PARP-1 selectively impairs KRAS-driven phenotypic and molecular features in intrahepatic cholangiocarcinoma.

OBJECTIVE: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with limited therapeutic options. KRAS mutations are among the most abundant genetic alterations in iCCA associated with poor clinical outcome and treatment response. Recent findings indicate that Poly(ADP-ribose)polymerase1 (PARP-1) is implicated in KRAS-driven cancers, but its exact role in cholangiocarcinogenesis remains undefined. DESIGN: PARP-1 inhibition was performed in patient-derived and established iCCA cells using RNAi, CRISPR/Cas9 and pharmacological inhibition in KRAS-mutant, non-mutant cells. In addition, Parp-1 knockout mice were combined with iCCA induction by hydrodynamic tail vein injection to evaluate an impact on phenotypic and molecular features of Kras-driven and Kras-wildtype iCCA. Clinical implications were confirmed in authentic human iCCA. RESULTS: PARP-1 was significantly enhanced in KRAS-mutant human iCCA. PARP-1-based interventions preferentially impaired cell viability and tumourigenicity in human KRAS-mutant cell lines. Consistently, loss of Parp-1 provoked distinct phenotype in Kras/Tp53-induced versus Akt/Nicd-induced iCCA and abolished Kras-dependent cholangiocarcinogenesis. Transcriptome analyses confirmed preferential impairment of DNA damage response pathways and replicative stress response mediated by CHK1. Consistently, inhibition of CHK1 effectively reversed PARP-1 mediated effects. Finally, Parp-1 depletion induced molecular switch of KRAS-mutant iCCA recapitulating good prognostic human iCCA patients. CONCLUSION: Our findings identify the novel prognostic and therapeutic role of PARP-1 in iCCA patients with activation of oncogenic KRAS signalling.

Prospective study of computer-aided detection of colorectal adenomas in hospitalized patients.

BACKGROUND: Adenoma detection with polypectomy during total colonoscopy reduces the incidence of colorectal cancer (CRC) and colorectal cancer-associated mortality. The adenoma detection rate (ADR) is an established quality indicator, which is associated with a decreased risk for interval cancer. An increase in ADR could be demonstrated for several artificially intelligent, real-time computer-aided detection (CADe) systems in selected patients. Most studies concentrated on outpatient colonoscopies. This sector often lacks funds for applying costly innovations like CADe. Hospitals are more likely to implement CADe and information about the impact of CADe in the distinct patient cohort of hospitalized patients is scarce. METHODS: In this prospective, randomized-controlled study, we compared colonoscopies performed with or without computer-aided detection (CADe) system (GI Genius, Medtronic) performed at University Medical Center Schleswig-Holstein, Campus Luebeck. The primary endpoint was ADR. RESULTS: Overall, 232 patients were randomized with n = 122 patients in the CADe arm and n = 110 patients in the control arm. Median age was 66 years (interquartile range 51-77). Indication for colonoscopy was most often workup for gastrointestinal symptoms (88.4%) followed by screening, post-polypectomy and post-CRC surveillance (each 3.9%). Withdrawal time was significantly prolonged (11 vs. 10 min, p = 0.039), without clinical relevance. Complication rate was not different between the arms (0.8% vs. 4.5%; p = 0.072). The ADR was significantly increased in the CADe arm compared to the control (33.6% vs. 18.1%, p = 0.008). ADR increase was particularly strong for the detection in elderly patients aged ≥50 years (OR 6.3, 95% CI 1.7 - 23.1, p = 0.006). CONCLUSION: The use of CADe is safe and increases ADR in hospitalized patients.

Markers of cell death predict therapy response in patients with cirrhosis and hepatorenal syndrome.

BACKGROUND AND AIMS: Hepatorenal syndrome is a major complication in patients with cirrhosis and associated with high mortality. Predictive biomarkers for therapy response are largely missing. Cytokeratin18-based cell death markers are significantly elevated in patients with complications of chronic liver disease, but the role of these markers in patients with HRS treated with vasoconstrictors and albumin is unknown. METHODS: We prospectively analyzed a total of 138 patients with HRS, liver cirrhosis without HRS and acute kidney injury treated at the University Medical Center Mainz between April 2013 and July 2018. Serum levels of M30 and M65 were analyzed by ELISA and clinical data were collected. Predictive ability was assessed by Kaplan-Meier curves, logistic regression and c-statistic. Primary endpoint was response to therapy. RESULTS: M30 and M65 were significantly increased in patients with HRS compared to non-HRS controls (M30: p < 0.0001; M65: p < 0.0001). Both serum markers showed predictive ability for dialysis- and LTX-free survival but not overall survival. Logistic regression confirmed M30 and M65 as independent prognostic factors for response to therapy. A novel predictive score comprising bilirubin and M65 showed highest predictive ability to predict therapy response. CONCLUSIONS: Serum levels of M30 and M65 can robustly discriminate patients into responders and non-responders to terlipressin therapy with a good predictive ability for dialysis- and LTX-free survival in cirrhotic patients. Cell death parameters might possess clinical relevance in patients with liver cirrhosis and HRS.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

13 C-Methacetin Breath Test Predicts Survival in Patients With Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

INTRODUCTION: The 13 C-methacetin breath test ( 13 C-MBT) is a dynamic method for assessing liver function. This proof-of-concept study aimed to investigate the association between 13 C-MBT values and outcomes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). METHODS: A total of 30 patients with HCC were prospectively recruited. Of these, 25 were included in baseline and 20 in longitudinal analysis. 13 C-MBTs were performed before the first and second TACE session. Patients were followed for at least 1 year. RESULTS: At baseline, the median 13 C-MBT value was 261 µg/kg/hr (interquartile range 159-387). 13 C-MBT, albumin-bilirubin, Child-Pugh, and Model for End-Stage Liver Disease scores were associated with overall survival in extended univariable Cox regression ( 13 C-MBT: standardized hazard ratio [sHR] 0.297, 95% confidence interval [CI] 0.111-0.796; albumin-bilirubin score: sHR 4.051, 95% CI 1.813-9.052; Child-Pugh score: sHR 2.616, 95% CI 1.450-4.719; Model for End-Stage Liver Disease score: sHR 2.781, 95% CI 1.356-5.703). Using a cutoff of 140 µg/kg/hr at baseline, 13 C-MBT was associated with prognosis (median overall survival 28.5 months [95% CI 0.0-57.1] vs 3.5 months [95% CI 0.0-8.1], log-rank P < 0.001). Regarding prediction of 90-day mortality after second 13 C-MBT, the relative change in 13 C-MBT values yielded an area under the receiver-operating characteristic curve of 1.000 ( P = 0.007). DISCUSSION: Baseline and longitudinal 13 C-MBT values predict survival of patients with HCC undergoing TACE. The relative change in 13 C-MBT values predicts short-term mortality and may assist in identifying patients who will not benefit from further TACE treatment.

[Current Studies and Evidence in Cholangiocarcinoma]. / Aktuelle Studien und Evidenz zum Cholangiokarzinom.

Cholangiocarcinoma (CCA) is the second most common type of primary liver cancer and includes a group of intra- and extrahepatic bile tract cancers. Prognosis of patients with CCA remains poor due to high recurrence rates after curative resections and often late diagnosis in advanced stages of the disease. Curative therapy is a complete resection that requires complex surgical procedures and potentially pre-operative induction of liver hypertrophy to ensure sufficient postoperative liver function. Adjuvant therapy with capecitabine for 6 months is well established in clinical routine. The therapeutic landscape for advanced stages is constantly progressing, due to new results of clinical phase II/III trials. On the one hand, molecular analyses have paved the way to effective targeted therapies for subgroups of CCA patients with alterations in FGFR2- or IDH1-signaling. On the other hand, immune-oncological approaches in combination with chemotherapy have resulted in safe and effective treatments for unselected patient cohorts. Further studies will investigate molecular-driven as well as immune-combination treatments in earlier stages of the disease and will result in new therapy options and better prognosis for CCA patients in the near future.

Efficacy and Safety of Atezolizumab and Bevacizumab in the Real-World Treatment of Advanced Hepatocellular Carcinoma: Experience from Four Tertiary Centers.

The combination of atezolizumab and bevacizumab (A + B) is the new standard of care for the systemic first-line treatment of hepatocellular carcinoma (HCC). However, up to now there are only few data on the safety and efficacy of A + B in real life. We included patients with advanced HCC treated with A + B as first-line therapy at four cancer centers in Germany and Austria between December 2018 and August 2021. Demographics, overall survival (OS), and adverse events were assessed until 15 September 2021. We included 66 patients. Most patients had compensated cirrhosis (n = 34; 52%), while Child-Pugh class B cirrhosis was observed in 23 patients (35%), and class C cirrhosis in 5 patients (8%). The best responses included a complete response (CR) in 7 patients (11%), a partial response (PR) in 12 patients (18%), stable disease (SD) in 22 patients (33%), and progressive disease in 11 patients (17%). The median progression-free (PFS) survival was 6.5 months, while the median overall survival (OS) was not reached in this cohort (6-month OS: 69%, 12-month OS: 60%, 18-month OS: 58%). Patients with viral hepatitis seemed to have a better prognosis than patients with HCC of non-viral etiology. The real-world PFS and OS were comparable to those of the pivotal IMBRAVE trial, despite including patients with worse liver function in this study. We conclude that A + B is also highly effective in a real-life setting, with manageable toxicity, especially in patients with compensated liver disease. In patients with compromised liver function (Child B and C), the treatment showed low efficacy and, therefore, it should be well considered before administration to these patients.