Nora Schweitzer

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

UNLABELLED Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.

Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade.

Background:Application of curative therapy for hepatocellular carcinoma is crucially dependent on underlying liver function. Using the recently described ALBI grade we examined the long-term impact of liver dysfunction on survival of early-stage hepatocellular carcinoma (HCC) patients.Methods:This cohort study comprised 2559 HCC patients from different geographic regions, all treated with curative intent. We also examined the relation between indocyanine green (ICG) clearance and ALBI score. Survival was measured from the date of treatment to the date of death or last follow-up.Results:The ALBI score correlated well with ICG clearance. Among those undergoing surgical resection, patients with ALBI grade-1 (good liver function) survived approximately twice as long as those with ALBI grade-2 (less good liver function), although more than 90% of these patients were classified as Child–Pugh (C-P) grade A. In the cohort receiving ablative therapies, there was a similar difference in survival between ALBI grade-1 and grade-2. Cox regression analysis confirmed that the ALBI score along with age, gender, aetiology and tumour factors (AFP, tumour size/number and vascular invasion) independently influenced survival in HCC patients receiving curative treatments.Conclusions:The ALBI score represents a simple approach to the assessment of liver function in patients with HCC. After potentially curative therapy, those with ALBI grade-1 survived approximately twice as long as those with ALBI grade-2. These data suggest that ALBI grade-1 patients are appropriately treated with surgical resection whereas ALBI grade-2 patients may, where the option exists, be more suitable for liver transplantation or the less invasive curative ablative therapies.British Journal of Cancer (2016) 114, 744–750; doi:10.1038/bjc.2016.33 www.bjcancer.com

Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients

BACKGROUND & AIMS GALAD and BALAD-2 are statistical models for estimating the likelihood of the presence of hepatocellular carcinoma (HCC) in individual patients with chronic liver disease and the survival of patients with HCC, respectively. Both models use objective measures, particularly the serum markers α-fetoprotein (AFP), AFP-L3, and des-γ-carboxyprothrombin. We aimed to validate these models in an international cohort of patients with HCC and assess their clinical performance. METHODS We collected data on cancer diagnosis and outcomes of 6834 patients (2430 with HCC and 4404 with chronic liver disease) recruited from Germany, Japan, and Hong Kong. We also collected data from 229 patients with other hepatobiliary tract cancers (cholangiocarcinoma or pancreatic adenocarcinoma) and 92 healthy individuals (controls). For reference, the original UK cohort (on which the GALAD model initially was built and BALAD-2 was validated) was included in the analysis. We assessed the effects of tumor size and etiology on GALAD model performance, and its ability to correctly discriminate HCC from other hepatobiliary cancers. We assessed the performance of BALAD-2 in patients with different stages of HCC. RESULTS In all cohorts, the area under the receiver operating characteristic curve (AUROC), quantifying the ability of GALAD to discriminate patients with HCC from patients with chronic liver disease, was greater than 0.90-similar to the series on which the model originally was built (AUROC, 0.97). GALAD discriminated patients with HCC from those with other hepatobiliary cancers with an AUROC value of 0.95; values were slightly lower for patients with small unifocal HCCs, ranging from 0.85 to 0.95. Etiology and treatment of chronic viral hepatitis had no effect on the performance of this model. BALAD-2 analysis assigned patients with HCC to 4 distinct prognostic groups-overall and when patients were stratified according to disease stage. CONCLUSIONS We validated the performance of the GALAD and BALAD-2 models for the diagnosis of HCC and predicting patient survival, respectively (based on levels of the serum markers AFP, AFP-L3, and des-γ-carboxyprothrombin), in an international cohort of almost 7000 patients. These systems might be used in HCC surveillance and determination of patient prognosis.

p21 promotes sustained liver regeneration and hepatocarcinogenesis in chronic cholestatic liver injury

Background and aims The cyclin-dependent kinase inhibitor p21 has been implicated as a tumour suppressor. Moreover, recent genetic studies suggest that p21 might be a potential therapeutic target to improve regeneration in chronic diseases. The aim of this study was to delineate the role of p21 in chronic liver injury and to specify its role in hepatocarcinogenesis in a mouse model of chronic cholestatic liver injury. Methods The degree of liver injury, regeneration and tumour formation was assessed in Mdr2−/− mice and compared with Mdr2/ p21−/− mice. Moreover, the role of p21 was evaluated in hepatoma cells in vitro and in human hepatocellular carcinoma (HCC). Results Mdr2−/− mice developed HCCs as a consequence of chronic inflammatory liver injury. In contrast, tumour development was profoundly delayed in Mdr2/ p21−/− mice. Delayed tumour development was accompanied by markedly impaired liver regeneration in Mdr2/ p21−/− mice. Moreover, the regenerative capacity of the Mdr2/ p21−/− livers in response to partial hepatectomy declined with age in these mice. Hepatocyte transplantation experiments revealed that impaired liver regeneration was due to intrinsic factors within the cells and changes in the Mdr2/ p21−/− microenvironment. In human HCCs, a subset of tumours expressed p21, which was associated with a significant shorter patient survival. Conclusions We provide experimental evidence that p21 is required for sustained liver regeneration and tumour development in chronic liver injury indicating that p21 needs to be tightly regulated in order to balance liver regeneration and cancer risk. Moreover, we identify p21 as a negative prognostic marker in human HCC.

Surgical treatment for intrahepatic cholangiocarcinoma in Europe : a single center experience

Intrahepatic cholangiocarcinoma is the second most common primary liver tumor. The aim of this study was to analyze retrospectively the outcome of surgical treatment and prognostic factors. Clinical, histopathological and treatment data of 221 patients treated from 1995 to 2010 at our institution were investigated. Univariate and multivariate analysis of the patients data was performed. Patients after R0 and R1 resection presented an overall survival of 67% and 54.5% after 1 year and 40% and 36.4% after 3 years, respectively. The survival of patients without resection of the tumor was dismal with 26% and 3.4% after 1 and 3 years, respectively. Survival after resection was not statistically different in cases with R0 versus R1 resection (P = 0.639, log rank). Univariate Cox regression revealed that higher T stages are a significant hazard for survival (P = 0.048, hazard ratio (HR): 1.211, 95% confidence interval (CI): 1.002–2.465). Patients with tumor recurrence had a significantly inferior long‐term survival when compared to patients without recurrence (P < 0.001, log rank). Presence of lymph node metastasis (N1) was an independent prognostic factor for survival after resection in risk‐adjusted multivariate Cox regression (P < 0.001, HR: 2.577, 95% CI: 1.742–3.813). Adjuvant chemotherapy did not improve patient survival significantly (P = 0.550, log rank). Surgical resection is still the best treatment option for intrahepatic cholangiocarcinoma regarding the patients long‐term survival. R0 and R1 resection enable both better survival rates when compared to surgical exploration without resection. T status, N status, and tumor recurrence seem to be the most important prognostic factors after resection.

The effect of adjuvant chemotherapy in patients with intrahepatic cholangiocarcinoma: a matched pair analysis

PurposeThe purpose of this study was to identify prognostic factors of patients with intrahepatic cholangiocarcinoma (ICC) treated with resection and to investigate the effect of adjuvant chemotherapy (CT).MethodsPatients with ICC diagnosed between 2000 and 2015 treated at Hannover Medical School were included. Clinicopathologic characteristics were analyzed in univariate and multivariate analysis. In a matched pair survival analysis, patients with or without adjuvant CT were matched by these prognostic factors.ResultsTwo hundred and ten patients were included. Median survival was 28.7 months, 1-, 3-, and 5-year survival rates were 72.8%, 29.6%, and 14.1%, respectively. In multivariate analysis, lymph node involvement (p = 0.006, HR 1.84), larger tumor size (p = 0.013, HR 1.79), vascular invasion (p = 0.038, HR 1.70), and prolongation of prothrombin time (p < 0.001, HR 4.20) were significantly related to poor survival. Thirty-nine patients received adjuvant CT of which 60% had lymph node involvement. Each 25 patients with and without adjuvant CT were matched to the identified prognostic factors. The median survival of patients with adjuvant CT was 33.5 months, compared to 18 months in the control group (p = 0.002). The 1-, 3-, and 5-year survival rates were 96, 36, and 12%, compared to 60, 4, and 0% in non-treated patients.ConclusionsWe identified several prognostic factors for patients with ICC treated with resection. Our data support the use of adjuvant CT in patients with ICC. The results of prospective randomized controlled studies will clarify the role of adjuvant CT in the future.

Experience from a real-life cohort: outcome of 606 patients with hepatocellular carcinoma following transarterial chemoembolization

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Transarterial chemoembolization (TACE) has been accepted as the standard care for intermediate stage disease. Methods: In this study, we characterized 606 with HCC patients from Hannover Medical School treated with TACE. Results: 606 with HCC patients treated with TACE were identified between 2000 and 2015. Most patients (59.8%) were at intermediate stage. Following TACE, most patients subsequently received systemic therapy or best supportive care (BSC), whereas 227 (37.5%) patients were bridged to potentially curative local treatments. Depending on subsequent therapies, median post-TACE survival ranged from 7 to 162 months. Ascites, cholinesterase, c-reactive and alpha-feto protein and tumor size were identified as prognostic factors. These factors as well as the HAP, mHAP-II and STATE score also determined post-TACE survival independent of subsequent therapies. Hepatic function progressively deteriorated with repeated TACE sessions. Despite that, post-TACE survival was not shortened in frequently treated patients (≥5 times) as compared to patients treated 4 times or less (p = not significant [n.s.]). Patients treated ≥5 times with TACE received significantly more often systemic therapy following TACE (37.3%) as compared to patients with 3–4 (30.1%), 2 (27.4%) and 1 (21.8%) sessions (p < .05). Conclusion: TACE is performed in a heterogeneous population as bridging therapy to other local treatments and palliative therapy. The long-term survival following TACE is determined by baseline tumor, patient-related factors and by subsequent therapies. Post-TACE survival is not shorter in patients with frequent treatments (≥5), and the rate of subsequent systemic treatments is higher compared to less frequently treated patients.

Risk estimation for biliary tract cancer: Development and validation of a prognostic score

Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival.

Second-Line Treatment in Pancreatic Cancer Patients: Who Profits?--Results From the CONKO Study Group.

Objectives With increasing numbers of therapeutic options in inoperable pancreatic cancer (PAC), patients tend to receive more than just a first line (FL) therapy. Methods All patients who started FL for PAC at our institution (1997–2012) were retrospectively studied to identify patients and treatment characteristics. Significant parameters in regard to second-line (SL) related survival were looked for as the basis for a prognostic model. This score was validated in a patient cohort from the CONKO-003 study. Results Two hundred eighty of 521 (53.7%) patients received SL therapy, median overall survival (OS) from the beginning of SL (OS2) was 5.1 months. Significant more SL patients had undergone surgery, a higher Karnofsky performance state (KPS) and a duration of FL longer than 4 months. Prognostic factors impacting OS2 were KPS, carbohydrate antigen 19-9 levels at start of SL and the duration of FL. These 3 factors establish a prognostic score—validated in CONKO-003—for SL patients with 3 subgroups: “good” (median OS2, 9.3 months), “intermediate” (median OS2, 7.1 months), “poor” prognosis (median OS2, 3.8 months; P < 0.001). Conclusions Among patients with PAC, more than 50% receive SL therapy. Our prognostic model identifies 3 subgroups and can identify patients with a maximum benefit of SL therapy.

Gray scale and contrast-enhanced ultrasound imaging of malignant liver tumors of vascular origin

Objectives Malignant vascular tumors of the liver are rare. The aim of this study was to investigate the applicability of gray scale and contrast-enhanced ultrasonography in patients with epithelioid hemangioendothelioma (EHE) of the liver and hepatic angiosarcoma (HA) and to describe the clinical presentation. Methods We retrospectively analyzed all patients with epithelioid hemangioendothelioma or hemangiosarcoma of the liver from 1998 to 2011, who underwent ultrasound investigation. We describe the findings in gray scale and contrast-enhanced ultrasound and the clinical course of the disease of seven patients with EHE and five patients with HA. Results Ultrasound investigation in EHE showed mostly multiple hypoechoic irregular lesions close to the liver capsule and with a halo in some cases. Contrast enhancement revealed inhomogeneously and through all contrast phases vascularized tumors with a rim enhancement in 50%, with or without early wash out. All tumors had avascular parts. HA presented as multiple and irregular hypo-, iso- or hyperechoic lesions. After contrast enhancement, hypervascularization with individual patterns was evident in all patients. Of five, three had liquid parts. Patients with HA were significantly older (58 vs. 37 years, p = 0.014) and presented with lower thrombocyte counts (84 vs. 264, p = 0.0025) and with higher CEA levels (4.6 vs. 1.5, p = 0.03). Conclusion EHE and HA are inhomogeneous tumors, explaining the high inter-individual variability and heterogeneity in ultrasound examination. The presence of multifocal lesions, heterogeneity and undefined margins may differentiate EHE or HA from hemangioma. A biopsy is essential in the diagnosis of vascular tumors.