RESUMEN
BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Derivación Gástrica , Laparoscopía , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Humanos , Obesidad Mórbida/cirugía , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Derivación Gástrica/efectos adversos , Estilo de Vida , Gastrectomía/efectos adversos , Gastrectomía/métodos , Resultado del TratamientoRESUMEN
OBJECTIVE: Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis. DESIGN: This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16- monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis. RESULTS: The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. CONCLUSIONS: The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers. CLINICAL TRIALS: Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.
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Biopsia Líquida , Cirrosis Hepática , Hígado , Enfermedad del Hígado Graso no Alcohólico , Humanos , Biomarcadores , Cromatografía Liquida , Hígado/patología , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Proteínas de Unión al GTP rab , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD. DESIGN: The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) ≥25 kg/m2). Liver/non-liver-related events and survival free of transplantation were recorded during the follow-up, compared by log-rank testing and reported by adjusted HR. RESULTS: Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the PNPLA3 I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069). CONCLUSIONS: Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. LAY SUMMARY: NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico/complicaciones , Delgadez/complicaciones , Población Blanca , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/mortalidad , Enfermedad del Hígado Graso no Alcohólico/patología , Pronóstico , Tasa de Supervivencia , Delgadez/mortalidad , Delgadez/patologíaRESUMEN
BACKGROUND & AIMS: The incidence of metabolic syndrome-related hepatocellular carcinoma (MS-HCC) is increasing worldwide. High resection risks are anticipated because of underlying steatohepatitis, but long-term results are unknown. To clarify the outcomes following liver resection in patients with MS-HCC and to compare the outcomes of MS-HCC to HCV-related HCC (HCV-HCC). METHODS: All the consecutive patients undergoing liver resection for HCC in six high-volume HPB units between 2000 and 2012 were retrospectively considered. The patients with MS-HCC were identified and matched one-to-one with HCV-HCC patients without metabolic syndrome. Matching was based on age, cirrhosis, Child-Pugh class, portal hypertension, HCC number and diameter and liver resection extension. RESULTS: Among 1563 patients undergoing liver resection for HCC in the study period, 96 (6.1%) had MS-HCC. They were matched with 96 HCV-HCC patients. All patients were Child-Pugh class A, 22.9% had cirrhosis. Forty-one patients per group (42.7%) required major hepatectomy. The MS-HCC group had a higher prevalence of steatohepatitis (25.0% vs. 9.4%, p=0.004). Operative mortality was 2.1% (1 MS-HCC, 3 HCV-HCC, p=0.621). Morbidity and liver failure rates were similar between the two groups. In the multivariate analysis, cirrhosis, major hepatectomy, and MELD >8, but not steatohepatitis, impacted severe morbidity and liver failure rates. The MS-HCC group had better 5-year overall survival (65.6% vs. 61.4%, p=0.031) and recurrence-free survival (37.0% vs. 27.5%, p=0.077). Independent negative prognostic factors were HCV-HCC, multiple HCC, microvascular invasion, and satellite nodules. CONCLUSIONS: Liver resection is safe for MS-HCC, as for HCV-HCC. Cirrhosis, but not steatohepatitis, affects short-term outcomes. MS-HCC is associated with excellent long-term outcomes, better than HCV-HCC.
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Carcinoma Hepatocelular/cirugía , Hepatectomía/métodos , Hepatitis C Crónica/complicaciones , Neoplasias Hepáticas/cirugía , Síndrome Metabólico/etiología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/virología , Femenino , Estudios de Seguimiento , Hepatitis C Crónica/virología , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/virología , Masculino , Síndrome Metabólico/epidemiología , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate whether metabolic changes in the primary tumour during and after preoperative radiochemotherapy (RCT) can predict the histopathological response in patients with locally advanced rectal cancer as well as disease-free survival (DFS) and overall survival (OS). METHODS: Consecutive patients with cT2-4 N0-2 rectal adenocarcinoma were included. (18)F-FDG PET/CT was performed at baseline, at the end of the second week of RCT (early PET/CT) and before surgery (late PET/CT). The PET/CT results were compared with histopathological data (ypT0 N0 vs. ypT1-4 N0-2 as well as TRG1 vs.TRG2-5) and survival. RESULTS: The study included 126 patients. Among 124 patients in whom TNM classification was available, 28 (22.6 %) were ypT0 N0, and among all 126 patients, 31 (24.6 %) were TRG1. The areas under the curve of the early response index (RI) for identifying non-complete pathological response (non-cPR) were 0.74 (95 % CI 0.61 - 0.87) for ypT1-4 N0-2 patients and 0.75 (95 % CI 0.62 - 0.88) for TRG2-5 patients. The optimal cut-off for differentiating patients with non-cPR and cPR was found to be a reduction of 61.2 % (83.1 % sensitivity and 65 % specificity in ypT1-4 N0-2 patients; 85.4 % sensitivity and 65.2 % specificity in TRG2-5 patients). The optimal cut-off for late RI could not be found. The qualitative analysis of images obtained after RCT demonstrated 81.5 % sensitivity and 61.3 % specificity in predicting TRG2-5. After a median follow-up of 68 months, the low number of patients with local/distant recurrence or who had died did not allow the value of PET/CT for predicting DFS and OS to be calculated. CONCLUSION: The early assessment of response to RCT by (18)F-FDG PET/CT can predict non-cPR allowing practical modification of preoperative treatment. Conversely, late RI is not sufficiently accurate for guiding the decision as to whether local excision or even observation is appropriate in an individual patient. Qualitative analysis of late PET/CT images is also not sensitive enough alone to rule out the presence of residual disease.
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Adenocarcinoma/diagnóstico por imagen , Quimioradioterapia Adyuvante/efectos adversos , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias del Recto/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Valor Predictivo de las Pruebas , Neoplasias del Recto/terapia , Análisis de SupervivenciaRESUMEN
OBJECTIVES: To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. METHODS: Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. RESULTS: Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between "HCCs + HGDNs" versus LGDNs (p < 0.05); sensitivity, specificity, and accuracy for the diagnosis of "HCCs + HGDNs" were 96.8 %, 100 %, 97.4 % respectively when combining hyperintensity on DWI and hypointensity on DPI, and 90.9 %, 81.0 %, 83.6 % respectively when lesion-to-liver ratio was <0.95. CONCLUSIONS: Hyperintensity on DWI, especially in association with hypointensity on DPI, and low lesion-to-liver ratios should raise the suspicion of HCC, or at least of HGDN, thus helping the characterization of atypically enhancing lesions. KEY POINTS: ⢠Usefulness of DWI and ADC is shown in differential diagnosis of cirrhotic nodules. ⢠Correlation of DWI with DPI improves differential diagnosis of cirrhotic nodules. ⢠Characterization of atypically enhancing lesions becomes more confident.
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Carcinoma Hepatocelular/diagnóstico , Imagen de Difusión por Resonancia Magnética , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Medios de Contraste , Diagnóstico Diferencial , Femenino , Humanos , Hígado/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
PURPOSE: In a phase I/II trial, patients with locally advanced rectal cancer received preoperative radiotherapy (RT) and concurrent with 5-fluorouracil (5-FU) and gefitinib. Results were promising. To elucidate the molecular and biological effects, we replicated the schedule in the LoVo human colorectal adenocarcinoma cell line. METHODS: RT (2 Gy daily for 3 days), 5-FU (0.3, 0.6, 1.25, 2.5, 5, 10 µM) and gefitinib (0.2, 0.4, 0.8 µM) were administered alone, in double combinations and all together. We assessed viable cells, cell cycle, cyclin, p53 and p21 expression, signalling pathways by means of phosphorylated epidermal growth factor receptor (p-EGFR), p-AKT and p-ERK 1-2 and clonogenic capacity. RESULTS: RT and 5-FU were cytotoxic. Gefitinib was cytostatic. RT reduced clonogenic capacity more than 5-FU. 5-FU induced more cell death than RT, but surviving cells were proliferative (cyclins and p-EGFR increased). 5-FU + RT had a synergistic effect. Gefitinib, enhancing G1 accumulation, reduced proliferation of cells surviving 5-FU and 5-FU + RT. It slightly increased the cytotoxicity of RT and 5-FU. CONCLUSIONS: As gefitinib limited the proliferation rate of cells surviving 5-FU and 5-FU + RT in the LoVo cell line, it may be a useful addition to chemotherapy and RT in rectal cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/radioterapia , Fluorouracilo/uso terapéutico , Quinazolinas/uso terapéutico , Línea Celular Tumoral , Terapia Combinada , Gefitinib , Humanos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVES: To evaluate if the Human epidermal growth factor receptor 2 (HER-2) expression levels may be used as potential prognostic marker in high grade T1 blad- der cancer (T1G3) METHODS: Specimens from transurethral resection of bladder tumour (TURBT) of 103 patients with high-grade T1 bladder cancer were collected. This pathologic database was reviewed. Four-year follow-up data were matched with pathologic data. Eighty-three patients entered the study. HER-2 staining was performed. Patients were grouped for HER-2 status. Statistical analysis included Kaplan Meier survival analysis and Log-rank test. RESULTS: Pathological review of TURBT specimens confirmed high-grade T1 transitional cell bladder cancer in all patients. Median follow-up was 12 months (mean 23,5; range 3-48). Twenty-one patients (25.4%) present strong HER-2 expression (3+), 28 (33.7%) moderate expression (2+), 26 (33.7%) weak staining (1+) and 8 (9.6%) negative expression (0). Thirty- one patients of 83 (37.4%) had not evidence of disease, 41 (49.4%) recurred, 11 (13.2%) had a progression of disease. Forty-one patients had high grade T1 recurrence. Patients with HER-2 status 0 did not showed progression of disease. Patients with HER-2 status 3+, undergoing cys- tectomy because progression of disease, had a pathological stage > pT2 and a nodal involve- ment. Median Disease-Free Survival (DFS) for all patients was 12 months (DFS probability (pDFS) = 49.3%; 95% CI, -11.1/+10.1). Median DFS in HER-2 groups was 8 (pDFS 37.5%; 95% CI,-28.8/+29.9), 24 (pDFS 46.1%; 95% CI,-19.5/+17.5), 20 (pDFS 46.4%; 95% CI,-18.8/+16.9) and 10 months (pDFS 47.6%; 95% CI,-21.9/+19.1) respectively in HER-2 status 0,1+,2+,3+. Log-Rank test is not statistically significant (p = 0,39). CONCLUSIONS: This study showed that HER-2 expression does not represent a prognostic mark- er of recurrence/progression of disease in high-grade T1 bladder cancer.
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Carcinoma de Células Transicionales/química , Proteínas de Neoplasias/análisis , Receptor ErbB-2/análisis , Neoplasias de la Vejiga Urinaria/química , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/cirugía , Cistectomía/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
AIM: To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity. METHODS: We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/m2), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity. RESULTS: The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p<0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH. CONCLUSIONS: Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy.
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Diabetes Mellitus Tipo 2 , Errores Innatos del Metabolismo , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Adulto , Anciano , Biopsia , Colesterol , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Fibrosis , Humanos , Errores Innatos del Metabolismo/complicaciones , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Mórbida/complicaciones , Obesidad Mórbida/epidemiología , Obesidad Mórbida/cirugía , Prevalencia , Adulto JovenRESUMEN
CONTEXT: Nonalcoholic steatohepatitis (NASH) is considered the hepatic counterpart of metabolic syndrome. OBJECTIVE: This work aimed to investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion (BPD) in a 5-year follow-up study. METHODS: This prospective study was conducted at Policlinico Universitario Agostino Gemelli. A total of 37 patients underwent fine-needle liver biopsy during BPD. Ultrasonography-guided percutaneous liver biopsy was obtained 5 years after the operation. The primary outcome of our study was histologic NASH reversal at 5-year follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years with those in whom NASH had disappeared. RESULTS: At follow-up, NASH had reversed in 56.5% of the patients. The NAFLD activity score (NAS) improved from 3.7 ± 0.93 to 2 ± 1.11 (Pâ <â .001). Fibrosis reversed in 16% patients (Pâ =â .022), and 32% improved (95% CI, 0.05-0.54). No significant differences in body mass index or clinical parameters changes explained the effect of surgery on NASH, apart from the measure of insulin sensitivity post surgery. The Homeostasis Model Assessment of Insulin Resistance decreased from 3.31â ±â 1.72 at baseline to 1.73â ±â 1.08 (Pâ <â .001) after BPD, and the Matsuda index improved from 2.66â ±â 1.79 to 4.73â ±â 3.05 (Pâ <â .001). The lipid profile normalized (total cholesterol from 4.75â ±â 1.18 to 3.32â ±â 0.77 mmol/L, Pâ <â .001; low-density lipoprotein cholesterol from 2.92â ±â 0.91 to 1.60â ±â 0.51 mmol/L, Pâ =â .0001; high-density lipoprotein cholesterol from 0.97â ±â 0.33 to 1.10â ±â 0.35 mmol/L, Pâ =â .023; triglycerides from 2.52â ±â 1.6 to 1.47â ±â 0.67 mmol/L, Pâ =â .003). Neural network analysis showed that the end-study Matsuda index discriminated between responders and nonresponders with high accuracy (receiver operating characteristic area under the curveâ =â 0.98%). CONCLUSION: Remission of NASH is driven by reversal of whole-body insulin resistance post intervention.
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Cirugía Bariátrica , Resistencia a la Insulina/fisiología , Enfermedad del Hígado Graso no Alcohólico/cirugía , Adulto , Anciano , Desviación Biliopancreática , Biopsia con Aguja Fina , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Italia , Hígado/patología , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad Mórbida/complicaciones , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease and ranges from simple steatosis to nonalcoholic steatohepatitis. Recently, a platelet role in NAFLD pathogenesis and progression has been reported in mouse models and in patients. We investigated whether platelets are involved in liver and systemic inflammation processes in NAFLD. In this exploratory study we recruited 24 consecutive patients with biopsy-proven diagnosis of NAFLD and 17 healthy volunteers. We measured plasma levels of inflammatory markers by ELISA. We investigated hemostatic and inflammatory transcripts in circulating platelets and leukocytes from NAFLD patients. We analyzed platelet and neutrophil extracellular traps (NET) accumulations in liver sinusoids using CD42 and H3 citrullinated histones immunohistochemical staining on liver biopsies. NAFLD patients had increased inflammation markers and lipolysaccharides plasma levels. We found significant increase of inflammatory transcripts in circulating platelets and not in leukocytes of NAFLD subjects compared with healthy controls. We demonstrated increased intrahepatic platelet accumulation that correlated with NAFLD activity score (NAS) score and intrahepatic neutrophil extracellular traps (NET) formation in liver biopsies of NAFLD patients. NET formation was higher in livers with higher NAS and inflammation scores. The presence of low-grade systemic inflammation and proinflammatory changes of circulating platelets indicate that platelets participate on systemic inflammatory changes associated with NAFLD. Liver platelet accumulation and liver NET formation, together with low-grade endotoxemia, suggest that platelets may act to protect the liver from invading microorganisms by favoring local NET formation.
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Plaquetas/fisiología , Inflamación/patología , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Adulto , Biomarcadores/sangre , Femenino , Regulación de la Expresión Génica , Hemostasis , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
PURPOSE: To prospectively differentiate, at magnetic resonance (MR) imaging, patients with locally advanced nonmucinous rectal cancer who will respond to long-course chemotherapy and radiation therapy (CRT) from those who will not respond, with histopathologic results as the reference standard. MATERIALS AND METHODS: Institutional review board approval for this study was obtained, and all patients provided written informed consent. High-spatial-resolution T2-weighted MR images were acquired before and 6-8 weeks after CRT in 53 patients (33 men, 20 women; mean age, 63 years; age range, 42-79 years). Patients were categorized as responders to CRT (patients with T3 cancer that converted to T2 or a lower stage, patients with T4 cancer that converted to T3 or a lower stage) or as nonresponders (patients with stable or progressive disease). At the posttreatment MR imaging examination, a decrease in signal intensity was considered to represent a morphologic response with fibrosis. Before CRT and surgery, tumor volume was calculated at MR imaging by multiplying cross-sectional area by section thickness. Tumor length was measured at MR imaging and in the histopathologic specimen. Nodal downstaging was evaluated. The relationship between pathologic response, morphologic MR imaging response, and percentage volume reduction was evaluated with the Mann-Whitney-Wilcoxon two-sample test. RESULTS: Morphologic response assessment with MR imaging achieved a positive predictive value (PPV) of 84.2% (32 of 38) and a negative predictive value (NPV) of 66.7% (10 of 15). Volume reduction extent (> or = 70%) was significantly different between patients in whom disease was downstaged and those in whom it was not downstaged (P = .000005) and showed additional diagnostic value, with an overall accuracy of 86.8% (46 of 53). Presurgical MR imaging and histopathologic tumor length did not show a significant difference. MR imaging accuracy for lymph node (N) stage was 86.8% (46 of 53) on the basis of morphologic criteria. CONCLUSION: After CRT, morphologic and volumetric evaluation at MR imaging had a high PPV and a low NPV for response assessment. The detection of small clusters of residual tumor cells within fibrosis remains a problem. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/250/3/730/DC1.
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Quimioterapia Adyuvante/métodos , Imagen por Resonancia Magnética/métodos , Cuidados Preoperatorios/métodos , Radioterapia Adyuvante/métodos , Neoplasias del Recto/diagnóstico , Neoplasias del Recto/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Capecitabine-based radiochemotherapy (cbRCT) is standard for preoperative long-course radiochemotherapy of locally advanced rectal cancer. This prospective, parallel-group, randomised controlled trial investigated two intensification regimens. cT4 lesions were excluded. PRIMARY OBJECTIVE: pathological outcome (TRG 1-2) among arms. MATERIALS AND METHODS: Low-located cT2N0-2M0, cT3N0-2M0 (up to 12â¯cm from anal verge) presentations were treated with cbRCT randomly intensified by either radiotherapy boost (Xelac arm) or multidrug concomitant chemotherapy (Xelox arm). Xelac: concomitant boost to bulky site (45â¯Gy/1.8â¯Gy/die, 5 sessions/week to the pelvis, +10â¯Gy at 1â¯Gy twice/week to the bulky) plus concurrent capecitabine (1650â¯mg/mq/die). Xelox: 45â¯Gy to the pelvisâ¯+â¯5.4â¯Gy/1.8â¯Gy/die, 5 sessions/week to the bulky siteâ¯+â¯concurrent capecitabine (1300â¯mg/mq/die) and oxaliplatin (130â¯mg/mq on days 1,19,38). Surgery was planned 7-9â¯weeks after radiochemotherapy. RESULTS: From June 2005 to September 2013, 534 patients were analysed: 280 in Xelac, 254 in Xelox arm. Xelox arm presented higher Gâ¯≥â¯3 haematologic (pâ¯=â¯0.01) and neurologic toxicity (pâ¯<â¯0.001). Overall, 98.5% patients received curative surgery. The tumour regression grade distribution did not differ between arms (pâ¯=â¯0.102). TRG 1+2 rate significantly differed: Xelac arm 61.7% vs. Xelox 52.3% (pâ¯=â¯0.039). Pathological complete response (ypT0N0) rates were 24.4 and 23.8%, respectively (p non-significant). Median follow-up:5.62â¯years. Five-year disease-free survival rate were 74.7% (Xelac) and 73.8% (Xelox), respectively (pâ¯=â¯0.444). Five-year overall survival rate were 80.4% (Xelac) and 85.5% (Xelox), respectively (pâ¯=â¯0.155). CONCLUSION: Xelac arm significantly obtained higher TRG1-2 rates. No differences were found about clinical outcome. Because of efficacy on TRG, inferior toxicity and good compliance, Xelac schedules or similar radiotherapy dose intensification schemes could be considered as reference treatments for cT3 lesions.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina/administración & dosificación , Quimioradioterapia/métodos , Oxaloacetatos/administración & dosificación , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Estudios Prospectivos , Neoplasias del Recto/mortalidadRESUMEN
PURPOSE: The aim of this study is to evaluate the long term survival of the addition of gefitinib to chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC). METHODS AND MATERIALS: This previously published multicentre, open-label, phase I-II study, enrolled patients (pts) with LARC to receive CRT with concurrent 5-fluorouracil continuous intravenous infusion and a dose escalation of orally administered gefitinib, followed 6-8â¯weeks later by surgery. An intra-operative radiotherapy boost of 10â¯Gy was planned. Adjuvant chemotherapy was administrated in ypN1-2 pts. After a median f/u of >10â¯years, we analyzed Local Control (LC), Metastasis Free Survival (MFS), Disease Free Survival (DFS), Disease Specific Survival (DSS) and Overall Survival (OS). Predictive endpoints of clinical outcomes were tested by univariate and multivariate analysis. Variables analyzed included: age, gefitinib dose and interruptions, adjuvant CT, surgery type, ypT, ypN, and TRG grade. We have also analyzed late toxicity according to CTCAEv4. RESULTS: Of the 41 initially enrolled pts, 39 were evaluable (27M, 12F). With a median f/u of 133â¯months, LC, MFS, DFS, OS and DSS at 5â¯years were 84%; 71%; 64%; 87% and 92%, respectively. The OS and DSS at 10â¯years were 61,5% and 76%, respectively. Grade 3-4 late toxicity occurred in 38% of pts: sexual (28,2%) and gastrointestinal toxicities (10,2%). CONCLUSION: Long term outcomes and late toxicity were similar to previously reported series. The addition of gefitinib did not improve outcomes in LARC. Gefitinib is not recommended for rectal cancer patients who received 5-FU based preoperative CRT. Further studies may identify if gefitinib is beneficial in selected group of patients.
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AIM: To characterize the survival of cirrhotic patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) and to ascertain the factors predicting the achievement of disease control (DC). METHODS: The cirrhotic patients with BCLC stage C HCC evaluated by the Hepatocatt multidisciplinary group were subjected to the investigation. Demographic, clinical and tumor features, along with the best tumor response and overall survival were recorded. RESULTS: One hundred and ten BCLC stage C patients were included in the analysis; the median overall survival was 13.4 mo (95%CI: 10.6-17.0). Only alphafetoprotein (AFP) serum level > 200 ng/mL and DC could independently predict survival but in a time dependent manner, the former was significantly associated with increased risk of mortality within the first 6 mo of follow-up (HR = 5.073, 95%CI: 2.159-11.916, P = 0.0002), whereas the latter showed a protective effect against death after one year (HR = 0.110, 95%CI: 0.038-0.314, P < 0.0001). Only patients showing microvascular invasion and/or extrahepatic spread recorded lower chances of achieving DC (OR = 0.263, 95%CI: 0.111-0.622, P = 0.002). CONCLUSION: The BCLC stage C HCC includes a wide heterogeneous group of cirrhotic patients suitable for potentially curative treatments. The reverse and time dependent effect of AFP serum level and DC on patients' survival confers them as useful predictive tools for treatment management and clinical decisions.
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OBJECTIVE: To evaluate the efficacy of immunocytochemistry (ICC) performed on smears processed by thin-layer cytology (TLC). STUDY DESIGN: During the period January 2001-September 2003, 3,573 consecutive fine needle aspiration biopsies were processed with both conventional smears (CSs) and TLC diagnosed by a single pathologist; 113 required immunocytochemical study. CSs were fixed in ethanol whereas TLC slides were processed with the ThinPrep 2000 method (Cytyc Co., Marlborough, Massachusetts, U.S.A); both were stained with Papanicolaou stain. ICC staining was carried out on only TLC slides. RESULTS: The 113 cytologic cases were grouped as follows: 32 thyroid nodules with 16 histologic controls (HCs), 24 lymph nodes (regardless of location) with 15 HCs, 18 liver and pancreatic lesions (3 HCs), 11 lung nodules (6 HCs), 5 kidney and adrenal gland lesions (1 HC), 6 abdominal (2 HCs) and 4 mediastinal masses (1 HC), 6 salivary gland tumors (3 HCs), 4 bone masses (2 HCs) and 3 subcutaneous lesions (1 HC). ICC contributed to the diagnosis in 104 cases (92%), whereas it was inconclusive in 9. The cytologic diagnoses were histologically confirmed in 46 of 50 cases (92%). CONCLUSION: ICC can be successfully applied on TLC slides with better results than on CSs, and its yield can be useful in making the correct diagnosis on fine needle aspiration biopsy.
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Biopsia con Aguja Fina/métodos , Inmunohistoquímica/métodos , Neoplasias/diagnóstico , Neoplasias/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Citodiagnóstico/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Coloración y EtiquetadoRESUMEN
PURPOSE: To evaluate the impact on T downstaging of the vasculature supplying blood flow to rectal cancer evaluated by color Doppler ultrasound. METHODS AND MATERIALS: Color Doppler images were graded in 29 T3-staged rectal carcinoma patients sonographically just before chemoradiation. Any arterial vessels detected in rectal masses were assigned one of two grades: vascularity was considered as grade 1 for vessels feeding the periphery and as grade 2 for vessels coursing in all rectal masses within its peripheral and central portions. The pulsatility indices (PI = peak systolic velocity - end-diastolic velocity/time-averaged maximum velocity) were calculated in the central and peripheral portions. RESULTS: The pathologic observations showed a change in stage in 15 of the 23 patients graded 2, positive predictive value 65.2% (p = 0.047), and in one of the six rectal cancers graded 1 (negative predictive value, 83.3%). The minimal peripheral PI values in rectal cancer graded 2 were higher in nonresponding (2.2 +/- 1.3) than in responding lesions (1.6 +/- 0.7) p = 0.01. CONCLUSION: Vascularity graded 2 associated with low peripheral PI values are indicators of therapy outcome. Vascularity graded 1 and high peripheral PI values in graded 2 have negative predictive value.
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Adenocarcinoma/irrigación sanguínea , Neoplasias del Recto/irrigación sanguínea , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Adenocarcinoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Neoplasias del Recto/radioterapia , Resultado del Tratamiento , Ultrasonografía Doppler en ColorRESUMEN
PURPOSE: To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy. METHODS AND MATERIALS: Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation +/- chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score (Cancer 1994;73:2680-2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40-143 months). RESULTS: Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1-2 and TRG3-5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0-2: 5% vs. pT3-4: 19%, p = 0.007; pN0: 7% vs. pN1-3: 26%, p = 0.002; TRG1-2: 2% vs. TRG3-5: 17%, p = 0.013; metastasis-free survival: pT0-2: 86% vs. pT3-4: 62%, p = 0.005; pN-: 86% vs. pN*: 42%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 66%, p = 0.004; disease-free survival: pT0-2: 83% vs. pT3-4: 54%, p = 0.001; pN0: 80% vs. pN1-3: 39%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 58%, p < 0.001; and overall survival: pT0-2: 85% vs. pT3-4: 65%, p = 0.007; pN0: 86% vs. pN1-3: 45%, p < 0.001; TRG1-2: 89% vs. TRG3-5: 68%, p = 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN (p < 0.001) and TRG (p = 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement (p < 0.0001). CONCLUSIONS: By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N* disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy.