Exploring the impact of durvalumab on biliary tract cancer: insights from real-world clinical data.

INTRODUCTION: This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes. METHODS: A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies. RESULTS: Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052). CONCLUSION: This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.

Solitary Fibrous Tumours of the Orbit - Clinical Pathology, Therapy and Prognosis. / Solitär fibröse Tumoren der Orbita ­ klinisch-pathologische Charakteristik, Therapie und Prognose.

BACKGROUND: Solitary fibrous tumours are rare. The aim of this study is to describe the clinical features, therapy and outcome of affected patients and to identify factors associated with recurrence. METHODS: Retrospective study of a cohort of 20 patients who underwent surgery for orbital solitary fibrous tumour at the University Department of Oral and Maxillofacial Surgery between 2002 and 2023. Demographic, clinical, and therapeutic data as well as tumour follow-up results were collected. Tumour volume and molecular genetic mutations were retrospectively determined. RESULTS: The median patient age was 49.5 years at initial surgery. The left orbit was affected in 65% of cases. The most common clinical symptom was proptosis (80%). This was reported with a mean lateral difference of 3.9 mm (range: 1 - 10 mm). The tumours were localised predominantly in the intra- and extraconal space, craniolateral quadrant and middle third. The median tumour volume was 7.66 cm³ (range 2.15 - 12.57 cm³). In all patients, the diagnosis was made by pathological examination. All tumours investigated showed a NAB2-STAT6 mutation. The most frequently detected mutation was the fusion NAB2 exon 4 - STAT6 exon 2. All patients were initially managed with frontolateral orbitotomy. Incomplete resection (R1-status) occurred in 35% (n = 7). The recurrence rate was 25% (n = 5), with a median disease-free interval of 45.5 months (range 23 - 130). 80% (n = 4) of recurrences were initially R1-resected. CONCLUSION: Orbital solitary fibrous tumours are rare tumours and are clinically manifested by signs of displacement of orbital structures. Diagnosis is made by histology and immunohistochemistry and can be proven with the molecular genetic detection of the NAB2-STAT6 mutation. The therapy of choice is complete surgical resection. R1-resection is more likely in the intraconal location as well as in location in the posterior third of the orbit - due to difficult surgical accessibility. The greatest risk factor for the development of recurrence is incomplete surgical excision. Late recurrences are possible, which is why a long-term connection to a specialised clinic is necessary.

Prognostic relevance of autophagy-related markers LC3, p62/sequestosome 1, Beclin-1 and ULK1 in colorectal cancer patients with respect to KRAS mutational status.

BACKGROUND: Autophagy is a cellular pathway that regulates transportation of cytoplasmic macromolecules and organelles to lysosomes for degradation. Autophagy is involved in both tumorigenesis and tumour suppression. Here we investigated the potential prognostic value of the autophagy-related proteins Beclin-1, p62, LC3 and uncoordinated (UNC) 51-like kinase 1 (ULK1) in a cohort of colorectal cancer (CRC) specimens. METHODS: In this study, we analysed the immunoexpression of the autophagy-related proteins p62, LC3, Beclin-1 and ULK1 in 127 CRC patients with known KRAS mutational status and detailed clinical follow-up. RESULTS: Survival analysis of p62 staining showed a significant correlation of cytoplasmic (not nuclear) p62 expression with a favourable tumour-specific overall survival (OS). The prognostic power of cytoplasmic p62 was found in the KRAS-mutated subgroup but was lost in the KRAS wildtype subgroup. Survival analysis of Beclin-1 staining did not show an association with OS in the complete cohort. LC3 overexpression demonstrated a slight, though not significant, association with decreased OS. Upon stratifying cases by KRAS mutational status, nuclear (not cytoplasmic) Beclin-1 staining was associated with a significantly decreased OS in the KRAS-mutated subgroup but not in the KRAS wildtype CRCs. In addition, LC3 overexpression was significantly associated with decreased OS in the KRAS-mutated CRC subgroup. ULK1 expression was not correlated to survival. CONCLUSIONS: Immunohistochemical analyses of LC3, p62 and Beclin-1 may constitute promising novel prognostic markers in CRC, especially in KRAS-mutated CRCs. This strategy might help in identifying high-risk patients who would benefit from autophagy-related anticancer drugs.

The Impact of Cancer-Associated Fibroblasts on the Biology and Progression of Colorectal Carcinomas.

(1) Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. Cancer-associated fibroblasts (CAFs) are major components of CRC's tumour microenvironment (TME), but their biological background and interplay with the TME remain poorly understood. This study investigates CAF biology and its impact on CRC progression. (2) The cohort comprises 155 cases, including CRC, with diverse localizations, adenomas, inflammations, and controls. Digital gene expression analysis examines genes associated with signalling pathways (MAPK, PI3K/Akt, TGF-ß, WNT, p53), while next-generation sequencing (NGS) determines CRC mutational profiles. Immunohistochemical FAP scoring assesses CAF density and activity. (3) FAP expression is found in 81 of 150 samples, prevalent in CRC (98.4%), adenomas (27.5%), and inflammatory disease (38.9%). Several key genes show significant associations with FAP-positive fibroblasts. Gene set enrichment analysis (GSEA) highlights PI3K and MAPK pathway enrichment alongside the activation of immune response pathways like natural killer (NK)-cell-mediated cytotoxicity via CAFs. (4) The findings suggest an interplay between CAFs and cancer cells, influencing growth, invasiveness, angiogenesis, and immunogenicity. Notably, TGF-ß, CDKs, and the Wnt pathway are affected. In conclusion, CAFs play a significant role in CRC and impact the TME throughout development.

PD-L1 expression associates with favorable survival of patients with cancer of unknown primary (CUP) not treated with checkpoint inhibitors.

PURPOSE: Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients. METHODS: Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines. RESULTS: Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0-18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0-37.0 versus 10 months, 95 %CI 3.1-16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4). CONCLUSION: PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care.

Comparison of the sixth and the seventh editions of the UICC classification for perihilar cholangiocarcinoma.

BACKGROUND: The seventh edition of the TNM classification separates extrahepatic bile duct tumors into perihilar and distal tumors and further changes the definition of the TNM classification. The impact of the seventh edition on stage-based prognostic prediction for patients with perihilar cholangiocarcinoma was evaluated. METHODS: Between January 1998 and March 2010, 223 consecutive patients with perihilar cholangiocarcinoma underwent surgery at the West German Cancer Center. Median survival times were calculated for the 195 evaluable patients (excluding those with in-hospital mortality) after separate classification by both sixth and seventh editions. RESULTS: Median overall survival was increased in patients classified using the seventh compared with the sixth edition (UICC I: 56.5 vs 23.75 months; II: 45.9 vs 31.6 months; III: 21.3 vs. 8.76 months; IV: 7.03 vs 5.93 months). The T category of the seventh edition did not alter median survival times of T1 (54.07 months) and T4 (7.83 months) cases, but median survival was prolonged for T2 patients (29.4 vs 31.6 months), and shortened for T3 patients (19.43 vs 11.8 months) staged using the seventh edition. According to Cox proportional hazards regression analysis, patient survival was better predicted by the seventh edition UICC stage and pT categories (p=0.0014 and p=0.0396, respectively), than the corresponding sixth edition categories (p=0.4376 and p=0.0926, respectively). CONCLUSIONS: The UICC seventh edition TNM classification for perihilar cholangiocarcinoma improves separation of patients with intermediate stage tumors compared with the sixth edition. The prognostic value of the UICC staging system has been strengthened by the introduction of the seventh edition.

Canonical Thyroid Hormone Receptor ß Action Stimulates Hepatocyte Proliferation in Male Mice.

CONTEXT: 3,5,3'-L-triiodothyronine (T3) is a potent inducer of hepatocyte proliferation via the Wnt/ß-catenin signaling pathway. Previous studies suggested the involvement of rapid noncanonical thyroid hormone receptor (TR) ß signaling, directly activating hepatic Wnt/ß-catenin signaling independent from TRß DNA binding. However, the mechanism by which T3 increases Wnt/ß-catenin signaling in hepatocytes has not yet been determined. OBJECTIVE: We aimed to determine whether DNA binding of TRß is required for stimulation of hepatocyte proliferation by T3. METHODS: Wild-type (WT) mice, TRß knockout mice (TRß KO), and TRß mutant mice with either specifically abrogated DNA binding (TRß GS) or abrogated direct phosphatidylinositol 3 kinase activation (TRß 147F) were treated with T3 for 6 hours or 7 days. Hepatocyte proliferation was assessed by Kiel-67 (Ki67) staining and apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Activation of ß-catenin signaling was measured in primary murine hepatocytes. Gene expression was analyzed by microarray, gene set enrichment analysis (GSEA), and quantitative reverse transcription polymerase chain reaction. RESULTS: T3 induced hepatocyte proliferation with an increased number of Ki67-positive cells in WT and TRß 147F mice (9.2% ±â€…6.5% and 10.1% ±â€…2.9%, respectively) compared to TRß KO and TRß GS mice (1.2% ±â€…1.1% and 1.5% ±â€…0.9%, respectively). Microarray analysis and GSEA showed that genes of the Wnt/ß-catenin pathway-among them, Fzd8 (frizzled receptor 8) and Ctnnb1 (ß-catenin)-were positively enriched only in T3-treated WT and TRß 147F mice while B-cell translocation gene anti-proliferation factor 2 was repressed. Consequently, expression of Ccnd1 (CyclinD1) was induced. CONCLUSIONS: Instead of directly activating Wnt signaling, T3 and TRß induce key genes of the Wnt/ß-catenin pathway, ultimately stimulating hepatocyte proliferation via CyclinD1. Thus, canonical transcriptional TRß action is necessary for T3-mediated stimulation of hepatocyte proliferation.

Cumulative mean fluorescent intensities of HLA specific antibodies predict antibody mediated rejections after kidney transplantation.

It is still not fully elucidated which pretransplant donor-specific HLA antibodies (DSA) are harmful after kidney transplantation. In particular, it needs to be clarified whether cumulative mean fluorescence intensities (MFI) against multiple HLA specificities have a predictive value for allograft function. Our retrospective single centre study analyzed preformed HLA antibodies determined by Luminex™ Single Antigen Bead (SAB) assay, including C1q addition, in relation to rejection and clinical outcome in 255 cross match negative kidney allograft recipients. Only 33 recipients (13%) of the total cohort showed early AMR during the first year posttransplant, but in patients with pre-transplant DSA the rate was increased to 15 out of 40 (38%). Three year graft survival was significantly shorter in patients with histological signs of AMR compared with patients without AMR or with no biopsy (74%, 92%, and 97%, respectively, p < 0.0001). In patients with HLA-DSA, a cumulative MFI value of all HLA antibodies of more than 103.000 indicated the highest risk for AMR posttransplant (p = 0.01). In conclusion, in patients with HLA-DSA, the cumulative MFI value may help to further stratify the risk of AMR after kidney transplantation.

Hemodynamic support by left ventricular assist devices reduces cardiomyocyte DNA content in the failing human heart.

BACKGROUND: Whether adult cardiomyocytes have the capacity to regenerate in response to injury and, if so, to what extent are still issues of intense debate. In human heart failure, cardiomyocytes harbor a polyploid genome. A unique opportunity to study the mechanism of polyploidization is provided through the setting of hemodynamic support by left ventricular assist devices. Hence, the cardiomyocyte DNA content, nuclear morphology, and number of nuclei per cell were assessed before and after left ventricular assist device support. METHODS AND RESULTS: In 23 paired myocardial samples, cardiomyocyte ploidy was investigated by DNA image cytometry, flow cytometry, and in situ hybridization. Nuclear cross-sectional area and perimeters were measured morphometrically, and the binucleated cardiomyocytes were counted. The median of the cardiomyocyte DNA content and the number of polyploid cardiomyocytes both declined significantly from 6.79 c to 4.7 c and 40.2% to 23%, whereas a significant increase in diploid cardiomyocytes from 33.4% to 50.3% and in binucleated cardiomyocytes from 4.5% to 10% after unloading was observed. CONCLUSIONS: The decrease in polyploidy and increase in diploidy after left ventricular assist device suggest a numeric increase in diploid cardiomyocytes (eg, through cell cycle progression with completion of mitosis or by increased stem cells). The cardiac regeneration that follows may serve as a morphological correlate of the recovery observed in some patients after unloading.

[Percutaneous liver biopsy before organ removal-Impact on organ allocation and costs in liver transplantation]. / Perkutane Leberbiopsie vor Organentnahme ­ Einfluss auf Organallokation und Kosten in der Lebertransplantation.

BACKGROUND: The value and safety of percutaneous liver biopsy (PLB) in brain-dead donors before organ removal and its impact on organ allocation and costs of liver transplantation (LT) in the Eurotransplant (ET) region is still a matter of ongoing debate. MATERIAL AND METHODS: A PLB was performed in 36 brain-dead organ donors. The complication rate, ultrasonography findings, macroscopic evaluation and histological results of PLB and donor characteristics were analyzed. Additionally, a nationwide survey was conducted among 11 liver transplantation experts. The need for PLB and its impact on the liver allocation process were evaluated. Possible cost savings were calculated for different scenarios based on cost data provided by the German Organ Transplantation Foundation. RESULTS: No complications of PLB were observed. The survey revealed that the PLB has a substantial impact on the allocation of donor organs, especially in organs fulfilling extended donor criteria (EDC). The cost calculation revealed an enormous potential for cost savings due to an optimized organ allocation process and avoidance of futile organ procurement. CONCLUSION: The PLB is a safe procedure and has tremendous potential for the optimization of the organ allocation process before organ procurement by reducing the cold ischemia time, avoiding unnecessarily discarding donor organs and saving costs. These data emphasize the clinical relevance and impact of PLB on the organ allocation process.

Computed tomography-guided biopsy of radiologically unclear lesions in advanced skin cancer: A retrospective analysis of 47 cases.

BACKGROUND: Radiological imaging such as computed tomography (CT) is used frequently for disease staging and therapy monitoring in advanced skin cancer patients. Detected lesions of unclear dignity are a common challenge for treating physicians. The aim of this study was to assess the frequency and outcome of CT-guided biopsy (CTGB) of radiologically unclear, suspicious lesions and to depict its usefulness in different clinical settings. METHODS: This retrospective monocentric study included advanced skin cancer patients (melanoma, Merkel cell carcinoma, squamous cell carcinoma, angiosarcoma, cutaneous lymphoma) with radiologically unclear lesions who underwent CTGB between 2010 and 2018. RESULTS: Of 59 skin cancer patients who received CTGB, 47 received CTGB to clarify radiologically suspicious lesions of unclear dignity. 32 patients had no systemic therapy (cohort A), while 15 patients received systemic treatment at CTGB (cohort B). In both cohorts, CTGB revealed skin cancer metastasis in a large proportion of patients (37.5%, 40.0%, respectively), but benign tissue showing inflammation, fibrosis or infection in an equally large percentage (37.5%, 46.7%, respectively). Additionally, a significant number of other cancer entities was found (25.0%, 13.3%, respectively). In patients receiving BRAF/MEK inhibitors, CTGB confirmed suspicious lesions as skin cancer metastasis in 83.3%, leading to treatment change. In immune checkpoint inhibitor-treated patients, skin cancer metastasis was confirmed in 11.1% of patients only, whereas benign tissue changes (inflammation/fibrosis) were found in 77.8%. CONCLUSIONS: Our results highlight the relevance of clarifying radiologically unclear lesions by CTGB before start or change of an anti-tumour therapy to exclude benign alterations and secondary malignancies.

Protocol liver biopsies in stable long-term pediatric liver transplant recipients: risk or benefit?

BACKGROUND: Follow-up after pediatric liver transplantation (LTX) is challenging and needs to be refined to extend graft survival as well as general functional health and patients´ quality of life. Strategies towards individual immunosuppressive therapy seem to play a key role. Our aim was to evaluate protocol liver biopsies (PLB) as a tool in personalized follow up after pediatric LTX. PATIENTS AND METHODS: Our retrospective analysis evaluates 92 PLB in clinically asymptomatic pediatric patients after LTX between 2009 and 2019. Histological findings were characterized using the Desmet scoring system. In addition to PLB, other follow-up tools like laboratory parameters, ultrasound imaging and transient elastography were evaluated. Risk factors for development of fibrosis or inflammation were analyzed. RESULTS: PLB revealed a high prevalence of graft fibrosis (67.4%) and graft inflammation (47.8%). Graft inflammation was significantly (P = 0.0353*) more frequent within the first 5 years after transplantation compared to later time points. Besides conventional ultrasound, the measurement of liver stiffness using transient elastography correlate with stage of fibrosis (r = 0.567, P = <0.0001***). Presence of donor-specific anti-human leukocyte antigen antibodies in blood correlates with grade of inflammation in PLB (r = 0.6040, P = 0.0018 **). None of the patients who underwent PLB suffered from intervention-related complications. Histopathological results had an impact on clinical decision making in one-third of all patients after PLB. CONCLUSION: PLB are a safe and useful tool to detect silent immune-mediated allograft injuries in the context of normal liver parameters.

Impermeability to blood of the E-vita open plus hybrid stent-graft: experimental and clinical evaluation.

PURPOSE: To evaluate the impermeability to blood of the modified E-vita open plus hybrid stent-graft in animal experiments and initial clinical applications in the replacement of the ascending aorta and aortic arch combined with antegrade stent-grafting of the descending aorta. METHODS: In 3 acute pig experiments, a tightly woven hybrid stent-graft (18 x 50-mm) was implanted in the descending aorta. Blood loss was measured after clamp release in fully heparinized animals by wrapping the aortic segment in a polyethylene bag. For histological examination, 12-mm-diameter stent-grafts were interposed in the abdominal aorta of 6 minipigs. The animals were sacrificed and studied after 3, 6, and 9 weeks. Between October 2008 and October 2009, 9 patients were treated for 6 type I dissections and 3 thoracic aortic aneurysms using the new prosthesis. Blood loss and blood replacement were evaluated. RESULTS: Mean blood loss under heparinization was 35+/-4 mL/min in the animal model. Histological examination of the explanted grafts demonstrated buildup of neointima. In the clinical cases, the mean blood loss within the first 24 hours was 489 mL; no re-exploration for bleeding was required. During a 6-month follow-up, no thrombus formation was seen within the vascular graft and no embolic event occurred. CONCLUSION: The new low-porosity hybrid prosthesis proved to be absolutely tight in animal experiments; histological examination demonstrated endothelial cell ingrowth with a trend to hyperplasia in this small-diameter graft. These results were confirmed in the clinical cases by the extremely minimal blood loss and an uneventful course.

Surgical treatment of Klatskin tumor: liver resection versus transplantation.

BACKGROUND: Our objective was to evaluate liver transplantation as a treatment option for Klatskin tumor. Results for transplanted patients suffering from hilar cholangiocarcinoma were therefore compared to patients after hemihepatectomy. METHODOLOGY: In a retrospective case-control study, seven patients transplanted for hilar cholangiocarcinoma were matched in terms of UICC stage with seven patients who underwent resection of the hilar bifurcation combined with a hemihepatectomy. RESULTS: Median survival was 22 months (range 1-55 months) for patients after liver resection and 64 months (range 1-138 months) for patients after liver transplantation. One and three year overall survival was 71% and 43% after liver resection versus 71% and 57% after liver transplantation. One patient from each group died within one month after surgery. Fatal cerebral bleeding and post-resection liver failure leading to multi-organ failure and sepsis were the causes of early mortality. Three patients are currently alive: one with 64 months after transplantation and two patients with 42 and 55 months after liver resection. CONCLUSIONS: Based on our findings and recently published promising results using liver transplantation for Klatskin tumor, it seems worthwhile to reconsider its potential use in the light of multimodal tumor treatment.

Characterization of two types of intranuclear hepatocellular inclusions in NAFLD.

Nuclear inclusions (NI) are a common finding in hepatocytes from patients with liver disease especially in diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) but studies examining the shape and content of these inclusions in detail are lacking. In this study we define two distinct types of NI in NAFLD: inclusions bounded by the nuclear membrane, containing degenerative cell organelles and heterolysosomes (type1) and inclusions with deposits of glycogen but without any kind of organelles and delimiting membrane (type2). NI in 77 paraffin-embedded patients of NAFLD including NAFL and non-alcoholic steatohepatitis (NASH) were analyzed. In 4-12% of type1 NI immunopositivity for the autophagy-associated proteins LC3B, ubiquitin, p62/sequestosome1, cathepsin D and cathepsin B were detected with co-localizations of ubiquitin and p62; type2 NI showed no immunoreactivity. Three-dimensional reconstructions of isolated nuclei revealed that NI type1 are completely enclosed within the nucleus, suggesting that NI, although probably derived from cytoplasmic invaginations, are not just simple invaginations. Our study demonstrates two morphologically different types of inclusions in NAFLD, whereby both gained significantly in number in advanced stages. We suggest that the presence of autophagy-associated proteins and degenerated organelles within type1 NI plays a role in disease progression.

Combined analysis of hypoxia-inducible factor 1 alpha and metallothionein indicates an aggressive subtype of colorectal carcinoma.

PURPOSE: Hypoxia-inducible factor 1 (HIF-1) is a hypoxia-induced transcription factor that regulates gene expression in critical pathways involved in tumour growth and metastasis. Metallothionein (MT) is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. The present study aimed to analyse the prognostic impact of HIF-1alpha and MT expression in colorectal cancer and to evaluate a possible link of combined HIF-1alpha and MT expression with colorectal cancer progression. MATERIALS AND METHODS: We investigated the relationship of HIF-1alpha and MT with each other and clinicopathological parameters including proliferative activity (Ki67) and apoptosis (terminal desoxyribonucleotide transferase-mediated dUTP nick-end labelling) using immunohistochemistry. RESULTS: HIF-1alpha expression was identified as an independent prognostic parameter in multivariate survival analysis and characterised an aggressive cancer phenotype. In addition, HIF-1alpha was significantly linked to an increased expression of MT. CONCLUSIONS: HIF-1alpha expression qualified as an independent prognostic and characterised an aggressive cancer phenotype associated with an increased expression of MT. Our study suggests that MT can be added to the complex biological pathways induced by hypoxia in human cancer tissue.

Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients.

AIM: To investigate potential triggering factors leading to acute liver failure (ALF) as the initial presentation of autoimmune hepatitis (AIH). METHODS: A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients (9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver (AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data (liver enzymes, MELD-score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients. RESULTS: The majority of patients with ALF were female (84.6%) and mean age was 43.6 ± 14.9 years. Interestingly, none of the patients with ALF was positive for anti-liver kidney microsomal antibody (LKM). We could identify potential triggering factors in 26/52 (50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF (57.7%), virus-induced ALF (30.8%), and preceding surgery in general anesthesia (11.5%), respectively. Unfortunately, 6 out of 52 patients (11.5%) did not survive ALF and 3 patients (5.7%) underwent liver transplantation (LT). Comparing data of survivors and patients with non-recovery following treatment, MELD-score (P < 0.001), age (P < 0.05), creatinine (P < 0.01), and finally, ALT-values (P < 0.05) reached statistical significance. CONCLUSION: Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome.

Comparison of the sixth and the seventh editions of the UICC classification for intrahepatic cholangiocarcinoma.

BACKGROUND: The current seventh edition of the TNM classification for intrahepatic cholangiocarcinoma (ICC) includes tumor number, vascular invasion, lymph node involvement but no longer the tumor size as compared to the sixth edition. The impact of the seventh edition on stage-based prognostic prediction for patients with ICC was evaluated. METHODS: Between 03/2001 and 02/2013, 98 patients with the diagnosis of an ICC were surgically treated at our center. Median survival times were calculated for these patients after separate classification by both sixth and seventh editions. RESULTS: Median overall survival was increased in patients classified to the lower tumor stages I and II using the seventh as compared to the sixth edition: stage I (54.9 vs. 47.3 months), stage II (19.9 vs. 18.9 months), stage III (17.2 vs. 19.9 months), and stage IV (23.2 vs. 15.3 months), respectively. The seventh edition definition of the T category resulted in an increased median survival regarding the T1 (50.4 vs. 47.3 months) as well as the T2 category (19.9 vs. 15.6 months) and revealed a reduced median survival of patients within the T3 (21.6 vs. 24.8 months) as well as the T4 category (19.9 vs. 27.0 months). CONCLUSIONS: The UICC seventh edition TNM classification for ICC improves separation of patients with intermediate stage tumors as compared to the sixth edition. The prognostic value of the UICC staging system has been improved by the seventh edition. Trial registration The data for this study have been retrospectively registered and the study has been approved by the ethic committee of the medical faculty of the University Hospital of Essen, Germany (license number 15-6353-BO).

Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma.

The production of prostaglandins is regulated by cyclooxygenases (COXs), which also have a role in tumour development and progression in various human malignancies, including cholangiocarcinoma. Limited information is available of the correlation of COX-2 protein expression and prognosis in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to determine the clinical significance of COX-2 expression in ICC. In addition the correlation of COX-2 expression and apoptosis/proliferation was analysed. COX-2 expression was determined immunohistochemically in 62 resected ICCs. Proliferation was assessed using Ki67-immunohistochemistry, and apoptosis was measured with the TdT-mediated dUTP nick-end-labelling technique. COX-2 was identified as an independent prognostic factor (P = 0.028) in resected ICC by survival analysis. High levels of COX-2 expression were found to be associated both with reduced apoptosis and increased proliferation of tumour cells. This study demonstrates the independent prognostic value of the COX-2 expression in resected ICC, thus, offering a potential additional adjuvant therapeutic approach with COX-2 inhibitors.