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1.
Medicine (Baltimore) ; 100(35): e26918, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477122

RESUMO

BACKGROUND: Radical pancreaticoduodenectomy is the only possible cure for pancreatic head adenocarcinoma, and although several RCT studies have suggested the extent of lymph node dissection, this issue remains controversial. This article wanted to evaluate the survival benefit of different lymph node dissection extent for radical surgical treatment of pancreatic head adenocarcinoma. METHODS: A total of 240 patients were assessed for eligibility in the study, 212 of whom were randomly divided into standard lymphadenectomy group (SG) or extended lymphadenectomy group (EG), there were 97 patients in SG and 95 patients in EG receiving the radical pancreaticoduodenectomy. RESULT: The demography, histopathology and clinical characteristics were similar between the 2 groups. The 2-year overall survival rate in the SG was higher than the EG (39.5% vs 25.3%; P = .034). The 2-year overall survival rate in the SG who received postoperative adjuvant chemotherapy was higher than the EG (60.7% vs 37.1%; P = .021). There was no significant difference in the overall incidence of complications between the 2 groups (P = .502). The overall recurrence rate in the SG and EG (70.7% vs 77.5%; P = .349), and the patterns of recurrence between 2 groups were no significant differences. CONCLUSION: In multimodality therapy system, the efficacy of chemotherapy should be based on the appropriate lymphadenectomy extent, and the standard extent of lymphadenectomy is optimal for resectable pancreatic head adenocarcinoma. The postoperative slowing of peripheral blood lymphocyte recovery might be 1 of the reasons why extended lymphadenectomy did not result in survival benefits. CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT02928081) in October 7, 2016. https://clinicaltrials.gov/.


Assuntos
Adenoma/cirurgia , Excisão de Linfonodo/normas , Neoplasias Pancreáticas/cirurgia , Adenoma/epidemiologia , Adenoma/mortalidade , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Excisão de Linfonodo/métodos , Excisão de Linfonodo/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/mortalidade , Pancreaticoduodenectomia/métodos , Pancreaticoduodenectomia/normas , Pancreaticoduodenectomia/estatística & dados numéricos , Modelos de Riscos Proporcionais , Estudos Prospectivos , Método Simples-Cego
2.
Nat Commun ; 12(1): 2281, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863879

RESUMO

Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.


Assuntos
Adenoma/imunologia , Colite/patologia , Neoplasias Colorretais/imunologia , Fibroblastos/imunologia , Interleucina-11/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Adenoma/genética , Adenoma/mortalidade , Adenoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Colite/induzido quimicamente , Colite/imunologia , Colo/citologia , Colo/imunologia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Intervalo Livre de Doença , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Genes Reporter , Proteínas de Fluorescência Verde/genética , Humanos , Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/genética , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Organoides , Cultura Primária de Células , Estudos Retrospectivos , Transcriptoma/imunologia , Microambiente Tumoral/imunologia
3.
Best Pract Res Clin Endocrinol Metab ; 35(1): 101521, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766428

RESUMO

Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterised by excess cortisol secretion due to either ACTH-dependent conditions [commonly an ACTH-producing pituitary adenoma (Cushing's disease)] or ACTH-independent causes (with most common aetiology being a benign adrenal adenoma). Overall, the annual incidence of CS ranges between 1.8 and 3.2 cases per million population. Mortality in active CS is elevated compared to the general population, and a number of studies support the view that survival is also compromised even after apparent successful treatment. The main cause of death is cardiovascular disease highlighting the negative impact of cortisol excess on cardiovascular risk factors. Early diagnosis and prompt treatment of the cortisol excess, as well as vigilant monitoring and stringent control of cardiovascular risk factors are key elements for the long-term prognosis of these patients.


Assuntos
Síndrome de Cushing/epidemiologia , Adenoma Hipofisário Secretor de ACT/complicações , Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma Hipofisário Secretor de ACT/epidemiologia , Adenoma Hipofisário Secretor de ACT/mortalidade , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/mortalidade , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Causas de Morte , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/mortalidade , Humanos , Hidrocortisona/metabolismo , Incidência , Mortalidade , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/epidemiologia , Hipersecreção Hipofisária de ACTH/mortalidade
4.
Cancer Med ; 10(8): 2855-2864, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33314646

RESUMO

BACKGROUND: Real-world data for patients with positive colorectal cancer (CRC) screening stool-tests demonstrate that adenoma detection rates are lower when endoscopists are blinded to the stool-test results. This suggests adenoma sensitivity may be lower for screening colonoscopy than for follow-up to a known positive stool-based test. Previous CRC microsimulation models assume identical sensitivities between screening and follow-up colonoscopies after positive stool-tests. The Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) was used to explore the impact on screening outcomes when assuming different adenoma sensitivity between screening and combined follow-up/surveillance colonoscopies. METHODS: Modeled screening strategies included colonoscopy every 10 years, triennial multitarget stool DNA (mt-sDNA), or annual fecal immunochemical test (FIT) from 50 to 75 years. Outcomes were reported per 1000 individuals without diagnosed CRC at age 40. Base-case adenoma sensitivity values were identical for screening and follow-up/surveillance colonoscopies. Ranges of adenoma sensitivity values for colonoscopy performance were developed using different slopes of odds ratio adjustments and were designated as small, medium, or large impact scenarios. RESULTS: As the differences in adenoma sensitivity for screening versus follow-up/surveillance colonoscopies became greater, life-years gained (LYG) and reductions in CRC-related incidence and mortality versus no screening increased for mt-sDNA and FIT and decreased for screening colonoscopy. The LYG relative to screening colonoscopy reached >90% with FIT in the base-case scenario and with mt-sDNA in a "medium impact" scenario. CONCLUSIONS: Assuming identical adenoma sensitivities for screening and follow-up/surveillance colonoscopies underestimate the potential benefits of stool-based screening strategies.


Assuntos
Adenoma/diagnóstico , Adenoma/epidemiologia , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Adenoma/mortalidade , Neoplasias Colorretais/mortalidade , Seguimentos , Humanos , Incidência , Programas de Rastreamento/métodos , Modelos Teóricos , Anos de Vida Ajustados por Qualidade de Vida , Sensibilidade e Especificidade
5.
Cancer Res ; 80(23): 5203-5215, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33051252

RESUMO

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. SIGNIFICANCE: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.


Assuntos
Adenocarcinoma/patologia , Adenoma/patologia , Neoplasias Colorretais/patologia , Epigênese Genética , Proteínas de Filamentos Intermediários/genética , Microtúbulos/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenoma/genética , Adenoma/mortalidade , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Proteínas de Filamentos Intermediários/química , Proteínas de Filamentos Intermediários/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Microtúbulos/genética , Microtúbulos/patologia , Polimerização , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Med Sci Monit ; 26: e922585, 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32716010

RESUMO

BACKGROUND The incidence of osteoclast-like giant cell tumor of the pancreas (OGTP) is very low, and relatively little OGTP clinical data is available. The present study, therefore, sought to conduct a more comprehensive analysis of the clinical characteristics and prognosis of OGTP. MATERIAL AND METHODS A large population-based cohort analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) registry. We conducted a systematic assessment of the demographic and clinical characteristics of these patients, in addition to assessing available prognostic and therapeutic data corresponding to their disease. We further compared overall survival (OS) in these OGTP and pancreatic adenocarcinoma (PA) patient cohorts, adjusting for sex, grade, stage, and surgical treatment by propensity score matching (PSM). RESULTS We included a total of 47 OGTP patients and 73 150 PA patients in the present analysis. The mean ages of PA and OGTP diagnosis were 68.0 and 62.8 years, respectively. Compared with PA patients, OGTP patients were more likely to be female (70.2% versus 48.7%, P<0.01), to have early-stage disease, to have lower rates of lymph node metastasis (17.0% versus 28.8%, P<0.01) and distant metastasis (17.0% versus 45.1%, P<0.01), and to have higher rates of tumor resection (70.2% versus 15.4%, P<0.01). OGTP patients also had a significantly longer median OS than did PA patients (13 months versus 6 months; hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.37-0.57, P<0.0001). No significant differences in tumor site preferences were detected. Our findings also suggested that being female, having early-stage disease, and undergoing surgical resection may be associated with a more favorable prognosis in patients with OGTP. CONCLUSIONS OGTP patients had distinctive clinical characteristics and a better prognosis compared with PA patients. Understanding these differences will help clinicians accurately recognize these diseases. Radical resection was beneficial to the survival of OGTP patients.


Assuntos
Adenoma/patologia , Carcinoma Ductal Pancreático/patologia , Tumores de Células Gigantes/patologia , Neoplasias Pancreáticas/patologia , Adenoma/metabolismo , Adenoma/mortalidade , Idoso , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Tumores de Células Gigantes/metabolismo , Tumores de Células Gigantes/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Osteoclastos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Resultado do Tratamento
7.
Aging (Albany NY) ; 12(11): 10337-10358, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32428869

RESUMO

Colorectal cancer (CRC) is a major health problem in elderly people because of its high incidence and high mortality rate. Despite early screening programs, more than half of CRC patients are diagnosed at advanced stages. Fibroblast activation protein-α (FAP) expression in cancer-associated fibroblasts (CAFs) has been associated with a higher risk of metastases and poor survival. Here, we have analyzed the immunohistochemical expression of FAP in 41 adenoma-carcinoma sequences. In addition, FAP expression was analyzed individually and in combination with ß-catenin (BCAT), CD44 and Cyclin-D1 expression in primary tumors and in their corresponding lymph node and liver metastases (n=294). Finally, soluble FAP (sFAP) levels in plasma from CRC patients (n=127) were also analyzed by ELISA. FAP was expressed only in CRC tissue and its expression level was found to be higher in tumors exhibiting deeper local invasion and poorer cancer cell differentiation. FAP and concomitant nuclear BCAT expression in cancer cells at the infiltrating front of primary tumors and in lymph node metastases was independently associated with 5- and 10-year cancer specific and disease-free survival. Moreover, lower sFAP levels correlated with poorer survival. These findings support the potential importance of FAP as a biomarker of CRC development and progression.


Assuntos
Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma/secundário , Neoplasias Colorretais/patologia , Gelatinases/metabolismo , Neoplasias Hepáticas/secundário , Metástase Linfática/patologia , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Adenoma/sangue , Adenoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Fibroblastos Associados a Câncer/metabolismo , Carcinoma/sangue , Carcinoma/mortalidade , Colo/patologia , Neoplasias Colorretais/sangue , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Gelatinases/análise , Humanos , Mucosa Intestinal/patologia , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Linfonodos/patologia , Masculino , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Serina Endopeptidases/análise
8.
Virchows Arch ; 477(4): 527-534, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32296928

RESUMO

The distinction between well-differentiated intrahepatic cholangiocarcinoma (iCCA) from its morphological mimics such as bile duct adenoma (BDA) and hamartoma (BDH) can be challenging, particularly in small biopsies. Although a few cases of BDA and BDH have been reported to undergo malignant transformation into iCCA, their neoplastic versus benign nature remains debated. DNA flow cytometry was performed on 47 formalin-fixed paraffin-embedded samples of iCCA, 14 BDA, and 18 BDH. Aneuploidy was detected in 22 iCCA (47%) but in none of the 32 BDA and BDH samples. Among the 34 iCCA patients who underwent complete resection and were followed up to tumor recurrence, tumor-related death, or at least for 1 year, the overall recurrence or death rates (regardless of flow cytometric results) were 18, 56, and 71% within 1, 3, and 5 years, respectively. The 1-, 3-, and 5-year recurrence or death rates in 18 iCCA patients with aneuploidy were 28, 66, and 66%, respectively, whereas 16 iCCA patients in the setting of normal DNA content had 1-, 3-, and 5-year rates of 6, 44, and 72%, respectively. Although aneuploid tumors were associated with worse outcomes during the first 3 years, this difference was not statistically significant (hazard ratio = 1.4, p = 0.473) in the present sample size. In conclusion, the frequency of aneuploidy was significantly higher in iCCA (47%) than in its benign morphological mimics (0%), suggesting that it may potentially serve as a diagnostic marker of malignancy in challenging situations. Our findings also suggest that most BDAs and BDHs, if not all, are benign entities and may not represent precursor lesions to iCCAs that often harbor aneuploidy. Although a larger cohort will be necessary to further determine the prognostic significance of aneuploidy in iCCA patients after resection, the patients with aneuploid tumors may have a higher risk for tumor progression, especially during the first 3 years.


Assuntos
Adenoma/genética , Aneuploidia , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , DNA de Neoplasias/genética , Citometria de Fluxo , Hamartoma/genética , Adenoma/mortalidade , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Bases de Dados Factuais , Diagnóstico Diferencial , Progressão da Doença , Feminino , Hamartoma/mortalidade , Hamartoma/patologia , Hamartoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Fatores de Tempo
9.
Sci Rep ; 10(1): 5892, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32246094

RESUMO

ST2 (also known as IL1RL1) is the critical functional receptor for interleukin (IL)-33 in stimulating regulatory T cell (Treg) expansion and function in physiological and pathological conditions. We examined the correlation between ST2 cell expression and FoxP3 positive Tregs in both colorectal adenoma and cancer (CRC) microenvironment by real-time PCR, immunohistochemistry (IHC) and double immunofluorescences. The clinicopathological and prognostic significance of cellular ST2-positive cells and FoxP3-positive Tregs in patients with adenoma and CRC were evaluated. Real-time PCR results revealed increased expression levels of ST2 and FoxP3 mRNAs in both adenoma and CRC tissues as compared with control tissues. IHC analysis confirmed increased densities of ST2-positive cells in both the adenoma/CRC epithelium and stroma, which show a close positive linear association with the densities of FoxP3-positive Tregs in respective compartments. Pathological feature analysis showed that densities of ST2-positive cells in the tumor stroma were notably associated with degree of dysplastic grading in patients with adenoma, and disease stages and lymph node metastasis in patients with CRC. Kaplan-Meier survival curves suggested that CRC patients with high densities of ST2-positive cells in the stroma tend to have a shorter overall survival. We therefore concluded that increased densities of ST2-postive cells relate to Treg accumulation within the adenoma/CRC microenvironment, suggesting the IL-33/ST2 pathway as a potential contributor for immunosuppressive milieu formation that impact disease stage and prognosis in patients with CRC.


Assuntos
Adenoma/imunologia , Neoplasias Colorretais/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia , Adenoma/mortalidade , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Colo/imunologia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Proteína 1 Semelhante a Receptor de Interleucina-1/análise , Interleucina-33/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Reto/imunologia , Reto/patologia , Reto/cirurgia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo , Evasão Tumoral
10.
Gastroenterology ; 158(2): 291-302, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622622

RESUMO

Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.


Assuntos
Adenoma/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Adenoma/mortalidade , Adenoma/patologia , Carcinogênese/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Metilação de DNA , Progressão da Doença , Epigênese Genética , Humanos , Instabilidade de Microssatélites , Mutação
11.
Mol Med Rep ; 20(4): 3276-3284, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432167

RESUMO

Studies have revealed that genetic and functional aberrations of oncogenes, tumor­suppressor genes, signaling pathways and receptors are among the most prominent events in pituitary tumorigenesis, and a potent biomarker would be helpful for early diagnosis, subsequent treatment and disease control. The present study investigated the expression signatures of solute carrier family 20 member 1, also known as phosphate transporter 1 (SLC20A1) and the Wnt/ß­catenin signaling pathway in 52 patients with somatotroph adenomas. According to immunohistochemistry analysis, the H­score of SLC20A1 was 222.6±15.2 in invasive tumor samples and 144.5±30.4 in non­invasive tumor samples (P<0.01), while the H­scores of ß­catenin were 210.1±21.4 and 134.9±32.7, respectively (P<0.05). The H­scores of Wnt inhibitory factor 1 (Wif1) exhibited the opposite trend, with scores of 134.5±22.7 and 253.6±14.8, respectively (P<0.01). The H­scores of SLC20A1 were negatively associated with those of Wif1 in somatotroph adenomas (correlation coefficient r=­0.367). The mean progression­free survival in the low SLC20A1 group was longer than that in the group with high SLC20A1 H­scores (P=0.024). Reverse transcription­quantitative PCR (RT­qPCR) and western blotting confirmed the interference efficiency of the segments short hairpin (Sh)­B­SLC20A1 and Sh­C­SLC20A1. Cell proliferation experiments revealed that the cell viability of the Sh­B­SLC20A1 group was 76.3±4.5, 65.7±3.7 and 53.1±3.2% of that of control GH3 cells after 24, 48 and 72 h of transfection, respectively, while the cell viability of the Sh­C­SLC20A1 group was 86.4±5.7, 75.6±4.4 and 67.5±3.8%, respectively (P<0.05). ELISA analysis demonstrated the growth hormone (GH) levels in the Sh­B­SLC20A1 and Sh­C­SLC20A1 groups to be 34.7±10.4 and 54.6±14.4%, respectively, of that of control GH3 cells (P<0.05). The transmembrane invasion assay revealed that knocking down SLC20A1 significantly suppressed cell invasion in the Sh­B­SLC20A1 and Sh­C­SLC20A1 groups. RT­qPCR and western blotting demonstrated that Sh­B­SLC20A1 and Sh­C­SLC20A1 evidently increased the levels of Wif1 and secreted frizzled­related protein 4. The present data suggested that SLC20A1 levels are positively associated with tumor size, invasive behavior and tumor recurrence in somatotroph adenomas. Furthermore, SLC20A1 may be associated with the activation of the Wnt/ß­catenin signaling pathway.


Assuntos
Adenoma , Regulação Neoplásica da Expressão Gênica , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Proteínas de Neoplasias/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/biossíntese , Via de Sinalização Wnt , Adenoma/metabolismo , Adenoma/mortalidade , Adenoma/patologia , Adolescente , Adulto , Intervalo Livre de Doença , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/mortalidade , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , beta Catenina/metabolismo
12.
Pituitary ; 22(5): 520-531, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432313

RESUMO

BACKGROUND: Personalized postoperative management of patients with pituitary adenomas requires an early risk stratification system. METHODS: We reviewed 501 cases operated between 10/27/2011 and 5/5/2016 by a single neurosurgeon. We determined biochemical remission and tumor resection at 3 months, and biochemical recurrence, tumor recurrence, radiation and reoperation during follow-up. We considered age, gender, tumor diameter, cavernous sinus invasion (CSI) by MRI, diagnostic category (clinical, biochemical and immunohistochemical), and proliferation markers in a Cox proportional hazards model. We built predictive models with the significant parameters and used Kaplan-Meier survival curves for time-dependent analyses. RESULTS: The 501 cases comprised 141 functional and 360 nonfunctional adenomas. Tumor diameter, CSI, and ki-67 index predicted long-term events. Model 1 (CSI, diameter ≥ 2.9 cm and ki-67 > 3%) identified 18 (3.6%) adenomas and predicted persistent hypersecretory syndrome and residual tumor with 98.7% specificity (OR 8.6; CI 3.0-24.7). Model 2 (ki-67 > 3% and CSI) identified 48 (9.6%) adenomas and had 93.1% specificity (OR 3.3; CI 1.8-6.0). Model 3 (ki-67 > 3%, mitoses and p53, former "atypical" adenoma) identified 26 (5.2%) adenomas and had 96.0% specificity (OR 2.3; CI 1.0-5.0). Model 1 best predicted the long-term event-free survival and was strengthened when Knosp 3-4 CSI grades were used. Model 2 better identified the smaller adenomas at risk. Among the WHO 2017 special PA subtypes, patients with silent corticotroph adenoma had a lower event-free survival than ACTH-negative nonfunctional adenomas. CONCLUSION: Use of CSI, ki-67 and tumor diameter in prediction models facilitates tailored surveillance and management of patients with pituitary adenomas.


Assuntos
Adenoma/cirurgia , Neoplasias Hipofisárias/cirurgia , Adenoma/mortalidade , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Hipofisárias/mortalidade , Modelos de Riscos Proporcionais
13.
Endocrine ; 65(2): 393-398, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31267325

RESUMO

OBJECTIVE: To evaluate the impact of temozolomide (TMZ) introduction on the survival of patients with pituitary carcinoma (PC) compared to aggressive pituitary adenoma (APA). METHODS: Retrospective analysis of the Surveillance Epidemiology and End-Results database (SEER), including patients diagnosed with PC or APA between 1973 and 2015. Age-adjusted Kaplan-Meier analyses were performed, comparing all-cause mortality (ACM) rates before the year 2006, the time of TMZ introduction ("period 1"), and afterwards ("period 2"), in patients harboring PC and APA. RESULTS: Among 107 patients, 18 (16.8%) harbored PC. The prevalence of PC and APA was comparable between genders, ethnicities and age strata. Patients harboring any pituitary tumor (PC or APA) had comparable risk for ACM and disease-specific mortality between the two time periods. However, among patients harboring PC, the risk for ACM was significantly lower in period 2 vs. period 1 (p = 0.021), becoming comparable to the risk of ACM in patients diagnosed with APA (p = 0.48). CONCLUSIONS: In this large cancer-database-based analysis we observed improved overall survival in patients harboring PC in the years following the introduction of TMZ.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Temozolomida/uso terapêutico , Adenoma/mortalidade , Idoso , Carcinoma/mortalidade , Feminino , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/mortalidade , Prevalência , Estudos Retrospectivos
14.
Medicina (B Aires) ; 79(3): 191-196, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31284253

RESUMO

Clinical presentation, treatment and its results were evaluated during long-term follow-up of 37 patients older than 65 years with pituitary adenoma. Causes of death were also evaluated. It was a retrospective and cross-sectional study. Prevalence of incidentalomas was 43% (16), macroadenomas 70.3% (26) and giant adenomas 16.2% (6). The most frequent tumor phenotype was the non-functioning adenoma (76%). The prevalence of visual field defects and neurological symptoms was 56% and 57% respectively. We found normal pituitary function in 54%, partial deficiency in 30% and panhypopituitarism in 16%. Thirty-two patients were treated, 5 were lost to follow-up without receiving treatment. Surgery was indicated in 18. Of those operated by trans-sphenoidal approach, 23% had postsurgical complications and 54% improved the visual field. By trans-craneal approach, 50% had post-surgical complications and 33% visual field improvement. During follow-up (55.1 ± 48.7 months) no tumor regrowth was observed, except in a giant adenoma. Four operated patients died, two due to causes related to tumor. Fourteen were not operated, 11 with non-functioning adenoma and normal visual field were periodically controlled and 3 with secreting adenomas received medical treatment. No tumor growth was observed during follow-up (43.7 ± 38.0 months). We did not observe tumor progression in elderly patients with non-functioning adenoma and normal visual field, so we suggest watchful approach and periodic control. When there are visual field defects, trans-sphenoidal surgery can be considered safe and effective. In secreting adenomas and depending on the associated comorbidities, medical treatment would be the appropriate approach.


Assuntos
Adenoma/terapia , Neoplasias Hipofisárias/terapia , Adenoma/diagnóstico , Adenoma/mortalidade , Adenoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Estudos Transversais , Feminino , Humanos , Masculino , Hormônios Hipofisários , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
15.
Int J Med Sci ; 16(6): 813-821, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337954

RESUMO

Background and Objective: Colorectal cancer (CRC) is a major health problem in developed countries. Adenomatous lesions in the large bowel are the main precursors of CRC and the adenoma-adenocarcinoma sequence still provides a solid model for research on carcinogenesis. The finding of local renin-angiotensin systems (RAS) has been crucial to understand the role of this peptidergic system in cancer and has opened new perspectives in the study of colorectal carcinogenetic processes. Methods: In this study we analyzed the immunohistochemical expression of three main RAS receptors (AT1, AT2 and MAS) in a large series of CRC samples (n=161), including uninvolved intestinal mucosa-adenoma-adenocarcinoma sequences from the same patients (n=50). Results: 1) AT1 and AT2 showed a biphasic expression pattern along the sequence. The expression significantly decreased in adenomas with respect to uninvolved mucosa but increased in CRCs. 2) AT2 expression was lower in advanced CRCs with high local invasion (pT4), high stage (IV), high nodal (N2) and vascular invasion. 3) MAS receptor was moderately expressed in the uninvolved mucosa and in adenomas. This expression increased very significantly in CRC tissues. Conclusions: These results suggest that: 1) RAS receptors are differentially regulated as the genetic and epigenetic alterations accumulate throughout the uninvolved mucosa-adenoma-CRC sequence. 2) Loss of AT2 expression could contribute to the aggressive behavior of advanced CRC cells.


Assuntos
Adenocarcinoma/genética , Adenoma/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/mortalidade , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Epigênese Genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/genética
16.
Comput Math Methods Med ; 2019: 2476565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915155

RESUMO

Introduction: Colorectal cancer (CRC), if not detected early, can be costly and detrimental to one's health. Colonoscopy can identify CRC early as well as prevent the disease. The benefit of screening colonoscopy has been established, but the optimal frequency of follow-up colonoscopy is unknown and may vary based on findings from colonoscopy screening and patient age. Methods: A partially observed Markov process (POMP) was used to simulate the effects of follow-up colonoscopy on the development of CRC. The POMP uses adenoma and CRC growth models to calculate the probability of a patient having colorectal adenomas and CRC. Then, based on mortality, quality of life, and the costs associated with diagnosis, treatment, and surveillance of colorectal cancer, the overall costs and increase in quality-adjusted life years (QALYs) are calculated for follow-up colonoscopy scenarios. Results: At the $100,000/QALY gained threshold, only one follow-up colonoscopy is cost-effective only after screening at age 50 years. The optimal follow-up is 8.5 years, which gives 84.0 QALYs gained/10,000 persons. No follow-up colonoscopy was cost-effective at the $50,000 and $75,000/QALY gained thresholds. The intervals were insensitive to the findings at screening colonoscopy. Conclusion: Follow-up colonoscopy is cost-effective following screening at age 50 years but not if screening occurs later. Following screening at age 50 years, the optimal follow-up interval is close to the currently recommended 10 years for an average risk screening but does not vary by colonoscopy result.


Assuntos
Adenoma/diagnóstico por imagem , Neoplasias do Colo/diagnóstico por imagem , Colonoscopia/métodos , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Adenoma/economia , Adenoma/mortalidade , Fatores Etários , Idoso , Algoritmos , Neoplasias do Colo/economia , Neoplasias do Colo/mortalidade , Colonoscopia/economia , Simulação por Computador , Detecção Precoce de Câncer/economia , Feminino , Seguimentos , Custos de Cuidados de Saúde , Humanos , Masculino , Cadeias de Markov , Informática Médica/métodos , Pessoa de Meia-Idade , Probabilidade , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Reprodutibilidade dos Testes , Programa de SEER , Sensibilidade e Especificidade , Estados Unidos
17.
World J Gastroenterol ; 25(11): 1387-1397, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30918431

RESUMO

BACKGROUND: Endoscopic papillectomy (EP) for benign ampullary neoplasms could be a less-invasive alternative to pancreatoduodenectomy (PD). There are some problems and limitations with EP. The post-EP resection margins of ampullary tumors are often positive or uncertain because of the burning effect of EP. The clinical outcomes of resected margin positive or uncertain cases after EP remain unknown. AIM: To investigate the clinical outcomes of resected margin positive or uncertain cases after EP. METHODS: Between January 2007 and October 2018, all patients with ampullary tumors who underwent EP at Kobe University Hospital were included in this study. The indications for EP were as follows: adenoma, as determined by preoperative endoscopic biopsy, without bile/pancreatic duct extension, according to endoscopic ultrasound or intraductal ultrasound. The clinical outcomes of resected margin positive or uncertain cases after EP were retrospectively investigated. RESULTS: Of the 45 patients, 29 were male, and 16 were female. The mean age of the patients was 65 years old. Forty-one patients (89.5%) underwent en bloc resection, and 4 patients (10.5%) underwent piecemeal resection. After EP, 33 tumors were histopathologically diagnosed as adenoma, and 12 were diagnosed as adenocarcinoma. The resected margins were positive or uncertain in 24 patients (53.3%). Of these cases, 15 and 9 were diagnosed as adenoma and adenocarcinoma, respectively. Follow-up observation was selected for all adenomas and 5 adenocarcinomas. In the remaining 4 adenocarcinoma cases, additional PD was performed. Additional PD was performed in 4 cases, and residual carcinoma was found after the additional PD in 1 of these cases. In the follow-up period, local tumor recurrence was detected in 3 cases. Two of these cases involved primary EP-diagnosed adenoma. The recurrent tumors were also adenomas detected by biopsy. The remaining case involved primary EP-diagnosed adenocarcinoma. The recurrent tumor was also an adenocarcinoma. All of the recurrent tumors were successfully treated with argon plasma coagulation (APC). There was no local or lymph node recurrence after the APC. The post-APC follow-up periods lasted for 57.1 to 133.8 mo. No ampullary tumor-related deaths occurred in all patients. CONCLUSION: Resected margin positive or uncertain cases after EP could be managed by endoscopic treatment including APC, even in cases of adenocarcinoma. EP could become an effective less-invasive first-line treatment for early stage ampullary tumors.


Assuntos
Adenocarcinoma/cirurgia , Adenoma/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Margens de Excisão , Recidiva Local de Neoplasia/cirurgia , Esfinterotomia Endoscópica/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/diagnóstico por imagem , Adenoma/mortalidade , Adenoma/patologia , Idoso , Ampola Hepatopancreática/diagnóstico por imagem , Ampola Hepatopancreática/patologia , Ampola Hepatopancreática/cirurgia , Coagulação com Plasma de Argônio , Biópsia/métodos , Neoplasias do Ducto Colédoco/diagnóstico por imagem , Neoplasias do Ducto Colédoco/mortalidade , Neoplasias do Ducto Colédoco/patologia , Duodenoscopia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasia Residual , Pancreaticoduodenectomia , Estudos Retrospectivos , Resultado do Tratamento , Incerteza
18.
Sci Rep ; 9(1): 1489, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728413

RESUMO

Patients with pancreatic adenocarcinoma (PDAC) still face a very limited prognosis. At early stage, surgical tumor resection might offer long-term survival but disease recurrence is common and the existing stratification algorithms are often unsuitable to identify patients who particularly benefit from surgery. Here, we investigated the potential role of bone sialoprotein (BSP) as a circulating marker in patients undergoing resection of PDAC. We used ELISA to determine serum concentrations of BSP in a cohort of 132 PDAC patients as well as 39 healthy controls. Circulating BSP levels were significantly higher in PDAC patients compared to healthy controls. Notably, elevated preoperative BSP levels above the ideal cut-off value of 4743 pg/ml turned out as a significant predictor for an impaired postoperative survival. The potential of preoperative BSP levels as a prognostic marker was further underlined by uni- and multivariate Cox-regression analyses including various tumour- and patient-specific. Finally, high tumoral BSP expression was also associated with a significantly impaired long-term survival. In conclusion, we identified a novel role of circulating BSP as a biomarker in PDAC patients undergoing tumor resection. Such data might help to establish new preoperative stratification strategies to better identify patients who particularly benefit from tumor resection.


Assuntos
Adenoma/mortalidade , Sialoproteína de Ligação à Integrina/análise , Neoplasias Pancreáticas/mortalidade , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Carcinoma Ductal Pancreático/patologia , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Sialoproteína de Ligação à Integrina/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Prognóstico
19.
World Neurosurg ; 121: e45-e53, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30196178

RESUMO

OBJECTIVE: The present study was conducted to evaluate the levels of Cdk2, cyclin E, p21, and p27 in growth hormone adenomas (GHPAs) and analyze their association with clinicopathologic features. METHODS: We collected 46 GHPA specimens and clinical materials from March 2012 to December 2015 at Beijing Tiantan Hospital. We analyzed the expression of Cdk2, cyclin E, p21, and p27 using immunohistochemistry, quantitative real-time polymerase chain reaction, Western blot, and methylation-specific polymerase chain reaction and sequencing. RESULTS: The levels of cyclin E and Cdk2 were much greater in the invasive group than in the noninvasive group (P < 0.05). Significant differences were found between cyclin E and p21 and tumor size (P < 0.05) and between cyclin E expression and invasion (P < 0.05). Tumors were more likely to require whole resection in patients with low cyclin E expression (P < 0.05). The high-level p27 group had better progression-free survival than did the low-level p27 group (P < 0.01). Quantitative real-time polymerase chain reaction and Western blot analysis revealed a similar trend for Cdk2, cyclin E, p21, and p27 protein levels in growth hormone specimens (P < 0.01). An average of 33 CpG sites per sample were analyzed using matrix-assisted laser desorption ionization time-of-flight mass array, and in 7 of the 33 CpG sites, the methylation levels of p27 were >50%. Statistically significant differences were found in 4 CpG sites between the invasive and noninvasive specimens (P < 0.01). CONCLUSIONS: Overexpression of cyclin E/Cdk2 and loss of p27 appears to be associated with a poor prognosis and might play a role in the treatment of GHPAs in the future.


Assuntos
Adenoma/metabolismo , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Proteínas Oncogênicas/metabolismo , Adenoma/mortalidade , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
20.
Gastroenterology ; 156(3): 604-613.e3, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30296436

RESUMO

BACKGROUND & AIMS: Colorectal cancer (CRC) can be prevented by colonoscopy and polypectomy. Endoscopic mucosal resection (EMR) is performed to remove large laterally spreading colonic lesions that have a high risk of progression to CRC. Endoscopically invisible micro-adenomas at the margins of the EMR site might contribute to adenoma recurrence, which occurs in 15% to 30% of patients who undergo surveillance. We aimed to determine the efficacy of adjuvant thermal ablation of the EMR mucosal defect margin in reducing polyp recurrence. METHODS: We performed a prospective study of 390 patients with large laterally spreading colonic lesions (≥ 20 mm, n = 416) referred for EMR at 4 tertiary centers in Australia. After complete lesion excision by EMR, lesions were randomly assigned to thermal ablation of the post-EMR mucosal defect margin (n = 210) or no additional treatment (controls, n = 206). We performed surveillance colonoscopies with standardized photo documentation and biopsies of the scar after 5 to 6 months. Patient, procedure, and lesion characteristics were similar between the groups. The primary endpoint was detection of lesion recurrence at first surveillance colonoscopy. RESULTS: A significantly lower proportion of patients who received thermal ablation of the post-EMR mucosal defect margin had evidence of recurrence at first surveillance colonoscopy (10/192, 5.2%) than controls (37/176, 21.0%) (P < .001). The relative risk of recurrence in the thermal ablation group was 0.25 compared with the control group (95% confidence interval 0.13-0.48). Rates of adverse events were similar between the groups. CONCLUSIONS: In a multicenter randomized trial, thermal ablation of the post-EMR mucosal defect margin significantly reduced polyp recurrence at first surveillance colonoscopy, compared with no additional treatment. Routine implementation of this simple and safe technique could increase the utility of EMR, decrease surveillance burdens, and reduce morbidity and mortality from CRC. ClinicalTrials.gov no: NCT01789749.


Assuntos
Adenoma/patologia , Adenoma/cirurgia , Ablação por Cateter/métodos , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Ressecção Endoscópica de Mucosa/métodos , Adenoma/mortalidade , Adulto , Idoso , Austrália , Biópsia por Agulha , Neoplasias do Colo/mortalidade , Colonoscopia/métodos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Estudos Prospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
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