RESUMEN
PURPOSE: Gastrinoma with Zollinger-Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features. METHODS: Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort. RESULTS: Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively. CONCLUSION: MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.
Asunto(s)
Gastrinoma , Neoplasia Endocrina Múltiple Tipo 1 , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Síndrome de Zollinger-Ellison , Humanos , Síndrome de Zollinger-Ellison/diagnóstico , Síndrome de Zollinger-Ellison/tratamiento farmacológico , Síndrome de Zollinger-Ellison/cirugía , Gastrinoma/patología , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Tumores Neuroendocrinos/complicaciones , Somatostatina/uso terapéutico , Neoplasias Pancreáticas/patologíaRESUMEN
PURPOSE: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. METHODS: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. RESULTS: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. CONCLUSIONS: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.
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Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Neoplasias Duodenales/patología , Metástasis Linfática/diagnóstico , Estadificación de Neoplasias/normas , Tumores Neuroendocrinos/patología , Cuidados Preoperatorios , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Duodenales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/cirugía , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Effective target therapies for intrahepatic cholangiocarcinoma (ICC) have not been identified so far. One of the reasons may be the genetic evolution from primary (PR) to recurrent (REC) tumors. We aim to identify peculiar characteristics and to select potential targets specific for recurrent tumors. Eighteen ICC paired PR and REC tumors were collected from 5 Italian Centers. Eleven pairs were analyzed for gene expression profiling and 16 for mutational status of IDH1. For one pair, deep mutational analysis by Next Generation Sequencing was also carried out. An independent cohort of patients was used for validation. RESULTS: Two class-paired comparison yielded 315 differentially expressed genes between REC and PR tumors. Up-regulated genes in RECs are involved in RNA/DNA processing, cell cycle, epithelial to mesenchymal transition (EMT), resistance to apoptosis, and cytoskeleton remodeling. Down-regulated genes participate to epithelial cell differentiation, proteolysis, apoptotic, immune response, and inflammatory processes. A 24 gene signature is able to discriminate RECs from PRs in an independent cohort; FANCG is statistically associated with survival in the chol-TCGA dataset. IDH1 was mutated in the RECs of five patients; 4 of them displayed the mutation only in RECs. Deep sequencing performed in one patient confirmed the IDH1 mutation in REC. CONCLUSIONS: RECs are enriched for genes involved in EMT, resistance to apoptosis, and cytoskeleton remodeling. Key players of these pathways might be considered druggable targets in RECs. IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.
Asunto(s)
Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , Perfilación de la Expresión Génica , Isocitrato Deshidrogenasa/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.
Asunto(s)
Biomarcadores de Tumor/genética , Colangiocarcinoma/diagnóstico , Colangitis Esclerosante/diagnóstico , Regulación Neoplásica de la Expresión Génica , Cirrosis Hepática Biliar/diagnóstico , Adulto , Anciano , Área Bajo la Curva , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Colangiocarcinoma/sangre , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Colangitis Esclerosante/sangre , Colangitis Esclerosante/genética , Colangitis Esclerosante/patología , Diagnóstico Diferencial , Femenino , Perfilación de la Expresión Génica , Humanos , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Masculino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Curva ROCRESUMEN
Multiple genetic variants influence the risk for development of primary biliary cirrhosis (PBC). To explore the cumulative effects of known susceptibility loci on risk, we utilized a weighted genetic risk score (wGRS) to evaluate whether genetic information can predict susceptibility. The wGRS was created using 26 known susceptibility loci and investigated in 1840 UK PBC and 5164 controls. Our data indicate that the wGRS was significantly different between PBC and controls (P=1.61E-142). Moreover, we assessed predictive performance of wGRS on disease status by calculating the area under the receiver operator characteristic curve. The area under curve for the purely genetic model was 0.72 and for gender plus genetic model was 0.82, with confidence limits substantially above random predictions. The risk of PBC using logistic regression was estimated after dividing individuals into quartiles. Individuals in the highest disclosed risk group demonstrated a substantially increased risk for PBC compared with the lowest risk group (odds ratio: 9.3, P=1.91E-084). Finally, we validated our findings in an analysis of an Italian PBC cohort. Our data suggested that the wGRS, utilizing genetic variants, was significantly associated with increased risk for PBC with consistent discriminant ability. Our study is a first step toward risk prediction for PBC.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Cirrosis Hepática Biliar/genética , Alelos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Curva ROC , Reproducibilidad de los ResultadosRESUMEN
AIM: The aim of this paper was to evaluate the effects of a very long distance swimming task on psychological, biomechanical and physiological responses. Eight swimmers (age 21.0 ± 1.2 years; stature 1.80 ± 0.07 m; body mass 76.7 ± 11.0 kg; means ± SD) participated in a 25-km trial in a swimming pool. METHODS: Before and immediately after the trial, swimmers underwent a 50-m sprint test, during which we assessed velocity, stroke rate (SR), stroke length (SL) and psychological condition (rate of perceived exertion [RPE] and profile of mood state [POMS] questionnaire). During the 25-km trial we determined also elbow angle, heart rate (HR) and lactate concentration ([La]). RESULTS: Velocity, SR and SL during the sprint test after the trial decreased compared to before from 1.91 ± 0.01 m·s⻹, 0.94 ± 0.01 cycles·s⻹ and 1.99 ± 0.02 m·cycle⻹ to 1.45 ± 0.01 m·s⻹, 0.78 ± 0.01 cycles·s⻹ and 1.84 ± 0.03 m·cycle⻹, respectively (P<0.05). During the 25-km trial, velocity and SL decreased significantly, while SR and elbow angle did not change. Velocity and SR during the sprint test after the trial were significantly higher than those during the trial. RPE and fatigue (POMS subscale) increased significantly, while the other negative POMS subscales and vigor decreased significantly. HR decreased significantly at 20 km, then increasing significantly at 25 km, while [La] did not change. CONCLUSION: These results suggest that, despite the occurrence of fatigue, as evidenced by the drop in velocity and changes in psychological profile, swimmers were able to complete the 25-km trial by adopting a conservative pacing, unveiling also a reserve in maximum performance.
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Rendimiento Atlético/fisiología , Natación/fisiología , Natación/psicología , Fatiga/fisiopatología , Frecuencia Cardíaca/fisiología , Humanos , Esfuerzo Físico/fisiología , Adulto JovenRESUMEN
Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10â»4, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.
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Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Cirrosis Hepática Biliar/genética , Transducción de Señal/genética , Algoritmos , Canadá , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Italia , Desequilibrio de Ligamiento , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
The altered expression of micro-RNA (miRNA) has been associated with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to establish specific miRNA expression patterns in the serum and mucosa of inflammatory bowel disease (IBD) patients (UC and CD with colonic involvement) at different stages of the disease. Serum and biopsies from nine active CD (aCD), nine inactive CD (iCD), nine active UC (aUC) and nine inactive UC (iUC) and serum from 33 healthy subjects were collected. Up to 700 miRNAs were evaluated by the TaqMan human miRNA array. The ΔCt values were obtained using the mean expression values of all expressed miRNAs in a given sample as a normalization factor for miRNA real-time quantitative polymerase chain reaction data. The levels of serum miRNAs in CD and UC patients were different to healthy subjects. Thirteen serum miRNAs were expressed commonly in CD and UC patients. Two miRNAs were higher and four miRNAs were lower in the serum of aCD than iCD. No serum miRNA was regulated exclusively in aUC compared with iUC patients. Four miRNAs were higher and three miRNAs were lower in the mucosa of aCD than iCD. Two miRNAs were higher and three miRNAs were lower in the mucosa of aUC than iUC. No serum miRNAs coincided with tissue miRNAs in aCD and aUC patients. Our results suggest the existence of specific miRNA expression patterns associated with IBD and their different stages and support the utility of miRNA as possible biomarkers. This pilot study needs to be validated in a large prospective cohort.
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Enfermedades Inflamatorias del Intestino/genética , MicroARNs/biosíntesis , Adulto , Progresión de la Enfermedad , Femenino , Marcadores Genéticos/genética , Humanos , Enfermedades Inflamatorias del Intestino/fisiopatología , Mucosa Intestinal/metabolismo , Masculino , MicroARNs/sangre , MicroARNs/genética , Análisis por Micromatrices , Persona de Mediana Edad , TranscriptomaRESUMEN
Motor imagery (M.I.) is a mental state in which real movements are evoked without overt actions. There is some behavioural evidence that M.I. declines with ageing. The neurofunctional correlates of these changes have been investigated only in two studies, but none of the these studies has measured explicit correlations between behavioural variables and the brain response, nor the correlation of M.I. and motor execution (M.E.) of the same acts in ageing. In this paper, we report a behavioural and functional magnetic resonance imaging (fMRI) experiment that aimed to address this issue. Twenty-four young subjects (27 ± 5.6 years) and twenty-four elderly subjects (60 ± 4.6 years) performed two block-design fMRI tasks requiring actual movement (M.E.) or the mental rehearsal (M.I.) of finger movements. Participants also underwent a behavioural mental chronometry test in which the temporal correlations between M.I. and M.E. were measured. We found significant neurofunctional and behavioural differences between the elderly subjects and the young subjects during the M.E. and the M.I. tasks: for the M.E. task, the elderly subjects showed increased activation in frontal and prefrontal (pre-SMA) cortices as if M.E. had become more cognitively demanding; during the M.I. task, the elderly over-recruited occipito-temporo-parietal areas, suggesting that they may also use a visual imagery strategy. We also found between-group behavioural differences in the mental chronometry task: M.I. and M.E. were highly correlated in the young participants but not in the elderly participants. The temporal discrepancy between M.I. and M.E. in the elderly subjects correlated with the brain regions that showed increased activation in the occipital lobe in the fMRI. The same index was correlated with the premotor regions in the younger subjects. These observations show that healthy elderly individuals have decreased or qualitatively different M.I. compared to younger subjects.
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Envejecimiento/fisiología , Mapeo Encefálico , Encéfalo/irrigación sanguínea , Imaginación/fisiología , Movimiento/fisiología , Desempeño Psicomotor/fisiología , Adulto , Anciano , Señales (Psicología) , Femenino , Lateralidad Funcional/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Modelos Lineales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Adulto JovenRESUMEN
Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10(-11)) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10(-10)) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10(-7)) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.
Asunto(s)
Cadenas beta de HLA-DP/genética , Cadenas HLA-DRB1/genética , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/inmunología , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Italia , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca/genéticaRESUMEN
A functional variant in the Fc receptor-like 3 (FCRL3) gene is associated with the susceptibility to several autoimmune diseases. In this study, we examined whether the FCRL3 is associated with susceptibility to primary biliary cirrhosis (PBC) by comparing the two different ethnic groups, Japanese and Italians. We enrolled 232 patients with PBC and 230 controls in Japanese, and 216 PBC and 180 controls in Italians. Minor allele frequency of fcrl3_3 (-169 T>C) in the patients with PBC and controls was 0.20 and 0.09 in Japanese and 0.24 and 0.21 in Italians, respectively. We found a significant association of fcrl3_3 with PBC only in Japanese (P = 9.64 × 10(-7) ). These findings support the presence of common FCRL3-related pathological pathways in several autoimmune diseases, especially in Asians.
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Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cirrosis Hepática Biliar/genética , Receptores Inmunológicos/genética , Población Blanca/genética , Anciano , Enfermedades Autoinmunes/etnología , Enfermedades Autoinmunes/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Italia , Cirrosis Hepática Biliar/etnología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
To examine the genetics of susceptibility to primary biliary cirrhosis (PBC), genome-wide association studies GWAS have been performed in patients of European ancestry and have shown the significant associations of IL12-related pathways, SPIB, IRF5-TNPO3, and 17q12-21. We tested whether these findings could be extended to a Japanese cohort, 303 Japanese PBC and 298 controls. We failed to detect significant associations at IL12A (rs574808, rs1075498) and IL12RB2 (rs3790567). There was no genetic variance at IRF5-TNPO3 (rs10488631) in Japanese. A single nucleotide polymorphism (SNP) at SPIB (rs3745516) reached nominal significance, but the corrected P value did not reach significance. For the 17q12-21 region, two SNPs had nominally significant associations [GSDMB (rs2305480, P = 0.022) and ZPBP2 (rs11557467, P = 0.021)] and we noted a significant P value at a SNP in IKZF3 (rs939327, P = 0.0024, P(c) = 0.017) after correction for multiple comparisons. Thus, these results indicate a haplotype on 17q12-21 with a similar association in Japanese and European PBC.
Asunto(s)
Pueblo Asiatico/genética , Cromosomas Humanos Par 17/genética , Cirrosis Hepática Biliar/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Factores Reguladores del Interferón/genética , Subunidad p35 de la Interleucina-12/genética , Cirrosis Hepática Biliar/etnología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-12/genética , beta Carioferinas/genéticaRESUMEN
BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.
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Neoplasias Gastrointestinales/mortalidad , Neoplasias Pulmonares/mortalidad , Neoplasias Primarias Secundarias/epidemiología , Tumores Neuroendocrinos/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Incidencia , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/patología , Tumores Neuroendocrinos/patología , Estudios RetrospectivosRESUMEN
This study examined the impact of L-acetylcarnitine treatment on metabolic parameters and body composition in patients with lipodystrophy syndrome secondary to antiretroviral treatment in human immunodeficiency virus (HIV) infection. A total of 9 HIV-1 infected patients with lipodystrophy syndrome (4F/5M, age 41+/-5 years, HIV duration 8+/-2 years, BMI 23.7+/-3.4 kg/m(2), on protease inhibitors and nucleoside analogue Reverse Transcriptase inhibitors) were evaluated before and after 8 months of therapy with L-acetylcarnitine (2 g/die) and 9 matched healthy subjects served as control subjects. In all patients fasting plasma glucose, insulin concentrations (for evaluation of surrogate indexes of insulin sensitivity), lipid profile, lipid oxidation (by indirect calorimetry), body composition (by DEXA), and intramyocellular triglyceride (IMCL) content of the calf muscles (by (1)H NMR spectroscopy) were assessed. After this therapy, in HIV-1 patients, the IMCL content of the soleus had significantly decreased (p=0.03). Plasma FFAs (0.79+/-0.31 to 0.64+/-0.25; p<0.05) and Respiratory Quotient (0.83+/-0.18 to 0.72+/-0.16; p<0.03) also decreased. Insulin sensitivity was significantly lower prior (HOMA-IS 0.56+/-0.30) and nonstatistically different than controls after therapy (0.72+/-0.49 vs. 0.78+/-0.42) whilst the percentage of fat in the legs increased (p=0.05). Eight months of L-acetylcarnitine treatment increased lipid oxidation, decreased intramyocellular triglyceride content, and induced a more physiological distribution of fat deposits.
Asunto(s)
Acetilcarnitina/uso terapéutico , Composición Corporal/efectos de los fármacos , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Adulto , Glucemia , Estudios de Casos y Controles , Femenino , Síndrome de Lipodistrofia Asociada a VIH/sangre , Humanos , Insulina/sangre , Lípidos/sangre , Persona de Mediana EdadRESUMEN
BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.
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Hepatitis Autoinmune/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Azatioprina/uso terapéutico , Biopsia , Budesonida/uso terapéutico , Ciclosporina/uso terapéutico , Encuestas de Atención de la Salud , Humanos , Metiltransferasas/metabolismo , Ácido Micofenólico/uso terapéutico , Rituximab/uso terapéutico , Tacrolimus/uso terapéuticoRESUMEN
Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.
Asunto(s)
Colangitis Esclerosante/genética , Predisposición Genética a la Enfermedad , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Alelos , Colangitis Esclerosante/etnología , Colangitis Esclerosante/inmunología , Etnicidad , Expresión Génica , Frecuencia de los Genes , Cadenas beta de HLA-DQ/clasificación , Cadenas beta de HLA-DQ/inmunología , Cadenas HLA-DRB1/clasificación , Cadenas HLA-DRB1/inmunología , Humanos , Desequilibrio de Ligamiento , Países Escandinavos y Nórdicos , Población BlancaRESUMEN
The idea that tumor initiation and progression are driven by a subset of cells endowed with stem-like properties was first described by Rudolf Virchow in 1855. 'Cancer stem cells', as they were termed more than a century later, represent a subset of tumor cells that are able to generate all tumorigenic and nontumorigenic cell types within the malignancy. Although their existence was hypothesized >150 years ago, it was only recently that stem-like cells started to be isolated from different neoplastic malignancies. Interestingly, Virchow, in suggesting a correlation between cancer and the inflammatory microenvironment, also paved the way for the 'Seed and Soil' theory proposed by Paget a few years later. Despite the time that has passed since these two important concepts were suggested, the relationships between Virchow's 'stem-like cells' and Paget's 'soil' are far from being fully understood. One emerging topic is the importance of a stem-like niche in modulating the biological properties of stem-like cancer cells and thus in affecting the response of the tumor to drugs. This review aims to summarize the recent molecular data concerning the multilayered relationship between cancer stem cells and tumor-associated macrophages that form a key component of the tumor microenvironment. We also discuss the therapeutic implications of targeting this synergistic interplay.
Asunto(s)
Macrófagos/patología , Terapia Molecular Dirigida/tendencias , Neoplasias/inmunología , Neoplasias/terapia , Células Madre Neoplásicas/patología , Animales , Humanos , Macrófagos/metabolismo , Terapia Molecular Dirigida/métodos , Neoplasias/genética , Neoplasias/patología , Células Madre Neoplásicas/metabolismo , Nicho de Células Madre/fisiología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
The pharmacokinetics of chenodeoxycholic and ursodeoxycholic acids are reviewed in this article. Chenodeoxycholic acid is well absorbed by the intestine, whereas the absorption of ursodeoxycholic acid is incomplete. They are extracted efficiently by the liver, conjugated with glycerine and taurine, secreted in bile, and then undergo enterohepatic circulation with the endogenous bile acids. Therapeutic bile acids are metabolised by intestinal bacteria to lithocholic acid which is mainly excreted with faeces. Since the large majority of bile acid is confined within the enterohepatic circulation (resulting in low serum concentrations) their volume of distribution is relatively high. Despite the high hepatic extraction, the clearance of therapeutic bile acids is relatively low because of the highly efficient enterohepatic recirculation. Elimination of therapeutic bile acids mainly occurs in the faeces either unmodified or after biotransformation. At present the main clinical indication for therapeutic bile acids is ursodeoxycholic acid treatment for chronic cholestatic liver disease. In these patients, ursodeoxycholic acid is efficiently absorbed but its hepatic uptake and biliary secretion are impaired, thus leading to reduced biliary enrichment and high serum concentrations of this exogenous bile acid. In patients with cystic fibrosis-associated liver disease, bile acid malabsorption also occurs, thus indicating the need for higher dosages. The volume of distribution and clearance of ursodeoxycholic acid reduced in the presence of liver disease. Also in this case, elimination mainly occurs with the faeces but, in the presence of severe cholestasis, renal clearance may become relevant. Sulphation or conjugation with glucose and N-acetylglucosamine facilitate urinary excretion.