Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Imaging and prognostic characterization of fat-containing hepatocellular carcinoma subtypes.

PURPOSE: Steatohepatitic hepatocellular carcinoma (SH-HCC) is characterized by intratumoral fat with > 50% inflammatory changes. However, intratumoral fat (with or without inflammation) can also be found in not-otherwise specified HCC (NOS-HCC). We compared the imaging features and outcome of resected HCC containing fat on pathology including SH-HCC (> 50% steatohepatitic component), NOS-HCC with < 50% steatohepatitic component (SH-NOS-HCC), and fatty NOS-HCC (no steatohepatitic component). MATERIAL AND METHODS: From September 2012 to June 2021, 94 patients underwent hepatic resection for fat-containing HCC on pathology. Imaging features and categories were assessed using LIRADS v2018. Fat quantification was performed on chemical-shift MRI. Recurrence-free and overall survival were estimated. RESULTS: Twenty-one patients (26%) had nonalcoholic steatohepatitis (NASH). The median intra-tumoral fat fraction was 8%, with differences between SH-HCC and SH-NOS-HCC (9.5% vs. 5% p = 0.03). There was no difference in major LI-RADS features between all groups; most tumors were classified as LR-4/5. A mosaic architecture on MRI was rare (7%) in SH-HCC, a fat in mass on CT was more frequently depicted (48%) in SH-HCC. A combination of NASH with no mosaic architecture on MRI or NASH with fat in mass on CT yielded excellent specificity for diagnosing SH-HCC (97.6% and 97.7%, respectively). The median recurrence-free and overall survival were 58 and 87 months, with no difference between groups (p = 0.18 and p = 0.69). CONCLUSION: In patients with NASH, an SH-HCC may be suspected in L4/LR-5 observations with no mosaic architecture at MRI or with fat in mass on CT. Oncological outcomes appear similar between fat-containing HCC subtypes.

Are patients with hepatocellular carcinoma and portal vein tumour thrombosis candidates for liver transplantation?

In this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting - in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. While acknowledging the superior outcomes offered by LT for patients with portal vein tumour thrombosis, the counterargument is that expected survival in such patients is still below accepted thresholds for LT and, indeed, the levels achieved for other patients who receive transplants beyond the Milan criteria. Based on the available evidence, it seems too early for consensus guidelines to recommend such an approach, however, it is hoped that with higher quality evidence and standardised downstaging protocols, LT may soon be more widely indicated, including for this population with high unmet clinical need.

Pathological overview of steatohepatitic hepatocellular carcinoma in a surgical series.

AIMS: According to the last WHO classification, steatohepatitic hepatocellular carcinoma (SH-HCC) is recognized as a distinct HCC subtype, even though a consensual definition is still lacking. The objectives of the study were to carefully describe the morphological features of SH-HCC and evaluate its impact on prognosis. METHODS AND RESULTS: We conducted a single-centre retrospective study including 297 surgically resected HCC. Pathological features including SH criteria (steatosis, ballooning, Mallory-Denk bodies, fibrosis, and inflammation) were assessed. SH-HCC was defined by the presence of at least four of the five SH criteria and the SH component represented >50% of the tumour area. According to this definition, 39 (13%) HCC cases corresponded to SH-HCC and 30 cases (10%) corresponded to HCC with an SH component (<50%). SH criteria in SH-HCC and non-SH-HCC were distributed as follows: ballooning (100% versus 11%), fibrosis (100% versus 81%), inflammation (100% versus 67%), steatosis (92% versus 8%), and Mallory-Denk bodies (74% versus 3%). Inflammation markers (c-reactive protein [CRP] and serum amyloid A [SAA]) were significantly more expressed in SH-HCC compared to non-SH-HCC (82% versus 14%, P = <0.001). Five-year recurrence-free survival (RFS) and 5-year overall survival (OS) were similar for SH-HCC and non-SH-HCC (P = 0.413 and P = 0.866, respectively). The percentage of SH component does not impact OS and RFS. CONCLUSION: We confirm in a large cohort the relatively high prevalence (13%) of SH-HCC. Ballooning is the most specific criteria for this subtype. The percentage of the SH component does not impact prognosis.

Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82).

BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV+ cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. METHODS: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. DISCUSSION: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. TRIAL REGISTRATION: NCT05528952.

Performances and variability of CT radiomics for the prediction of microvascular invasion and survival in patients with HCC: a matter of chance or standardisation?

OBJECTIVES: To measure the performance and variability of a radiomics-based model for the prediction of microvascular invasion (MVI) and survival in patients with resected hepatocellular carcinoma (HCC), simulating its sequential development and application. METHODS: This study included 230 patients with 242 surgically resected HCCs who underwent preoperative CT, of which 73/230 (31.7%) were scanned in external centres. The study cohort was split into training set (158 patients, 165 HCCs) and held-out test set (72 patients, 77 HCCs), stratified by random partitioning, which was repeated 100 times, and by a temporal partitioning to simulate the sequential development and clinical use of the radiomics model. A machine learning model for the prediction of MVI was developed with least absolute shrinkage and selection operator (LASSO). The concordance index (C-index) was used to assess the value to predict the recurrence-free (RFS) and overall survivals (OS). RESULTS: In the 100-repetition random partitioning cohorts, the radiomics model demonstrated a mean AUC of 0.54 (range 0.44-0.68) for the prediction of MVI, mean C-index of 0.59 (range 0.44-0.73) for RFS, and 0.65 (range 0.46-0.86) for OS in the held-out test set. In the temporal partitioning cohort, the radiomics model yielded an AUC of 0.50 for the prediction of MVI, a C-index of 0.61 for RFS, and 0.61 for OS, in the held-out test set. CONCLUSIONS: The radiomics models had a poor performance for the prediction of MVI with a large variability in the model performance depending on the random partitioning. Radiomics models demonstrated good performance in the prediction of patient outcomes. CLINICAL RELEVANCE STATEMENT: Patient selection within the training set strongly influenced the performance of the radiomics models for predicting microvascular invasion; therefore, a random approach to partitioning a retrospective cohort into a training set and a held-out set seems inappropriate. KEY POINTS: • The performance of the radiomics models for the prediction of microvascular invasion and survival widely ranged (AUC range 0.44-0.68) in the randomly partitioned cohorts. • The radiomics model for the prediction of microvascular invasion was unsatisfying when trying to simulate its sequential development and clinical use in a temporal partitioned cohort imaged with a variety of CT scanners. • The performance of the radiomics models for the prediction of survival was good with similar performances in the 100-repetition random partitioning and temporal partitioning cohorts.

The Safety and Effectiveness of Hepatic Transarterial Embolic Locoregional Therapy in Patients with Contraindications to Hepatectomy after Portal Vein Embolization.

The safety and effectiveness of hepatic transarterial embolic locoregional therapy (LRT) was assessed, including transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), in patients who underwent portal vein embolization (PVE) before major hepatectomy in whom surgery was then contraindicated. Adverse events (AEs) were graded according to the Society of Interventional Radiology classification of AEs. Tumor response was assessed based on the Response Evaluation Criteria In Solid Tumors 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated. Fifteen patients underwent 37 transarterial LRTs (25 TACEs, 11 TAREs, and 1 bland embolization), most (73%) with hepatocellular carcinoma. Eleven AEs occurred in 7 patients, including 2 Grade 3/5 (severe) and 2 Grade 4/5 (life-threatening) events. The best response was partial response in 4 (27%) and stable disease in 10 (66%) patients. The median OS and PFS were 42 (95% CI, 35-49 months) and 33 months (95% CI, 24-42 months), respectively. In conclusion, hepatic transarterial LRT can be considered as a therapeutic option in patients with contraindicated liver surgery after PVE.

Plain language summary of the TOPAZ-1 study: durvalumab and chemotherapy for advanced biliary tract cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy. WHAT WERE THE RESULTS OF THE STUDY?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area: What's new 12 months later?

INTRODUCTION AND OBJECTIVES: The lockdown policy introduced in 2020 to minimize the spread of the COVID-19 pandemic, significantly affected the management and care of patients affected by hepatocellular carcinoma (HCC). The aim of this follow-up study was to determine the 12 months impact of the COVID-19 pandemic on the cohort of patients affected by HCC during the lockdown, within six French academic referral centers in the metropolitan area of Paris. MATERIALS AND METHODS: We performed a 12 months follow-up of the cross-sectional study cohort included in 2020 on the management of patients affected by HCC during the first six weeks of the COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Overall survival were compared between the groups. Predictors of mortality were analysed with Cox regression. RESULTS: From the initial cohort, 575 patients were included (n = 263 Exposed_COVID, n = 312 Unexposed_COVID). Overall and disease free survival at 12 months were 59.9 ± 3.2% vs 74.3 ± 2.5% (p<0.001) and 40.2 ± 3.5% vs 63.5 ± 3.1% (p<0.001) according to the period of exposure (Exposed_COVID vs Unexposed_COVID, respectively). Adjusted Cox regression revealed that the period of exposure (Exposed_COVID HR: 1.79, 95%CI (1.36, 2.35) p<0.001) and BCLC stage B, C and D (BCLC B HR: 1.82, 95%CI (1.07, 3.08) p = 0.027 - BCLC C HR: 1.96, 95%CI (1.14, 3.38) p = 0.015 - BCLC D HR: 3.21, 95%CI (1.76, 5.85) p<0.001) were predictors of death. CONCLUSIONS: Disruption of routine healthcare services because of the pandemic translated to reduced 1 year overall and disease-free survival among patients affected by HCC, in the metropolitan area of Paris, France.

Performance of non-invasive biomarkers compared with invasive methods for risk prediction of posthepatectomy liver failure in hepatocellular carcinoma.

BACKGROUND: Posthepatectomy liver failure (PHLF) is a rare but dreaded complication. The aim was to test whether a combination of non-invasive biomarkers (NIBs) and CT data could predict the risk of PHLF in patients who underwent resection of hepatocellular carcinoma (HCC). METHODS: Patients with HCC who had liver resection between 2012 and 2020 were included. A relevant combination of NIBs (NIB model) to model PHLF risk was identified using a doubly robust estimator (inverse probability weighting combined with logistic regression). The adjustment variables were body surface area, ASA fitness grade, male sex, future liver remnant (FLR) ratio, difficulty of liver resection, and blood loss. The reference invasive biomarker (IB) model comprised a combination of pathological analysis of the underlying liver and hepatic venous pressure gradient (HVPG) measurement. Various NIB and IB models for prediction of PHLF were fitted and compared. NIB model performances were validated externally. Areas under the curve (AUCs) were corrected using bootstrapping. RESULTS: Overall 323 patients were included. The doubly robust estimator showed that hepatitis C infection (odds ratio (OR) 4.33, 95 per cent c.i. 1.29 to 9.20; P = 0.001), MELD score (OR 1.26, 1.04 to 1.66; P = 0.001), fibrosis-4 score (OR 1.36, 1.06 to 1.85; P = 0.001), liver surface nodularity score (OR 1.55, 1.28 to 4.29; P = 0.031), and FLR volume ratio (OR 0.99, 0.97 to 1.00; P = 0.014) were associated with PHLF. Their combination (NIB model) was fitted externally (2-centre cohort, 165 patients) to model PHLF risk (AUC 0.867). Among 129 of 323 patients who underwent preoperative HVPG measurement, NIB and IB models had similar performances (AUC 0.753 versus 0.732; P = 0.940). A well calibrated nomogram was drawn based on the NIB model (AUC 0.740). The risk of grade B/C PHLF could be ruled out in patients with a cumulative score of less than 160 points. CONCLUSION: The NIB model provides reliable preoperative evaluation with performance at least similar to that of invasive methods for PHLF risk prediction.

Outcome of liver cancer patients with SARS-CoV-2 infection: An International, Multicentre, Cohort Study.

BACKGROUND & AIMS: Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. METHODS: Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. RESULTS: Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84-11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24-12.74], 11.76% [95% CI 4.73-22.30], 20.69% [95% CI 11.35-31.96] and 34.52% [95% CI 17.03-52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49-4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29-7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. CONCLUSIONS: This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period.

Liver surface nodularity on non-contrast MRI identifies advanced fibrosis in patients with NAFLD.

OBJECTIVES: To evaluate the diagnostic performance of liver surface nodularity (LSN) for the assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We retrospectively analysed patients with pathologically proven NAFLD who underwent liver MRI. Demographic, clinical, and laboratory data (including FIB-4 scores) were gathered. The SAF score was used to assess NAFLD. MRI-proton density fat fraction (PDFF) and LSN were determined on pre-contrast MR sequences. ROC curve analysis was performed to evaluate the diagnostic performance of MRI-LSN for the diagnosis of advanced (F3-F4) liver fibrosis. RESULTS: The final population included 142 patients. Sixty-seven (47%) patients had non-alcoholic steatohepatitis (NASH), and 52 (37%) had advanced fibrosis. The median MRI-PDFF increased with the grades of steatosis: 8.1%, 18.1%, and 31% in S1, S2, and S3 patients, respectively (p < 0.001). The area under the ROC curve (AUC) of MRI-LSN ≥ 2.50 was 0.838 (95%CI 0.767-0.894, sensitivity 67.3%, specificity 88.9%, positive and negative predictive values 77.8% and 82.5%, respectively) for the diagnosis of advanced fibrosis. Combining FIB-4 and MRI-LSN correctly classified 103/142 (73%) patients. This was validated in an external cohort of 75 patients. CONCLUSIONS: MRI-LSN has good diagnostic performance in diagnosis of advanced fibrosis in NAFLD patients. A combination of FIB-4 and MRI-LSN derived from pre-contrast MRI could be helpful to detect advanced fibrosis. KEY POINTS: • MRI-LSN ≥ 2.5 was accurate for the diagnosis of advanced hepatic fibrosis in NAFLD patients. • The combination of FIB-4 and MRI-LSN improved the detection of advanced fibrosis. • MRI-LSN can be easily derived by unenhanced MRI sequences that are routinely acquired.

Microangiopathy associated with gemcitabine: a drug interaction with nab-paclitaxel? A case series and literature review.

PURPOSE: Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence. METHODS: Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients' data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine. RESULTS: Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler's Side Effect of Drugs) and 0.01% in the gemcitabine's summary of product characteristics. Literature review outlined an increase of gemcitabine's plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine's effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase's activity (responsible for gemcitabine's metabolism) and increases gemcitabine's active metabolite concentrations (gemcitabine triphosphate) in tumor tissues. CONCLUSION: High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.

Health-related quality-of-life impact of pembrolizumab versus best supportive care in previously systemically treated patients with advanced hepatocellular carcinoma: KEYNOTE-240.

BACKGROUND: Health-related quality of life (HRQoL) is an important outcome measure and prognostic indicator in hepatocellular carcinoma (HCC). KEYNOTE-240 (NCT02702401) assessed the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with HCC who previously received sorafenib. This study presents the results of a prespecified exploratory analysis of patient-reported outcomes. METHODS: Patients completed the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and its HCC supplement (EORTC QLQ-HCC18) electronically at baseline; at weeks 2, 3, 4, 6, 9, 12, and 18; and then every 9 weeks until 1 year or end of treatment, and at the 30-day safety follow-up visit. RESULTS: The HRQoL population included 271 and 127 patients randomly assigned to pembrolizumab and placebo, respectively. From baseline to week 12, changes in both scores were similar between pembrolizumab and placebo; global health status/QoL scores were stable. The proportions of patients who improved, remained stable, or deteriorated across all functional domain and symptom scores were generally similar between pembrolizumab and placebo. Time to deterioration was similar between the 2 arms based on the prespecified analysis of EORTC QLQ-HCC18 domains of abdominal swelling, fatigue, and pain. CONCLUSION: Pembrolizumab preserved HRQoL during treatment for advanced HCC. Combined with efficacy and safety results from KEYNOTE-240, these findings support a positive benefit/risk profile for pembrolizumab in a second-line treatment setting for patients with HCC who previously received sorafenib.

Computed Tomography-Derived Liver Surface Nodularity and Sarcopenia as Prognostic Factors in Patients with Resectable Metabolic Syndrome-Related Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to assess the prognostic value of liver surface nodularity (LSN) and sarcopenia from preoperative computed tomography (CT) in patients with resectable metabolic syndrome (MS)-related hepatocellular carcinoma (HCC). METHODS: Patients with MS undergoing hepatectomy for HCC between 2006 and 2018 at a single center were retrospectively analyzed. LSN and sarcopenia were assessed on preoperative CT scans, and their association with severe (Clavien-Dindo grade 3-5) postoperative complications was analyzed on multivariate analysis. The influence of LSN and sarcopenia on overall survival (OS) and recurrence-free survival (RFS) was assessed. RESULTS: Overall, 110 patients (92 men [84%], mean 67.7 ± 7.7 years of age) were analyzed. Severe postoperative complications occurred in 34/110 (31%) patients. Patients with severe complications had a significantly higher LSN score (area under the receiver operating characteristic curve 0.68 ± 0.05, optimal cut-off > 2.50) and were more frequently sarcopenic (47% vs. 13% without major complications, p < 0.001). Multivariate analysis identified sarcopenia (odds ratio [OR] 6.51, 95% confidence interval [CI] 2.08-20.39; p < 0.001), LSN > 2.50 (OR 7.05, 95% CI 2.13-23.35; p < 0.001), and preoperative portal vein embolization (PVE; OR 6.06, 95% CI 1.71-21.48; p = 0.005) as independent predictors of severe complications. LSN and sarcopenia had no influence on OS. Stratification according to a combination of LSN > 2.50 and sarcopenia predicted the risk of severe postoperative complications from 7% (no sarcopenia and LSN ≤2.50) to 71% (sarcopenia and LSN > 2.50; p < 0.001), as well as RFS from 61 months (95% CI 40-82) to 17 months (95% CI 9-25; p = 0.033). Results remained significant in 52 patients without advanced fibrosis. CONCLUSIONS: The combination of LSN and sarcopenia derived from routine preoperative CT seems to help predict severe postoperative complications and stratification of RFS in patients with MS and resectable HCC.

Transarterial chemoembolisation enhances programmed death-1 and programmed death-ligand 1 expression in hepatocellular carcinoma.

AIMS: Immunotherapies represent a new alternative therapeutic approach for hepatocellular carcinomas (HCCs), and have shown promising results when used in combination therapy. The aim of this study was to evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression profiles in a cohort of surgically treated HCCs. METHODS AND RESULTS: A total of 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD-1 and of PD-L1 were analysed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analysed. Follow-up data were retrieved from patients' charts. PD-1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD-L1 expression (≥1%) in ICs and PD-L1 expression in tumour cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD-1 expression (<1%) was associated with strong and diffuse glutamine synthetase overexpression (8% versus 27%, P = 0.024). HCCs from patients with TACE pretreatment showed significantly higher PD-L1 expression in TCs than those from patients without TACE pretreatment (2% versus 0.4%, P = 0.027). PD-1 expression in ICs and PD-L1 expression in both ICs and TCs were higher in TACE-resected tumours than in corresponding pre-TACE biopsies (respectively: 1.8% versus 8.1%, P = 0.034; 0.8% versus 7.1%, P = 0.032; and 0% versus 2.4%, P = 0.043). CONCLUSION: Our results, showing increases in PD-1 expression and PD-L1 expression in HCCs following TACE, support the use of TACE in combination with immunotherapy in selected cases to optimise tumour response.

Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma.

Aberrant c-Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c-Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c-Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c-Met status, and the prevalent off-target activity of these agents, which may indicate that c-Met inhibition is incomplete. In contrast, selective c-Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c-Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c-Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child-Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c-Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c-Met status. Thus, c-Met inhibition continues to be an active area of research in HCC, with well-designed trials in progress to investigate the benefit of selective c-Met inhibitors. (Hepatology 2018;67:1132-1149).

Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance.

We recently identified a histological subtype of hepatocellular carcinoma (HCC), designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this variant, we investigated its prognostic value in two large series of patients with HCC treated by either surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than six cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, alpha-fetoprotein level, satellite nodules, and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: hazard ratio, 3.03; 95% confidence interval, 1.38-6.65; P = 0.006; and 2.76; 1.63-4.67; P < 0.001; RFA series: 2.37; 1.36-4.13; P = 0.002; and 2.19; 1.35-3.54; P = 0.001, respectively). Its prognostic value was retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness. No other baseline parameter was independently associated with recurrence in the RFA series. CONCLUSION: The MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. (Hepatology 2018;68:103-112).

Combining imaging and tumour biopsy improves the diagnosis of combined hepatocellular-cholangiocarcinoma.

BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is by definition a highly heterogeneous tumour, which significantly impacts its diagnosis. The aim of the study was to evaluate the diagnostic performance of imaging using computed tomography and/or magnetic resonance (MR) and biopsy for the diagnosis of cHCC-CCA. METHODS: cHCC-CCA resected between December 2006 and April 2017 with available pre-operative imaging and tumour biopsy were retrospectively included. cHCC-CCA diagnosis was based on morphological and immunophenotypical features. A total of 21 cHCC-CCA were compared to 21 intrahepatic cholangiocarcinoma (iCCA) as controls. All biopsies were reviewed. Two radiologists reviewed the cases and classified tumours into four patterns (type 1 [progressive enhancement of the entire lesion, iCCA type], type 2 [arterial enhancement with washout, HCC type], type 3 [mixed pattern with combinations of 1, 2 and 4] and type 4 [atypical pattern, areas of arterial enhancement without washout and/or hypovascular]). RESULTS: The presence of a type 3 pattern at imaging had a 48% sensitivity and 81% specificity for cHCC-CCA diagnosis. The initial diagnosis performed on biopsy was cHCC-CCA in 8/21 patients (38%). After reviewing and including immunophenotypical markers, two more cases were diagnosed as cHCC-CCA (48% sensibility, 100% specificity). When either imaging or biopsy suggested the diagnosis of cHCC-CCA, the sensitivity and specificity were 60% and 82% respectively. CONCLUSIONS: We showed that a two-step strategy combining imaging as the first step and biopsy as the second step improved the diagnostic performance of cHCC-CCA.