Effect of lipoprotein (a) on the analytical determination of low-density lipoprotein cholesterol (LDLc) and its influence on pharmacological treatment with atorvastatin.

Lipoprotein(a) (Lp(a)) and Low-density lipoprotein cholesterol (LDLc) is an important risk factor for atherosclerotic cardiovascular disease. The objective of this study was to determine the impact of Lp(a) concentration both on the indirect analytical measurement of LDLc and on the efficacy of dyslipidaemia treatment using the atorvastatin statin. Two retrospective studies were conducted, one with 340 patients and another with 107 patients treated with atorvastatin. Lp(a) concentrations were measured by turbidimetry with an assay independent of the size of the apo(a) isoform. LDLc was calculated using the Friedewald equation and the corrected LDLc was calculated using the Dahlén equation. A strong positive correlation was observed between the serum Lp(a) concentration and the LDLc-overestimation percentage (r = 0.960, p < .001). It was also observed that as the Lp(a) concentration rose there was no significant variation in the percentage decrease in corrected LDLc during atorvastatin treatment (r = 0.186, p > .05). The concentration of LDLc obtained by using the Friedewald equation included Lp(a) cholesterol. The lowering of LDLc in patients treated with atorvastatin depended solely on accessible LDL cholesterol and not on Lp(a) cholesterol.

Immunotherapy-induced isolated ACTH deficiency in cancer therapy.

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

LAT-1 and GLUT-1 Carrier Expression and Its Prognostic Value in Gastroenteropancreatic Neuroendocrine Tumors.

Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors.

Evaluation of 177Lu-Dotatate treatment in patients with metastatic neuroendocrine tumors and prognostic factors.

BACKGROUND: 177Lu peptide receptor radionuclide therapy (PRRT) is a recently approved therapy in Spain that has been demonstrated to be a well-tolerated therapy for positive somatostatin receptor advanced gastroenteropancreatic neuroendocrine tumors. AIM: To determine the impact of PRRT on quality of life, radiologic and metabolic response, overall survival, prognostic factors and toxicity. METHODS: Thirty-six patients treated with 177Lu-PRRT from 2016 to 2019 were included. The most frequent location of the primary tumor was the gastrointestinal tract (52.8%), pancreas (27.8%), and nongastropancreatic neuroendocrine tumor (11.1%). The liver was the most common site of metastasis (91.7%), followed by distant nodes (50.0%), bone (27.8%), peritoneum (25.0%) and lung (11.1%). Toxicity was evaluated after the administration of each dose. Treatment efficacy was evaluated by two parameters: stable disease and disease progression in response evaluation criteria in solid tumors 1.1 criterion and prognostic factors were tested. RESULTS: From 36 patients, 55.6% were men, with a median age of 61.1 ± 11.8 years. Regarding previous treatments, 55.6% of patients underwent surgery of the primary tumor, 100% of patients were treated with long-acting somatostatin analogues, 66.7% of patients were treated with everolimus, 27.8% of patients were treated with tyrosine kinase inhibitor, and 27.8% of patients were treated with interferon. One patient received radioembolization, three patients received chemoembolization, six patients received chemotherapy. Hematological toxicity was registered in 14 patients (G1-G2: 55.5% and G3: 3.1%). Other events presented were intestinal suboclusion in 4 cases, cholestasis in 2 cases and carcinoid crisis in 1 case. The median follow-up time was 3 years. Currently, 24 patients completed treatment. Nineteen are alive with stable disease, two have disease progression, eight have died, and nine are still receiving treatment. The median overall survival was 12.5 mo (95% confidence interval range: 9.8-15.2), being inversely proportional to toxicity in previous treatments (P < 0.02), tumor grade (P < 0.01) and the presence of bone lesions (P = 0.009) and directly proportional with matching lesion findings between Octreoscan and computed tomography pre-PRRT (P < 0.01), , primary tumor surgery (P = 0.03) and metastasis surgery (P = 0.045). In a multivariate Cox regression analysis, a high Ki67 index (P = 0.003), a mismatch in the lesion findings between Octreoscan and computed tomography pre-PRRT (P < 0.01) and a preceding toxicity in previous treatments (P < 0.05) were risk factors to overall survival. CONCLUSION: Overall survival was inversely proportional to previous toxicity, tumor grade and the presence of bone metastasis and directly proportional to matching lesion findings between Octreoscan and computed tomography pre-PRRT and primary tumor and metastasis surgery.

Analysis of expression of the PD-1/PD-L1 immune checkpoint system and its prognostic impact in gastroenteropancreatic neuroendocrine tumors.

The immune checkpoint based therapy targeting the programmed death-1 (PD-1) receptor and its PD-L1 ligand has recently been approved for the therapy of different malignant conditions, but not yet for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this context, we evaluated the expression of PD-1 and PD-L1 in GEP-NETs and its potential correlations with clinical outcomes. Expression of PD-1/PD-L1 was analyzed by immunohistochemistry in 116 GEP-NETs and 48 samples of peritumoral tissue. In addition, the expression of these molecules was assessed by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with GEP-NETs (n = 32) and healthy controls (n = 32) and in intratumoral mononuclear cells (TMCs) (n = 3). Expression of PD-L1 and PD-1 was detected by immunohistochemistry in 6% and 1% of tumor tissue samples, respectively, and in 8% of peritumoral tissue samples, for both markers. We also observed that PD-1 expression by TMCs was associated with metastatic disease at diagnosis, and the levels of circulating PD-1+ PBMCs were associated with progressive disease upon follow-ups. In addition, circulating PD-1+ PBMCs were significantly correlated with PD-L1 expression by tumor cells. Our data suggest that PD-1/PD-L1 is expressed in 1 to 8% of GEP-NETs, and that this feature is significantly associated with disease evolution (p < 0.01).

Tendencias de la mortalidad por diabetes en España: por el buen camino / Trends in mortality from diabetes in spain: on the right way

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Aggressiveness of the tall cell variant of papillary thyroid carcinoma is independent of the tumor size and patient age.

The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is characterized by tall columnar cells with a height of at least three times their width. TCV usually presents at an older age, has a larger size and exhibits more extrathyroidal extension and metastases than classical PTC. The current study compared TCV with the classical and follicular variants (CaFVs) of PTC to determine if, irrespective of the age at diagnosis and tumor size, TCV is more aggressive than its classical and follicular counterparts. A total of 16 (3.66%) patients with TCV were identified in a series of 437 patients with PTC from the Clinical University Hospital (Santiago de Compostela, Spain) between 1990 and 2010. The patient clinicopathological features and B-Raf proto-oncogene (BRAF)V600E mutational status were compared with 34 cases of CaFVs of PTC matched for tumor size and patient age. The TCV series included 11 females and 5 males aged 15-74 years (median, 57 years). In total, 15 (93.8%) patients underwent total or near-total thyroidectomy, 1 underwent lobectomy and 5 (31.3%) underwent lymph node dissection. In the TCV series, the tumor size ranged from 5-45 mm (median, 19 mm). Compared with the CaFVs, the TCV of PTC exhibited a significantly higher prevalence of extrathyroidal extension [9/16 (56.3%) vs. 5/34 (14.7%) cases; P=0.007], lymph node metastases [9/16 (56.3%) vs. 9/34 (26.4%) cases; P=0.04], stage III/IV at presentation [10/16 (62.5%) vs. 7/34 (20.5%) cases; P=0.009] and BRAFV600E mutation [12/16 (80.0%) vs. 7/25 (28.0%) cases; P=0.004]. The TCV series also harbored more multifocal papillary carcinomas (50.0% vs. 26.4%), lymphovascular invasion (37.5% vs. 29.4%) and distant metastases (6.2% vs. 0.0%), as compared with the matched patient cohort. In conclusion, the TCV of PTC is frequently associated with BRAFV600E mutation and is more aggressive than the CaFVs of PTC, regardless of tumor size and patient age at diagnosis.

Long-term outcome of multimodal therapy for giant prolactinomas.

Giant prolactinomas are rare tumors characterized by their large size, compressive symptoms, and extremely high prolactin secretion. The aim of this study is to describe our experience with a series of 16 giant prolactinomas cases in terms of clinical presentation, therapeutic decisions, and final outcomes. Retrospective analysis of adult patients diagnosed with giant prolactinomas at the endocrine departments of three university tertiary hospitals. We included 16 patients (43.7 % women); mean age at diagnosis: 42.1 ± 21 years. The most frequent presentation was compressive symptoms. The delay in diagnosis was higher in women (median of 150 months vs. 12 in men; p = 0.09). The mean maximum tumor diameter at diagnosis was 56.9 ± 15.5 mm, and mean prolactin levels were 10,995.9 ± 12,157.8 ng/mL. Dopamine agonists were the first-line treatment in 11 patients (mean maximum dose: 3.9 ± 3.2 mg/week). Surgery was the initial treatment in five patients and the second-line treatment in six. Radiotherapy was used in four cases. All patients but one, are still with dopamine agonists. After a mean follow-up of 9 years, prolactin normalized in 7/16 patients (43.7 %) and 13 patients (81 %) reached prolactin levels lower than twice the upper limit of normal. Mean prolactin level at last visit: 79.5 ± 143 ng/mL. Tumor volume was decreased by 93.8 ± 11.3 %, and final maximum tumor diameter was 18.4 ± 18.8 mm. Three patients are actually tumor free. Giant prolactinomas are characterized by a large tumor volume and extreme prolactin hypersecretion. Multimodal treatment is frequently required to obtain biochemical and tumor control.

"Bulky mass": metastasis of poorly differentiated follicular thyroid carcinoma: a case report.

Poorly differentiated follicular thyroid carcinoma (PDFC) is a tumor of follicular cell origin with intermediate attributes between well-differentiated carcinomas and anaplastic carcinomas. The majority of patients presenting with distant metastases have locally advanced tumors, being lungs and bones the most common sites affected. We present a case of a patient with a painful bulky mass at the left thorax-abdominal wall as an uncommon distant metastasis of a PDFC. After thyroidectomy, a pre-ablative 131I whole-body scan showed distant metastases on the neck, both lungs, and lateral chest-abdominal wall, so the administration of I for thyroid remnant ablation stimulated with RH-TSH was decided.

Betahidroxibutirato capilar en la monitorizacion de la cetoacidosis diabetica / Capillary beta-hydroxybutyrate determination for monitoring diabetic ketoacidosis

Fundamento y objetivo La cetoacidosis diabetica (CAD) es la complicacion aguda mas grave de la diabetes mellitus tipo 1. Su tratamiento con insulina viene guiado por los valores obtenidos en las determinaciones de glucemia y los cambios gasometricos, mientras que los niveles de beta-hidroxibutirato (BHB) raramente son determinados. El objetivo del estudio fue evaluar la utilidad de la monitorizacion de BHB capilar en el curso y resolucion de una CAD. Pacientes y metodos Se estudiaron 30 pacientes diabeticos tipo 1 con CAD a los que se les aplica un protocolo estandar, con monitorizacion de glucosa y gasometria venosas, cetonuria semicuantitativa y BHB capilar. Para el seguimiento se establecieron a priori tres grupos de acuerdo con el tiempo de recuperacion segun criterios bioquimicos (grupo 1: < 24h; grupo 2: 24-48h; grupo 3: > 48h) y se correlacionaron las (..)(AU)

Background and objective: Diabetic ketoacidosis (DKA) is the most severe acute metaboliccomplication of type 1 diabetes mellitus. Insulin treatment is commonly guided by plasmaglucose levels and changes in venous blood gases, while -hydroxibutyrate (BHB) levels arerarely measured. The study objective was to evaluate the value of capillary BHB monitoring inthe course and resolution of DKA.Patients and methods: Thirty patients with type 1 diabetes admitted for DKA were enrolled. Astandard protocol including monitoring of blood glucose, venous blood gases, semiquantitativeketonuria, and capillary BHB was used. Patients were divided into three groups by time to DKAresolution (group 1: < 24 h, group 2: 24-48 h, group 3: >48 h), and BHB results were compared toall other biochemical measurements.Results: Mean laboratory results upon admission were: blood glucose 415 (standard deviation[SD] 106) mg/dL; bicarbonate 9.6 (SD 1.5) mmol/L; pH 7.13 (SD 0.04); BHB 4.33 (SD 0.48)mmol/L, and ketonuria 3+ in 22 patients and 4+ in 6. BHB correlated well with bicarbonate(r = -0.24139; P = 0.0161) and pH (r = -0.56419; P < 0.0001). BHB normalized earlier than ketonuriain all cases (group 1: 15.5 vs 18.8 hours P < 0.05; group 2: 18.2 vs 23.5 hours P < 0.01; group3: 37.3 vs 41.7 hours P < 0.01). Ten percent of patients still had ketonuria when blood ketonelevels were already normal (<0.5 mmol/L).Conclusion: BHB measurement is an easy, practical, and reliable monitoring method in DKA andmay be used as a parameter to adjust insulin treatment (AU)

[Capillary beta-hydroxybutyrate determination for monitoring diabetic ketoacidosis]. / Betahidroxibutirato capilar en la monitorización de la cetoacidosis diabética.

BACKGROUND AND OBJECTIVE: Diabetic ketoacidosis (DKA) is the most severe acute metabolic complication of type 1 diabetes mellitus. Insulin treatment is commonly guided by plasma glucose levels and changes in venous blood gases, while ß-hydroxibutyrate (BHB) levels are rarely measured. The study objective was to evaluate the value of capillary BHB monitoring in the course and resolution of DKA. PATIENTS AND METHODS: Thirty patients with type 1 diabetes admitted for DKA were enrolled. A standard protocol including monitoring of blood glucose, venous blood gases, semiquantitative ketonuria, and capillary BHB was used. Patients were divided into three groups by time to DKA resolution (group 1:<24 h, group 2: 24-48 h, group 3: >48 h), and BHB results were compared to all other biochemical measurements. RESULTS: Mean laboratory results upon admission were: blood glucose 415 (standard deviation [SD] 106) mg/dL; bicarbonate 9.6 (SD 1.5) mmol/L; pH 7.13 (SD 0.04); BHB 4.33 (SD 0.48) mmol/L, and ketonuria 3+ in 22 patients and 4+ in 6. BHB correlated well with bicarbonate (r=-0.24139; P=0.0161) and pH (r=-0.56419; P<0.0001). BHB normalized earlier than ketonuria in all cases (group 1: 15.5 vs 18.8 hours P<0.05; group 2: 18.2 vs 23.5 hours P<0.01; group 3: 37.3 vs 41.7 hours P<0.01). Ten percent of patients still had ketonuria when blood ketone levels were already normal (<0.5 mmol/L). CONCLUSION: BHB measurement is an easy, practical, and reliable monitoring method in DKA and may be used as a parameter to adjust insulin treatment.

Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: prevalence, evolution of hormone dysfunction and genetic analysis.

OBJECTIVES: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. DESIGN: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. RESULTS: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. CONCLUSION: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.