In silico characterization of LZTS3, a potential tumor suppressor

Members of the leucine zipper tumor suppressor (LZTS) protein family are thought to play roles in cell growth modulation. The two currently known members were identified by analyzing genomic and chromosomal alterations reported to be either involved or deleted in various types of cancer, suggesting a causative relationship. By means of computational biology, we have now identified a novel member of the LZTS protein family named LZTS3. The corresponding gene was localized to chromosome 20p13 and consisted of three exons. The novel LZTS3 protein demonstrated a high similarity to LAPSER1/LZTS2 and FEZ1/LZTS1, two members of the LZTS family. The conserved FEZ1 domain contains a leucine zipper m…

Transarterial chemoembolization versus sorafenib in patients with hepatocellular carcinoma and extrahepatic disease

BackgroundSorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.MethodsA total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.ResultsPatients with liver cirrhosis, high…

Additional file 2: of Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Table S2. Predefined disease limited toxicities. List with the disease limited toxicities associated with afatinib in this study. (DOC 36 kb)

Coupled variable selection for regression modeling of complex treatment patterns in a clinical cancer registry.

For determining a manageable set of covariates potentially influential with respect to a time-to-event endpoint, Cox proportional hazards models can be combined with variable selection techniques, such as stepwise forward selection or backward elimination based on p-values, or regularized regression techniques such as component-wise boosting. Cox regression models have also been adapted for dealing with more complex event patterns, for example, for competing risks settings with separate, cause-specific hazard models for each event type, or for determining the prognostic effect pattern of a variable over different landmark times, with one conditional survival model for each landmark. Motivat…

Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma

Simple Summary Individual patients with liver cancer have a highly variable clinical course. Hence, there is an urgent need to identify new prognostic markers to determine prognosis and select specific therapies. Expression of two key enzymes in pyrimidine synthesis was analyzed in a large, well-characterized cohort of patients with liver cancer. Dysregulated expression of these enzymes was associated with shorter survival of the patients. A combined score of both markers was found to be a statistically independent prognostic marker. Abstract Patients with hepatocellular carcinoma (HCC) have a highly variable clinical course. Therefore, there is an urgent need to identify new prognostic mar…

Immunonutritive Scoring in Patients With Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: Prognostic Nutritional Index or Controlling Nutritional Status Score?

ObjectivesThe Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are immunonutritive scoring systems with proven predictive ability in various cancer entities, including hepatocellular carcinoma (HCC). We performed the first evaluation of the CONUT score for patients undergoing transarterial chemoembolization (TACE) and compared CONUT and PNI in the ability to predict median overall survival (OS).MethodsBetween 2010 and 2020, we retrospectively identified 237 treatment-naïve patients with HCC who underwent initial TACE at our institution. Both scores include the albumin level and total lymphocyte count. The CONUT additionally includes the cholesterol level. …

CONKO-005: Adjuvant therapy in R0 resected pancreatic cancer patients with gemcitabine plus erlotinib versus gemcitabine for 24 weeks—A prospective randomized phase III study.

4007 Background: Adjuvant chemotherapy with gemcitabine (Gem) for 6 months significantly improves survival of pancreatic cancer patients. CONKO-005 was designed to evaluate an additional effect of ...

Influence of Lymphangio (L), Vascular (V), and Perineural (Pn) Invasion on Recurrence and Survival of Resected Intrahepatic Cholangiocarcinoma

(1) Background: Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy. Besides tumor, nodal, and metastatic status, the UICC TNM classification describes further parameters such as lymphangio- (L0/L1), vascular (V0/V1/V2), and perineural invasion (Pn0/Pn1). The aim of this study was to analyze the influence of these parameters on recurrence and survival. (2) Methods: All surgical explorations for patients with ICC between January 2008 and June 2018 were collected and further analyzed in our institutional database. Statistical analyses focused on perineural, lymphangio-, and vascular invasion examined histologically and their influence on tumor recurrence and survival. (3) Results: Of 2…

The addition of TACE to palliative chemotherapy is associated with extended survival in unresectable intrahepatic cholangiocarcinoma

Stagewise pseudo-value regression for time-varying effects on the cumulative incidence

In a competing risks setting, the cumulative incidence of an event of interest describes the absolute risk for this event as a function of time. For regression analysis, one can either choose to model all competing events by separate cause-specific hazard models or directly model the association between covariates and the cumulative incidence of one of the events. With a suitable link function, direct regression models allow for a straightforward interpretation of covariate effects on the cumulative incidence. In practice, where data can be right-censored, these regression models are implemented using a pseudo-value approach. For a grid of time points, the possibly unobserved binary event s…

Hepatic vein tumor thrombosis in patients with hepatocellular carcinoma: Prevalence and clinical significance.

Abstract Background There is strong evidence that portal vein tumor thrombosis (PVTT) is associated with poor survival in patients with hepatocellular carcinoma (HCC). However, data regarding the clinical significance of hepatic vein tumor thrombosis (HVTT) is rare, particularly in Western patients. Objective To determine the HVTT prevalence in a Western patient population and its impact on survival. Methods We included 1310 patients with HCC treated in our tertiary referral center between January 2005 and December 2016. HVTT and PVTT were diagnosed with contrast‐enhanced cross‐sectional imaging. Overall survival (OS) was calculated starting from the initial HCC diagnosis, and in a second s…

TAP-polymorphisms in juvenile onset psoriasis and psoriatic arthritis.

Abstract Juvenile onset psoriasis is strongly associated with the HLA-class I genes Cw6 and B57 whereas patients with psoriatic arthritis show an increased frequency of HLA-B27. It is unclear whether additional major histocompatibility genes also increase disease susceptibility. The TAP genes (transporter associated with antigen processing) encode two membrane-spanning proteins that translocate antigenic peptides from the cytoplasm into the endoplasmic reticulum. Comparison of 60 patients with juvenile onset psoriasis, 63 psoriatic arthritis patients, and 101 caucasoid controls revealed an increase of the TAP1 ∗ 0101 allele in the psoriasis group, that could not be explained by linkage to o…

Systemic Therapies in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide in the human population. Due to late diagnosis and/or advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefit are available in up to 70% of patients. During the last decades, no effective conventional cytotoxic systemic therapy was available contributing to the dismal prognosis in patients with advanced disease. However, a better knowledge of molecular hepatocarcinogenesis provides today the opportunity for targeted therapy. Positive data from the pivotal phase III SHARP trial assessing the efficacy and safety of the multikinase inhibitor sorafenib broade…

Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma.

Inhibition of the renin-angiotensin system (RAS) was associated with longer survival in patients with different solid malignancies.The objective of this study was to investigate the effect of RAS inhibitor (RASi) treatment (angiotensin-converting enzyme inhibitors or angiotensin-II-receptor blockers) on survival of patients with hepatocellular carcinoma (HCC).Patients diagnosed with HCC and Child-Pugh A between 1992 and 2013 who received sorafenib, experimental therapy, or best supportive care were eligible for the Vienna cohort. The Mainz cohort included patients with HCC and Child-Pugh A who received sorafenib treatment between 2007 and 2016. The association between RASi and overall survi…

TGFβ-activated kinase 1 (TAK1) is activated and predicts prognosis in hepatocellular carcinoma

Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) is the strongest survival-limiting factor after liver transplantation (LT) in patients with HCC. In the face of donor organ shortage, it is necessary to identify factors associated with HCC recurrence in order to maximize the utility of the available grafts. OBJECTIVE: To study the phenomenon of HCC recurrence after LT at a European transplantation centre over the past 20 years. METHODS: Data from 304 HCC patients who underwent LT were prospectively recorded. Clinical and pathological factors were assessed for their association with recurrence. RESULTS: Fifty-one patients (16.8%) had HCC recurrence after LT. Patients exceeding the…

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-fre…

Non‐bacterial thrombotic endocarditis in a patient with pancreatic carcinoma

Nonbacterial thrombotic endocarditis (NBTE) is a rare condition that most often accompanies a malignant disease and involves a hypercoagulable state. We report the incidental finding of a rare case of an NBTE affecting the tricuspid valve in a patient with metastatic pancreatic carcinoma complicated by severe venous and arterial thromboembolisms.

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months…

Fatigue in SLE: diagnostic and pathogenic impact of anti-N-methyl-D-aspartate receptor (NMDAR) autoantibodies.

ObjectivesWe explored the impact of circulating anti-N-methyl-D-aspartate receptor (NMDAR) antibodies on the severity of fatigue in patients with systemic lupus erythematosus (SLE).MethodsSerum samples of 426 patients with SLE were analysed for the presence of antibodies to the NR2 subunit of the NMDAR. In parallel, the severity of fatigue was determined according to the Fatigue Scale for Motor and Cognitive functions questionnaire. In a subgroup of patients with SLE, the hippocampal volume was correlated with the levels of anti-NR2 antibodies. Isolated immunoglobulin G from patients with anti-NR2 antibodies were used for murine immunohistochemical experiments and functional assays on neuro…

Actin binding LIM protein 3 (abLIM3).

LIM domain proteins were demonstrated to play key roles in various biological processes such as embryonic development, cell lineage determination, and cancer differentiation. Actin binding LIM protein 1 (abLIM1) was reported to be localized in a genomic region often deleted in human cancers and suggested to be involved in axon guidance. Recently, existence of a second family member was reported, actin binding LIM protein 2. By means of computational biology and comparative genomics, we now characterized an additional, third member of the actin binding LIM protein subgroup, actin binding LIM protein 3 (abLIM3). The human mRNA sequence was previously annotated as differentially regulated in h…

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation

Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; media…

Sorafenib perpetuates cellular anti-cancer effector functions by modulating the cross talk between macrophages and natural killer cells.

Alternatively polarized macrophages (Mϕ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anticancer immune responses. We investigated if sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed natural killer (NK) cell responses. In vivo experiments were conducted with sorafenib (25 mg/kg)-treated C57BL/6 wildtype as well as hepatitis B virus (HBV) and lymphotoxin transgenic mice with and without HCC. Monocyte-derived Mϕ or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with sorafenib (0.07-5.0 μg/mL) and cocultured with autologous NK cells. Mϕ and NK cell activation was analyzed …

Prognostic factors and outcomes of patients with hepatocellular carcinoma in non-cirrhotic liver

To report the outcome of patients with hepatocellular carcinoma (HCC) in non-cirrhotic liver depending on the mode of primary treatment and to define clinicopathological factors influencing patients' prognosis.A retrospective analysis of an unselected cohort of 105 patients was performed. Overall survival (OS) was estimated by the Kaplan-Meier method and potentially prognostic factors were analyzed in Cox regression models.OS of the whole cohort at 1, 3, and 5 years was 66%, 47%, and 29%, respectively. Tobacco consumption, ECOG0, macroscopic vascular invasion, continuous tumor diameter, and treatment other than resection were predictors of decreased OS in the whole cohort. Resection was per…

Application of patient derived liver cancer cell lines for phenotypic characterization and therapeutic target identification

Concurrent autoimmune diseases in patients with autoimmune hepatitis.

Although the pathomechanisms of autoimmune diseases in various organs remain unresolved, an accumulation of autoimmune diseases in individual patients has been observed. An overlap of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis has been well documented. However, the overlap of autoimmune diseases other than PBC or PSC has not yet been investigated in a large cohort.The goal of our analysis was to investigate the incidence of concurrent autoimmune diseases in patients with AIH.We analyzed our cohort of 278 patients with AIH for concurrent autoimmune diseases.A total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Be…

Immunonutritive Scoring for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: Evaluation of the CALLY Index

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with m…

Validierung des Vorhersagemodells SNACOR nach transarterieller Chemoembolisation von hepatozellulären Karzinomen

Comparison of resection and transarterial chemoembolisation in the treatment of advanced intrahepatic cholangiocarcinoma--a single-center experience.

Abstract Aims The aim of this study is to evaluate factors associated with the outcome after surgical resection and to compare the efficacy of surgery to transarterial chemoembolisation (TACE) in patients with advanced intrahepatic cholangiocarcinoma (IHC). Materials and methods 273 patients with IHC treated in our department between 1997 and 2012 were included in our study. Patients were divided according to therapy into surgical ( n  = 130), TACE ( n  = 32), and systemic chemotherapy/best supportive care ( n  = 111) groups. Clinicopathological characteristics and survival were reviewed retrospectively. Results The 1-, 3-, and 5-year survival rates in patients after surgical resection were…

Defer or treat? Reasons for treatment decisions in patients with chronic hepatitis C genotype 1 in the early era of directly acting antiviral agents

Abstract Background In chronic genotype 1 hepatitis C, telaprevir or boceprevir plus peginterferon and ribavirin have become the new standard of care. Aim of this study was to identify factors contributing to the decision whether to defer or treat with the current triple regimens. Methods Prospective assessment of eight parameters on 0-4-point scales by the attending physician at a German tertiary referral centre between 1st September 2011 and 31st December 2012. Results 307 patients were evaluated at least once by one of the 11 hepatologists involved; 267 patients were considered, but only 163 were recommended to receive triple therapy. Multivariate regression analysis revealed that a high…

P125 Internet-based exercise therapy in patients with systemic lupus erythematodes – systemic lupus erythematodes exercise program (SLEEP)

Background The SLEEP study examines the effect of an exercise therapy against a control group with TAU therapy (Treatment as usual) in SLE to identify the effect of regular physical activity on muscular development. Furthermore, we investigate the effect of physical activity on disease activity and especially on fatigue syndrome. Molecular biological markers such as cfDNA and exosomes also detect the degree of the prostration of the patients. Methods Thirty SLE patients with laboratory as well as clinically stable status were included. The intervention group initially consisted of 24 patients, of which 12 were aerobically and 12 anaerobically active. In contrast, eight patients were include…

Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Abstract Background Recurrence of hepatocellular carcinoma after orthotopic liver transplantation not amenable to surgical approaches is associated with poor outcome. Aims Retrospective evaluation of the safety and efficacy of sorafenib in patients with post-transplant hepatocellular carcinoma recurrence. Methods Patients with post-transplant hepatocellular carcinoma recurrence were treated with sorafenib. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria of AEs version 3.0, tumour response was evaluated according to Response Evaluation Criteria in Solid Tumours. Results First-line therapy after recurrence was surgery ( n  = 6), radiation therapy ( n  = 1…

Effektivität der sequentiellen systemischen Therapie bei Patienten mit einem fortgeschrittenen HCC - Erfahrungen aus dem klinischen Alltag

Hepatitis B virus-specific T-cell responses during IFN administration in a small cohort of chronic hepatitis B patients under nucleos(t)ide analogue treatment.

The effect of pegylated interferon-α (IFN) add-on therapy on HBV-specific T-cell responses was evaluated in 12 patients with stable, undetectable hepatitis B virus (HBV) load under nucleos(t)ide analogue therapy. Peripheral blood mononuclear cells were isolated at week 0, 4, 8, 12, 24 and 48 of IFN add-on therapy. Quantity and quality of circulating HBV S- and core-specific CD4 and CD8 T cells were analysed ex vivo by flow cytometry. HBV S- and core-specific CD4 T-cell numbers modestly increased within 8 weeks of IFN administration (P = 0.0391 and P = 0.0195), whereas HBV-specific CD8 T cells in general showed only minor changes under IFN add-on therapy. Functionality of HBV-specific CD4 bu…

PD-1 targeted immunotherapy in advanced hepatocellular carcinoma: efficacy and safety data from an international multicenter real-world cohort

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition- and life style-associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)-treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. METHODS Five thousand and ninety-three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed wi…

sj-docx-1-tan-10.1177_17562864211051497 – Supplemental material for Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus

Supplemental material, sj-docx-1-tan-10.1177_17562864211051497 for Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus by Sinah Engel, Simone Boedecker, Paul Marczynski, Stefan Bittner, Falk Steffen, Arndt Weinmann, Andreas Schwarting, Frauke Zipp, Julia Weinmann-Menke and Felix Luessi in Therapeutic Advances in Neurological Disorders

Clinicopathologic features and prognosis of young patients with hepatocellular carcinoma in a large German cohort.

GOALS AND BACKGROUND Hepatocellular carcinoma in non-hepatitis B virus endemic areas is rare in patients younger than 40 years of age. The aim of this study was to characterize young patients in a large German cohort in comparison with older patients with regard to underlying liver disease, clinical management, and survival. STUDY We analyzed the clinical data and medical records of 1108 consecutive patients with confirmed hepatocellular carcinoma. Twenty-five patients (2%) were younger than 40 years of age. We compared this subgroup with patients older than 40 years of age. RESULTS Underlying chronic liver disease was less common in young patients and detectable in only 56% of patients. Fi…

Validation of clinical scoring systems ART and ABCR after transarterial chemoembolization of hepatocellular carcinoma

Portal vein infiltration in patients with hepatocellular carcinoma: The relevance of correct classification.

e15651 Background: Portal vein invasion (PVI) is has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). Patients with PVI are classified as stage C in the BCLC score and systemic therapy is recommended. Patients with minor PVI are frequently misclassified due to radiological challenges in determining malignant PVI or non-adherence to guidelines. The concept of resection or TACE in limited PVI is sometimes followed with the assumption of a negligible influence on survival. Aim of this study is the reevaluation of PVI and the analysis of the impact of a misclassification. Methods: 763 patients with HCC of a total of 1413 were extracted from the clinical re…

Extent of portal vein tumour thrombosis in patients with hepatocellular carcinoma: The more, the worse?

BACKGROUND & AIMS Portal vein tumour thrombosis (PVTT) has a significant impact on the prognosis of patients with hepatocellular carcinoma (HCC). The degree of PVTT varies from sub-/segmental invasion to complete occlusion of the main trunk. Aim of this study was to evaluate whether the degree of PVTT correlates with prognosis. METHODS A total of 1317 patients with HCC treated at our tertiary referral centre between January 2005 and December 2016 were included. PVTT was diagnosed by contrast-enhanced computed tomography or magnetic resonance imaging. The extent of PVTT was documented according to the Liver Cancer Study Group of Japan classification: Vp0 = no PVTT, Vp1 = segmental portal vei…

Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95-and TRAIL receptor-mediated apoptosis and chemotherapy

Hepatocellular carcinoma (HCC) is highly resistant to chemotherapy, leading to a poor prognosis of advanced disease. Inhibitors of histone deacetylase (HDACi) induce re-differentiation in tumor cells and thereby re-establish sensitivity towards apoptotic stimuli. HDACi are entering the clinical stage of tumor treatment, and several substances are currently being tested in clinical trials to prove their efficacy in the treatment of leukemias and solid tumors. In this study, we investigated the impact of the HDACi valproic acid (VA) on TRAIL- and CD95-mediated apoptosis in hepatoma cells, as well as its sensitizing effect on a chemotherapeutic agent. Treatment of HepG2 cells with VA increased…

The impact of portal vein tumor thrombosis on survival in patients with hepatocellular carcinoma treated with different therapies: A cohort study.

Background Portal vein tumor thrombosis (PVTT) is a frequent complication of hepatocellular carcinoma (HCC), which leads to classification as advanced stage disease (regardless of the degree of PVTT) according to the Barcelona Clinic Liver Cancer Classification. For such patients, systemic therapy is the standard of care. However, in clinical reality, many patients with PVTT undergo different treatments, such as resection, transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), or best supportive care (BSC). Here we examined whether patients benefited from such alternative therapies, according to the extent of PVTT. Methods This analysis included therapy-naïve …

Patterns of liver injury in COVID-19 - a German case series.

BACKGROUND: Reports of liver injury in patients with novel coronavirus disease 2019 (COVID-19) are emerging from China and the USA. A wide variety of liver function test abnormalities and few cases of severe liver failure have been reported. No data on the hepatic phenotype from Europe are available at current. METHODS: We report a case series of 44 consecutive patients hospitalized for COVID-19 in Germany. RESULTS: At the time of admission, aspartate aminotransferase greater than the upper limit of normal was present in 70%, while alanine aminotransferase was elevated in 15.8%. Markers of cholestatic liver injury were altered only in a minority of patients. During hospitalization, 31% and …

Sunitinib in patients with advanced hepatocellular carcinoma after progression under sorafenib treatment.

<i>Objective:</i> To evaluate the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) after progression under sorafenib treatment. <i>Methods:</i> Sunitinib was administered at 37.5 mg daily (4-weeks-on/2-weeks-off schedule) after progression under sorafenib treatment. Adverse events (AEs) were assessed using NCI-CTCAE v3.0, and tumor response was evaluated according to RECIST. Data were analyzed retrospectively. <i>Results:</i> Eleven patients with metastatic disease were treated. Seven patients (64%) presented with no liver cirrhosis, including 3 patients with a history of liver transplantation. The first radiologic…

Neurale Netzwerke zur Vorhersage des Überlebens nach TACE bei Patienten mit HCC

Predicting survival after transarterial chemoembolization for hepatocellular carcinoma using a neural network: A Pilot Study.

BACKGROUND AND AIMS Deciding when to repeat and when to stop transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) can be difficult even for experienced investigators. Our aim was to develop a survival prediction model for such patients undergoing TACE using novel machine learning algorithms and to compare it to conventional prediction scores, ART, ABCR and SNACOR. METHODS For this retrospective analysis, 282 patients who underwent TACE for HCC at our tertiary referral centre between January 2005 and December 2017 were included in the final analysis. We built an artificial neural network (ANN) including all parameters used by the aforementioned risk scores a…

Maligne Leberveneninfiltration bei Patienten mit Hepatozellulärem Karzinom

Improved prediction of survival by a risk factor-integrated inflammatory score in Sorafenib treated hepatocellular carcinoma

Background and aims Inflammation affects progression of hepatocellular carcinoma (HCC). We therefore postulate that systemic inflammatory markers could help to predict prognosis in HCC patients receiving sorafenib therapy. Methods Overall survival (OS) of HCC patients receiving palliative sorafenib treatment was correlated with the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS) and the modified GPS (mGPS) along with clinicopathological parameters. Predictors of OS were assessed by multivariable Cox regression and receiver operating characteristics and area under the curve (ROC-AUC) analyses.…

In silico characterization of an Iroquois family-related homeodomain protein.

Homeobox genes have been demonstrated to play important roles during cancer differentiation and embryonic development. The subset of Iroquois-related homeobox genes (IRXs) have furthermore been. demonstrated to be involved in several embryonic developmental processes such as patterning of the anterior-posterior and dorso-ventral axis, as well as specific regions of the central nervous system, and differentiation of the otic vesicle, branchial epithelium, and limbs. We have characterized a novel homeodomain protein and corresponding gene by means of computational biology. Since the protein sequence displayed high similarity to the human IRX proteins, the newly identified homeodomain protein …

Current Strategies to Identify Patients That Will Benefit from TACE Treatment and Future Directions a Practical Step-by-Step Guide

Abstract Treatment of hepatocellular carcinoma (HCC) depends on the stage of disease. In the Western Hemisphere, the Barcelona Clinic Liver Cancer classification (BCLC) is the preferred staging system. Approximately one-third of patients initially present with intermediate-stage disease. For these patients, transarterial chemoembolization (TACE) is the treatment of choice. However, the intermediate-stage comprises a heterogeneous subgroup of patients with considerable differences in tumor burden and liver function. In addition, differences in individual factors that are not captured by the BCLC framework, such as the tumor growth pattern, degree of hypervascularity, and vascular supply, com…

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need.Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patie…

Genome-wide analysis of factors regulating gene expression in liver

In recent decades, multiple individual genes have been studied with respect to their level of expression in liver tissue and in many cases substantial progress has been made in identifying individual factors promoting gene expression in liver. However, the overall picture is still undefined and general rules or factors regulating gene expression in liver have not yet been established. Thus, a genome-wide screen for factors regulating gene expression in liver is of high interest, as it may reveal common regulatory mechanisms for most genes highly expressed in liver. These factors represent potential new targets in liver disease associated with differential gene expression. Using a novel bioi…

Validierung der Vorhersagemodelle STATE und START in der TACE-Therapie bei Patienten mit hepatozellulärem Karzinom

Predictive Scores in Primary Biliary Cirrhosis

GOALS The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND PBC is a chronic autoimmune liver disease with a female gender predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic…

CXCR4 and hif-1α as prognostic molecular markers for stage 3 colon cancer patients: post hoc analysis of the randomized, multicenter phase 3 PETACC-2 trial dataset

Adjuvant colon cancer (CC) therapy and survival have greatly evolved over the last decades. Research shifted towards a more biological tumour understanding and unlocked new therapies and disease mo...

Role of Immunotherapy in the Management of Hepatocellular Carcinoma: Current Standards and Future Directions

The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (HCC) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. In phase II studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval …

Survival Prediction in Intrahepatic Cholangiocarcinoma: A Proof of Concept Study Using Artificial Intelligence for Risk Assessment

Several scoring systems have been devised to objectively predict survival for patients with intrahepatic cholangiocellular carcinoma (ICC) and support treatment stratification, but they have failed external validation. The aim of the present study was to improve prognostication using an artificial intelligence-based approach. We retrospectively identified 417 patients with ICC who were referred to our tertiary care center between 1997 and 2018. Of these, 293 met the inclusion criteria. Established risk factors served as input nodes for an artificial neural network (ANN). We compared the performance of the trained model to the most widely used conventional scoring system, the Fudan score. Pr…

Fernmetastasen bei Patienten mit intrahepatischem Cholangiokarzinom: Einfluss der Metastasen-Lokalisation

Überlebensvorhersage für Patienten mit nicht-resezierbarem intrahepatischen Cholangiokarzinom unter Chemotherapie: Vergleich von Tumormarkern und Bildgebung

Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus

Background: The aim was to evaluate the diagnostic potential of serum neurofilament light chain (sNfL) measurements in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Methods: sNfL levels were determined by single molecule array assay in a retrospective cross-sectional cohort of 144 patients with systemic lupus erythematosus (SLE). After log-transformation of sNfL levels, mean sNfL levels were compared between NPSLE patients and SLE patients without neuropsychiatric disease using Student’s t test. Furthermore, the association of different neuropsychiatric manifestations with sNfL levels was assessed using a one-way analysis of variance (ANOVA) with post hoc analysis. As…

Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men.

B-cell activating factor of the tumour necrosis factor family (BAFF) is a cytokine, mainly produced by hematopoietic cells (e.g. monocytes/macrophages, dendritic cells), indispensable for B-cell maturation. The BLISS studies have demonstrated that blocking BAFF by the human monoclonal antibody belimumab is a valuable therapeutic approach in patients with clinically and serologically active systemic lupus erythematosus (SLE). However, the defined sources of BAFF, which contributes to SLE, are still unclear. Recent findings show that BAFF expression is not restricted to myeloid cells. Since lupus nephritis is the main cause of morbidity and mortality for SLE patients, the aim of this study wa…

Refining Prognosis in Chemoembolization for Hepatocellular Carcinoma: Immunonutrition and Liver Function

A combination of albumin-bilirubin (ALBI) grading and the Prognostic Nutritional Index (PNI) was identified recently as a highly predictive tool for patients with hepatocellular carcinoma (HCC) undergoing tumor ablation. The present study evaluated this combination in patients undergoing transarterial chemoembolization (TACE). Between 2010 and 2020, 280 treatment-naïve patients were retrospectively identified. The influence of ALBI grade, PNI and the novel ALBI-PNI on the median overall survival (OS) was assessed. In the next step, the prognostic ability of the combined approach was compared to established scoring systems. Both ALBI grade 2−3 and a low PNI were highly predictive for median …

HILPDA is upregulated, predicts prognosis and promotes cancer progression in hepatocellular carcinoma

P-066 S-1 in combination with epirubicin and oxaliplatin (EOS) in Caucasian patients (pts) with advanced or metastatic gastric cancer (AGC): Results of a phase I study

Current bioinformatics tools in genomic biomedical research (Review).

On the advent of a completely assembled human genome, modern biology and molecular medicine stepped into an era of increasingly rich sequence database information and high-throughput genomic analysis. However, as sequence entries in the major genomic databases currently rise exponentially, the gap between available, deposited sequence data and analysis by means of conventional molecular biology is rapidly widening, making new approaches of high-throughput genomic analysis necessary. At present, the only effective way to keep abreast of the dramatic increase in sequence and related information is to apply biocomputational approaches. Thus, over recent years, the field of bioinformatics has r…

BlotBase: a northern blot database.

With the availability of high-throughput gene expression analysis, multiple public expression databases emerged, mostly based on microarray expression data. Although these databases are of significant biomedical value, they do hold significant drawbacks, especially concerning the reliability of single gene expression profiles obtained by microarray data. Simultaneously, reliable data on an individual gene's expression are often published as single northern blots in individual publications. These data were not yet available for high-throughput screening. To reduce the gap between high-throughput expression data and individual highly reliable expression data, we designed a novel database "Blo…

Impact of Individual Components of the Metabolic Syndrome on the Outcome of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib

<b><i>Background/Aim:</i></b> Individual components of the metabolic syndrome (MS) such as obesity or diabetes mellitus impair the prognosis of patients with hepatocellular carcinoma (HCC) following curative treatment approaches or transarterial therapies. The aim of this retrospective study was to assess the impact of these factors on the overall survival (OS) of patients with advanced HCC treated with sorafenib. <b><i>Methods:</i></b> Univariate and multivariate analyses were performed to assess the impact of individual components of the MS on the OS of 152 consecutive patients with advanced HCC treated with sorafenib. <b><i>Resu…

Metabolic syndrome and its association with fatty liver disease after orthotopic liver transplantation

The metabolic syndrome (MetS) might contribute to morbidity after orthotopic liver transplantation (OLT). For this reason, we searched for MetS-associated risk factors and analyzed the link with nonalcoholic fatty liver disease (NAFLD) in OLT recipients. De novo MetS affected 32.9% of our cohort (n = 170) within 2 years after OLT. Multivariate analysis identified glycosylated hemoglobin (HbA1c) levels ≥5% [odds ratio (OR) = 3.5; 95% confidence interval (CI) = 1.56-8.13, P = 0.003], diabetes mellitus (OR = 4.31, CI = 1.69-10.99, P = 0.002), and arterial hypertension (OR = 4.59, CI = 1.46-14.49, P = 0.009) as independent risk factors for de novo MetS. MetS incidence correlated with steroid do…

Relevanz einer extrahepatischen Metastasierung bei Patienten mit hepatozellulärem Karzinom

High pretreatment static and dynamic alpha‐fetoprotein values predict reduced overall survival in hepatocellular carcinoma

Abstract Background Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha‐fetoprotein (AFP) is a well‐established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. Objective We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. Methods Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenber…

Characterization of OEBT, a LIM protein

LIM Proteins have been demonstrated to play key roles in pattern formation during embryonic development, cell lineage determination, and cancer differentiation. These proteins are characterized by their conserved LIM domain, which functions as a specific protein-binding site. Recently, two new members of the LIM protein family, PRICKLE1 and PRICKLE2, were characterized in silico and demonstrated to be human orthologues of the Drosophila Prickle proteins. We report on an additional member of this protein family, over-expressed breast tumor protein (OEBT). The corresponding gene was mapped to human chromosome 6p22.31. Orthologues in mouse and rat with 72 and 54% identities on a protein level …

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 pati…

Safety and Efficacy of Sorafenib in Patients With Advanced Hepatocellular Carcinoma in Consideration of Concomitant Stage of Liver Cirrhosis

GOALS AND BACKGROUND: The multikinase inhibitor sorafenib provides survival benefit for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LCI) Child-Pugh A. We report our experiences with sorafenib in advanced HCC, particularly in patients with LCI Child-Pugh B/C, where only limited data are available in regard to safety and efficacy of sorafenib. METHODS: Thirty-four patients with advanced HCC were treated with sorafenib regardless of liver function and prior anticancer therapy. Adverse events (AEs) were graded using Common Toxicity Criteria version 3.0, tumor response was assessed according to Response Evaluation Criteria in Solid Tumors. RESULTS: Fifteen patients…

Survival of patients with unresectable cholangiocarcinoma undergoing palliative chemotherapy - real world data from a German tertiary care center

Regorafenib Efficacy After Sorafenib in Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation:A Retrospective Study

Background and aim Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared to best supportive care (BSC) in LT-patients after sorafenib discontinuation. Methods This observational multicenter retrospective study included LT-patients with HCC-recurrence who discontinued first-line sorafenib. Group-1 was constituted by regorafenib-treated patients, while control group was selected among patients treated with best supportive care (BSC) due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant prog…

The GALAD Score as Potential Screening Test for Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis: An International Multicenter Study

The prevalence of nonalcoholic steatohepatitis (NASH) is rising rapidly and is currently the most common chronic liver disease in Western populations. Hepatocellular carcinoma (HCC) is a major complication of NASH and the current performance of screening approaches based on ultrasound shows limitations. To facilitate earlier diagnosis, this international multicenter study, with eight German and one Japanese center participating, tests the potential benefit of applying the biomarkers AFP, AFP-L3, DCP and related scores for HCC screening in NASH patients. In the retrospective German cohort, 126 NASH patients with newly diagnosed HCC and 231 NASH control patients without HCC were enrolled. In …

Genetic association of autoimmune hepatitis and human leucocyte antigen in German patients

To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1.Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies.Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compare…

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

Background & Aims 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. Methods Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Results Median overall survival (OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) a…

Validation of clinical scoring systems ART and ABCR after transarterial chemoembolization of hepatocellular carcinoma.

Abstract Purpose To perform an external validation of the Assessment for Retreatment with Transarterial Chemoembolization (ART) and α-fetoprotein (AFP), Barcelona Clinic Liver Cancer (BCLC), Child–Pugh, and response (ABCR) scores and to compare them in terms of prognostic power. Materials and Methods From 2000 to 2015, 871 patients with hepatocellular carcinoma underwent transarterial chemoembolization at a tertiary referral hospital, and 176 met all inclusion and exclusion criteria for both scores and were analyzed. Nineteen percent (n = 34) had BCLC stage A disease and 81% had stage B disease. Thirty-nine patients (22%) presented with elevated AFP levels. Overall survival was calculated. …

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction

Abstract Background Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. Methods RNA interference was per…

Survival analysis of proposed BCLC-B subgroups in hepatocellular carcinoma patients

Background & Aims The BCLC-staging system is used to facilitate treatment decisions in patients with hepatocellular carcinoma (HCC). Owing to the observed clinical heterogeneity of the intermediate stage BCLC-B, a subclassification was proposed taking Child–Pugh score and extended criteria for transplantation into account. Analysis of the prognostic significance of a proposed subclassification of the BCLC-B score in a European cohort of HCC patients. Methods Eight hundred and eighty four consecutive HCC patients were retrospectively analysed. Patients with stage BCLC-B were grouped according to the proposed subclassification. Baseline patient and tumour characteristics, therapy and overall …

sj-docx-1-tan-10.1177_17562864211051497 – Supplemental material for Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus

Supplemental material, sj-docx-1-tan-10.1177_17562864211051497 for Association of serum neurofilament light chain levels and neuropsychiatric manifestations in systemic lupus erythematosus by Sinah Engel, Simone Boedecker, Paul Marczynski, Stefan Bittner, Falk Steffen, Arndt Weinmann, Andreas Schwarting, Frauke Zipp, Julia Weinmann-Menke and Felix Luessi in Therapeutic Advances in Neurological Disorders

LASS6, an additional member of the longevity assurance gene family

Longevity assurance genes (LAGs) represent a subgroup of the homeobox gene family. Five mammalian homologs have been reported, and the corresponding proteins have previously been investigated with respect to their key role in ceramide synthesis. However, members of the LAG family have been shown to be involved in cell growth regulation and cancer differentiation. In an effort to characterize additional members of the LAG family, we have screened the latest releases of genomic databases and report on the bioinformatic characterization of yet another member, LAG1 longevity assurance homolog 6 (LASS6). Like other LAG family members, the LASS6 protein contained a homeodomain and LAG1 domain. In…

Supplemental material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre

Supplemental Material for Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre by Friedrich Foerster, Maria Hoppe-Lotichius, Johanna Vollmar, Jens U Marquardt, Arndt Weinmann, Marcus-Alexander Wörns, Gerd Otto, Tim Zimmermann and Peter R Galle in United European Gastroenterology Journal

Genetics of hepatocellular carcinoma.

The completely assembled human genome has made it possible for modern medicine to step into an era rich in genetic information and high-throughput genomic analysis. These novel and readily available genetic resources and analytical tools may be the key to unravel the molecular basis of hepatocellular carcinoma (HCC). Moreover, since an efficient treatment for this disease is lacking, further understanding of the genetic background of HCC will be crucial in order to develop new therapies aimed at selected targets. We report on the current status and recent developments in HCC genetics. Special emphasis is given to the genetics and regulation of major signalling pathways involved in HCC such …

Risikostratifizierung bei fortgeschrittenen Gallengangskarzinomen: Validierung des A.L.A.N. Scores

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Background To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with ad…

Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma

Abstract Background Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. Methods A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level,…

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1–5 and 8–12 of a 28-day cycle, REG on days 2–22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose …

Fernmetastasen bei Patienten mit intrahepatischem Cholangiokarzinom: Wie wichtig ist die Lokalisation?

The relationship between BAFF serum levels, anti-NMDAR autoantibodies and fatigue in patients with systemic lupus erythematosus and multiple sclerosis.

Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categori…

Clinical Frailty Scale for Risk Stratification in Patients with Sars-Cov-2 Infection

Predictive factors for adverse outcomes in patients with COVID-19 are urgently needed. Data related to the applicability of the Clinical Frailty Scale (CFS) for risk stratification in patients with COVID-19 are currently lacking. We investigated the ability of CFS to predict need for mechanical ventilation and the duration of hospital stays in European patients with COVID-19. In total, 42 patients with confirmed COVID-19 infection admitted to the University Medical Center Mainz between March 3 and April 15 2020 were included into this validation study and data were retrospectively analyzed. CFS was assessed at admission in all patients. Patients were followed for need for mechanical ventil…

Die Leberfunktion vor Lebertransplantation bestimmt das Überleben nach Lebertransplantation beim hepatozellulären Karzinom

Sarcopenia as prognostic factor for survival after orthotopic liver transplantation

Background and aim Body composition has emerged as a prognostic factor for end-stage liver disease. We therefore investigated muscle mass, body fat and other clinical-pathological variables as predictors of posttransplant survival. Methods A total of 368 patients, who underwent orthotopic liver transplantation (OLT) at our institution, were assessed prior to OLT and followed for a median of 9.0 years (range 2.0-10.0 years) after OLT. Psoas, erector spinae and the combined paraspinal muscle area, as well as the corresponding indices normalized by body-height squared, were quantified by a lumbar (L3) cross-sectional computed tomography. In addition, absolute body fat and bone density were est…

Lipid droplets and associated proteins in viral hepatitis

Colony-Stimulating Factor-1

A noninvasive means to predict the onset and recurrence of lupus nephritis (LN) before overt renal injury is needed to optimize and individualize treatment. Colony-stimulating factor-1 (CSF-1) is expressed by kidney tubules at the onset of LN, increases with disease progression, and spills into the circulation in lupus-prone mice. We tested the hypothesis that amplified expression of CSF-1 detected in the serum or urine correlates with intrarenal CSF-1 expression and histopathology (increased macrophage accumulation, activity indices) and clinical kidney disease activity and predicts the onset and recurrence of nephritis in patients with systemic lupus erythematosus (SLE). We found increase…

Non-bacterial thrombotic endocarditis in a patient with pancreatic carcinoma

Application of Patient-Derived Liver Cancer Cells in Personalized Treatment Approach: Phenotypic Characterization and Therapeutic Target Identification

Integrative genomic analyses identified 14-3-3 zeta as a potential molecular driver of sorafenib resistance in HCC patients

Stress protein/peptide complexes derived from autologous tumor tissue as tumor vaccines.

Vaccination of inbred mice with tumor-derived stress proteins hsp70, hsp90, and gp96/grp94 elicits a protective immunity to the tumor from which the vaccine was purified. There is now comprehensive experimental evidence that the antigenicity of tumor-derived hsp70, hsp90, and gp96 preparations results from diverse arrays of endogenous peptide antigens complexed with these stress proteins. Vaccination with tumor-derived stress protein/peptide complexes leads to their uptake and processing by professional antigen-presenting cells and to presentation of associated tumor peptide antigens to cytotoxic T cells. This induces a tumor-specific cytotoxic T cell response. The attractiveness of the con…

Targeting tumor-initiating cells and compensatory YAP pathway to overcome sorafenib resistance in hepatocellular carcinoma

CellMinerHCC: a microarray-based expression database for hepatocellular carcinoma cell lines.

Background & Aims Therapeutic options for hepatocellular carcinoma (HCC) still remain limited. Development of gene targeted therapies is a promising option. A better understanding of the underlying molecular biology is gained in in vitro experiments. However, even with targeted manipulation of gene expression varying treatment responses were observed in diverse HCC cell lines. Therefore, information on gene expression profiles of various HCC cell lines may be crucial to experimental designs. To generate a publicly available database containing microarray expression profiles of diverse HCC cell lines. Methods Microarray data were analyzed using an individually scripted R program package. Dat…

Application of patient-derived liver cancer cells for phenotypic characterization and therapeutic target identification.

Primary liver cancer (PLC) ranks among the most lethal solid cancers worldwide due to lack of effective biomarkers for early detection and limited treatment options in advanced stages. Development of primary culture models that closely recapitulate phenotypic and molecular diversities of PLC is urgently needed to improve the patient outcome. Long-term cultures of 7 primary liver cancer cell lines of hepatocellular and cholangiocellular origin were established using defined culture conditions. Morphological and histological characteristics of obtained cell lines and xenograft tumors were analyzed and compared to original tumors. Time course analyses of transcriptomic and genomic changes were…

Liver Resection for Intrahepatic Cholangiocarcinoma—Single-Center Experience with 286 Patients Undergoing Surgical Exploration over a Thirteen Year Period

Background: Intrahepatic cholangiocarcinoma (iCCA) accounts for about 10% of primary liver cancer. Surgery is the only potentially curative treatment. We report on our current series of 229 consecutive hepatic resections for iCCA, which is one of the largest Western single-center series published so far. Methods: Between January 2008 to December 2020, a total of 286 patients underwent 307 surgical explorations for intended liver resection of iCCA at our department. Data were analyzed with regard to (1) preoperative treatment of tumor, (2) operative details, (3) perioperative morbidity and mortality, (4) histopathology, (5) outcome measured by tumor recurrence, treatment of recurrence and su…

Midterm follow-up after DC-BEAD™-TACE of Hepatocellular Carcinoma (HCC)

Abstract Aim To determine local response, its predictors and survival and complication rates after DC-Bead™-TACE in patients with hepatocellular carcinoma (HCC). Materials and methods DC-Beads™ are non-resorbable, polyvinyl-alcoholic hydrophilic microspheres. They release high amounts of chemotherapeutics directly into the tumour. Delivery is sustained over time, tumour feeders are embolised. We used beads from 100–300 to 500–700 μm loaded with Doxorubicin (max. 150 mg/4 ml). Fifty patients (mean age: 68.5 ± 8.8 years) with HCC were analysed. DC-Bead™-TACE was performed once or repeated in two-month intervals. Imaging scans (CT or MRI) were done one-month following each procedure. To evalua…

No Evidence for Classic Thrombotic Microangiopathy in COVID-19

Background: Coronavirus disease-2019 (COVID-19) triggers systemic infection with involvement of the respiratory tract. There are some patients developing haemostatic abnormalities during their infection with a considerably increased risk of death. Materials and Methods: Patients (n = 85) with SARS-CoV-2 infection attending the University Medical Center, Mainz, from 3 March to 15 May 2020 were retrospectively included in this study. Data regarding demography, clinical features, treatment and laboratory parameters were analyzed. Twenty patients were excluded for assessment of disseminated intravascular coagulation (DIC) and thrombotic microangiopathy (TMA) due to lack of laboratory data. Resu…

The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib.

Abstract Background Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Aims/methods Univariate/multivariate analyses were conducted to identify retrospectively the impact of baseline characteristics on the survival of 110 patients with advanced HCC treated with sorafenib. Results Median survival of the whole cohort was 6.7 months, median survival in Child-Pugh A, B, C patients was 10.5, 6.1 and 3.0 months and median survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C/D was 6.8/2.6 months. Presence of ascites, presence of macrovascular invas…

PD-8 Regorafenib with TAS-102 in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY)

Liver vein infiltration in patients with hepatocellular carcinoma in a large German cohort

The role of sarcopenia in patients with intrahepatic cholangiocarcinoma: Prognostic marker or hyped parameter?

BACKGROUND & AIMS Sarcopenia has emerged as a prognostic parameter in numerous cancer entities. Current research favours its role as a determining factor for overall survival (OS) in patients with intrahepatic cholangiocarcinoma (ICC); however, it is unclear whether sarcopenia is a truly independent survival predictor if combined with established prognostic factors. METHODS Between 1997-2018, 417 patients with histopathologically confirmed ICC were referred to our centre, of whom 293 were included in this study. Cross-sectional imaging, laboratory examinations and histopathological reports were retrospectively analysed. Psoas muscle index (PMI) as easy-to-measure marker of sarcopenia was ca…

Hepatocellular carcinoma in patients with autoimmune hepatitis.

To evaluate and confirm the low incidence of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH). At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare.In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH.Eighty-nine patients (32%) were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed H…

Additional file 1: of Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program

Table S1. Main inclusion and exclusion criteria. Contains the main inclusion and exclusion criteria for patient selection in this study. (DOC 35 kb)

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis

Background & Aims The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. Methods We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD …

Trends in Epidemiology, Treatment, and Survival of Hepatocellular Carcinoma Patients Between 1998 and 2009

The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009.HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear.In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated.The number of patients presenting each year (64 vs…

CXCR4 and hif-1α as prognostic molecular markers for stage 3 colon cancer patients: post hoc analysis of the randomized, multicenter phase 3 PETACC-2 trial dataset

CXCR4 and hif-1α as prognostic molecular markers for stage 3 colon cancer patients: post hoc analysis of the randomized, multicenter phase 3 PETACC-2 trial dataset