Papel do antigeno carboidrato 19.9 como marcador de agressividade no carcinoma medular de tireoide

O carcinoma medular da tireoide (CMT) é um tumor maligno raro originário de células C parafoliculares da tireoide e corresponde a 4% das neoplasias malignas dessa glândula. O CMT apresenta-se como um tumor esporádico (75-80%) ou na forma hereditária (20-25%). O único tratamento curativo disponível no momento para o CMT é cirúrgico. No entanto, isso só é possível em casos em que o diagnóstico é realizado precocemente e a doença encontra-se restrita a glândula. Nos pacientes com doença avançada, onde as opções terapêuticas tradicionais como quimioterapia e radioterapia não são efetivas, os inibidores tirosino-quinase tem demonstrado eficácia na sobrevida livre de progessão da doença. Níveis de calcitonina sérica, um biomarcador específico para céluas C tireoideanas, e o antígeno-carcinoembrionário (CEA) são amplamente utilizados como marcadores no diagnóstico e seguimento dos pacientes com CMT. No entanto, estudos recentes têm indicado que níveis séricos elevados do antígeno carboidrato 19.9 (CA19.9), marcador tumoral bem estabelecido no em neoplasias pancreáticas, como um potencial marcador de agressividade e mortalidade em indivíduos com CMT avançado. O objetivo desse trabalho foi avaliar o papel do CA19.9 como marcador de agressividade tumoral em pacientes com CMT. Amostras tumorais de pacientes com CMT atendidos no Serviço de Endocrinologia do HCPA foram avaliados para expressão do CA19.9 por imunohistoquimica, através de anticorpo especifico. Para estudar a hipótese de os níveis de CA19.9 observados em pacientes com CMT estarem associados à desdiferenciação das células C, também avaliamos a expressão tecidual de CD133, um marcador para a identificação de células-tronco cancerígenas (CSC). A leitura das lâminas foi realizada por patologista, e quantificação da expressão foi inicialmente realizada pelo método de h-score. Adicionalmente as amostras foram classificadas de acordo com o padrão de expressão observado: células individuais, focos ou difuso. Setenta pacientes com CMT foram incluídos no estudo, 57,1% apresentavam a forma hereditária e 42,9% a forma esporádica. A idade média ao diagnóstico foi 36.1 (±16.3) anos e 58,6% foram do sexo feminino. A mediana dos níveis de calcitonina e CEA foram de 536pg/ml (49,35-1300,5) e 21,3ng/ml (3,6-52,6), respectivamente. Aproximadamente 53% dos pacientes apresentavam metástases locais e 20% à distância ao diagnóstico. Das 64 amostras de tumor primário disponíveis para analise, 56 (87,5%) apresentaram expressão do CA19.9, com mediana de h-score 14 (2-30). De forma semelhante, o CD133 estava expresso em 90.5% das amostras de tumor primário, no entanto não se observou nenhuma correlação entre os dois marcadores estudados (r=- 0.09; P=0.74). Não foram observadas diferenças na expressão de CA19.9 sobre idade, sexo, níveis 11 séricos calcitonina ou CEA (P>0,05). Curiosamente amostras de CMT hereditário tinham maior expressão de CA19.9 que amostras de CMT esporádico. Observamos três padrões de expressão distintos para o CA19.9: células individuais, focal e difuso. A maioria das amostras (64,3%) apresentaram o padrão de expressão focal. O padrão de células individuais foi observado em 17 (30,3%) das amostras e o padrão difuso em 3 (5,4%). As formas esporádica e hereditária da doença apresentaram diferentes padrões de expressão. De forma interessante, o CMT esporádico mostrouse associado ao padrão de células individuais (70,6%), enquanto a forma hereditária foi associada ao padrão focal de expressão (63,9%) (P=0,04). Adicionalmente, o padrão de células individuais foi associado a metástases local (P=0,055) enquanto que o padrão difuso, a metástases à distância (P=0,032). Nossos resultados demonstram expressão do CA19.9 na maioria das amostras de CMT. Diferenças nos níveis de expressão do CA19.9 não foram associadas às características clínicas ou oncológicas, sendo no entanto significativamente mais elevados em amostras de CMT hereditário. Três padrões de expressão distintos foram observados, sendo que o padrão difuso foi associado à presença de metástases à distância ao diagnóstico. Em conclusão, o CA19.9 é amplamente expresso no CMT e apresenta características distintas de outros marcadores atualmente utilizados. Estudos adicionais podem definir o papel desse marcador no manejo de pacientes de CMT.Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from parafollicular C-cell of the thyroid and corresponds to 4% of malignant neoplasms of this gland. MTC presents as a sporadic tumor (75-80%) or in hereditary form (20-25%). The only curative treatment currently available for MTC is surgical. However, this is only possible in cases of early diagnosis and the disease is restricted to the gland. In patients with advanced disease, where traditional therapeutic options such as chemotherapy and radiotherapy are not effective, tyrosine kinase inhibitors have demonstrated efficacy in disease-free survival. Levels of serum calcitonin, a specific biomarker for thyroid C-cells, and carcinoembryonic antigen (CEA) are widely used as markers in the diagnosis and follow-up of patients with MTC. However, recent studies have indicated that elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well established tumor marker in pancreatic neoplasms, are a potential marker of aggression and mortality in individuals with advanced MTC. The objective of this study was to evaluate the role of CA19.9 as a marker of tumor aggressiveness in patients with MTC. Tumor samples from MTC patients treated at the HCPA Endocrinology Service were evaluated for expression of CA19.9 by immunohistochemistry using a specific antibody. To study the hypothesis that CA19.9 levels observed in patients with MTC are associated with C-cell dedifferentiation, we also assessed the tissue expression of CD133, a marker for the identification of cancer stem cells (CSC). The reading of the slides was performed by a pathologist, and quantification of the expression was initially performed by the h-score method. Additionally, the samples were classified according to the observed expression pattern: individual cells, focal or diffuse. Seventy patients with MTC were included in the study, 57.1% presented the hereditary form and 42.9% presented sporadic form. The mean age at diagnosis was 36.1 (± 16.3) years and 58.6% were female. The median levels of calcitonin and CEA were 536pg/ml (49.35-1300.5) and 21.3ng/ml (3.6-52.6), respectively. Approximately 53% of the patients had local metastases and 20% at a distance at diagnosis. Of the 64 primary tumor samples available for analysis, 56 (87.5%) presented CA19.9 expression, with median h-score 14 (2-30). Similarly, CD133 was expressed in 90.5% of the primary tumor samples. However, no correlation was observed between the two markers studied (r=-0.09; P=0.74). No differences in CA19.9 expression were observed on age, sex, serum calcitonin or CEA levels (P>0.05). Curiously, samples of hereditary MTC had higher CA19.9 expression than sporadic MTC samples. We observed three distinct expression patterns for 13 CA19.9: individual cells, focal and diffuse. Most of the samples (64.3%) had the focal expression pattern. The individual cell pattern was observed in 17 (30.3%) of the samples and the diffuse pattern in 3 (5.4%). The sporadic and hereditary forms of the disease presented different patterns of expression. Interestingly, sporadic CMT was associated with the individual cell pattern (70.6%), while the hereditary form was associated with the focal expression pattern (63.9%) (P=0.04). In addition, the individual cell pattern was associated with local metastases (P=0.055) while the diffuse pattern, with distant metastases (P=0.032). Our results demonstrate expression of CA19.9 in the majority of MTC samples. Differences in CA19.9 expression levels were not associated with clinical or oncological features disease but it were significantly higher in hereditary MTC samples. Three distinct expression patterns were observed, and the diffuse pattern was associated with the presence of distant metastases at diagnosis. In conclusion, CA19.9 is widely expressed in MTC and presents distinct characteristics of other markers currently used. Additional studies may define the role of this marker in the management of MTC patients

Medullary thyroid carcinoma beyond surgery : advances, challenges, and perspectives

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies

Neoadjuvant multikinase inhibitor in patients with locally advanced unresectable thyroid carcinoma

Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up. Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms “Neoadjuvant therapy” AND “Thyroid carcinoma.” Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70–84% of tumor reduction allowing surgery. Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas

Effect of 3'UTR RET variants on RET mRNA secondary structure and disease presentation in medullary thyroid carcinoma

The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients. Objective To evaluate the frequency of the RET 3’UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism. Methods Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3’UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package. Results The mean age of MTC diagnosis was 48.5±15.5 years and 57.9%were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3’UTR variants (|D’| = -1, r2 = 1 and |D’| = -1, r2 = 0,967). Patients harboring the S836S/3’UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P<0.001, respectively). Accordingly, RNA folding analyses demonstrated different RNA secondarystructure predictions for WT(TCCGT), S836S(TTCGT) or 3’UTR(GTCAC) haplotypes. The S836S/3’UTR haplotype presented a greater number of double helices sections and lower levels of minimal free energy when compared to the wild-type haplotype, suggesting that these variants provides the most thermodynamically stable mRNA structure, which may have functional consequences on the rate of mRNA degradation. Conclusion The RET S836S polymorphism is in LD with 3’UTR variants. In silico analysis indicate that the 3’UTR variants may affect the secondary structure of RET mRNA, suggesting that these variants might play a role in posttranscriptional control of the RET transcripts

Biometria dos órgãos linfoides e composição físico- química da carne de frangos de crescimento lento alimentados com bagaço de mandioca e complexo enzimático / Biometry of lymphoid organs and physical-chemical composition of meat of slow growth chickens fed with cassava bagasse and enzymatic complexes

Objetivou-se no presente trabalho avaliar a biometria dos órgãos linfoides e composição físico-química da carne de frangos de crescimento lento alimentados com bagaço de mandioca com e sem complexo enzimático fúngico. Foram utilizadas 250 aves, Pescoço Pelado Vermelho, com 90 dias de idade. O delineamento experimental foi o inteiramente casualizado (DIC) em esquema fatorial (2 X 2 + 1), sendo dois níveis de inclusão do bagaço de mandioca (10 e 20%), presença e ausência do complexo enzimático e dieta controle, totalizando cinco tratamentos, cinco repetições e dez aves por unidade experimental. Foram avaliados a biometria dos órgãos linfoides (baço, bursa e timo), gordura abdominal, luminosidade (L*), coloração (a* e b*), pH, força de cisalhamento (FC), perda de peso por cozimento (PPCO), análises químicas e deposição de proteína e gordura da carne do peito. A inclusão de 10 e 20% do bagaço de mandioca com e sem complexo enzimático influenciaram (p&lt;0,05) o peso relativo do baço e o parâmetro de cor (b*), não havendo efeito (p&gt;0,05) sobre o peso da bursa e do timo, parâmetro de cor (a*), luminosidade (L*), pH, força de cisalhamento (FC), perda de peso por cozimento (PPCO), análises químicas, deposição de proteína e gordura da carne. Recomenda-se o uso de até 20% de bagaço de mandioca, não sendo opção tecnicamente viável a utilização do complexo enzimático fúngico, xilanase e amilase, nas dietas para frangos de crescimento lento.

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity &gt; 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI