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Due to the lack of biomarkers predictive of response to atezolizumab-bevacizumab, the standard of care for advanced HCC, we analyzed baseline and early on-treatment variation of peripheral lymphocyte populations of 37 prospective patients treated by atezolizumab-bevacizumab and in 15 prospective patients treated by sorafenib or lenvatinib (TKIs). RNAseq analysis followed by RT-PCR validation on patients-derived PBMC was also performed. At first imaging, re-evaluation 13 patients receiving atezolizumab-bevacizumab, showed an objective response, 17 stable disease, while 7 were nonresponders. Baseline CD8+ and CD8+PD-L1+ peripheral lymphocytes were lower in responders versus nonresponders (T-test, p = 0.012 and 0.004, respectively). At 3 weeks, 28 of 30 responders displayed a rise of CD8+PD1+ lymphocytes with a positive mean fold change of 4.35 (±5.6 SD), whereas 6 of 7 nonresponders displayed a negative fold change of 0.89 (±0.84 SD). These changes were not observed in patients treated by TKIs. TRIM56, TRIM16, TRIM64, and Ki67 mRNAs were validated as upregulated in responders versus nonresponders after 3 weeks after treatment start, providing possible evidence of immune activation. Baseline CD8+ and CD8+PD-L1+ peripheral lymphocytes and early changes in CD8+PD1+ lymphocytes predict response to atezolizumab-bevacizumab providing noninvasive markers to complement clinical practice in the very early phases of treatment of HCC patients.
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Anticuerpos Monoclonales Humanizados , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Bevacizumab/uso terapéutico , Antígeno B7-H1 , Estudios Prospectivos , Leucocitos Mononucleares , Linfocitos T CD8-positivos , Biomarcadores de Tumor , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
BACKGROUND: In Italy, the incidence of SARS-CoV-2 infection peaked in April and November 2020, defining two pandemic waves of coronavirus disease 2019 (COVID-19). This study compared the characteristics and outcomes of patients with inflammatory bowel disease (IBD) and SARS-CoV-2 infections between pandemic waves. METHODS: Observational longitudinal study of IBD patients with SARS-CoV-2 infection. Patients with established diagnoses of IBD and of SARS-CoV-2 infection were consecutively enrolled in two periods: (i) first wave, from 1 March 2020 to 31 May 2020; and (ii) second wave, from 15 September to 15 December 2020. RESULTS: We enrolled 937 IBD patients (219 in the first wave, 718 in the second wave). Patients of the first wave were older (mean ± SD: 46.3 ± 16.2 vs. 44.1 ± 15.4 years, p = 0.06), more likely to have ulcerative colitis (58.0% vs. 44.4%, p < 0.001) and comorbidities (48.9% vs. 38.9%; p < 0.01), and more frequently residing in Northern Italy (73.1% vs. 46.0%, p < 0.001) than patients of the second wave. There were no significant differences between pandemic waves in sex (male: 54.3% vs. 53.3%, p = 0.82) or frequency of active IBD (44.3% vs. 39.0%, p = 0.18). The rates of negative outcomes were significantly higher in the first than second wave: pneumonia (27.8% vs. 11.7%, p < 0.001), hospital admission (27.4% vs. 9.7%, p < 0.001), ventilatory support (11.9% vs. 5.4%, p < 0.003) and death (5.5% vs. 1.8%, p < 0.007). CONCLUSION: Between the first and second SARS-CoV-2 pandemic waves, demographic, clinical and geographical features of IBD patients were different as were the symptoms and outcomes of infection. These differences are likely due to the different epidemiological situations and diagnostic possibilities between the two waves.
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COVID-19 , Enfermedades Inflamatorias del Intestino , Humanos , Masculino , COVID-19/epidemiología , Estudios Longitudinales , Pandemias , SARS-CoV-2 , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/epidemiologíaRESUMEN
BACKGROUND & AIMS: Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD. METHODS: Initial and long-term (>3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression. RESULTS: 248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (<3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P < .01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence. CONCLUSIONS: GFD adherence changes over time in <10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input.
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Enfermedad Celíaca , Dieta Sin Gluten , Adulto , Enfermedad Celíaca/diagnóstico , Estudios de Seguimiento , Humanos , Cooperación del Paciente , Estudios RetrospectivosRESUMEN
BACKGROUND & AIM: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. PATIENTS AND METHODS: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. RESULTS: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p = 0.006) were associated with HCC recurrence. CONCLUSION: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. LAY SUMMARY: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.
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Antivirales/efectos adversos , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/epidemiología , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Cirrosis Hepática/epidemiología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/epidemiología , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Hepatitis C Crónica/virología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Respuesta Virológica Sostenida , Adulto JovenRESUMEN
BACKGROUND: Several randomized clinical trials comparing different bowel preparations (BP) have shown similar efficacy; however, there is a lack of real-world studies on this topic. AIMS: This study aims to identify the most effective BP regimen in a real-world setting and any predictors of inadequate BP. METHODS: A retrospective single-center study was conducted over 14 months at an academic hospital including outpatient colonoscopies in which adult patients did not teach on how to perform BP before colonoscopy. Colonoscopies with 1L-PEG, 2L-PEG and picosulphate mixtures were considered. A multivariable analysis for factors associated to poor BP was fitted. RESULTS: Overall, 1779 patients (51 %F, 60±14) years were included. The 1L-PEG regimen provided a higher rate of BP adequacy at multivariate analysis (adjusted OR 2.30, 95 %CI 1.67-3.16,p < 0.001) and was associated with higher median Boston Bowel Preparation Scale score (p < 0.001), higher rate of right-colon cleansing (p < 0.001) and exam completion (p = 0.04). Furthermore, we identified male sex, history of constipation, active smoking, previous pelvic surgery, concomitant psychiatric/neurological or chronic kidney diseases as predictors of inadequate BP. CONCLUSIONS: This is the largest real-world study comparing 1L-PEG to other BP regimens. Our results suggest 1L-PEG provides better BP in a non-controlled setting, improving clinical practice quality and minimizing the need for repeated colonoscopies and saving healthcare resources.
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BACKGROUND AND AIMS: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib. METHODS: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the "Training Group" (215 patients) and the "Validation Group" (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image. RESULTS: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named "SARCO-MELD" based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment.
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Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/µL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.
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Tofacitinib is approved for several immune-mediated inflammatory diseases, but safety concerns have recently been raised. We searched PubMed (accessed on 27 February 2023) for original articles regarding tofacitinib's cancer risk when used for rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriatic arthritis, and ankylosing spondylitis. Of the 2047 initial records, 22 articles describing 26 controlled studies (including 22 randomized controlled trials) were selected. In the comparison between tofacitinib and any control treatment, the relative risk (RR) for any cancer was 1.06 (95% CI, 0.86-1.31; p = 0.95). In separate comparisons between tofacitinib and either a placebo or biological therapy, no difference was found in the overall cancer risk (vs. placebo, RR = 1.04; 95% CI, 0.44-2.48; p = 0.95; vs. biological drugs, RR = 1.06; 95% CI, 0.86-1.31; p = 0.58). When tofacitinib was compared to tumor necrosis factor (TNF) inhibitors, the overall cancer RR was 1.40 (95% CI, 1.06-2.08; p = 0.02). Similarly, significant results were obtained for all cancers, except for non-melanoma skin cancer (RR = 1.47; 95% CI, 1.05-2.06; p = 0.03), and for this skin cancer alone (RR = 1.30; 95% CI, 0.22-5.83; p = 0.88). In conclusion, no difference in the overall cancer risk was found between tofacitinib and either a placebo or biological drugs, while a slightly higher risk was found in patients treated with tofacitinib than anti-TNF agents. Further studies are needed to better define the cancer risk of tofacitinib therapy.
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INTRODUCTION: Immune check point inhibitors have recently entered the armamentarium of advanced hepatocellular carcinoma (HCC) treatment. Among them, the combination of atezolizumab plus bevacizumab has pushed it a step forward; however, a number of patients still present primary non-responses without any biomarker to predict responses to different options. Here, we aimed to identify a putative baseline biomarker to predict the response to atezolizumab-bevacizumab, by investigating whether baseline PD1+ and PD-L1+ peripheral granulocyte percentages might offer a non-invasive, cheap, and easily feasible assay. METHODS: A prospective Italian cohort of 34 patients treated by atezolizumab-bevacizumab was tested to assay the baseline percentage of peripheral granulocytes and their PD1 and PD-L1 expression. The neutrophil to lymphocyte ratio (NLR) was also considered, and all data were compared with the clinical course of patients. RESULTS: A low-baseline PD1+ peripheral granulocyte percentage turned out to predict responder patients (mean ±SD of PD1+ granulocyte percentage in responders versus non-responders: 9.9 ± 9.1 vs. 29.2 ± 17.6; student's t-test, p < 0.01). In line, patients identified by a low PD1+ granulocyte percentage displayed a longer TTP (log-rank test, p < 0.0001). A lower granulocyte percentage on total white blood cells, irrespective of PD1 or PD-L1 expression, is also associated with responses to atezolizumab-bevacizumab (log-rank test, p < 0.05). No predictive value was observed for either the PD-L1+ granulocyte percentage or NLR. CONCLUSIONS: A low-baseline PD1+ peripheral granulocyte percentage is associated with responses to atezolizumab-bevacizumab treatment in advanced HCC. These findings encourage evaluating this minimally invasive, cheap, and easy test in further independent cohorts and outlining the relevance of innate immunity in the response to immune-checkpoint inhibitors.
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INTRODUCTION: Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post-liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post-LT HCC recurrence. METHODS: This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. RESULTS: At the time of lenvatinib initiation, 95.6% (n = 43) of patients had Child-Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin-bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow-up duration of 12.9 months (95% confidence interval [CI]: 11.2-14.7), the median progression-free survival and overall survival (OS) were 7.6 (95% CI: 5.3-9.8) months, and 14.5 (95% CI: 0.8-28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0-30.4 months], p = 0.003). The most common adverse events were hypertension (n = 25, 55.6%), fatigue (n = 17, 37.8%), and anorexia (n = 14, 31.1%). CONCLUSION: Lenvatinib showed consistent efficacy and toxicity profiles in patients with post-LT HCC recurrence that were comparable to those reported from previous studies among non-LT HCC patients. The baseline ALBI grade correlated with better OS in post-LT lenvatinib-treated patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Albúmina Sérica , Biomarcadores de Tumor , BilirrubinaRESUMEN
OBJECTIVES: Data on SARS-CoV-2 disease (COVID-19) in adult coeliac disease (CD) are lacking. The aim of the present study is to evaluate the epidemiology and clinical features of COVID-19 in adult coeliac patients regularly followed-up at our centre since January 2015. METHODS: Data about general health status and clinical features of laboratory-confirmed COVID-19 were prospectively collected over the phone. Data about CD were retrospectively collected from clinical notes. Prevalence and incidence of COVID-19 were compared between the coeliac cohort and the figures in the general population of Lombardy, Northern Italy between 20 February to 5 June 2020 provided by the Italian National Institute of Health (Istituto Superiore di Sanità) and the Lombardy regional government. RESULTS: Nine out of 324 patients contracted COVID-19, thus resulting in a prevalence of 2.78% [95% confidence interval (CI) 0.98-4.58] and an incidence rate of 8.15/1000 person-month (95% CI 4.24-15.66). Prevalence of COVID-19 ascertained by means of nasal swab was 1.79% (95% CI 0.22-3.35) and the incidence rate 5.26/1000 person-month (95% CI 2.19-12.63), without difference from the general population. Clinical type of CD, age, sex, duration and adherence to a gluten-free diet, and mucosal healing did not differ between coeliac patients with and without COVID-19. None of the 9 patients with COVID-19 required hospitalization. CONCLUSION: Patients with CD do not seem to carry an increased risk of COVID-19 compared to the general population and their disease course is mild.