miR-383-5p, miR-181a-5p, and miR-181b-5p as Predictors of Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.

Cyclin A in nonfunctioning pituitary adenomas.

PURPOSE: Assess cyclin A in nonfunctioning pituitary adenomas (NFPA) and compare its expression in non-invasive and non-proliferative tumors with invasive and proliferative tumors (12× higher risk of recurrence). METHODS: Quantitative real time polymerase chain reaction to analyze cyclin A using normal pituitary gland as reference. Fold change (FC) > 1 was considered as increased. Tumor invasion was based on Knosp criteria (grades 3-4 considered invasive) and proliferation on the presence of at least two of three criteria: Ki-67 ≥ 3%; mitoses > 2/10; positive p53. Both groups were compared with Mann-Whitney test considering p value < 0.05 as statistically significant. RESULTS: Thirty-one patients with NFPA were included. Tumors were mainly of gonadotrophic origin (74.2%), followed by corticotrophic (19.4%) and lactotrophic (3.2%) origins and null-cell adenomas (3.2%). Median tumor diameter was 3.5 cm (1.8-8.0) and Ki-67 was 3.0% (0.3-11%). Sixteen patients had tumors classified as non-invasive and non-proliferative and 15 as invasive and proliferative. Median FC was 0.31 in all tumors (0.13-1.94). Cyclin A was not related to invasion or proliferation (FC 0.41 in non-invasive and non-proliferative tumors and FC 0.30 in invasive and proliferative tumors; p = 0.968). Four (12.9%) patients had tumors that exhibited increased cyclin A [median FC of 1.04 (1.02-1.94)]-three of gonadotrophic origin and one null-cell adenoma, with two tumors classified as non-invasive and non-proliferative and two tumors classified as invasive and proliferative. Median tumor diameter in these samples was 3.4 cm (2.4-3.6) and Ki-67 was 5.1% (2-11%). CONCLUSIONS: Cyclin A was increased in a minority of NFPA and does not seem to be related to invasion or proliferation.

Secondary glioblastoma metastasis outside the central nervous system in a young HIV-infected patient.

Glioblastoma is the most common adult primary brain tumor that occurs in the central nervous system and is characterized by rapid growth and diffuse invasiveness with respect to the adjacent brain parenchyma, which renders surgical resection inefficient. Although it is a highly infiltrative tumor, it is rarely disseminated beyond the central nervous system, wherein extracranial metastasis is a unique but rare manifestation of this kind of tumor. It is very common for acquired immunodeficiency syndrome (AIDS) patients to be infected with the human immunodeficiency virus (HIV), which suggests that a possible association between HIV infection and tumor development exists. In this paper, we present a new case of a young patient's HIV-associated glioblastoma, with glioblastoma metastasis within the T9 vertebral body and lymph nodes in the anterior neck tissue. Initially, the patient was diagnosed with a grade III plastic astrocytoma. The patient lived a normal life for a year while being treated with temozolomide, radiotherapy, and highly active antiretroviral therapy. However, the tumor quickly evolved into a glioblastoma. We believe that the drastic progression of the tumor from a grade III anaplastic astrocytoma to a metastatic glioblastoma is due to the HIV infection that the patient had acquired, which contributed to a weakened immune system, thus accelerating progression of the cancer.

Clinical significance of filamin A in patients with acromegaly and its association with somatostatin and dopamine receptor profiles.

Filamin-A (FLNA) plays a crucial role in somatostatin receptor (sst) subtype-2 signaling in somatotropinomas. Our objective was to investigate the in vivo association between FLNA and sst2 expression, sst5 expression, dopamine receptor subtype-2 (D2) expression, somatostatin receptor ligand (SRL) responsiveness and tumor invasiveness in somatotropinomas. Quantitative real-time PCR was used to evaluate the absolute mRNA copy numbers of FLNA/sst2/sst5/D2 in 96 somatotropinomas. FLNA, sst2 and sst5 protein expression levels were also evaluated using immunohistochemistry. The Knosp-Steiner criteria were used to evaluate tumor invasiveness. Median FLNA, sst2, sst5 and D2 copy numbers were 4,244, 731, 156 and 3,989, respectively. Thirty-one of the 35 available tumors (89%) were immune positive for FLNA in the cytoplasm and membrane but not in the nucleus. FLNA and sst5 expression were positively correlated at the mRNA and protein levels (p < 0.001 and p = 0.033, respectively). FLNA was positively correlated with sst2 mRNA in patients who were responsive to SRL (p = 0.014, R = 0.659). No association was found between FLNA and tumor invasiveness. Our findings show that in somatotropinomas FLNA expression positively correlated with in vivo sst5 and D2 expression. Notably, FLNA was only correlated with sst2 in patients who were controlled with SRL. FLNA was not associated with tumor invasiveness.

Molecular evidence and clinical importance of ß-arrestins expression in patients with acromegaly.

ß-arrestins seem to have a role in endocytosis and desensitization of somatostatin receptor subtype 2 (sst2) and could be associated with the responsiveness to somatostatin receptor ligands (SRL) in patients with acromegaly. To investigate the in vivo correlation between ß-arrestins 1 and 2 with sst2, sst5 and dopamine receptor subtype 2 (D2) expressions, and the association of ß-arrestins with response to first-generation SRL and invasiveness in somatotropinomas. ß-arrestins 1 and 2, sst2, sst5 and D2 mRNA expressions were evaluated by quantitative real-time RT-PCR on tumoral tissue of 96 patients. Moreover, sst2 and sst5 protein expressions were also evaluated in 40 somatotropinomas by immunohistochemistry. Response to SRL, defined as GH <1 µg/l and normal IGF-I levels, was assessed in 40 patients. The Knosp-Steiner criteria were used to define invasiveness. Median ß-arrestin 1, ß-arrestin 2, sst2, sst5 and D2 mRNA copy numbers were 478; 9375; 731; 156; and 3989, respectively. There was a positive correlation between ß-arrestins 1 and 2 (R = 0.444, P < 0.001). However, no correlation between ß-arrestins and sst2, sst5 (mRNA and protein levels) or D2 was found. No association was found between ß-arrestins expression and SRL responsiveness or tumour invasiveness. Although previous data suggest a putative correlation between ß-arrestins and sst2, our data clearly indicated that no association existed between ß-arrestins and sst2, sst5 or D2 expression, nor with response to SRL or tumour invasiveness. Therefore, further studies are required to clarify whether ß-arrestins have a role in the response to treatment with SRL in acromegaly.

As mucinas e o NCAM (CD56) na colangiocarcinogênese intra-hepática / Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Introduction: Cholangiocarcinoma is the second most common malignant neoplasm of the hepatobiliary system. During cholangiocarcinogenesis phenotypic changes occur in the ductal epithelium, including the expression of mucins (MUC). However, the evaluating studies of the expression of mucins in the different stages of cholangiocarcinogenesis are scarce. CD56 has also contributed in differentiating benign ductal proliferation and cholangiocarcinoma; however, its expression has not been evaluated in dysplastic epithelium of the bile duct yet. Objective: To assess immunohistochemical profile of (MUC) 1, 2, 5, 6, and CD56 in cholangiocarcinoma, pre-neoplastic and reactive lesions in the epithelium of intrahepatic bile ducts. Material and methods: Immunohistochemical expression of MUC 1, 2, 5, 6, and CD56 were studied for 11 cases of cholangiocarcinoma and 83 intrahepatic bile ducts (67 reactive and 16 dysplastic). Variables were considered significant when p < 0.05. Results: The expression of MUC1 occurred in about 90% of the cholangiocarcinomas, contrasting with the low frequency of positive cases in reactive and dysplastic bile ducts (p < 0.001). However, there was no statistically significant difference in the expression of MUC5, MUC6 and CD56 between the reactive or dysplastic lesions and cholangiocarcinoma. The anti-MUC2 antibody was negative in all cases. Conclusions: MUC1 contributed for the differential diagnosis between cholangiocarcinoma and pre-neoplastic and reactive/regenerative lesions of intrahepatic bile ducts, and it should compose the antibodies panel aiming at improvement of these differential diagnoses. In contrast, MUC2, MUC5, MUC6 and CD56 were not promising in differentiating all the phases of cholangiocarcinogenesis...

Introdução: O colangiocarcinoma é a segunda neoplasia maligna mais comum do sistema hepatobiliar. Durante a colangiocarcinogênese podem ocorrer alterações fenotípicas do epitélio ductal, incluindo a expressão de mucinas. Entretanto, os estudos que avaliam a expressão das mucinas nas diferentes etapas da colangiocarcinogênese são escassos. O CD56, apesar de contribuir na diferenciação entre as proliferações ductais benignas e o colangiocarcinoma, ainda não teve a sua expressão avaliada no epitélio displásico dos ductos biliares. Objetivos: Analisar o perfil das mucinas (MUC) 1, 2, 5, 6 e do CD56 no colangiocarcinoma, nas lesões pré-neoplásicas e reacionais de ductos biliares intra-hepáticos. Material e métodos: A expressão imuno-histoquímica da MUC 1, 2, 5, 6 e do CD56 foram avaliadas em 11 colangiocarcinomas e 83 ductos biliares intra-hepáticos (67 reativos e 16 displásicos). As variáveis foram consideradas como significativas quando p < 0,05. Resultados: A expressão da MUC1 ocorreu em cerca de 90% dos colangiocarcinomas, contrastando com a baixa frequência de casos positivos nos ductos biliares reativos ou displásicos (p < 0,001). Não houve diferença estatisticamente significativa na expressão de MUC5, MUC6 e CD56 entre as lesões reativas, displásicas e o colangiocarcinoma. O anticorpo anti-MUC2 foi negativo em todos os casos. Conclusão: A MUC1 contribuiu no diagnóstico diferencial entre o colangiocarcinoma e as lesões pré-neoplásicas e reacionais/regenerativas dos ductos biliares intra-hepáticos, e deve compor o painel de anticorpos a ser empregado visando o aprimorando destes diagnósticos diferenciais. Contrariamente, a MUC2, MUC5, MUC6 e o CD56 não se mostraram promissoras na diferen...