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Supplementary Data from Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

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Supplementary Fig. S3 from Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growth-inhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer. [Mol Cancer Ther 2008;7(11):3509–18]

Pneumonia in liver transplant recipients is one of the most common infections in the early phase after transplantation. The diagnosis is based on clinical signs combined with positive microbiological samples taken from the lower respiratory tract. However, the role of bacterial colonization is not clear, nor is its association with pneumonia or its long-term consequences. The aim of this study was to investigate the association between positive microbiological findings and clinically relevant pneumonia and analyze different clinical and laboratory parameters for their association with pneumonia in liver transplant recipients.This was a retrospective analysis of 266 adult orthotopic liver transplantations between January 2008 and December 2013. A multidisciplinary in-house specialist panel established and confirmed the diagnosis of clinically relevant pneumonia in microbiologically positive patients.Of the 266 transplantations analyzed, 54 patients (20%) showed microbiologically positive trachea-bronchial cultures during the first 21 days after liver transplantation. Of those 54 patients, 24 (44.4%) had pneumonia as rated by the multidisciplinary specialist panel. Presence of gram-negative Enterobacteriaceae (P = .013) and positive chest radiologic findings (P = .035) were associated with pneumonia in microbiological-positive patients. Although patients with pneumonia had the lowest long-term survival, those without pneumonia but with positive microbiological cultures had still worse survival compared with the Model for End-Stage Liver Disease-matched control group without positive cultures (P = .012).Gram-negative Enterobacteriaceae and positive radiologic findings were associated with pneumonia in liver transplant recipients with positive microbiological trachea-bronchial cultures. Recipients with bacterial colonization without pneumonia also showed decreased long-term survival.

Background/Aim: Adenocarcinoma of the pancreas is one of the most aggressive malignant diseases in humans. Characteristics of this tumour type are poor response to radiotherapy and chemotherapeutic agents as well as metastasis in the absence of an organ capsule. The best therapeutic option is surgical removal of the tumour followed by chemotherapy or radiotherapy. Yet, even after surgical R0-resection, the 5-year survival probability is only about 20% because of the high recurrence rate of this tumour and complications due to metastases. Furthermore, recent studies have shown that the perioperative period is a particularly vulnerable phase, during which tumour progression and metastasis may be facilitated. The effects of analgesics administered during the perioperative period are still unknown. The present work investigated the effects of analgesics on pancreatic cancer cell migration in vitro. Materials and Methods: The migratory potential of pancreatic cancer cells was analysed using a Cell Migration Assay Kit with a Boyden chamber, in which cells migrate through a semi-permeable membrane under different stimuli. Cell concentration was measured by reading fluorescence (Ex/Em=530/590 nm) in a plate reader. Results: Migration in PANC-1 pancreatic cancer cells was significantly decreased after 24 h stimulation with 100 μM of ropivacaine, 100 nM of sufentanil, 1,000 μM of ropivacaine and 1,000 nM of sufentanil. In the PaTu 8988t cell line, incubation with 10 μM of ropivacaine caused a slight but statistically significant increase in migration, whereas lidocaine, metamizole and paracetamol did not significantly affect migration. Conclusion: The risk of tumour progression and metastasis seems to be increased during major oncological surgical interventions. The recent advances in the molecular and biological understanding of pathogenesis of pancreatic cancer have not yet significantly improved patient outcome. Therefore, further studies are needed to identify the underlying mechanisms of this aggressive tumour and establish new therapeutic options for the future.

Purpose Metastatic oesophageal cancer is commonly considered as a palliative situation with a poor prognosis. However, there is increasing evidence that well-selected patients with a limited number of liver metastases (ECLM) may benefit from a multimodal approach including surgery. Methods A systematic review of the current literature for randomized trials, retrospective studies, and case series with patients undergoing hepatectomies for oesophageal and oesophagogastric junction cancer liver metastases was conducted up to the 31st of August 2021 using the MEDLINE (PubMed) and Cochrane Library databases. Results A total of 661 articles were identified. After removal of duplicates, 483 articles were screened, of which 11 met the inclusion criteria. The available literature suggests that ECLM resection in patients with liver oligometastatic disease may lead to improved survival and even long-term survival in some cases. The response to concomitant chemotherapy and liver resection seems to be of significance. Furthermore, a long disease-free interval in metachronous disease, low number of liver metastases, young age, and good overall performance status have been described as potential predictive markers of outcome for the resection of liver metastases. Conclusion Surgery may be offered to carefully selected patients to potentially improve survival rates compared to palliative treatment approaches. Studies with standardized patient selection criteria and treatment protocols are required to further define the role for surgery in ECLM. In this context, particular consideration should be given to neoadjuvant treatment concepts including immunotherapies in stage IVB oesophageal and oesophagogastric junction cancer.

End-ileostomy after two-staged ileocolic resection is frequently performed in Crohn’s disease patients at high risk for postoperative complications. However, there is paucity on data regarding the morbidity after the stoma reversal. One hundred thirty patients undergoing closure of end-ileostomy between 1994 and 2016 were included. Data collection was retrospective in 11 first, and it was prospective in 119 last patients. Anastomotic complications were defined as anastomotic leak, perianastomotic abscess, and perianastomotic peritonitis. The median interval between ileostomy construction and reversal was 4.0 months. Ninety-seven of 121 patients with available data (80%) gained weight between both surgeries. Hemoglobin level increased between surgeries in 107 patients (85%). Fifteen patients (11.5%) received parenteral fluid substitution or parenteral nutrition between both surgeries. There were 37 hospital readmissions during the time between stoma construction and reversal (29%). After ileostomy reversal, 14 patients developed anastomotic complications (11%). By multivariate regression analysis, preoperative steroid intake (hazard ratio 4.5, 95% CI: 1.11–18.0, p = 0.035) and hospital readmission for infectious complications (HR 4.5, 95% CI: 1.11–18.0, p = 0.035) were statistically significantly associated with an increased risk to develop postoperative anastomotic complications. There were no postoperative deaths. Closure of end-ileostomy could be complicated by some serious morbidity. These risks should be taken into consideration weighing carefully between the one- and two-stage ileocolic resection in Crohn’s disease patients.

Objectives To evaluate intraoperative contrast‐enhanced ultrasound (IoCEUS) and intraoperative shear wave elastography (IoSWE) for characterization of focal pancreatic lesions (FPLs) in correlation with postoperative histologic results. Thereby, the impact of intraoperative ultrasound (US) on pancreas surgery was evaluated. Methods Intraoperative CEUS and SWE data from 54 patients, who underwent pancreas surgery between 2017 and 2019, were analyzed retrospectively. Ultrasound examinations were performed with multifrequency linear/T‐shaped transducers (3–9 MHz) on a high‐end US device (LOGIQ E9; GE Healthcare, Chicago, IL). To analyze FPL stiffness by SWE, regions of interest were placed to measure the shear wave speed (meters per second) and stiffness (kilopascals). After intravenous bolus injections of 2.4 to 10 mL of sulfur hexafluoride microbubbles, a dynamic analysis of FPL microvascularization from arterial to late phases was performed using IoCEUS considering hypoenhancement/irregular vascularization of macrocystic/small solid FPL malignancy criteria. Ultrasound findings were correlated with postoperative histologic results. The impact of intraoperative US on surgery was documented in each case. Results Of 54 FPLs, IoCEUS could correctly characterize 39 of 39 malignant and 6 of 15 benign FPLs; IoSWE 29 of 39 as malignant and 7 of 15 as benign. Intraoperative CEUS's sensitivity was 100%; specificity, 40%; accuracy, 83.3%; positive predictive value, 81.3%; and negative predictive value, 100% (P

Der Einsatz des intraoperativen Ultraschalls ist gangige Praxis in der Chirurgie der parenchymatosen Organe. Neben der reinen Moglichkeit, Lasionen zu detektieren, ermoglichen Perfusions- und Elastizitatsanalysen mittels farbkodierter Dopplersonographie und Kontrastmittelultraschall sowie Elastographie hochsensitive und -spezifische Differenzialdiagnostik, gerade auch in der onkologischen Chirurgie. Diese Arbeit gibt eine Ubersicht uber die vorhandenen Moglichkeiten intraoperativer Sonographie sowie einen Ausblick auf zukunftige Entwicklungen. Literaturrecherche und Darstellung der Evidenz intraoperativer Ultraschalldiagnostik, Diskussion von Grundlagenarbeiten und Expertenempfehlungen Die moderne intraoperative Ultraschalldiagnostik ist eine hocheffiziente Technik zur Detektion und Charakterisierung fokaler Raumforderungen vor allem in der onkologischen Chirurgie. Ultraschalldiagnostik ist mit den Techniken der Perfusionsanalyse, der Kontrastmittelultraschalldiagnostik und Elastographie eine sehr sensitive und spezifische Methode, intraoperative Differenzialdiagnostik in Echtzeit und mit masigem technischem Aufwand durchzufuhren. So kann die praoperative Diagnostik verfeinert werden, was zum Teil zu einer Modifikation der Operationstaktik fuhrt. Zukunftige Weiterentwicklungen im Bereich der digitalen Bildfusion mit praoperativer Schnittbildgebung, der optischen Instrumentensteuerung und der molekular gezielten Tumortherapie werden die bereits hohe Bedeutung intraoperativer Sonographie nochmals verstarken.

Metastatic oesophageal cancer is commonly considered as a palliative situation with a poor prognosis. However, there is increasing evidence that well-selected patients with a limited number of liver metastases (ECLM) may benefit from a multimodal approach including surgery.A systematic review of the current literature for randomized trials, retrospective studies, and case series with patients undergoing hepatectomies for oesophageal and oesophagogastric junction cancer liver metastases was conducted up to the 31st of August 2021 using the MEDLINE (PubMed) and Cochrane Library databases.A total of 661 articles were identified. After removal of duplicates, 483 articles were screened, of which 11 met the inclusion criteria. The available literature suggests that ECLM resection in patients with liver oligometastatic disease may lead to improved survival and even long-term survival in some cases. The response to concomitant chemotherapy and liver resection seems to be of significance. Furthermore, a long disease-free interval in metachronous disease, low number of liver metastases, young age, and good overall performance status have been described as potential predictive markers of outcome for the resection of liver metastases.Surgery may be offered to carefully selected patients to potentially improve survival rates compared to palliative treatment approaches. Studies with standardized patient selection criteria and treatment protocols are required to further define the role for surgery in ECLM. In this context, particular consideration should be given to neoadjuvant treatment concepts including immunotherapies in stage IVB oesophageal and oesophagogastric junction cancer.

Der extreme Mangel an Spenderorganen in Deutschland fuhrt zu einer starken Diskrepanz zwischen Verfugbarkeit und Bedarf an Organen zur Lebertransplantation und, daraus folgend, zu einem Allokationsdilemma. Hieraus resultieren zum einen eine hohe Letalitat wahrend der Wartezeit und zum anderen, bei der aktuellen Organallokationspolitik, auch schlechte Ergebnisse der Transplantation, da bevorzugt extrem kranke Patienten ein Organ erhalten. Mogliche Losungsansatze sind 1) eine Verbesserung der Zahl postmortal gespendeter Organe, 2) innovative Ansatze zur verbesserten Nutzung suboptimaler Spenderorgane (z. B. von alteren, multimorbiden Spendern, verfetteten Lebern etc.), 3) eine Steigerung der Lebendspende und 4) geanderte/optimierte Allokationsregeln. Dabei wurden die Masnahmen 2 und 3 von einer deutlichen Zentralisierung der Lebertransplantation profitieren. Da voraussichtlich alle 4 Optionen in Deutschland in naherer Zukunft nicht umgesetzt werden konnen, werden Organmangel und das Allokationsdilemma bis auf weiteres bestehen bleiben.

In 1988, Rudolf Pichlmayr pioneered split liver transplantation (SLT), enabling the transplantation of one donor liver into two recipients - one pediatric and one adult patient. In the same year, Henri Bismuth and colleagues performed the first full right/full left split procedure with two adult recipients. Both splitting techniques were rapidly adopted within the transplant community. However, a SLT is technically demanding, may cause increased perioperative complications, and may potentially transform an excellent deceased donor organ into two marginal quality grafts. Thus, crucial evaluation of donor organs suitable for splitting and careful screening of potential SLT recipients is warranted. Furthermore, the logistic background of the splitting procedure as well as the organ allocation policy must be adapted to further increase the number and the safety of SLT. Under defined circumstances, in selected patients and at experienced transplant centers, SLT outcomes can be similar to those obtained in full organ LT. Thus, SLT is an important tool to reduce the donor organ shortage and waitlist mortality, especially for pediatric patients and small adults. The present review gives an overview of technical aspects, current developments, and clinical outcomes of SLT.

Due to the lack of data on asymptomatic SARS-CoV-2-positive persons in healthcare institutions, they represent an inestimable risk. Therefore, the aim of the current study was to evaluate the first 1,000,000 reported screening tests of asymptomatic staff, patients, residents, and visitors in hospitals and long-term care (LTC) facilities in the State of Bavaria over a period of seven months. Data were used from the online database BayCoRei (Bavarian Corona Screening Tests), established in July 2020. Descriptive analyses were performed, describing the temporal pattern of persons that tested positive for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) or antigen tests, stratified by facility. Until 15 March 2021, this database had collected 1,038,146 test results of asymptomatic subjects in healthcare facilities (382,240 by RT-PCR, and 655,906 by antigen tests). Of the RT-PCR tests, 2.2% (n = 8380) were positive: 3.0% in LTC facilities, 2.2% in hospitals, and 1.2% in rehabilitation institutions. Of the antigen tests, 0.4% (n = 2327) were positive: 0.5% in LTC facilities, and 0.3% in both hospitals and rehabilitation institutions, respectively. In LTC facilities and hospitals, infection surveillance using RT-PCR tests, or the less expensive but less sensitive, faster antigen tests, could facilitate the long-term management of the healthcare workforce, patients, and residents.

Background: Studies addressing the role of mechanical bowel preparation (MBP) in Crohn's disease (CD) patients are lacking. Methods: Consecutive elective colorectal resections for CD have been included in the present analysis. Exclusion criteria were small bowel resections not including colon, urgent surgeries, surgeries for cancer, and abdominoperineal resections for perianal disease. MBP was performed routinely between 1992 and 2004, omitted between 2005 and 2015, and reintroduced in 2016. Intraabdominal septic complications (IASC) were anastomotic leakage, intraabdominal abscess, intestinal fistula, and peritonitis. Results: Overall, 680 bowel resections for CD have been performed between 1992 and 2017. After exclusion of the above mentioned patients, 549 patients were included in the present analysis. The IASC rate was 12% in patients undergoing surgery after MPB as opposed to 24% when MBP was omitted (P < 0.001). By the multivariate analysis, preoperative MBP significantly reduced the risk of IASC (Hazard ratio 0.45; 95% CI, 0.23 - 0.86; P = 0.016). Preoperative weight loss (HR 2.0; 95% CI, 1.1 - 3.6; P = 0.024), penetrating disease (HR 2.6; 95% CI, 1.3 - 5.4; P = 0.01), and stapled as opposed to hand-sewn ileocolic anastomosis (HR 3.3; 95% CI, 1.4 - 7.7; P = 0.006) were associated with an increased risk of IASC. The positive impact of MBP was strongest on anastomotic complication rate in patients undergoing ileocolic resections for penetrating disease (11% vs 36%, P < 0.001). Conclusion: Preoperative MPB should be strongly considered before colorectal surgery in patients with CD, especially in patients undergoing ileocolic resections for penetrating disease.

Kolorektale Lebermetastasen (KLM) mit extensivem, bilobarem Verteilungsmuster bzw. kritischer intrahepatischer Lage benotigen fur eine kurative Zielsetzung komplexe chirurgische Resektionstechniken. In der vorliegenden Arbeit beschreiben wir aktuelle Techniken der hepatoonkologischen Chirurgie, mit denen auch bei vermeintlich grenzwertig kleinem gesundem Leberrest eine kurative Resektionsstrategie verfolgt werden kann. Es werden die Methoden der Pfortaderembolisation/-ligatur, der Kombination aus Resektion und Ablation, der zweizeitigen Resektionsstrategie und der „In-situ-split“-Resektion, auch unter „ALPPS“ („associating liver partition and portal vein ligation for staged hepatectomy“) bekannt, diskutiert. Kurz wird auch auf die extrahepatische oligometastasierte Situation eingegangen. Revision aktueller Literatur und Diskussion des an unserer Klinik entwickelten Verfahrens des „in situ split“. In den letzten Jahren wurden die chirurgischen Techniken, kolorektale Metastasen kurativ zu resezieren, signifikant erweitert, wodurch auch bei extensiver Metastasierung kurative Resektionen moglich wurden. Eingebettet in ein multimodales Therapiekonzept ist es essenziell, dass die Resektabilitat kolorektaler Metastasen auch in vermeintlich „aussichtslosen“ Fallen durch einen erfahrenen, hepatobiliaren Chirurgen beurteilt wird.

Sind metastasierte, refraktare Krebserkrankungen resistent gegenuber etablierten Tumortherapien, konnte eine biomodulatorische Therapie eine Chance auf anhaltende Remissionen bieten. Dieser palliative Ansatz basiert auf der „kommunikativen Reprogrammierung“ von Tumorsystemen, Anakoinosis genannt. Dabei werden Kommunikationswege der Tumorzellen mit ihrer Umgebung so verandert, dass die entarteten Zellen in den programmierten Zelltod gehen.

AIM: To evaluate the efficiency of intraoperative contrast enhanced ultrasound (Io-CEUS) for assessment of radiofrequency ablation (RFA) during liver tumor surgery. MATERIAL AND METHODS: Retrospective analysis was performed on a total number of 18 patients out of over 500 patients who underwent combined liver tumor surgery and RFAof 27 hepatic tumors between 02/2011 and 12/2016. Io-CEUS was performed by bolus injections of up to 10 ml sulphur hexaflourid microbubbles for diagnostic purposes. To guide the RFA up to 20 ml microbubbles were applied to monitor the procedure and assess the ablation status finally. A fully avascular area or absence of any residual vascularization intratumorally was considered technical success. These findings were correlated to findings of follow-up imaging results (CEUS, MRI, CT) at least 1 up to 40 months (mean 11 months) after surgery. RESULTS: 13 male and 5 female patients aged between 45-77 years (mean 59.2 +/- 17.1 years) with 26 malignant and one most probable benign hepatic lesion were treated with intraoperative RFA. Io-CEUS detected 23 preoperatively unknown liver lesions leading to a change in therapy in 13/ 18 cases (72,2%). All 27 treated lesions showed an avascular area immediately after RFA. According to follow-up imaging results (1 month - 3 years after surgery, mean follow-up time 11 months), 2/18 patients had local recurrences, 8 patients had distant intrahepatic recurrences or extrahepatic recurrence, 8 patients remained tumor-free. Thereby, a success rate of CEUS guided RFA of 89% could be obtained concerning the targeted liver lesions. CONCLUSION: Modern intraoperative ultrasound using B-mode and Io-CEUS is a valuable tool for optimization of diagnostic and therapeutic intraoperative liver procedures and ablative therapies.

More than half of all brain metastases show infiltrating rather than displacing growth at the macro-metastasis/brain parenchyma interface (MMPI), a finding associated with shorter survival. The Lymphoid Enhancer-binding Factor-1 (LEF1) is an epithelial-mesenchymal transition (EMT) transcription factor that is commonly overexpressed in brain-colonizing cancer cells. Here, we overexpressed LEF1 in an in vivo breast cancer brain colonization model. It shortened survival, albeit without engaging EMT at the MMPI. By differential proteome analysis, we identified a novel function of LEF1 as a regulator of the glutathione (GSH) system, the principal cellular redox buffer. LEF1 overexpression also conferred resistance against therapeutic GSH depletion during brain colonization and improved management of intracellular ROS. We conclude that besides EMT, LEF1 facilitates metastasis by improving the anti-oxidative capacity of epithelial breast cancer cells, in particular during colonization of the brain parenchyma. This article is protected by copyright. All rights reserved.

Melanoma is one of the most aggressive and lethal cancers worldwide. Despite recent progress in melanoma therapy, the prognosis for metastasized melanoma continues to be poor. Xanthohumol (XN), a prenylated chalcone derived from hop cones, is known to possess a broad spectrum of chemopreventive and anticancer activities. However, few studies have analyzed functional XN effects on melanoma cells and there have been no previous in vivo studies of its effects on metastasis. The aim of this study was to investigate the impact of XN on the tumorigenic and liver metastatic activity of melanoma cells. XN exhibited dose-dependent cytotoxic effects on human melanoma cell lines (Mel Ju, Mel Im) in vitro. Functional analysis in the subtoxic dose-range revealed that XN dose-dependently inhibited proliferation, colony formation, and migratory activity of melanoma cells. Subtoxic XN doses also induced markers of endoplasmic reticulum stress but inhibited the phosphorylation of the protumorigenic c-Jun N-terminal kinases (JNK). Furthermore, XN effects on hepatic metastasis were analyzed in a syngeneic murine model (splenic injection of murine B16 melanoma cells in C57/BL6 mice). Here, XN significantly reduced the formation of hepatic metastasis. Metastases formed in the liver of XN-treated mice revealed significantly larger areas of central necrosis and lower Ki67 expression scores compared to that of control mice. In conclusion, XN inhibits tumorigenicity of melanoma cells in vitro and significantly reduced hepatic metastasis of melanoma cells in mice. These data, in conjunction with an excellent safety profile that has been confirmed in previous studies, indicate XN as a promising novel agent for the treatment of hepatic (melanoma) metastasis.

Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.

BACKGROUND Declining numbers of deceased donors and prolonged waiting time emphasize the importance of living kidney donation. Furthermore, because of the changing age structures with increasingly older recipients, the question of acceptance of older donors is becoming more relevant. However, sufficient long-term outcome data, especially for older donors - including histopathological analysis - are lacking. The aim of this study was to analyze the Regensburg Living Donor Cohort with regard to age

Assessment of intraoperative quantitative shear wave elastography (SWE) and contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions (FLLs) during liver surgery using postoperative histopathological results as the gold standard. US data of 79 consecutive patients with 98 FLLs who underwent liver surgery between 08/2015 - 06/2017 were prospectively acquired and retrospectively analyzed. Multifrequency linear/T-shaped probes (6 - 9 MHz) were used to store cine loops of at least 5 s and images of B-mode, SWE and CEUS. The first CEUS loop was continuously documented over 1 min. in each case. Quantitative SWE analysis of FLLs was performed by placing 5 regions of interest to measure shear wave speed (m/s) and stiffness (kPa). CEUS was evaluated during the arterial, portal venous and late phase after i. v. bolus injections of 2.4 - 10 ml sulfur hexafluoride microbubbles. Postoperative histopathology after tumor resection or intraoperative biopsy was obtained to confirm findings of SWE and CEUS. Of 98 FLLs in 79 patients (mean age: 58 years sd ± 12y) 88 were malignant and 10 were benign ranging from 0.69 to 15.2 cm in size (mean: 2.8 cm, sd ± 2.25 cm). SWE characterized 73/88 FLLs correctly as malignant and 7/10 as benign using a cut-off value of 2.5 m/s/21.3 kPa (p 0.0005). The sensitivity was 83 %, specificity 70 %, accuracy 82 %. CEUS could correctly identify 86/88 malignant and 8/10 benign FLLs. The sensitivity was 98 %, specificity 80 %, accuracy 96 %. SWE could correctly identify 2 malignant FLLs which CEUS falsely characterized as benign. Intraoperative CEUS and SWE are excellent tools for the highly accurate visualization, characterization and malignancy assessment of hepatic tumors during liver surgery.ZIEL: Evaluation der intraoperativen Scherwellenelastografie (SWE) im Vergleich zum Kontrastmittelultraschall (CEUS) zur Charakterisierung fokaler Leberläsionen (FLLs) während Lebertumoroperationen in Korrelation zur postoperativen Histologie als Goldstandard. Es erfolgte eine prospektive Datenakquisition und retrospektive Analyse von US-Daten von 79 Patienten mit 98 FLLs, die zwischen August 2015 und Juni 2017 im Rahmen einer Lebertumoroperation einen intraoperativen US erhielten. Multifrequenz-Linear-/T-Sonden (6 – 9 MHz) wurden zur Akquisition von Cineloops 5 sek. sowie von B-Bild-, SWE- und CEUS-Bildern verwendet. Der erste CEUS-Loop wurde kontinuierlich über 1 min. gespeichert. Mittels 5 Regions-of-interest erfolgte die quantitative SWE-Auswertung der FLLs durch Messung des Shear-wave-speed (m/s) sowie der Festigkeit (kPa). Die CEUS–Evaluation erfolgte während arterieller, portalvenöser und venöser Spätphase nach i. v.-Bolus-Injektionen von 2,4 – 10 ml Sulphurhexaflourid-Mikrobläschen. CEUS- und SWE-Befunde wurden zur postoperativen Histopathologie nach Resektion/intraoperativer Biopsie korreliert. Von 98 FLLs bei 79 Patienten (im Mittel 58 Jahre SD ± 12 Jahre) waren 88 maligne und 10 benigne. Die Größe lag zwischen 0,69 und 15,2 cm (im Mittel 2,8 cm, SD ± 2,25 cm). Mittels SWE wurden 73/88 FLLs korrekt als maligne und 7/10 als benigne charakterisiert unter Anwendung eines Cut-off von 2,5 m/s/21,3 kPa (p 0,0005). Die Sensitivität betrug 83 %, die Spezifität 70 % und die Genauigkeit 82 %. CEUS konnte 86/88 maligne und 8/10 benigne FLLs korrekt charakterisieren. Die Sensitivität betrug 98 %, die Spezifität 80 % und die Genauigkeit 96 %. 2 von CEUS fälschlich als benigne charakterisierte FLLs konnten mittels SWE korrekt als maligne identifiziert werden. CEUS und SWE während Lebertumoroperationen ermöglichen eine exzellente intraoperative Lebertumordiagnostik durch hochauflösende Visualisierung und genaue Charakterisierung von FLLs.

Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions. CA extern

Background: Liver tumors that are extensive, multifocal, or critically located frequently require advanced techniques of liver resection including ‘functional augmentation' of liver segments. Here we describe the invention and stepwise establishment of a new technique - termed ‘in-situ split' liver resection or ‘ALPPS' - enabling liver resection in certain situations. Methods: The development of the technique in the first and the subsequent 8 patients in the index center, and also the method's spread throughout Germany and the world were reviewed. Results: In 2007, in the first patient, the new technique was developed intraoperatively by necessity. Due to the convincing outcome, it was deliberately applied again several months later in another patient, and thereafter (sparsely) used for liver resection for various indications. Following oral communication, the method spread throughout Germany, and later - mainly following the publication of the initial multicentric German series - very quickly disseminated worldwide. Currently, it is used for a very (if not overly) broad spectrum of indications by many hepatobiliary surgery centers. Conclusion: In-situ split/ALPPS is a newly developed technique for liver resection, which was established for very specific situations. This method has created a hype, and is currently used rather generously by many centers worldwide.

// Katharina M. Schmidt 1 , Claus Hellerbrand 2 , Petra Ruemmele 3 , Christoph W. Michalski 4 , Bo Kong 5 , Alexander Kroemer 1 , Christina Hackl 1 , Hans J. Schlitt 1 , Edward K. Geissler 1 , Sven A. Lang 1, 6 1 Department of Surgery, University Hospital Regensburg, Regensburg, Germany 2 Department of Internal Medicine I, University Hospital Regensburg, Germany 3 Department of Pathology, Hospital of Erlangen, Erlangen, Germany 4 Department of Surgery, University of Heidelberg, Germany 5 Department of Surgery, Technische Universitat Munchen (TUM), Munich, Germany 6 Department of Surgery, Universitat Freiburg, Freiburg, Germany Correspondence to: Sven A. Lang, email: sven.lang@klinik.uni-regensburg.de Keywords: mTORC2/RICTOR, PDAC, AKT, HIF-1 Received: September 12, 2016 Accepted: February 06, 2017 Published: February 20, 2017 ABSTRACT Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo . Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro . Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.