Impact of COVID-19 Pandemic on Colorectal Cancer Screening Program.

INTRODUCTION: One of the main clusters of coronavirus disease-2019 (COVID-19) has been identified in Italy. Following European and local guidelines, Italian endoscopy units modulated their activity. We aimed at analyzing the need and safety to continue selective colorectal cancer screening (CRCS) colonoscopies during the COVID-19 pandemic. PATIENTS AND METHODS: We carried out a retrospective controlled cohort study in our "COVID-free" hospital to compare data of the CRCS colonoscopies of the lockdown period (March 9 to May 4, 2020) with those of the same period of 2019 (control group). A pre/post endoscopic sanitary surveillance for COVID-19 infection was organized for patients and sanitary staff. RESULTS: In the lockdown group, 60 of 137 invited patients underwent endoscopy, whereas in the control group, 238 CRCS colonoscopies (3.9-fold) were performed. In the lower number of examinations during the lockdown, we found more colorectal cancers (5 cases; 8% vs. 3 cases; 1%; P = .002). The "high-risk" adenomas detection rate was also significantly higher in the "lockdown group" than in controls (47% vs. 25%; P = .001). A multiple regression analysis selected relevant symptoms (hazard ratio [HR], 3.1), familiarity (HR, 1.99), and lockdown period (HR, 2.2) as independent predictors of high-risk lesions (high-risk adenomas and colorectal cancer). No COVID-19 infections were reported among staff and patients. CONCLUSIONS: The overall adherence to CRCS decreased during the pandemic, but the continuation of CRCS colonoscopies was efficacious and safe.

Toward Zero Hepatitis C Virus-Related Mortality as a Prerequisite for the Release of Resources in a Center for Follow-up of Liver Transplant.

Taking charge of a liver transplanted (LT) patient implies not only to follow up the transplanted organ (eg, immunosuppression and cancer risk) but also to deal with the prevailing patient's active problems. The recurrence of hepatitis C on the graft has historically been one of the main active problems to be addressed, leading to 30% to 40% mortality per se in these patients and has involved many resources in the hepatological centers responsible for the follow-up. We verified how much the availability of the new drugs with direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) has impacted the mortality within the assisted population, changing its characteristics and addressing new clinical issues in the LT-patients. We performed a retrospective comparison between 230 LT patients followed up during pre-DAA era (group 1, with 88 HCV RNA-positive) and 244 patients observed from 2014 onward when DAAs became available (group 2, with 79 HCV RNA-positive). Fifty-two antiviral therapies were performed in group 1 with 18 sustained virologic response (SVR) (35%) and 53 treatments, of which 37 were retreatments, in group 2 with 51 SVR (96%), P = .0001. Deaths for HCV-related causes were 19 of 33 (57%) in group 1 and 7 of 24 (24%) in group 2, P = .01. The Kaplan-Meier showed a dramatic reduction in excess mortality in HCV-LT patients after the availability of DAAs. These results suggest that HCV is no longer the main active problem of follow-up in liver transplants, therefore the resources can be relocated to take care of other clinical aspects.

Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study.

BACKGROUND: An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals. METHODS: According to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up. RESULTS: Nine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455-13.169). CONCLUSIONS: Our data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.

Sarcopenia is associated with reduced survival in patients with advanced hepatocellular carcinoma undergoing sorafenib treatment.

BACKGROUND: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and solid tumours. OBJECTIVE: Analyse the influence of sarcopenia on survival and treatment duration in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS: We conducted a multicentre, retrospective study on 96 patients with advanced HCC treated with sorafenib, all with available abdominal computed tomography (CT) scan within 30 days from treatment start. Anthropometric, laboratory, treatment and follow-up data were collected. Sarcopenia was defined by reduced skeletal muscle index calculated from an L3 section CT image. RESULTS: Sarcopenia was present in 49% of patients. Patients were divided into two groups according to sarcopenia: age was significantly higher in the sarcopenic group (SG) (66 years (31-87) versus 72 years (30-84), p = 0.04], with no difference in other baseline characteristics. The SG showed shorter overall survival (OS) (39 (95% confidence interval (CI) 26-50) versus 61 (95% CI 47-77) weeks (p = 0,01)) and shorter time on treatment (12.3 (95% CI 8-19) versus 25.9 (95% CI 15-33) weeks (p = 0.0044)). At multivariate analysis, sarcopenia was independently associated to reduced OS (p = 0.03) and reduced time on treatment (p = 0.001). CONCLUSION: Sarcopenia is present in almost half of patients with advanced HCC, and is associated with reduced survival and reduced duration of oral chemotherapy.

Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC.

BACKGROUND & AIMS: The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. METHODS: 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. RESULTS: 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14). CONCLUSIONS: The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. LAY SUMMARY: Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.

Liver Transplant in a Patient With Acquired Epidermolysis Bullosa and Associated End-Stage Liver Disease.

We report the first case of a liver transplant in a patient with epidermolysis bullosa acquisita and associated hepatitis B virus-hepatitis D virus cirrhosis and its inherent technical issues. Epidermolysis bullosa acquisita is an autoimmune multisystem disorder involving skin and mucosa characterized by the appearing of blisters and erosions. The more severe forms may result in nutritional compromise, anemia, osteopenia, dilated cardiomyopathy, laryngeal mucosal involvement, esophageal strictures, bladder, and kidney involvement requiring surgical intervention. Epidermolysis bullosa acquisita has become recognized as a multisystem disorder that poses several surgical challenges. This case shows that liver transplant is a feasible procedure in patients affected by epidermolysis bullosa acquisita. Patients with epidermolysis bullosa acquisita require a particular pretransplant assessment and a dedicated intra- and postoperative management of every invasive procedure that can traumatize the skin and mucosal epithelium to achieve an uneventful liver transplant. Epidermolysis bullosa acquisita does not represent a contraindication to liver transplant, and immunosuppression after transplant may favor a good systemic control of this immunologic disorder.

Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C.

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Treatment of genotype-1 hepatitis C recurrence after liver transplant improves survival in both sustained responders and relapsers.

The aim of this study was to evaluate the factors affecting the response to treatment and how it could affect survival in a large series of genotype-1 HCV-transplanted patients. Three-hundred and twenty six genotype-1 HCV patients were enrolled. One hundred and ninety-six patients (60.1%) were nonresponders and 130 (39.9%) showed negative HCV-RNA at the end of treatment. Eighty-four of them (25.8%) achieved sustained virological response, while 46 (14.1%) showed viral relapse. Five-year cumulative survival was significantly worse in nonresponders (76.4%) compared with sustained viral response (93.2) or relapsers (94.9%). Sustained responders and relapsers were therefore considered as a single 'response group' in further analysis. Pretreatment variables significantly associated with virological response at multivariate regression analysis were the absence of ineffective pretransplant antiviral therapy, the recurrence of HCV-hepatitis more than 1 year after transplant, an histological grading ≥4 at pretreatment liver biopsy, a pretreatment HCV-RNA level <1.2 × 10(6 ) IU/ml, and the absence of diabetes. As expected, also on-treatment variables (rapid and early virological response) were significantly associated to the response to antiviral treatment. In conclusion, this study shows that postliver transplant antiviral treatment results in beneficial effect on survival not only in sustained responders but also in relapsers.

HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b.

BACKGROUND: The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin. METHODS: For 48 weeks, 388 "naïve"genotype 1 patients were treated weekly with PEG-IFN α-2a or PEG-INF α-2b combined with daily ribavirin (1000-1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR). RESULTS: The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR:7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log10 IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI:3.2 to 7.4), were all independent predictors of SVR. CONCLUSION: Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01342003.

Treatment of recurrent genotype 4 hepatitis C after liver transplantation: early virological response is predictive of sustained virological response. An AISF RECOLT-C group study.

INTRODUCTION: Hepatitis C virus genotype 4 is predominant in the Middle East and Northern Africa, even if it has recently spread to Southern Europe. Data about the treatment of post-liver transplantation (LT) genotype 4 hepatitis C recurrence are scarce. We report a retrospective analysis of post-LT genotype 4 hepatitis C treatment in 9 Italian transplant centres, focusing on the overall survival rates and treatment outcome. RESULTS: Among 452 recipients, we identified 17 HCV genotype 4 patients (16 males, 1 female) transplanted between 1998 and 2007. All patients received combined antiviral treatment with conventional doses of interferon (recombinant or pegylated) and ribavirin after histological diagnosis of hepatitis C recurrence. The observed overall survival after LT was 100% at 1 year and 83.3% at 5 years. More than 1/3 (35.3%) of patients achieved a sustained virological response (SVR) and 40% (data available in 15 subjects) an early virological response (EVR), which was significantly associated with the achievement of SVR (overall accuracy: 85.7%; predictive values of EVR absence/presence 80/88.8%; chi-square p < 0.05). CONCLUSION: In conclusion, in post-LT genotype 4 hepatitis C treatment, SVR rates are similar to genotype 1. Patients who don't show an EVR are not likely to achieve a SVR.

Treatment of hepatitis C recurrence is less successful in female than in male liver transplant recipients.

It has been recently suggested that the risk of graft loss after liver transplantation (LT) may increase in female HCV patients. The aim of the study was to examine gender differences in HCV therapy tolerance and outcome in LT patients treated for HCV recurrence. A retrospective study was conducted on liver recipients with HCV recurrence, who were given antiviral therapy from 2001 to 2009 in 12 transplant centers in Italy. Sustained virological response (SVR), adherence-to-therapy, and side effects were evaluated. A multivariate logistic regression model was used after adjusting for possible confounders. The data regarding 342 treated patients were analyzed. SVR was reported in 38.8% of patients. At baseline, male and female did not differ in HCV viral load, histology, or rate of diabetes. SVR was lower in females than in males (29.5% vs. 42.1%; P=0.03). Adherence-to-therapy was also lower in females than in males 43.4% vs. 23.8%; P=0.001); anemia was the main reason for lower adherence. In a multivariate analysis in patients Genotype1, female gender (P<0.04), early virological response (P<0.0001), and adherence to therapy (P<0.0001) were independent predictors for SVR. In conclusion, female gender represents an independent negative prognostic factor for the outcome of HCV antiviral therapy after LT.

Gas exchanges and pulmonary vascular abnormalities at different stages of chronic liver disease.

BACKGROUND: It is unclear whether and to which extent respiratory function abnormalities may complicate the earliest stages of chronic liver disease (CLD). Aim of this study was to compare pulmonary capillary volumes and gas exchange efficiency of CLD patients with and without cirrhosis. METHODS: Sixty-seven participants (mean age 56.5 years; women 22.4%) were divided into three groups (matched by age, sex, smoking) according to the baseline CLD stage as follows: (a) healthy controls (Group A, n=20); (b) non-cirrhotic CLD patients (Group B; n=23); (c) cirrhotic CLD patients (Group C; n=24). All participants underwent clinical assessment, respiratory function tests, gas exchange estimation by the alveolar diffusion of carbon monoxide (TLCO) measurement and 6-min walking test. Groups were compared by chi-square and one-way anova tests. RESULTS: Chronic liver disease patients had significantly lower levels of TLCO (Group B=17.7 ml/min mmHg, and Group C=14.2 ml/min mmHg) compared with healthy controls (Group A=24.4 ml/min mmHg). Consistent results were obtained when analyses were performed using TLCO expressed as percentage of the predicted value. TLCO adjusted for the alveolar volume was lower in cirrhotic patients compared with both controls and non-cirrhotic CLD patients (P<0.001 and P=0.035 respectively). Group C participants presented blood gas parameters tending to a compensated chronic respiratory alkalosis status compared with the other groups. CONCLUSIONS: Pulmonary microvascular and gas exchange modifications are present at early stages of CLD. Future studies should be focused at evaluating the pathophysiological mechanisms underlying this relationship.

Consensus interferon versus interferon-alpha 2b plus ribavirin in patients with relapsing HCV infection.

Management of HCV infection and related liver disease with treatment currently available lead to a sustained virological response in 20% of patients using interferon (IFN)-alpha mono-therapy and approximately 40-45% in those on combination therapy with ribavirin.The aim of the present investigation was to compare the effect of consensus interferon alphacon-1 (C-IFN), and IFN-alpha 2b plus ribavirin, in patients relapsing after treatment with interferon alone. A total of 112 randomised patients with relapsing HCV infection (M/F=53/59), were treated for 24 weeks with: (A) IFN-alpha 2b starting with 5/6MU/day till negativity of HCV-RNA followed by 3MU every other day, plus ribavirin 15mg/kg/day (n=34); (B) C-IFN 9microg/day (n=40); (C) ursodeoxycholic acid (UDCA; sodium salt) 450mg/day (n=37). At the end of treatment, patients were observed at follow-up for 24 weeks.Clearance of HCV-RNA was achieved by the end of treatment in 23 patients (68%) in Group A and 21 also showed a biochemical response with normal ALT; in Group B, 33 patients (82%) had both a virological and a biochemical response; in Group C, one patient cleared HCV-RNA. At the end of follow-up (sustained-response), 29% of patients in Group A (n=10/34) had negative PCR (seven patients relapsed at the 4th week, six at the 12th); in Group B, a sustained response was achieved in 58% (p<0.03; two patients relapsed at the 4th week, three at the 12th and five at the 24th).MAJOR SIDE EFFECTS COMPRISED: neutropenia (n=17) and decrease in Hb>1.5g/dl (n=33) in Group A, recurrence of psoriasis in two patients in Group B and abdominal discomfort and diarrhoea in 11 patients in Group C.Rapid clearance of circulating HCV-RNA was induced by C-IFN (66% at three weeks, 71% at six weeks): this was a good prognostic index both for end of treatment and sustained response. Treatment with C-IFN lead to a higher response rate compared to that of recombinant IFN-alpha 2b in association with ribavirin. The action of C-IFN is superior in the time taken to reach the maximal response rate during treatment and in the lower prevalence of relapse of the infection.

Amantadine and interferon in the combined treatment of hepatitis C virus in elderly patients.

Background: Treatment of hepatitis C virus (HCV) infection with interferon (IFN) in older patients may not be feasible on account of side effects: we, therefore, attempted combined treatment with amantadine hydrochloride (AH) in order to improve not only the flu-like symptoms associated with IFN but also the anti-viral effect. Methods: Patients over 65 years of age, (n=165), who had failed to eradicate HCV infection after previous treatment with IFN were randomized into three groups and treated for 12 months, group A received AH 100 mg twice per day; group B received IFNalpha-n(3) 6 M units every other day for 3 months followed by 3 MU and group C the same dose of IFNalpha-n(3), as in B, and AH 200 mg per day. Results: Group A, 42 patients agreed to undergo treatment (genotype 1b n=39); at the end of treatment 21 patients (50%) had normal ALT and seven (17%) negative polymerase chain reaction (PCR). HCV-RNA was not detectable in seven patients at the sixth month follow-up and in six (14%) after 23plus minus2 months. Group B, 39 patients accepted the treatment (genotype 1b n=31); at the end of treatment, 17 patients (44%) had normal ALT and 13 negative PCR (13%). HCV-RNA was not detectable in nine patients (23%) at the sixth month of follow-up and in eight (21%) after 22plus minus4 months. Group C, 38 patients accepted the treatment (genotype 1b n=32); at the end of treatment, 20 (53%) patients had normal ALT and 15 negative PCR (39%). HCV-RNA was not detectable in 15 patients at the sixth month follow-up and in 11 after 21plus minus4 months (29%). Forty-six patients did not accept the scheme of treatment and 26 of them had a follow-up of 20plus minus3 months. HCV-RNA copies and prevalence of genotype 1b were comparable to the treated groups: HCV-RNA was fluctuating or unchanged during the entire follow-up. Conclusions: AH associated with IFN was able to improve the negativization of HCV-RNA and sustained response to IFN and decreased the malaise associated with IFN; an increase in viral copies was observed under AH in about 40%.