Late Local Recurrence after Neoadjuvant Therapy and Radical Resection for Locally Advanced Rectal Cancer.

Neoadjuvant radiochemotherapy (RCT) and lately total neoadjuvant therapy (TNT) improved local recurrence rates of rectal cancer significantly compared to total mesorectal excision (TME) alone. Yet the occurrence and impact of late local recurrences after many years appears to be a distinct biological problem. We included n = 188 patients with rectal cancer after RCT and radical resection in this study; n = 38 of which had recurrent disease (sites: local (8.0%), liver (6.4%), lung (3.7%)). We found that 68% of all recurrences developed within the first two years. Four patients, however, experience recurrence >8 years after surgery. Here, we report and characterize four cases of late local recurrence (10% of patients with recurrent disease), suggesting that neoadjuvant therapy in principle delays local recurrence.

Establishing a New Platform to Investigate the Efficacy of Oncolytic Virotherapy in a Human Ex Vivo Peritoneal Carcinomatosis Model.

Oncolytic virotherapy constitutes a promising treatment option for many solid cancers, including peritoneal carcinomatosis (PC), which still represents a terminal stage of many types of tumors. To date, the in vitro efficacy of oncolytic viruses is mostly tested in 2D-cultured tumor cell lines due to the lack of realistic 3D in vitro tumor models. We have investigated the feasibility of virotherapy as a treatment option for PC in a human ex vivo peritoneum co-culture model. Human HT-29 cancer cells stably expressing marker genes GFP and firefly luciferase (GFP/luc) were cultured on human peritoneum and infected with two prototypic oncolytic viruses (GLV-0b347 and MeV-DsRed). Both viral constructs were able to infect HT-29 cells in patient-derived peritoneum with high tumor specificity. Over time, both GFP signal and luciferase activity decreased substantially, thereby indicating successful virus-induced oncolysis. Furthermore, immunohistochemistry stainings showed specific virotherapeutic infections of HT-29 cells and effective tumor cell lysis in infected co-cultures. Thus, the PC model established here provides a clinically relevant screening platform to evaluate the therapeutic efficacy of virotherapeutic compounds and also to investigate, in an autologous setting, the immunostimulatory potential of oncolytic viruses for PC in a unique human model system superior to standard 2D in vitro models.

Pharmacologic Targeting of MMP2/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model.

BACKGROUND: Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the molecular mechanisms of PC from CRC remain largely unclear. METHODS: We investigated the role of MMPs during peritoneal colonisation by CRC cell lines in a human ex vivo peritoneum model and in patient-derived CRC and corresponding PC samples. MMP2 and MMP9 were inhibited using the small-molecule inhibitors batimastat and the specific MMP2/9 inhibitor III. RESULTS: MMP2 and MMP9 were strongly upregulated in patient-derived samples and following peritoneal colonisation by CRC cells in the ex vivo model. MMP inhibition with batimastat reduced colonisation of HT29 and Colo205 cells by 36% and 68%, respectively (p = 0.0073 and p = 0.0002), while MMP2/9 inhibitor III reduced colonisation by 50% and 41%, respectively (p = 0.0003 and p = 0.0051). Fibronectin cleavage was enhanced in patient-derived samples of PC and during peritoneal colonisation in the ex vivo model, and this was inhibited by MMP2/9 inhibition. CONCLUSION: MMPs were upregulated in patient-derived samples and during peritoneal attachment of CRC cell lines in our ex vivo model. MMP2/9 inhibition prevented fibronectin cleavage and peritoneal colonisation by CRC cells. MMP inhibitors might thus offer a potential treatment strategy for patients with PC.

A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options.

OBJECTIVES: Peritoneal metastasis (PM) is commonly observed in patients with colorectal cancer (CRC). The outcome of these patients is poor, with an average survival of only six months without therapy, which requires a better understanding of PM biology and new treatment strategies. METHODS: We established and characterized a human ex vivo peritoneal model to investigate the mechanisms of peritoneal seeding and possible treatment options. For this, CRC cell lines and patient-derived tumor organoids were cultured together with human peritoneum to investigate the invasion of malignant cells and the effects of local chemotherapy. RESULTS: Fresh human peritoneum was cultured for up to three weeks in a stainless steel ring system, allowing for survival of all peritoneal structures. Peritoneal cell survival was documented by light microscopy and immunohistochemical staining. Further, immunohistological characterization of the tissue revealed CD3-positive T-lymphocytes and vimentin-positive fibroblasts within the peritoneum. In addition, extracellular matrix components (collagens, matrix metalloproteinases) were localized within the tissue. Coculture with CRC cell lines and patient-derived CRC organoids revealed that cancer cells grew on the peritoneum and migrated into the tissue. Coculture with CRC cells confirmed that hyperthermal treatment at 41 °C for 90 min significantly enhanced the intracellular entry of doxorubicin. Moreover, treatment with mitomycin C under hyperthermic conditions significantly reduced the amount of cancer cells within the peritoneum. CONCLUSIONS: This human ex vivo peritoneal model provides a stringent and clinically relevant platform for the investigation of PM and for further elucidation of possible treatment options.

Automated Non-Contact Respiratory Rate Monitoring of Neonates Based on Synchronous Evaluation of a 3D Time-of-Flight Camera and a Microwave Interferometric Radar Sensor.

This paper introduces an automatic non-contact monitoring method based on the synchronous evaluation of a 3D time-of-flight (ToF) camera and a microwave interferometric radar sensor for measuring the respiratory rate of neonates. The current monitoring on the Neonatal Intensive Care Unit (NICU) has several issues which can cause pressure marks, skin irritations and eczema. To minimize these risks, a non-contact system made up of a 3D time-of-flight camera and a microwave interferometric radar sensor is presented. The 3D time-of-flight camera delivers 3D point clouds which can be used to calculate the change in distance of the moving chest and from it the respiratory rate. The disadvantage of the ToF camera is that the heartbeat cannot be determined. The microwave interferometric radar sensor determines the change in displacement caused by the respiration and is even capable of measuring the small superimposed movements due to the heartbeat. The radar sensor is very sensitive towards movement artifacts due to, e.g., the baby moving its arms. To allow a robust vital parameter detection the data of both sensors was evaluated synchronously. In this publication, we focus on the first step: determining the respiratory rate. After all processing steps, the respiratory rate determined by the radar sensor was compared to the value received from the 3D time-of-flight camera. The method was validated against our gold standard: a self-developed neonatal simulation system which can simulate different breathing patterns. In this paper, we show that we are the first to determine the respiratory rate by evaluating the data of an interferometric microwave radar sensor and a ToF camera synchronously. Our system delivers very precise breaths per minute (BPM) values within the norm range of 20-60 BPM with a maximum difference of 3 BPM (for the ToF camera itself at 30 BPM in normal mode). Especially in lower respiratory rate regions, i.e., 5 and 10 BPM, the synchronous evaluation is required to compensate the drawbacks of the ToF camera. In the norm range, the ToF camera performs slightly better than the radar sensor.

Three dimensional cultivation increases chemo- and radioresistance of colorectal cancer cell lines.

Although 2D cell cultures are commonly used to predict therapy response, it has become clear that 3D cultures may better mimic the in vivo situation and offer the possibility of tailoring translational clinical approaches. Here, we compared the response of 2D and 3D colorectal cancer (CRC) cell lines to irradiation and chemotherapy. Classic 2D cultures and 3D spheroids of CRC cell lines (CaCo2, Colo205, HCT116, SW480) were thoroughly established, then irradiated with doses of 1, 4, or 10 Gy, using a clinical-grade linear accelerator. The response was assessed by immunohistochemistry, flow cytometry, and TUNEL assays. Upon irradiation, CRC 3D spheroids were morphologically altered. After irradiation with 10 Gy, annexin V/PI staining revealed a 1.8- to 4-fold increase in the apoptosis rate in the 2D cell cultures (95% CI 3.24±0.96), and a 1.5- to 2.4-fold increase in the 3D spheroids (95% CI 1.56±0.41). Irradiation with 1 Gy caused 3- and 4-fold increases in TUNEL positive cells in the CaCo2 and HCT116 (p = 0.01) 2D cultures, respectively, compared with a 2-fold increase in the 3D spheroids. Furthermore, the 2D and 3D cultures responded differently to chemotherapy; the 3D cultures were more resistant to 5-FU and cisplatin, but not to doxorubicin and mitomycin C, than the 2D cultures. Taken together, CRC cells cultured as 3D spheroids displayed markedly higher resistance to irradiation therapy and selected chemotherapeutic drugs than 2D cultures. This in vitro difference must be considered in future approaches for determining the ideal in vitro systems that mimic human disease.

Similar complication rates for irreversible electroporation and thermal ablation in patients with hepatocellular tumors.

Background To compare the frequency of adverse events of thermal microwave (MWA) and radiofrequency ablation (RFA) with non-thermal irreversible electroporation (IRE) in percutaneous ablation of hepatocellular carcinoma (HCC). Patients and methods We retrospectively analyzed 117 MWA/RFA and 47 IRE procedures (one tumor treated per procedure; 144 men and 20 women; median age, 66 years) regarding adverse events, duration of hospital and intensive care unit (ICU) stays and occurrence of a post-ablation syndrome. Complications were classified according to the Clavien & Dindo classification system. Results 70.1% of the RFA/MWA and 63.8% of the IRE procedures were performed without complications. Grade I and II complications (any deviation from the normal postinterventional course, e.g., analgesics) occurred in 26.5% (31/117) of MWA/RFA and 34.0% (16/47) of IRE procedures. Grade III and IV (major) complications occurred in 2.6% (3/117) of MWA/RFA and 2.1% (1/47) of IRE procedures. There was no significant difference in the frequency of complications (p = 0.864), duration of hospital and ICU stay and the occurrence of a post-ablation syndrome between the two groups. Conclusions Our results suggest that thermal (MWA and RFA) and non-thermal IRE ablation of malignant liver tumors have comparable complication rates despite the higher number of punctures and the lack of track cauterization in IRE.

Microfluidic enrichment, isolation and characterization of disseminated melanoma cells from lymph node samples.

For the first time in melanoma, novel therapies have recently shown efficacy in the adjuvant therapy setting, which makes companion diagnostics to guide treatment decisions a desideratum. Early spread of disseminated cancer cells (DCC) to sentinel lymph nodes (SLN) is indicative of poor prognosis in melanoma and early DCCs could therefore provide important information about the malignant seed. Here, we present a strategy for enrichment of DCCs from SLN suspensions using a microfluidic device (Parsortix™, Angle plc). This approach enables the detection and isolation of viable DCCs, followed by molecular analysis and identification of genetic changes. By optimizing the workflow, the established protocol allows a high recovery of DCC from melanoma patient-derived lymph node (LN) suspensions with harvest rates above 60%. We then assessed the integrity of the transcriptome and genome of individual, isolated DCCs. In LNs of melanoma patients, we detected the expression of melanoma-associated transcripts including MLANA (encoding for MelanA protein), analyzed the BRAF and NRAS mutational status and confirmed the malignant origin of isolated melanoma DCCs by comparative genomic hybridization. We demonstrate the feasibility of epitope-independent isolation of LN DCCs using Parsortix™ for subsequent molecular characterization of isolated single DCCs with ample application fields including the use for companion diagnostics or subsequent cellular studies in personalized medicine.

Postoperative cellular stress in the kidney is associated with an early systemic γδ T-cell immune cell response.

BACKGROUND: Basic science data suggest that acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI) is an inflammatory process involving the adaptive immune response. Little is known about the T-cell contribution in the very early phase, so we investigated if tubular cellular stress expressed by elevated cell cycle biomarkers is associated with early changes in circulating T-cell subsets, applying a bedside-to-bench approach. METHODS: Our observational pilot study included 20 consecutive patients undergoing endovascular aortic repair for aortic aneurysms affecting the renal arteries, thereby requiring brief kidney hypoperfusion and reperfusion. Clinical-grade flow cytometry-based immune monitoring of peripheral immune cell populations was conducted perioperatively and linked to tubular cell stress biomarkers ([TIMP-2]•[IGFBP7]) immediately after surgery. To confirm clinical results and prove T-cell infiltration in the kidney, we simulated tubular cellular injury in an established mouse model of mild renal IRI. RESULTS: A significant correlation between tubular cell injury and a peripheral decline of γδ T cells, but no other T-cell subpopulation, was discovered within the first 24 hours (r = 0.53; p = 0.022). Turning to a mouse model of kidney warm IRI, a similar decrease in circulating γδ T cells was found and concomitantly was associated with a 6.65-fold increase in γδ T cells (p = 0.002) in the kidney tissue without alterations in other T-cell subsets, consistent with our human data. In search of a mechanistic driver of IRI, we found that the damage-associated molecule high-mobility group box 1 protein HMGB1 was significantly elevated in the peripheral blood of clinical study subjects after tubular cell injury (p = 0.019). Correspondingly, HMGB1 RNA content was significantly elevated in the murine kidney. CONCLUSIONS: Our investigation supports a hypothesis that γδ T cells are important in the very early phase of human AKI and should be considered when designing clinical trials aimed at preventing kidney damage. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915446 . Registered on 5 Aug 2013.

DWI - histology: a possible means of determining degree of liver fibrosis?

OBJECTIVES: The aim of this study was to determine the diagnostic value of diffusion-weighted MRI of the liver at 3T to classify liver fibrosis/cirrhosis. METHODS: 62 patients who underwent both histopathological examination and diffusion-weighted imaging of the liver via 3T MRI within a period of 3 months were included in the study. The Ishak score (1-6) was used to determine the degree of fibrosis: No liver fibrosis (NLF; Ishak 0, n = 16), mild liver fibrosis (MLF; Ishak 1-2, n = 23), advanced liver fibrosis (ALF; Ishak 3-5, n = 12), and liver cirrhosis (LC; Ishak 6, n = 11). RESULTS: The corresponding ADC values for the individual patient groups were as follows: NLF: 1123 (SD 95.8); MLF: 1032 (SD 77.6); ALF: 962 (SD 68.8); LC: 1015 (SD 60.2) mm2/s. There is a significant difference between NLF and MLF (p = 0.004) and between MLF and ALF (p = 0.022). A significant difference between patients with ALF and LC (p = 0.117) could not be found. CONCLUSION: Liver fibrosis/cirrhosis lowers the ADC values of the liver parenchyma in 3T MRI. However, the degree of fibrosis can only be conditionally determined on the basis of ADC values.

Selenium-binding protein 1 is down-regulated in malignant melanoma.

Selenium-binding protein 1 (SELENBP1) expression is reduced in various epithelial cancer entities compared to corresponding normal tissue and has already been described as a tumor suppressor involved in the regulation of cell proliferation, senescence, migration and apoptosis. We identified SELENBP1 to be down-regulated in cutaneous melanoma, a malignant cancer of pigment-producing melanocytes in the skin, which leads to the assumption that SELENBP1 also functions as tumor suppressor in the skin, as shown by others e.g. for prostate or lung carcinoma. However, in vitro analyses indicate that SELENBP1 re-expression in human melanoma cell lines has no impact on cell proliferation, migration or tube formation of the tumor cells themselves when compared to control-transfected cells. Interestingly, supernatant taken from melanoma cell lines transfected with a SELENBP1 re-expression plasmid led to suppression of vessel formation of HMEC cells. Furthermore, SELENBP1 re-expression alters the sensitivity of melanoma cells for Vemurafenib treatment. The data also hint to a functional interaction of SELENBP1 with GPX1 (Glutathione peroxidase 1). Low SELENBP1 mRNA levels correlate inversely with GPX1 expression in melanoma. The re-expression of SELENBP1 combined with down-regulation of GPX1 expression led to reduction of the proliferation of melanoma cells. In summary, SELENBP1 influences the tumor microenvironment and SELENBP1 action is functionally influenced by GPX1.

The sentinel lymph node spread determines quantitatively melanoma seeding to non-sentinel lymph nodes and survival.

INTRODUCTION: Complete lymph node dissection (CLND) after a positive sentinel node (SN) biopsy provides important prognostic information in melanoma patients but has been questioned for therapeutic use recently. We explored whether quantification of the tumour spread to SNs may replace histopathology of non-sentinel nodes (NSNs) for staging purposes. PATIENTS AND METHODS: We quantified melanoma spread in SNs and NSNs in 128 patients undergoing CLND for a positive SN. In addition to routine histopathology, one-half of each of all 1496 SNs and NSNs was disaggregated into a single cell suspension and stained immunocytochemically to determine the number of melanoma cells per 106 lymph node cells, i.e. the disseminated cancer cell density (DCCD). RESULTS: We uncovered melanoma spread to NSNs in the majority of patients; however, the tumour load and the proportion of positive nodes were significantly lower in NSNs than in SNs. The relation between SN and NSN spread could be described by a mathematical function with DCCDNSN = DCCDSNc/101-c (c = 0.69; 95% confidence interval [CI]: 0.62-0.76). At a median follow-up of 67 months, multivariable Cox regression analyses revealed that DCCDSN (p = 0.02; HR 1.34, 95% CI: 1.05-1.71) and the total number of pathologically positive nodes (p = 0.02; HR 1.53, 95% CI: 1.07-2.22) were significant risk factors after controlling for age, gender, thickness of melanoma and ulceration status. A prognostic model based on DCCDSN and melanoma thickness predicted outcome as accurately as a model including pathological information of both SNs and NSNs. CONCLUSION: The assessment of DCCDSN renders CLND for staging purposes unnecessary.

Increasing Morbidity with Extent of Lymphadenectomy for Primary Malignant Melanoma.

BACKGROUND: According to current guidelines, complete lymphadenectomy (LAD) is indicated in melanoma patients with a positive sentinel lymph node. Whereas there is little evidence from randomized trials for a survival benefit of this procedure, its morbidity is not trivial. We aimed to assess clinical associations between risk factors and complications of LAD to guide decision making about this aspect of melanoma management. METHODS AND RESULTS: A cohort of 174 patients who had undergone LAD for primary melanoma was retrospectively analyzed, and multivariable logistic regression models were used to correlate patient risk factors, tumor characteristics, number of excised lymph nodes, and procedural details with the incidence of complications. The overall rate of LAD-associated complications was 41.4%, 33.9% being lymphatic complications. The number of excised lymph nodes was independently associated with development of lymphatic complications (odds ratio 3.90/12.78 if more than 10/20 lymph nodes had been removed, p = 0.01/<0.001, respectively). However, the number of excised lymph nodes had no influence on overall survival using a multivariable Cox proportional hazards regression analysis. CONCLUSIONS: In this retrospective cohort study, an important association was found between the extent of LAD and lymphatic complications. Further studies should evaluate the necessity and extent of aggressive LAD to balance survival benefit with morbidity of LAD procedures.

Outcome of primary percutaneous stent-revascularization in patients with atherosclerotic acute mesenteric ischemia.

Background Patients with acute mesenteric ischemia (AMI) often exhibit severe co-morbidities and significant surgical risks, leading to high perioperative morbidity. Purpose To investigate the feasibility of primary percutaneous stent-revascularization (PPSR) in atherosclerotic AMI and its impact on patients' outcome. Material and Methods Retrospective analysis of 19 consecutive patients (7 women, 12 men; median age, 69 years) with AMI caused by atherosclerotic, non-embolic stenoses/occlusions of the splanchnic arteries and PPSR. Alternative minimally invasive techniques were excluded. Clinical characteristics including the Charlson Comorbidity Index adjusted by age (CCIa) and symptom duration, technical and clinical success of PPSR, clinical course, 30-day mortality, and follow-up were evaluated and compared to literature data for surgical approaches. Technical success was defined as residual stenosis of <30% in diameter. Clinical success was defined as resolution of symptoms of AMI and/or normalization of serum lactate after sole PPSR. Results The majority of patients presented with severe co-morbidities (CCIa >4 in 17 of 19 patients, 89%). Median symptom duration was 50 h. Technical and clinical success rates of PPSR were 95% (21 of 22 arteries) and 53% (10 of 19 patients). Seven patients underwent subsequent laparotomy with bowel resection in four cases. Thirty-day mortality was 42% (8 of 19 patients). Conclusion In our study population of patients with atherosclerotic AMI, severe co-morbidities, prolonged acute symptoms, and significant perioperative risks PPSR of splanchnic stenoses were technically feasible and the clinical outcome was acceptable.

Liver surgery in cirrhosis and portal hypertension.

The prevalence of hepatic cirrhosis in Europe and the United States, currently 250 patients per 100000 inhabitants, is steadily increasing. Thus, we observe a significant increase in patients with cirrhosis and portal hypertension needing liver resections for primary or metastatic lesions. However, extended liver resections in patients with underlying hepatic cirrhosis and portal hypertension still represent a medical challenge in regard to perioperative morbidity, surgical management and postoperative outcome. The Barcelona Clinic Liver Cancer classification recommends to restrict curative liver resections for hepatocellular carcinoma in cirrhotic patients to early tumor stages in patients with Child A cirrhosis not showing portal hypertension. However, during the last two decades, relevant improvements in preoperative diagnostic, perioperative hepatologic and intensive care management as well as in surgical techniques during hepatic resections have rendered even extended liver resections in higher-degree cirrhotic patients with portal hypertension possible. However, there are few standard indications for hepatic resections in cirrhotic patients and risk stratifications have to be performed in an interdisciplinary setting for each individual patient. We here review the indications, the preoperative risk-stratifications, the morbidity and the mortality of extended resections for primary and metastatic lesions in cirrhotic livers. Furthermore, we provide a review of literature on perioperative management in cirrhotic patients needing extrahepatic abdominal surgery and an overview of surgical options in the treatment of hepatic cirrhosis.

RORγt(+) IL-22-producing NKp46(+) cells protect from hepatic ischemia reperfusion injury in mice.

BACKGROUND & AIMS: NKp46(+) cells are major effector cells in the pathogenesis of hepatic ischemia reperfusion injury (IRI). Nevertheless, the precise role of unconventional subsets like the IL-22-producing NKp46(+) cells (NK22) remains unknown. The purpose of this study was to examine the role of NK22 cells in IRI in transplantation, particularly with respect to regulation by the transcription factor ROR-gamma-t (RORγt). METHODS: To explore the role of NK22 cells in IRI in the absence of adaptive immunity, B6.RORγt-(gfp/wt)-reporter and B6.RORγt-(gfp/gfp)-knockout (KO) mice on a Rag KO background underwent 90min partial warm ischemia, followed by 24h of reperfusion. RESULTS: Rag KO mice that possess fully functional NKp46(+) cells, and Rag-common-γ-chain-double-KO (Rag-γc-DKO) mice that lack T, B and NKp46(+) cells, were used as controls. We found that Rag-γc-DKO mice lacking NK22 cells show more severe levels of hepatocellular damage (GPT, histological injury) when compared to both Rag-RORγt-reporter and Rag KO mice that possess NK22 cells. Importantly, Rag-RORγt-reporter and Rag KO mice undergoing IRI expressed high protein levels of both IL-22 and GFP (RORγt), suggesting a protective role for RORγt(+) NK22 cells in IRI. Therefore, we tested the hypothesis that RORγt critically protects from IRI through the induction of hepatic NK22 cells by studying Rag-Rorγt-DKO mice under IRI conditions. We found that the lack of RORγt(+) NK22 cells in Rag-Rorγt-DKO mice significantly enhanced IR-induced hepatocellular injury, a phenotype that could be reversed upon adoptive transfer of Rag-Rorγt-reporter NK22 cells into DKO mice. CONCLUSIONS: RORγt(+) NK22 cells play an important protective role in IRI in mice.

Morbidity of hepatic resection for intermediate and advanced hepatocellular carcinoma.

PURPOSE: According to current treatment guidelines, surgical resection of hepatocellular carcinoma (HCC) is mostly restricted to a limited subgroup of patients. Due to improved surgical techniques and perioperative management, liver resections may also be performed more extendedly and also in cirrhotic livers with clinical signs of portal hypertension in selected patients. In this study, the clinical and long-term outcomes of liver resection in HCC patients with or without liver cirrhosis were evaluated. METHODS: One hundred fifty-eight patients undergoing liver resection for primary HCC at our institution were identified. Logistic and Cox regression analyses were used to identify prognostic parameters for postoperative complications and survival. RESULTS: In our cohort of patients, there was no association between clinical parameters or extent of surgical resection and postoperative morbidity. Only Barcelona Clinic Liver Cancer (BCLC) stage C patients were at significantly higher risk for major complications (OR 5.27, P = 0.009). Risk factors influencing long-term survival were patient age (HR 1.026, P = 0.027) and BCLC stage C (HR 3.47, P = 0.002). Compared to patients without liver cirrhosis, BCLC stage A and B patients undergoing resection were at similar risk for the development of severe complications and long-term mortality. CONCLUSION: Liver resection as potentially curative therapy can be performed in selected patients in BCLC stage B, as well as in patients with clinical signs of portal hypertension. The resection of HCC-classified BCLC stage C is feasible but associated with significant morbidity and mortality.

Urinary biomarkers TIMP-2 and IGFBP7 early predict acute kidney injury after major surgery.

OBJECTIVE: To assess the ability of the urinary biomarkers IGFBP7 (insulin-like growth factor-binding protein 7) and TIMP-2 (tissue inhibitor of metalloproteinase 2) to early predict acute kidney injury (AKI) in high-risk surgical patients. INTRODUCTION: Postoperative AKI is associated with an increase in short and long-term mortality. Using IGFBP7 and TIMP-2 for early detection of cellular kidney injury, thus allowing the early initiation of renal protection measures, may represent a new concept of evaluating renal function. METHODS: In this prospective study, urinary [TIMP-2]×[IGFBP7] was measured in surgical patients at high risk for AKI. A predefined cut-off value of [TIMP-2]×[IGFBP7] >0.3 was used for assessing diagnostic accuracy. Perioperative characteristics were evaluated, and ROC analyses as well as logistic regression models of risk assessment were calculated with and without a [TIMP-2]×[IGFBP7] test. RESULTS: 107 patients were included in the study, of whom 45 (42%) developed AKI. The highest median values of biomarker were detected in septic, transplant and patients after hepatic surgery (1.24 vs 0.45 vs 0.47 ng/l²/1000). The area under receiving operating characteristic curve (AUC) for the risk of any AKI was 0.85, for early use of RRT 0.83 and for 28-day mortality 0.77. In a multivariable model with established perioperative risk factors, the [TIMP-2]×[IGFBP7] test was the strongest predictor of AKI and significantly improved the risk assessment (p<0.001). CONCLUSIONS: Urinary [TIMP-2]×[IGFBP7] test sufficiently detect patients with risk of AKI after major non-cardiac surgery. Due to its rapid responsiveness it extends the time frame for intervention to prevent development of AKI.