only translate on an improvement of well-known cardiovascular risk factors such as glycaemic control, dyslipidaemia, weight, or arterial hypertension but also might show benefits on endothelial function, coronary ischaemia, and heart failure. On the other hand, recent clinical trials aimed at studying cardiovascular episodes have been conducted with GLP-1 RAs. Only liraglutide and semaglutide have shown superiority in cardiovascular benefit compared with placebo. Although many of the mechanisms by which liraglutide and semaglutide produce a cardiovascular benefit are still unknown it would be desirable for these benefits to be incorporated into the therapeutic algorithms routinely used in clinical practice. The purpose of this review is to explore GLP-1 RA actions not only in cardiovascular risk factors (glucose, weight, and hypertension) but also the possible effects on established cardiovascular disease.

Hypogonadotropic hypogonadism in a patient with morbid obesity.

Obesity has recently become one of the most important public health problems. It is associated with a high rate of mortality, mainly because of cardiovascular disease, and can cause hormonal abnormalities such as hypogonadotropic hypogonadism. Weight loss is very beneficial for obese patients, because it results in improvement or even normalization of these conditions. In this report, we describe a morbidly obese patient with hypogonadotropic hypogonadism, which was probably caused by hyperprolactinemia and exacerbated by obesity-induced hormonal imbalances. After medical treatment for hyperprolactinemia and bariatric surgery, the patient's hormonal status became normal. Although morbid obesity can cause hypogonadotropic hypogonadism in men, the differential diagnosis should include other potential causes of hypogonadism if free testosterone levels are below normal.

[Prevalence of malnutrition in a mid-long term stay unit]. / Prevalencia de desnutrición en una unidad de media y larga estancia hospitalaria.

INTRODUCTION: Malnutrition is a common health problem, especially in hospitalized patients, where it's associated with longer hospital stays and higher rates of morbidity and mortality. Furthermore, current scientific advances and life expectancy increase, have produced a progressive increase of mid- to long-term stay units (UMLE). AIMS: To determinate the prevalence of malnutrition on admission to a mid- to long-term stay unit, using MNA and VGS and to analyze the possible factors/clinical features associated with malnutrition and its consequences. METHODS: Descriptive and transversal study conducted with 201 patients admitted consecutively for 12 months in an Universitary Hospital mid- to long-term stay unit (Valencia). Clinical, anthropometric, biochemical and nutritional history data were registered, as well as Charlson comorbidity scale, Pfeiffer cognitive scale, Barthel functional scale and presence of edema, ascitis and pressure ulcers. Nutritional status was evaluated in the first 24-72 hours of admission using MNA and VGS. Dysphagia was evaluated using EAT-10 and MECV-V questionnaires. RESULTS: The overall rate of malnutrition was 76,6%, being severe protein energy malnutrition the most common type (20,4%). Malnourished patients were older (p=0,002), presented greater dependence (p.

Introducción: La desnutrición es un problema de salud frecuente, especialmente en el ámbito hospitalario donde se asocia con estancias más prolongadas y mayor tasa de morbi-mortalidad. Por otro lado, los avances científicos actuales y la mayor expectativa de vida, han producido un aumento progresivo de unidades de media y larga estancia (UMLE). Objetivos: Determinar la prevalencia de desnutrición en una UMLE mediante el uso del MNA y la VGS, así como analizar los factores/características clínicas asociadas a la misma y sus repercusiones. Métodos: Estudio transversal, descriptivo de una cohorte formada por 201 pacientes ingresados en la UMLE de un Hospital universitario de forma consecutiva durante 12 meses. Se recogieron variables clínicas, antropométricas, bioquímicas e historia nutricional, así como escala de comorbilidad de Charlson, escala cognitiva de Pfeiffer, escala funcional de Barthel y presencia de edemas, ascitis y úlceras por presión. El estado nutricional fue evaluado en las primeras 24-72 horas de ingreso mediante el MNA y la VGS. La presencia de disfagia se evaluó mediante el cuestionario EAT-10 y el MECV-V. Resultados: La prevalencia global de desnutrición fue del 76,6%, siendo la desnutrición mixta grave la más prevalente (20.4%). Los pacientes desnutridos tenían más edad (p=0,002), mayor grado de dependencia (p.

Alterations of the female reproductive system in islet recipient receiving immunosuppression.

Pancreatic islet allotransplantation is an option for patients with unstable type 1 diabetes mellitus (T1DM). Major improvements in islet isolation techniques and the implementation of steroid-free immunosuppressive regimens can maintain insulin independence in the majority of T1DM for at least 1 year after transplantation. Recent studies have emphasized the impact of sirolimus on female reproductive tract. In this communication we report on the alterations of the female reproductive tract in 18 chronically immunosuppressed patients with T1DM following allogenic islet transplantation. Previous research has shown development of ovarian cysts in islet transplant patients receiving sirolimus. We extensively reevaluated this and other possible side effects on the female reproductive system. These side effects have been underestimated, although they are significant, requiring surgical or intensive medical treatment. Pre- and posttransplant gynecological evaluation should be performed to address the development of complications secondary to sirolimus in order to intervene sooner with alternative therapies.

Hemorragia alveolar difusa como primera manifestación clínica de un feocromocitoma / Diffuse Alveolar Hemorrhage as First Manifestation of a Pheochromocytoma

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