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Pancreatic cancer is one of the deadliest malignancies in humans and it is expected to play a bigger part in cancer burden in the years to come. Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all primary pancreatic malignancies. Recently, much attention has been given to PDAC, with significant advances in the understanding of the mechanisms underpinning disease initiation and progression, along with noticeable improvements in overall survival in both localized and metastatic settings. However, given their rarity, rare histological subtypes of pancreatic cancer have been underappreciated and are frequently treated as PDAC, even though they might present non-overlapping molecular alterations and clinical behavior. While some of these rare histological subtypes are true variants of PDAC that should be treated likewise, others represent separate clinicopathological entities, warranting a different therapeutic approach. In this review, we highlight clinical, pathological, and molecular aspects of rare histological types of pancreatic cancer, along with the currently available data to guide treatment decisions.

Should rare subtypes of pancreatic cancer be treated as its most common variant (ductal adenocarcinoma)? The most common type of pancreatic cancer is ductal adenocarcinoma. While much attention has been given to the molecular aspects and treatment aspects of this disease, rare variants of pancreatic cancer have been underappreciated. Some of them present unique molecular features that suggest different treatment approaches could lead to better outcomes. In this review, we summarize information on the clinical, pathological, and molecular features of rare subtypes of pancreatic cancer, along with subtype-specific data on treatment.

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INTRODUCTION: Neuroendocrine tumors [NETs] exhibit a wide range of clinical presentations, including the production of various hormones. Calcitonin, a sensitive marker for medullary thyroid cancer [MTC], is nonspecific and may be elevated in extra-thyroidal NETs. CASE REPORT: We present the case of a 64-year-old female patient who underwent total thyroidectomy due to a nodule in the isthmus, with a fine-needle aspiration biopsy indicating follicular neoplasia. Pathological examination revealed macro- and micro-nodular thyroid hyperplasia, along with a parathyroid adenoma. During postoperative follow-up, a progressive elevation of calcitonin was observed, reaching 64.2 pg/ml, while carcinoembryonic antigen levels remained normal. Since no MTC foci were found upon reviewing the thyroidectomy specimen, an investigation into the origin of the elevated calcitonin was initiated. Serum chromogranin A and specific neuronal enolase levels were within normal ranges. Tc-99m HYNIC-TOC scintigraphy yielded negative results. Additionally, an upper gastrointestinal endoscopy revealed a submucosal lesion in the second portion of the duodenum, with a biopsy confirming a grade 1 NET. The patient underwent Whipple surgery and hepatic metastasectomy. Postoperatively, a decrease in baseline serum calcitonin levels was observed. Seven years after surgery, she continues specialized monitoring with no biochemical or imaging evidence of disease. CONCLUSION: Serum calcitonin contributes to the diagnosis and monitoring of anterior intestine NETs.

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Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.

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Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, itcan also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT)and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastasesof MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

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Context: Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET, RAS, and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. Objective: To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Methods: Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Results: Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET-negative tumors, pathogenic variants were found in HRAS and NF1. The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET-positive cases, with losses in chromosomes 9 and 22 being the most prevalent. Conclusion: This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET-negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1).

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Postoperative anemia is a complex clinical issue that requires attention due to its ramifications on the patient's recovery and prognosis. Originating from multiple determinants, such as intraoperative blood loss, hemolysis, nutritional deficiencies, systemic inflammation and impact on the bone marrow, postoperative anemia has varied and often challenging presentations. Patients undergoing major surgical procedures, in particular, are susceptible to developing anemia due to the considerable associated blood loss. Accurate diagnosis plays a crucial role in the approach, requiring meticulous hematological analysis, including hemoglobin, hematocrit and reticulocyte count, as well as an in-depth investigation of the underlying causes. An additional challenge arises in the form of the excessive practice of phlebotomy during hospitalization for clinical monitoring. Although it is essential to assess the progression of anemia, frequent removal of blood may contribute to iatrogenic anemia, further delaying recovery and possibly increasing susceptibility to infection.

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BACKGROUND: Nephrocalcinosis (NC) is characterized by an excessive accumulation of calcium deposits in the kidneys. In children, it is often incidentally discovered with an uncertain prognosis. CASE-DIAGNOSIS/TREATMENT: A 3-month-old girl suspected to have a milk protein allergy underwent an ultrasound that revealed increased echogenicity in the kidney pyramids suggestive of medullary NC. At the age of 18 months, imaging findings revealed not only hyperechogenicity in the medulla but also in the cortex. Over the course of a long follow-up, her kidneys maintained size within the upper limits but showed an increase by age 7. Genetic analysis identified PKHD1 variants, which required structural predictive tools to guide clinical diagnosis. Until the age of 7, her kidney function has remained intact; however, her prognosis is uncertain. CONCLUSIONS: NC in newborns is a rare condition, but its incidence is rising. Recurrent urinary infections or kidney stones may lead to kidney failure. A proactive approach in sporadic NC enables an early diagnosis to orientate clinical supervision and facilitates counseling to support family planning decisions.

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Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient's family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband's deceased mother's paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.

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Colorectal cancer is the third most common neoplasm and the second most lethal worldwide. The most common histological type is adenocarcinoma, characterized by its glandular pattern. Medullary colon carcinoma is a rare histological variant of colorectal cancer, characterized by a predominantly solid architecture, poorly di?erentiated or undifferentiated morphology, often associated with an anomalous immunophenotype and microsatellite instability. The present study reports a case in an academic service of general surgery of a 74-year-old patient who presented with a tumor of the ascending colon, histologically with an exuberant lymphocytic in?ltrate, suggestive of large cell lymphoma, but which was revealed by subsequent immunohistochemistry to be medullary carcinoma of the colon with microsatellite instability.

O câncer colorretal é a terceira neoplasia mais comum e a segunda mais letal no mundo. O adenocarcinoma é o tipo histológico mais comum, caracterizado pelo seu padrão glandular. O carcinoma medular do cólon é uma variante histológica rara do câncer colorretal, caracterizada por uma arquitetura predominantemente sólida, morfologia pouco diferenciada ou indiferenciada, frequentemente associada a um imunofenótipo anômalo e instabilidade de microssatélites. O presente estudo relata um caso em um serviço acadêmico de cirurgia geral de um paciente de 74 anos que apresentou tumor de cólon ascendente, histologicamente com infiltrado linfocitário exuberante, sugestivo de linfoma de grandes células, mas que foi revelado através de exame subsequente imunohistoquímico como carcinoma medular do cólon com instabilidade de microssatélites.

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Background: The optimal cutoff value of calcitonin (Ctn) levels measured using an electrochemiluminescence immunoassay (ECLIA) obtained from the washout fluid of fine needle aspiration (FNA-Ctn) for the diagnosis of medullary thyroid carcinoma (MTC) is currently not established. We evaluated the diagnostic accuracy and clinical utility of FNA-Ctn for the diagnosis and location of MTC in patients with nodular or multinodular goiters. Methods: This was a case-control study nested on a prospective multicenter cohort of patients with nodular or multinodular goiter, normal or elevated serum Ctn, and thyroidectomy indications. Ctn and FNA-Ctn were measured using ECLIA methodology before surgery. From this nested cohort, MTC cases and controls (non-medullary pathology) were identified from the final pathological analysis. Cumulative incidence sampling of controls was randomly performed at a ratio of 1:2. Sensitivity, specificity, and area under the receiver operator curve (AUROC) were calculated for patients and the total number of thyroid nodules. Results: From 1272 patients included in the prospective cohort, 50 MTC cases and 105 controls were included. In this study, 286 thyroid nodules were evaluated (63 MTC and 223 non-MTCs). The median serum Ctn value was significantly higher in cases (525 pg/mL [interquartile range (IQR), 162.5-1.200]) than in controls (1.6 pg/mL [IQR, 0.5-5.6]; p < 0.001). The median FNA-Ctn value was significantly higher in MTC nodules (3.100 pg/mL [IQR, 450-45,200]) than in non-MTC nodules (0.5 pg/mL [IQR, 0.5-0.5]; p < 0.0001). In 11 MTC patients with multinodular goiter, the FNA-Ctn value was significantly higher in non-medullary nodules located in the same lobe where an MTC nodule was diagnosed (p = 0.0002). Overall, the FNA-Ctn AUROC was 0.99 [95% confidence interval, 0.98-1.0], and a threshold of ≥220 pg/mL showed 100% sensitivity and 98% specificity for MTC diagnosis. Conclusions: The use of FNA-Ctn measured by ECLIA showed adequate diagnostic accuracy for MTC diagnosis. Moreover, it may be clinically useful for localization in multinodular goiter when lobectomy is considered. Clinical Trial Registration: Clinicaltrials.gov NCT06067594.

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ABSTRACT Objective: Although 18F-sodium fluoride (18F-NaF) uptake is frequently observed in extraosseous metastases of medullary thyroid carcinoma (MTC) with calcification, it can also occur in metastatic sites without visible calcium deposition, leading to the hypothesis that visually undetectable calcium accumulation may be responsible for this uptake. The aim of this study was to indirectly support this hypothesis by analyzing the correlation between the degree of 18F-NaF uptake and radiodensity in extraosseous MTC metastases, since calcium deposition can increase attenuation even when not visually detectable. Subjects and methods: Extraosseous metastatic lesions of 15 patients with MTC were evaluated using 18F-NaF positron-emission tomography (PET)/computed tomography (CT) and segmented by levels of standardized uptake value (SUV). The correlation between mean SUV and mean Hounsfield unit (HU) values was assessed for the entire group of segments and for two subgroups with different mean HU values. Results: Very high correlations were observed between mean SUV and mean HU values for both the entire group of segments and the subgroup with a mean HU value greater than 130 (p = 0.92 and p = 0.95, respectively; p < 0.01). High correlation (p = 0.71) was also observed in the subgroup with mean HU values ranging from 20 to 130 (p < 0.01). Conclusion: The findings of the present study suggest that there is an association between 18F-NaF uptake and calcium deposition in extraosseous metastases of MTC, supporting the hypothesis that visually undetectable calcium accumulation may be responsible for 18F-NaF uptake in regions without visible calcium deposition.

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Abstract Postoperative anemia is a complex clinical issue that requires attention due to its ramifications on the patient's recovery and prognosis. Originating from multiple determinants, such as intraoperative blood loss, hemolysis, nutritional deficiencies, systemic inflammation and impact on the bone marrow, postoperative anemia has varied and often challenging presentations. Patients undergoing major surgical procedures, in particular, are susceptible to developing anemia due to the considerable associated blood loss. Accurate diagnosis plays a crucial role in the approach, requiring meticulous hematological analysis, including hemoglobin, hematocrit and reticulocyte count, as well as an in-depth investigation of the underlying causes. An additional challenge arises in the form of the excessive practice of phlebotomy during hospitalization for clinical monitoring. Although it is essential to assess the progression of anemia, frequent removal of blood may contribute to iatrogenic anemia, further delaying recovery and possibly increasing susceptibility to infection.

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Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians' Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results and conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II-V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; "berry node picking" is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

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Background: Calcitonin measurement is widely used in the diagnosis, prognosis, and follow-up of patients with medullary thyroid carcinoma (MTC). The prognostic value of undetectable postoperative calcitonin (POCal) in long-term disease outcomes remains uncertain. Objective: The aim of this study is to evaluate POCal as a prognostic marker for long-term MTC disease status. Methods: A retrospective cohort study was carried out. We collected data from the medical records of patients with MTC attending two tertiary teaching hospitals. Patients were divided according to POCal into two groups: undetectable (below the detection limit) or detectable. The outcome was determined at the last medical visit and defined as disease free (undetectable calcitonin and no evidence of disease on imaging), persistent disease (detectable calcitonin with or without structural disease), or disease-related death. Results: Three hundred thirty-four MTC patients were included in the study. The mean age at diagnosis was 41.1 ± 18.6 years; 202 patients (60.5%) were women; and 167 patients (50.0%) had sporadic MTC. The median tumor size was 2.0 cm (1.1-3.5 cm); 164 patients (49.1%) had lymph node metastasis and 63 patients (18.9%) had distant metastasis. At the first postoperative evaluation (3-6 months after surgery), 141 patients had undetectable POCal (mean age = 37.9 years, 70.9% women, median tumor size 1.5 cm [0.7-2.5 cm]; 28 [19.9%] had lymph node metastasis and none had distant metastasis). After a median follow-up of 7.7 years (2.1-13.2 years), 127 (90.1%) of these patients were free of disease, whereas 14 (9.9%) had persistent biochemical disease with stable calcitonin levels. No patient with undetectable POCal died of the disease. In the detectable POCal group (mean age = 42.9 years, 52.8% women, median tumor size 3.0 cm [1.8-4.2 cm]; 136 [70.5%] had lymph node metastasis and 63 [32.6%] had distant metastasis), 18 (9.2%) patients achieved disease-free status, 51 (26.6%) had biochemical disease, and 61 (31.6%) had persistent structural disease. Sixty-three (32.6%) patients died of disease-related events. Further analysis using a multivariate model identified undetectable POCal as an independent prognostic variable for disease-free status (HR = 5.33, CI = 2.86-9.94; p < 0.001). Conclusions: POCal is a strong prognostic marker for long-term disease-free survival and might help define follow-up strategies for MTC patients.

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Schistosomiasis is an endemic parasitic disease in several tropical countries. In Brazil, the only prevalent species of parasite responsible for schistosomiasis is Schistosoma mansoni. Neuroschistosomiasis is the second most frequent form of infection and the primary ectopic manifestation, with predominant involvement of the lower thoracic spinal cord and lumbar and lumbosacral regions. The frequent contact of children with contaminated ponds and the immaturity of their immune systems make this age group especially susceptible to infection by this parasite. Therefore, neuroschistosomiasis mansoni should always be considered in cases of transverse myelitis in children from endemic regions. The treatment for this condition is quite simple and effective, resulting in total recovery of neurological deficits if the diagnosis is made early.

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ABSTRACT Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians' Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results/conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II-V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; "berry node picking" is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

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Resumen ANTECEDENTES: El carcinoma medular de tiroides es un tumor maligno poco frecuente que se origina en las células parafoliculares tiroideas productoras de calcitonina. Si bien puede aparecer espontáneamente, la asociación familiar pocas veces es excepcional. Aunque la supervivencia en estadios iniciales es considerable, es frecuente la posibilidad de metástasis al momento del diagnóstico. CASO CLÍNICO: Paciente de 72 años, con un abultamiento en la región anterior del cuello y una adenopatía cervical izquierda de 15 días de evolución. La TAC, la ecografía y la biopsia reportaron: carcinoma bilateral de ovario poco diferenciado. Se procedió a la cirugía radical (histerectomía, doble anexectomía, linfadenectomía pélvica y para aórtica, omentectomía y apendicectomía) con la que se consiguió una citorreducción completa. En el estudio definitivo se encontraron metástasis de carcinoma medular de tiroides en ambos ovarios, miometrio y peritoneo. Enseguida se inició la quimioterapia con vandetanib. Después de 25 ciclos de tratamiento, la paciente continuó con el ácido zoledrónico y asintomática. Un mes después de finalizarlo comenzó con crisis comiciales que se trataron con quetiapina, con respuesta satisfactoria. Posteriormente, la paciente tuvo una celulitis facial que se trató con antibiótico y corticosteroide; tres semanas después falleció debido a insuficiencia multiorgánica. CONCLUSIONES: El carcinoma medular de tiroides es una rara localización de metástasis que aún requiere investigación que permita establecer protocolos de diagnóstico, tratamiento y estimación de la supervivencia.

Abstract BACKGROUND: Medullary thyroid carcinoma is a rare malignant tumor originating in the calcitonin-producing parafollicular thyroid cells. Although it can occur spontaneously, familial association is rarely exceptional. Although survival in early stages is considerable, the possibility of metastasis at the time of diagnosis is frequent. CLINICAL CASE: 72-year-old patient with a lump in the anterior neck region and left cervical adenopathy of 15 days of evolution. CT, ultrasound, and biopsy reported: bilateral poorly differentiated ovarian carcinoma. Radical surgery (hysterectomy, double adnexectomy, pelvic and para-aortic lymphadenectomy, omentectomy and appendectomy) was performed and complete cytoreduction was achieved. In the definitive study, metastases of medullary thyroid carcinoma were found in both ovaries, myometrium and peritoneum. Chemotherapy with vandetanib was then started. After 25 cycles of treatment, the patient continued with zoledronic acid and was asymptomatic. One month after the end of the treatment, she began to have comic crises that were treated with quetiapine, with satisfactory response. Subsequently, the patient had a facial cellulitis that was treated with antibiotics and corticosteroids; three weeks later she died due to multiorgan failure. CONCLUSIONS: Medullary thyroid carcinoma is a rare site of metastasis that still requires research to establish diagnostic and treatment protocols and to estimate survival.

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BACKGROUND: Cyclosporine is an immunosuppressive agent used effectively for treatment of a rare haematological disorder known as medullary aplasia. This drug prevents several side effects, including gingival enlargement (GE) which compromises aesthetics, phonetics and chewing, and also predisposes patients to periodontitis. CASE SUMMARY: This clinical case reports a 41-year-old woman who presented with cyclosporine-induced GE with underlying periodontitis and medullary aplasia. The management of the disease was approached through multidisciplinary strategy which allowed for accurate diagnosis and a strategic treatment based on the systemic condition and severity of oral pathology. The diagnosis was confirmed through histopathological analysis. The treatment was carried out in phases: Initial (oral hygiene motivation, mechanical supragingival plaque control, and non-surgical therapy); systemic treatment, corrective treatment, and maintenance. CONCLUSION: Multidisciplinary management of cyclosporine-induced GE and medullary aplasia allows for correct diagnosis and effective treatment of this pathological expression through a phased therapeutic approach.

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BACKGROUND: The autoimmune regulator (Aire) gene is critical for the appropriate establishment of central immune tolerance. As one of the main controllers of promiscuous gene expression in the thymus, Aire promotes the expression of thousands of downstream tissue-restricted antigen (TRA) genes, cell adhesion genes and transcription factor genes in medullary thymic epithelial cells (mTECs). Despite the increasing knowledge about the role of Aire as an upstream transcriptional controller, little is known about the mechanisms by which this gene could be regulated. RESULTS: Here, we assessed the posttranscriptional control of Aire by miRNAs. The in silico miRNA-mRNA interaction analysis predicted thermodynamically stable hybridization between the 3'UTR of Aire mRNA and miR-155, which was confirmed to occur within the cellular milieu through a luciferase reporter assay. This finding enabled us to hypothesize that miR-155 might play a role as an intracellular posttranscriptional regulator of Aire mRNA. To test this hypothesis, we transfected a murine mTEC cell line with a miR-155 mimic in vitro, which reduced the mRNA and protein levels of Aire. Moreover, large-scale transcriptome analysis showed the modulation of 311 downstream mRNAs, which included 58 TRA mRNAs. Moreover, miR-155 mimic-transfected cells exhibited a decrease in their chemotaxis property compared with control thymocytes. CONCLUSION: Overall, the results indicate that miR-155 may posttranscriptionally control Aire mRNA, reducing the respective Aire protein levels; consequently, the levels of mRNAs encode tissue-restricted antigens were affected. In addition, miR-155 regulated a crucial process by which mTECs allow thymocytes' migration through chemotaxis.

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O Tronco encefálico (TE) é uma estrutura singular do sistema nervoso central, pois nele passam tratos sensoriais ascendentes da medula espinal, tratos sensoriais da cabeça e do pescoço, os tratos descendentes motores originados no prosencéfalo (divisão mais rostral do encéfalo), e as vias ligadas aos centros de movimento dos olhos. Contém ainda os núcleos dos nervos cranianos e está envolvido na regulação do nível de consciência através de projeções ao prosencéfalo oriundas da formação reticular. Todas essas estruturas coexistem em um espaço muito exíguo, o que faz com que o TE seja um local muito sensível às alterações patológicas, sendo que os pacientes apresentam muitos sinais neurológicos mesmo com lesões muito pequenas nesse local. Compreender a anatomia interna do TE é essencial para o diagnóstico neurológico e a prática da medicina clínica. Outros profissionais da saúde também se beneficiam desse conhecimento para melhor manejo dos seus pacientes neurológicos. Essa revisão apresenta detalhes da anatomia macroscópica e microscópica do bulbo, bem como seus correlatos clínicos frente às lesões mais comuns dessa divisão particular do TE, conhecidas como síndromes bulbares.

The brainstem is a unique structure in the central nervous system, since it gives way to ascending sensory tracts from the spinal cord, sensory tracts from the head and neck, motor descending tracts originating from the forebrain, and the pathways connected to the eye movement centers. It also contains the cranial nerve nuclei and is involved in the regulation of consciousness levels through projections to the forebrain originating in the reticular formation. All these structures coexist in a very small space, which makes the brainstem very sensitive to pathological changes, with patients presenting several neurological symptoms even with very small brainstem lesions. Understanding the internal anatomy of the brainstem is essential for neurological diagnosis and the practice of clinical medicine. Other health professionals also benefit from this knowledge to better manage their neurological patients. This review presents detailed information on the macroscopic and microscopic anatomy of the medulla, as well as its clinical correlates in the face of the most common lesions of this particular division of the brainstem, known as medullary syndromes.

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