Medullary Thyroid Carcinoma: Clinical Presentation and Outcome in 219 Patients

Ante la baja frecuencia del carcinoma medular de tiroides (CMT), en el Departamento de Tiroides de SAEM nos propusimos realizar un estudio de cohorte, observacional, retrospectivo y multicéntrico. Se incluyeron 219 pacientes con diagnóstico histológico de CMT. El 65 % fueron mujeres, la edad promedio fue de 39 ± 20 años (1 a 84 años); 44-% de los casos fueron familiares. Las formas de presentación más frecuentes fueron nódulo tiroideo (58 %) y pesquisa genética por antecedente familiar (22 %). Si bien la citología tiroidea fue diagnóstica de CMT en el 39 % de los casos, fue determinante de indicación quirúrgica en el 79 %. En el 47 % de los pacientes el diagnóstico de CMT se obtuvo previamente al tratamiento quirúrgico inicial por punción aspiración con aguja fina (PAAF), estudio genético o nivel de calcitonina (CT)). El 65 % se presentó en estadios avanzados (TNM III y IV). El estudio del protoncogen RET se realizó en 162 pacientes (74 %). En el 49 % se observó mutación siendo la más frecuente (76 %) en el codón 634. La forma hereditaria más frecuentemente observada fue el síndrome de neoplasia endocrina múltiple (NEM) 2A (57 % de los casos familiares), seguida por carcinoma medular familiar (25 %) y NEM 2B (13 %). Los casos familiares tuvieron menor edad al diagnóstico y mayor frecuencia de diagnóstico prequirúrgico. Los casos índice tuvieron mayor edad al momento del diagnóstico, mayores niveles de antígeno carcinoembrionario (CEA) y CT prequirúrgicos, mayor proporción de estadios III y IV y mayor porcentaje de evidencia de enfermedad al momento de la última consulta que aquellos detectados por pesquisa. En 143 pacientes (65 %) se obtuvieron registros completos de seguimiento en los que se analizaron los factores relacionados con la evolución. La mediana de seguimiento fue de 44 meses: fallecieron 21 pacientes (14,6 %) y 122 (86 %) viven; 76 de estos (54 %) se encuentran libres de enfermedad. El grupo con evidencia de enfermedad se presentó en estadios más avanzados. Resultaron factores de mayor riesgo para evidencia de enfermedad: sexo masculino, CMT esporádico, niveles elevados de CT prequirúrgicos, estadio IV y presencia de metástasis. Los niveles de CT posquirúrgicos fueron menores en aquellos pacientes que en la evolución final no presentaron evidencia de enfermedad. El principal factor pronóstico de la evolución de los pacientes con CMT fue el estadio de presentación, determinando la importancia del diagnóstico precoz con el fin de poder implementar un tratamiento quirúrgico curativo en estadios menos avanzados.Due to the low frequency of medullary thyroid cancer (MTC), an observational, cohort, retrospective multicenter study was conducted at the Thyroid Department of the Endocrine and Metabolism Argentine Society (SAEM). We included 219 patients with histologically proven MTC, with a mean age of 39 ± 20 yr (range 1-84 years). Sixty five percent were women and 44% were familial cases. The most common presentations were thyroid nodule (58 %) and genetic screening due to family history (22 %). In 39 % of patients, diagnosis of MTC was made by fine needle aspiration, but cytology led to surgery in 79 %. In 47 % of patients, MTC was diagnosed by cytology, calcitonin (CT) levels or genetic studies prior to initial surgery. Sixty five percent of patients had advanced stages of the disease (TNM III or IV) at diagnosis. Proto-oncogene RET was studied in 162 patients (74 %). In 49% a mutation was reported, most frequently in codon 634 (76 %). Regarding hereditary forms of MTC, MEN 2A was the most frequent (57%), followed by familial MTC in 25 % and MEN 2B in 13 % of cases. Familial cases were younger subjects and had more frequently a pre-surgery diagnosis. Index cases were older, with higher CEA and CT levels, presented in more advanced stages and had more frequently evidence of disease at final assessment than patients who were diagnosed by genetic screening. Follow-up records of 143 patients were analyzed (65%); median time was 44 months; 21 patients died (14.6 %) and 122 survived (86 %), 76 showed no evidence of disease (NED) (54 %). High risk factors for evidence of disease at the final evaluation were: male gender, sporadic MTC, higher CT pre-surgery levels, stage IV and metastasis. Post surgery CT levels were lower in patients with NED. Stage at initial diagnosis was the main prognostic factor in patients with MTC, determining the importance of early detection for performing curative surgery in less advanced stages.Fil: Califano, I.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Deutsch, S.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Castro Jozami, L.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Fassi, J.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Lowenstein, A.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Balzaretti, M.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Novelli, J. L.. Centro de Tiroides “Dr. J.L. Novelli”; ArgentinaFil: Figari, M.. Hospital Italiano de Buenos Aires; ArgentinaFil: Olstein, G.. Gobierno de la Ciudad de Buenos Aires. Hospital Gral.de Agudos "ramos Mejia"; ArgentinaFil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Iorcansky, S.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Cabezón, C.. Sociedad Argentina de Endocrinologia y Metabolismo; ArgentinaFil: Departamento de Tiroides de la Sociedad Argentina de Endocrinología y Metabolismo

Long-term prognosis of patients with pediatric pheochromocytoma

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4%NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.publishersversionPeer reviewe

Genome-Wide Screen of Genes Required for Caffeine Tolerance in Fission Yeast

Isabel A. Calvo et al...Background An excess of caffeine is cytotoxic to all eukaryotic cell types. We aim to study how cells become tolerant to a toxic dose of this drug, and the relationship between caffeine and oxidative stress pathways. Methodology/Principal Findings We searched for Schizosaccharomyces pombe mutants with inhibited growth on caffeine-containing plates. We screened a collection of 2,700 haploid mutant cells, of which 98 were sensitive to caffeine. The genes mutated in these sensitive clones were involved in a number of cellular roles including the H2O2-induced Pap1 and Sty1 stress pathways, the integrity and calcineurin pathways, cell morphology and chromatin remodeling. We have investigated the role of the oxidative stress pathways in sensing and promoting survival to caffeine. The Pap1 and the Sty1 pathways are both required for normal tolerance to caffeine, but only the Sty1 pathway is activated by the drug. Cells lacking Pap1 are sensitive to caffeine due to the decreased expression of the efflux pump Hba2. Indeed, ?hba2 cells are sensitive to caffeine, and constitutive activation of the Pap1 pathway enhances resistance to caffeine in an Hba2-dependent manner. Conclusions/Significance With our caffeine-sensitive, genome-wide screen of an S. pombe deletion collection, we have demonstrated the importance of some oxidative stress pathway components on wild-type tolerance to the drug.This work was supported by Direccion General de Investigacion of Spain Grant BFU2006-02610, and by the Spanish program Consolider-Ingenio 2010 Grant CSD 2007-0020, to E.H.Peer reviewe

Genomic Binding Profiling of the Fission Yeast Stress-Activated MAPK Sty1 and the bZIP Transcriptional Activator Atf1 in Response to H2O2

10.1371/journal.pone.0011620PLoS ONE57

Phosphorylation-Independent Regulation of Atf1-Promoted Meiotic Recombination by Stress-Activated, p38 Kinase Spc1 of Fission Yeast

BACKGROUND:Stress-activated protein kinases regulate multiple cellular responses to a wide variety of intracellular and extracellular conditions. The conserved, multifunctional, ATF/CREB protein Atf1 (Mts1, Gad7) of fission yeast binds to CRE-like (M26) DNA sites. Atf1 is phosphorylated by the conserved, p38-family kinase Spc1 (Sty1, Phh1) and is required for many Spc1-dependent stress responses, efficient sexual differentiation, and activation of Rec12 (Spo11)-dependent meiotic recombination hotspots like ade6-M26. METHODOLOGY/PRINCIPAL FINDINGS:We sought to define mechanisms by which Spc1 regulates Atf1 function at the ade6-M26 hotspot. The Spc1 kinase was essential for hotspot activity, but dispensable for basal recombination. Unexpectedly, a protein lacking all eleven MAPK phospho-acceptor sites and detectable phosphorylation (Atf1-11M) was fully proficient for hotspot recombination. Furthermore, tethering of Atf1 to ade6 in the chromosome by a heterologous DNA binding domain bypassed the requirement for Spc1 in promoting recombination. CONCLUSIONS/SIGNIFICANCE:The Spc1 protein kinase regulates the pathway of Atf1-promoted recombination at or before the point where Atf1 binds to chromosomes, and this pathway regulation is independent of the phosphorylation status of Atf1. Since basal recombination is Spc1-independent, the principal function of the Spc1 kinase in meiotic recombination is to correctly position Atf1-promoted recombination at hotspots along chromosomes. We also propose new hypotheses on regulatory mechanisms for shared (e.g., DNA binding) and distinct (e.g., osmoregulatory vs. recombinogenic) activities of multifunctional, stress-activated protein Atf1