Chronic Treatment with Somatostatin Analogues in Recurrent Type 1 Gastric Neuroendocrine Tumors.

BACKGROUND: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. METHODS: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. RESULTS: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. CONCLUSIONS: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed.

Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE).

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs. SUBJECTS, MATERIALS, AND METHODS: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3. RESULTS: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%). CONCLUSION: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index. IMPLICATIONS FOR PRACTICE: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

[Managing the discharge of diabetic patients from the emergency department: a consensus paper]. / Documento de consenso sobre el manejo al alta desde urgencias del paciente diabético.

EN: Eighty to 90% of patients attended in emergency departments are discharged to home. Emergency department physicians are therefore responsible for specifying how these patients are treated afterwards. An estimated 30% to 40% of emergency patients have diabetes mellitus that was often decompensated or poorly controlled prior to the emergency. It is therefore necessary to establish antidiabetic treatment protocols that contribute to adequate metabolic control for these patients in the interest of improving the short-term prognosis after discharge. The protocols should also maintain continuity of outpatient care from other specialists and contribute to improving the long-term prognosis. This consensus paper presents the consensus of experts from 3 medical associations whose members are directly involved with treating patients with diabetes. The aim of the paper is to facilitate the assessment of antidiabetic treatment when the patient is discharged from the emergency department and referred to outpatient care teams.

ES: El 80-90% de los pacientes atendidos en los servicios de urgencias son dados de alta desde los mismos, y por tanto los facultativos de urgencias son los responsables del tratamiento al alta en dichos pacientes. Se estima que la frecuencia de diabetes mellitus en urgencias es de un 30-40% y en muchos casos dicha diabetes está descompensada o con un mal control metabólico previo, por lo que es necesario establecer pautas de tratamiento antidiabético adecuadas de cara al alta que contribuyan a un adecuado control metabólico de dichos pacientes y favorezca un mejor pronóstico a corto plazo tras el alta, así como mantener una continuidad con la atención ambulatoria por parte de otras especialidades y contribuir a una mejoría del pronóstico a largo plazo. El presente documento es por tanto un consenso de expertos de tres sociedades científicas implicadas directamente en la atención del paciente diabético, que pretende facilitar la valoración del tratamiento al alta desde urgencias en cuanto a la diabetes se refiere y su continuidad asistencial ambulatoria.

Unresectable Recurrent Multiple Meningioma: A Case Report with Radiological Response to Somatostatin Analogues.

Medical treatment of meningiomas is reserved for cases in which surgery and radiotherapy have failed. Given that a high percentage of meningiomas express somatostatin receptors, treatment with somatostatin analogues has been proposed. In addition, these medications have been shown to have an antiproliferative and antiangiogenic effect in vitro. To date, very few cases with clinical response and none with radiological response have been described. The case described here is the first to report a radiological response. A 76-year-old Caucasian male was first diagnosed with unresectable meningioma at age 47. The patient experienced multiple recurrences and underwent three surgeries and radiotherapy over the years from the initial diagnosis. Despite treatment, the disease continued its progression. Based on an Octreoscan positive for tumour uptake, therapy with extended-release somatostatin analogues was started. Although no clinical neurological improvement was observed, magnetic resonance imaging scans revealed a discreet but continuous radiological response over time. After >2 years of continuous administration of lanreotide, the patient remains progression free. In highly selected cases, somatostatin analogue treatment for meningioma may be beneficial. Based on our findings, treatment with somatostatin analogues should be maintained longer than previously described before evaluating treatment response.

[Gastroenteropancreatic neuroendocrine tumors: clinical characteristics, diagnosis and prognosis at Hospital Universitario Clínico San Carlos (Madrid)]. / Tumores neuroendocrinos gastroenteropancreáticos: características clínicas, proceso diagnóstico y pronóstico en el Hospital Universitario Clínico San Carlos (Madrid).

INTRODUCTION: Neuroendocrine tumors are a group of neoplasms arising from the neural crest and endoderm and very heterogeneous as regards localization, clinical behavior, aggressiveness, and prognosis. Pancreas and gastrointestinal tract are the most common sites where neuroendocrine tumors can be found. MATERIAL AND METHODS: A review was made of all cases of neuroendocrine tumors diagnosed at Hospital Universitario Clínico San Carlos (HUCSC) from January 2007 to May 2012. Data were compared to the results provided by the Registry of the Spanish Group on Neuroendocrine Tumors (RGETNE). RESULTS: The study cohort comprised 78 patients. Gastroenteric nonfunctional tumors were the most common neoplasms. Metastases were found at diagnosis in50.6% of patients, with nodal involvement being most prevalent. Tumors located in the rectum were associated to the highestrate of metastasis. Overall 2-year survival rate was 74.8% and was related to sex, Ki-67 expression, and presence of metastasis.

Diabetic foot units in Spain: knowing the facts using a questionnaire.

OBJECTIVE: To ascertain the number of diabetic foot units (DFUs) in Spain, the specialists working in them, and the population covered by them. MATERIAL AND METHODS: The Spanish Group on the Diabetic Foot (SGDF) prepared and agreed a questionnaire based on the recommendations of the 2011 International Consensus on the Diabetic Foot (ICDF). From October to December 2012, the questionnaire was sent to members of three scientific societies formed by professionals involved in the care of patients with diabetes mellitus. Population coverage of the responding centers and DFUs was estimated using the 2012 population census. RESULTS: Seventy five questionnaires were received, 64 of them from general hospitals, which accounted for 13% of the general hospitals of the National Health System. It was calculated that they provided coverage to 43% of the population. Thirty four centers answered that they had a DFU. Specialized diabetic foot care was only provided to 25% of the population. The number of different professionals working at diabetic foot units was 6.3±2.7. Classification of DFUs based on their complexity was as follows: 5 basic units (14.7%), 20 intermediate units (58.8%), and 9 excellence units (26.5%). CONCLUSIONS: The number of DFUs reported in this study in Spain is low, and allow for foot care of only one out of every four patients with diabetes. Spanish health system needs to improve diabetic foot care by creating new DFUs and improving the existing ones.

[Chromogranin A and neuroendocrine tumors]. / Cromogranina A y tumores neuroendocrinos.

Chromogranin A (CgA) is the most abundant granin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). As a tumor marker is moderately sensitive and nonspecific. Despite the limitations of testing methods, which require careful interpretation, especially in the case of gastrinomas, patients treated with somatostatin analogues, and poorly differentiated tumors, it is the best tumor marker in GEP-NETs and may be of value in other tumors with neuroendocrine differentiation. CgA may be used as a marker in blood or tissue samples through immunohistochemical techniques. CgA levels correlate with tumor burden and extension and may be used for diagnosis and monitoring of GEP-NETs, especially midgut carcinoids and endocrine pancreatic tumors. It is also useful as a prognostic marker for detection of recurrence and monitoring of response to different treatments.

[Thyroid dysfunction in patients with advanced renal cell carcinoma treated with sunitinib: a multifactorial issue]. / Disfunción tiroidea en los pacientes con carcinoma de células renales avanzado en tratamiento con sunitinib: un problema multifactorial.

OBJECTIVE: Several studies have reported the substantial prevalence of sunitinib-induced thyroid dysfunction. However, the underlying mechanism and the benefit of thyroid hormone replacement therapy remain to be determined. To evaluate the effect of sunitinib on thyroid function, we carried out a descriptive study in patients with advanced renal cell carcinoma. PATIENTS AND METHODS: A total of 24 patients treated by sunitinib between 2006 and 2008 at Hospital Clínico San Carlos were included. The data were collected retrospectively and analyzed with SPSS 15.0. RESULTS: Treatment duration was 30 weeks (18-42) [median (IQR)]. Five patients (20.8%) developed subclinical hypothyroidism and three (12.5%) developed overt hypothyroidism. The number of weeks needed to observe an increase in thyroid-stimulating hormone (TSH) values in these patients was 15 (6-20) [median (IQR)]. TSH levels were below the normal range in five patients (20.8%) before or during the treatment period, but the diagnosis of subclinical hyperthyroidism could not be established because of concomitant factors. Fourteen patients (58.3%) showed sunitinib adverse events, but these were not related to the development of hypothyroidism (p=0.388). CONCLUSIONS: Because of the high prevalence of sunitinib-induced hypothyroidism, thyroid function should be systematically monitored in patients with renal cell carcinoma treated with this drug. However, several pathophysiological and pharmacological factors may interfere with monitoring. Consequently, it might be useful to determine not only TSH and free T4 but also free T3 and, ideally, reverse T3. Evidence-based recommendations to manage hypothyroidism in oncology patients are not available at present.

[Evaluation of testosterone levels through distinct analytic methods in healthy men]. / Valoración de niveles de testosterona mediante diferentes métodos analíticos en varones sanos.

UNLABELLED: Plasma testosterone concentrations are essential for the diagnosis of several causes of hypogonadism, including late-onset hypogonadism. Defining the normal range for testosterone concentrations poses certain difficulties due to the changes that occur with age and the variability of the different analytical methods used. OBJECTIVES: To study normal ranges of testosterone in healthy young men and to compare the results of distinct analytical methods. MATERIAL AND METHODS: We recruited 20 healthy men with a mean age of 24.5 years (standard deviation (SD): 5.04) and a mean body mass index (BMI) of 23.8% (SD: 3.3). Total testosterone (TT) was measured by immunochemiluminescence (ICLA) and free testosterone (FT) by radioimmunoassay (RIA). Calculated free testosterone (FTc) and bioavailable testosterone (BT) were calculated using Vermeulen's formula. Serum lutropin (LH), follitropin (FSH) and sex hormone binding globulin (SHBG) were measured by immunoradiometric assays (IRMA). RESULTS: The mean concentrations were 20 nmol/l (SD: 4.96) for TT, 0.054 nmol/L (SD: 0.01) for FT, 0.3834 nmol/L (SD: 0.09) for FTc and 9.9 nmol/L (SD: 2.8) for BT. There was no correlation between testosterone measured by different methods other than an association between FT and FTc (r=0.662, p<0.003) and between FTc and BT (r=0.979, p<0.0001). An inverse correlation was found between BMI and TT concentrations (r: -0.52, p<0.017). CONCLUSIONS: The normal range for testosterone in healthy young men should be established in each laboratory based on the analytical method used.

[Neuroendocrine system of the pancreas and gastrointestinal tract: origin and development]. / Sistema neuroendocrino del páncreas y tracto gastrointestinal: origen y desarrollo.

Gastroenteropancreatic neuroendocrine tumours (GEP NETs) originate from the neuroendocrine cells through the gastrointestinal tract and endocrine pancreas. The embryologic development of the pancreas is a complex process that begins with the "stem cell" that come from the endodermus. These cells go through two phases: in the first transition the "stem cell" differentiates in exocrine and endocrine cells. This process is regulated by transcription factors such as Pdx1 ("insulin promoter factor 1"), Hlxb6 and SOX9. In the second transition the neuroendocrine cell differentiates in the 5 cell types (alpha, beta, delta, PP y epsilon.). This process is regulated through the balance between factors favoring differentiation (mainly neurogenin 3) and inhibitor factors which depend on Notch signals. The existence of a third transition in postnatal pancreas is hypothesized. The "stem cell" from pancreatic ducts would become adult beta cells, through autoduplication and neogenesis. In the small gut of the adult the stem cell are placed in the intestinal crypts and develop to villi in secretor lines (enterocytes, globet and Paneths cells) or neuroendocrine cells from which at least 10 cell types depend. This process is regulated by transcription factors: Math1, neurogenina 3 and NeuroD.

Association study of 69 genes in the ret pathway identifies low-penetrance loci in sporadic medullary thyroid carcinoma.

To date, few association studies have been done to better understand the genetic basis for the development of sporadic medullary thyroid carcinoma (sMTC). To identify additional low-penetrance genes, we have done a two-stage case-control study in two European populations using high-throughput genotyping. We selected 417 single nucleotide polymorphisms (SNP) belonging to 69 genes either related to RET signaling pathway/functions or involved in key processes for cancer development. TagSNPs and functional variants were included where possible. These SNPs were initially studied in the largest known series of sMTC cases (n = 266) and controls (n = 422), all of Spanish origin. In stage II, an independent British series of 155 sMTC patients and 531 controls was included to validate the previous results. Associations were assessed by an exhaustive analysis of individual SNPs but also considering gene- and linkage disequilibrium-based haplotypes. This strategy allowed us to identify seven low-penetrance genes, six of them (STAT1, AURKA, BCL2, CDKN2B, CDK6, and COMT) consistently associated with sMTC risk in the two case-control series and a seventh (HRAS) with individual SNPs and haplotypes associated with sMTC in the Spanish data set. The potential role of CDKN2B was confirmed by a functional assay showing a role of a SNP (rs7044859) in the promoter region in altering the binding of the transcription factor HNF1. These results highlight the utility of association studies using homogeneous series of cases for better understanding complex diseases.