Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Exocrine drainage in pancreas transplantation:Complications and management

The aim of this minireview is to compare various pancreas transplantation exocrine drainage techniques i.e.,bladder vs enteric.Both techniques have different difficulties and complications.Numerous comparisons have been made in the literature between exocrine drainage techniques throughout the history of pancreas transplantation,detailing complications and their impact on graft and patient survival.Specific emphasis has been made on the early postoperative management of these complications and the related surgical infections and their consequences.In light of the results,a number of bladder-drained pancreas grafts required conversion to enteric drainage.As a result of technical improvements,outcomes of the varied enteric exocrine drainage techniques(duodenojejunostomy,duodenoduodenostomy or gastric drainage)have also been discussed i.e.,assessing specific risks vs benefits.Pancreatic exocrine secretions can be drained to the urinary or intestinal tracts.Until the late 1990s the bladder drainage technique was used in the majority of transplant centers due to ease of monitoring urine amylase and lipase levels for evaluation of possible rejection.Moreover,bladder drainage was associated at that time with fewer surgical complications,which in contrast to enteric drainage,could be managed with conservative therapies.Nowadays,the most commonly used technique for proper driving of exocrine pancreatic secretions is enteric drainage due to the high rate of urological and metabolic complications associated with bladder drainage.Of note,10%to 40%of bladder-drained pancreata eventually required enteric conversion at no detriment to overall graft survival.Various surgical techniques were originally described using the small bowel for enteric anastomosis with Roux-en-Y loop or a direct side-to-side anastomosis.Despite the improvements in surgery,enteric drainage complication rates ranging from 2%-20%have been reported.Treatment depends on the presence of any associated complications and the condition of the patient.Intra-abdominal infection represents a potentially very serious problem.Up to 30%of deep wound infections are associated with an anastomotic leak.They can lead not only to high rates of graft loss,but also to substantial mortality.New modifications of established techniques are being developed,such as gastric or duodenal exocrine drainage.Duodenoduodenostomy is an interesting option,in which the pancreas is placed behind the right colon and is oriented cephalad.The main concern of this technique is the challenge of repairing the native duodenum when allograft pancreatectomy is necessary.Identification and prevention of technical failure remains the main objective for pancreas transplantation surgeons.In conclusion,despite numerous techniques to minimize exocrine pancreatic drainage complications e.g.,leakage and infection,no universal technique has been standardized.A prospective study/registry analysis may resolve this.

Polymorphism AGT2(rs4762)is involved in the development of dermatologic events:Proof-of-concept in hepatocellular carcinoma patients treated with sorafenib

BACKGROUND Dermatologic adverse events(DAEs)are associated with a better outcome in patients with hepatocellular carcinoma(HCC)irrespective of the therapeutic agent received.The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors(TKIs)to the skin or an immune-mediated reaction triggered by the oncologic treatment.As is the case in other conditions,individual genetic variants may partially explain a higher risk of DAEs.AIM To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.METHODS We first analyzed 27 single-nucleotide polymorphisms(SNPs)from 12 genes selected as potential predictors of adverse event(AE)development in HCC patients treated with sorafenib[Barcelona Clinic Liver Cancer 1(BCLC1)cohort].Three additional cohorts were analyzed for AGT1(rs699)and AGT2(rs4762)polymorphisms-initially identified as predictors of DAEs:BCLC2(n=79),Northern Italy(n=221)and Naples(n=69)cohorts,respectively.The relation between SNPs and DAEs and death were assessed by univariate and multivariate Cox regression models,and presented with hazard ratios and their 95%confidence intervals(95%CI).RESULTS The BCLC1 cohort showed that patients with arterial hypertension(AHT)(HR=1.61;P value=0.007)and/or AGT SNPs had an increased risk of DAEs.Thereafter,AGT2(rs4762)AA genotype was found to be linked to a statistically significant increased probability of DAEs(HR=5.97;P value=0.0201,AA vs GG)in the Northern Italy cohort by multivariate analysis adjusted for BCLC stage,ECOG-PS,diabetes and AHT.The value of this genetic marker was externally validated in the cohort combining the BCLC1,BCLC2 and Naples cohorts[HR=3.12(95%CI:1.2-8.14),P value=0.0199,AGT2(rs4762)AA vs AG genotype and HR=2.73(95%CI:1.18-6.32)P value=0.0188,AGT2(rs4762)AA vs GG genotype].None of the other gene variants tested were found to be associated with the risk of DAE development.CONCLUSION DAE development in HCC patients receiving TKIs could be explained by the AGT2(rs4762)gene variant.If validated in other anti-oncogenic treatments,it might be considered a good prognosis marker.