A phase II/III randomized clinical trial of CisPlatin plUs Gemcitabine and Nabpaclitaxel (GAP) as pReoperative chemotherapy versus immediate resection in patIents with resecTable BiliarY Tract Cancers (BTC) at high risk for recurrence: PURITY study.

BACKGROUND: Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). METHODS: PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. DISCUSSION: Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. TRIAL REGISTRATION: PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).

Is there an association between commonly employed biomarkers of liver fibrosis and liver stiffness in the general population?

INTRODUCTION AND OBJECTIVES: Surrogate biomarkers of liver fibrosis developed in tertiary care are increasingly used in general populations. We evaluated the association between liver stiffness (LS) and five continuous (AST/ALT, APRI, Forns Index, FIB-4, GGT) and two discrete biomarkers (BARD, BAAT) in a general population. PATIENTS AND METHODS: 636 (29%) of the 2159 citizens of the Bagnacavallo Study had LS measured by transient elastography. Using linear regression with univariate multiple imputation, we evaluated the association of LS with the above biomarkers in the total sample of 2159 citizens. RESULTS: The mean change of LS between the 5th and 95th internal percentile of any continuous biomarker was ≤1kPa. The mean change of LS between scores 0 and 3 of BARD and scores 0 and ≥3 of BAAT was >1kPa but of doubtful clinical relevance. CONCLUSION: We found a modest association between LS and seven biomarkers of liver fibrosis in a general population.

Circulating microRNAs as biomarkers for stratifying different phases of liver cancer progression and response to therapy.

Hepatocellular carcinoma (HCC) is the most common liver cancer and is among the leading causes of cancer-related death worldwide. There is no reliable biomarker for the early diagnosis of HCC. Circulating microRNAs (miRNAs) have attracted attention as potential biomarkers of disease. By small-RNA next-generation sequencing, the analysis of serum miRNAs led to the identification of molecular signatures able to discriminate advanced HCC from early HCC (n = 246); advanced HCC from CIRRHOSIS (n = 299); advanced HCC from HEALTHY (n = 320); HEALTHY from early HCC (n = 343); and HEALTHY from CIRRHOSIS (n = 414). Cirrhotic patients and early HCC patients exhibited similar serum miRNA profiles, yet a small number of miRNAs (n = 57) were able to distinguish these two classes of patients. A second objective of the study was to identify serum miRNAs capable of predicting the response to therapy in patients with advanced HCC. All patients were treated with sorafenib as first-line therapy: 24 were nonresponsive and 24 responsive. Analysis of circulating miRNAs revealed a 54 miRNAs signature able to separate the two subgroups. This study suggested that circulating miRNAs could be useful biomarkers for monitoring patients with liver diseases ranging from cirrhosis to advanced HCC and possibly predicting susceptibility to first-line treatment based on sorafenib.

Radial and longitudinal margins in surgery of perihilar cholangiocarcinoma: When R1 definition is associated with different prognosis.

BACKGROUND: Infiltrated margins of resection (R1) and lymph node invasion are dominant negative predictors of survival in patients with a resectable perihilar cholangiocarcinoma. Less clear is whether survival predictors stratify differently between R0 (tumor-free margins) and R1 patients and whether the prognosis of the latter patients is influenced by the pattern of neoplastic infiltration (ie, radial versus longitudinal infiltration). We retrospectively evaluated a series of reported resected perihilar cholangiocarcinoma to obtain insights on the predictive power of these histologic features. METHODS: The study includes 264 patients with perihilar cholangiocarcinoma treated between 2004 and 2019 in our center and followed up for >18 months. There were 176 patients with R0 (66.6%) and 88 patients with R1 (33.3%), 31 with radial infiltration only, 30 with longitudinal infiltration only, and 27 with both infiltration patterns. In all patients, the criteria for resection was the absence of metastatic involvement (ie, distant organ metastases, liver metastases, and lymph node metastases beyond the hepatoduodenal ligament). Histopathologic specimens of the resected tumors were centrally reviewed by a pathologist unaware of the clinical outcomes. RESULTS: Three- and 5-year long-term survival were significantly better in R0 (respectively) compared to R1 patients (55% and 42% vs 42% and 18%, respectively, P < .05). In R1 patients with radial infiltration only and those with radial + longitudinal infiltration, both disease-free and overall survival were worse than those with longitudinal infiltration only (median disease-free survival of 18 and 23 months, respectively, P < .05, median overall survival of 33 and 39 months, respectively, P < .05). At multivariable analysis, nodal status, side of hepatectomy, grading, and presence of radial margin infiltration were associated with long-term outcome. CONCLUSION: Radial infiltration of resection margins enhances the negative prognostic value of R1 margins in perihilar cholangiocarcinoma patients and should specifically be accounted for in the prediction of the outcome of adjuvant therapy.

Correction to: Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE­2 Study.

The listing of the author names and affiliations, which previously read.

Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol.

INTRODUCTION: Although sorafenib is the upfront standard of care for advanced hepatocellular carcinoma (HCC), molecular predictors of efficacy have not been identified yet. In the ALICE-1 study, rs2010963 of VEGF-A and VEGF-C proved to be independent predictive factors for progression-free survival (PFS) and overall survival (OS) in multivariate analysis. The ALICE-1 study results were confirmed in the ALICE-2 study, in which VEGF and VEGFR SNPs were analyzed. In the ePHAS study we analyzed the SNPs of eNOS. In univariate analysis, patients homozygous for an eNOS haplotype (HT1: T-4b at eNOS-786/eNOS VNTR) had significantly shorter median PFS and OS than those with other haplotypes. These data were confirmed in the validation set. METHODS: This nonpharmacological, interventional, prospective multicenter study aims to determine whether eNOS, HIF-1, VEGF, Ang2 and VEGFR polymorphisms play a role in predicting the objective response rate, PFS, and OS of advanced HCC patients treated with sorafenib. The study will involve 160 advanced HCC patients with Child-Pugh class A disease. The primary aim is to validate the prognostic or predictive roles of eNOS, Ang2, HIF-1, VEGF and VEGFR polymorphisms in relation to the clinical outcome (PFS) of HCC patients treated with sorafenib. CONCLUSIONS: Overall, our data may suggest that polymorphism analysis of the VEGF, VEGFR-2, HIF and eNOS genes can identify HCC patients who are more likely to benefit from sorafenib.