Impact of fellow participation on colon adenoma detection rates: a multicenter randomized trial.

BACKGROUND AND AIMS: There are limited and conflicting data on the impact of fellow participation in improving the colon adenoma detection rate. We performed a multicenter randomized controlled trial to evaluate whether fellow involvement might have a beneficial effect on adenoma detection rate. METHODS: The trial was conducted at 4 tertiary hospitals between April and December 2019. Eight hundred twelve patients were randomized to undergo colonoscopy performed by a fellow under the supervision of a staff endoscopist or by an attending physician alone. RESULTS: No significant differences in demographic or adenoma risk factors were detected between the 2 groups. The adenoma detection rate in the intervention group was 44.8% versus 37.1% in the control arm (P = .02). The mean number of adenomas per colonoscopy was significantly higher in the intervention group (0.65 ± 0.3 vs 0.53 ± 0.2 in the control arm, P < .001). The polyp detection rate was 69.7% in the intervention group and 62.5% in the control arm (P = .03), whereas rates of advanced and sessile/serrated adenoma detection were not different between the trial arms (P = .50 and .42, respectively). In the subgroup of more experienced fellows, the adenoma detection rate and polyp detection rate were 49.5% and 75.7%, respectively. No difference was observed between less-experienced fellows and attending physicians alone (P = .53 and 0.86, respectively). The level of bowel preparation and fellow involvement were significant predictors of increased adenoma detection rate in a multivariate analysis. CONCLUSIONS: Our multicenter trial represents the first prospective validation of the beneficial role of fellow involvement in colonoscopy procedures. (Clinical trial registration number: NCT03908229.).

Conditional survival analysis of hepatocellular carcinoma patients treated with radiofrequency ablation.

AIM: Survival estimates are commonly reported as survival from the first observation, but future survival probability changes based on the survival time already accumulated after therapy, otherwise known as conditional survival (CS). The aim of the study was to describe CS according to different prognostic variables in hepatocellular carcinoma (HCC) patients treated with radiofrequency ablation (RFA). METHODS: Data on 125 very early/early HCC patients treated with RFA between 1999 and 2007 were analyzed. Actuarial survival estimates were computed by means of Kaplan-Meier method and compared by log-rank test. The 5-year CS was calculated with stratification by several predictors for patients who had already survived up to 5 years from diagnosis. RESULTS: Median overall survival (OS) was 72 months (95% confidence interval [CI], 58-86). Age, Child-Pugh (CP), α-fetoprotein (AFP), Cancer of the Liver Italian Program (CLIP) score and type of recurrence (early vs late) were significant predictors of OS. The 5-year CS rates of the entire study cohort assessed at 1, 2, 3 and 5 years from the treatment were 49%, 48%, 30% and 34%, respectively. Subgroup analysis confirmed age and CP as significant predictors of CS at all time points, while the CS of subgroups stratified by AFP and CLIP did not differ significantly from the 3rd year after RFA onward, as more advanced patients had probably escaped early recurrence. CONCLUSION: CS analysis showed that the impact of different variables influencing OS is not linear over time after RFA. Information derived from the study can improve the current management of HCC patients.

Serum ferritin as a new prognostic factor in hepatocellular carcinoma patients treated with radiofrequency ablation.

BACKGROUND AND AIM: Hepatic iron accumulation is considered to be a cofactor that influences liver injury and hepatocarcinogenesis. Aim of this study is to determine whether serum ferritin (SF) levels relate to overall survival (OS) and time to recurrence (TTR) in hepatocellular carcinoma (HCC) patients treated with percutaneous radiofrequency ablation (RFA). METHODS: We measured SF levels in 103 HCC patients (median age 70, M/F = 82.5%/17.5%) who underwent RFA between 2005 and 2010. Correlation between SF and other prognostic factors at baseline was analyzed. SF levels were entered into a Cox model and their influence on OS and TTR was evaluated in univariate and multivariate analyses. RESULTS: SF did not correlate with α-fetoprotein (rho: -0.12, P = 0.22), neutrophil/lymphocyte ratio (rho: -0.1020, P = 0.30), Model for End-Stage Liver Disease (rho: 0.18, P = 0.06), Child-Pugh score (P = 0.5), or Barcelona Cancer of the Liver Clinic stage (P = 0.16). A log-rank test found the value of 244 ng/mL as the optimal prognostic cut-off point for SF. Median OS was 62 months (54-78) and survival rate was 97%, 65%, and 52% at 1, 4, and 5 years, respectively. Performance status and SF were the only predictors of OS at multivariate analysis. Median TTR was 38 months (34-49) with a recurrence-free survival rate of 82.5%, 26.2%, and 23.3% at 1, 4, and 5 years, respectively, while SF and age were the only predictors of TTR. CONCLUSIONS: SF level, possibly reflecting the degree of hepatic inflammation and fibrosis, is a negative risk factor for survival and recurrence after percutaneous RFA in HCC patients.

Use of tofacitinib as first or second-line therapy is associated with better outcomes in patients with ulcerative colitis: data from a real-world study.

BACKGROUND: Data regarding the real-world (RW) use of tofacitinib (TOF) in patients with ulcerative colitis (UC) are limited. We aimed to investigate TOF's RW efficacy and safety in Italian UC patients. RESEARCH DESIGN AND METHODS: A retrospective assessment of clinical and endoscopic activity was performed according to the Mayo score. The primary endpoints were to evaluate the effectiveness and safety of TOF. RESULTS: We enrolled 166 patients with a median follow-up of 24 (IQR 8-36) weeks. Clinical remission was achieved in 61/166 (36.7%) and 75/166 (45.2%) patients at 8-week and 24-week follow-ups, respectively. The optimization was requested in 27 (16.3%) patients. Clinical remission was achieved more frequently when TOF was used as a first/second line rather than a third/fourth line treatment (p = 0.007). Mucosal healing was reported in 46% of patients at the median follow-up time. Colectomy occurred in 8 (4.8%) patients. Adverse events occurred in 12 (5.4%) patients and severe in 3 (1.8%). One case of simple Herpes Zoster and one of renal vein thrombosis were recorded. CONCLUSIONS: Our RW data confirm that TOF is effective and safe in UC patients. It performs remarkably better when used as the first/second line of treatment.

Medical Systemic Therapies for Hepatocellular Carcinoma: Clinical Perspectives and Safety Profile.

A multidisciplinary approach based on clinical expertise and knowledge of molecular processes involved in hepatocarcinogenesis is needed for the proper management of hepatocellular carcinoma (HCC) patients. Such information must be considered in the context of pathobiology of the underlying liver disease. New drugs targeting specific molecular steps in pathways involved in HCC growth and development bear the promise to radically modify the pharmacological therapies currently in use in hepatooncology. Sorafenib was the first drug approved in the setting of advanced HCC, but although it produces some improvement in survival, the responses are not durable. In addition, there are significant side effects. Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and after progression following sorafenib failure; among them, tivantinib, an inhibitor of cMET receptor, showed interesting results in a recent phase-II study. Additional agents currently studied for the treatment of HCC patients are briefly examined in this review. Aim of this paper is to discuss the state of the art in the management of advanced HCC patients, with a particular interest for the description of their side effects.

Are hematopoietic stem cells involved in hepatocarcinogenesis?

THE LIVER HAS THREE CELL LINEAGES ABLE TO PROLIFERATE AFTER A HEPATIC INJURY: the mature hepatocyte, the ductular "bipolar" progenitor cell termed "oval cell" and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue.

Role of vaptans in the management of hydroelectrolytic imbalance in liver cirrhosis.

Ascites and hyponatremia are the most common complications in patients with liver cirrhosis and develop as a consequence of a severe impairment of liver function and portal hypertension. Increasing evidences support the central role of renal function alterations in the pathogenesis of hydroelectrolytic imbalances in cirrhotic patients, thus implying a dense cross-talk between liver and kidney in the systemic and splanchnic vascular homeostasis in such subjects. Since Arginin Vasopressin (AVP) hyperincretion occurs at late stage of cirrhosis and plays an important role in the development of refractory ascites, dilutional hyponatremia and finally hepato-renal syndrome, selective antagonists of AVP receptors V2 (vaptans) have been recently introduced in the therapeutic algorithm of advanced cirrhotic patients. Despite the promising results of earlier phase-two studies, randomized controlled trials failed to find significant results in terms of efficacy of such drugs both in refractory ascites and hyponatremia. Moreover, concerns on their safety profile arise, due to the number of potentially severe side effects of vaptans in the clinical setting, such as hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome. More robust data from randomized controlled trials are needed in order to confirm the potential role of vaptans in the management of advanced cirrhotic patients.

Post-recurrence survival in hepatocellular carcinoma after percutaneous radiofrequency ablation.

BACKGROUND: Overall survival in hepatocellular carcinoma patients treated with percutaneous radiofrequency ablation is influenced by both recurrence and successive treatments. We investigated post-recurrence survival after radiofrequency ablation. METHODS: Data on 103 early/intermediate patients initially treated with radiofrequency ablation and followed for a median of 78 months (range 68-82) were retrospectively analysed. If intrahepatic disease recurrence occurred within or contiguous to the previously treated area it was defined as local, otherwise as distant; recurrence classified as Barcelona Clinic Liver Cancer stage C was defined by neoplastic portal vein thrombosis or metastases. RESULTS: A total of 103 patients were included (82.5% male; median age 70 years, range 39-86). During follow-up, 64 recurrences were observed. Median overall survival was 62 months (95% confidence interval: 54-78) and survival rates were 97%, 65% and 52% at 1, 4 and 5 years, respectively. Median post-recurrence survival was 22 months (95% confidence interval: 16-35). Child-Pugh score, performance status, sum of tumour diameters at recurrence and recurrence patterns were independent predictors of post-recurrence survival. CONCLUSIONS: In patients with hepatocellular carcinoma after radiofrequency ablation, clinical and tumour parameters assessed at relapse, in particular the type of recurrence pattern, influence post-recurrence survival.

Fibrogenesis and fibrosis in inflammatory bowel diseases: Good and bad side of same coin?

Fibrogenesis in inflammatory bowel diseases is a complex phenomenon aimed at mucosal repair. However, it may provoke intestinal fibrosis with the development of strictures which require surgery. Therefore, fibrogenesis may be considered as a "two-faced" process when related to chronic intestinal inflammation. Many types of cells may be converted into the fibrogenic phenotype at different levels of the intestinal wall. A complex interaction of cytokines, adhesion molecules and growth factors is involved in the process. We report an overview of recent advances in molecular mechanisms of stricturizing Crohn's disease (CD) including the potential role of trasforming growth factor beta, protein kinase C and Ras, Raf and ERK proteins. Fibrotic growth factors such as vascular endothelial growth factor and platelet-derived growth factor, as well as the Endothelial-to-Mesenchymal Transition induced by transforming growth factor-ß, are considered. Finally, our experience, focused on tumor necrosis factor α (the main cytokine of inflammatory bowel diseases) and the link between syndecan 1 (a heparan sulphate adhesion molecule) and basic fibroblast growth factor (a strong stimulator of collagen synthesis) is described. We hypothesize a possible molecular pattern for mucosal healing as well as how its deregulation could be involved in fibrotic complications of CD. A final clinical point is the importance of performing an accurate evaluation of the presence of fibrotic strictures before starting anti-tumor necrosis α treatment, which could worsen the lesions.