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The accurate detection of malignant tissue during colorectal surgery impacts operation outcome. The non-invasive spectral imaging combined with machine learning (ML) methods showed to be promising for tumor identification. However, large spectral range implies large computing time. To reduce the number of features, ML methods (e.g. logistic regression and convolutional neuronal network CNN) were evaluated based on four physiological tissue parameters to automatically classify cancer and healthy mucosa in resected colon tissue. A ROC AUC of 0.81 was achieved with the CNN. This study shows that the use of only specific wavelengths bands can detect cancer.Clinical Relevance- These outcomes support the possibility to automatically classify colon tumor based on physiological parameters calculated using only specific wavelength bands. Hence, future image-guided colorectal surgeries can be performed with real-time multispectral imaging.

Traditional covalent semiconductors require complex processing methods for device fabrication due to their high cohesive energies. Here, we develop a stable, ligand-free perovskite semiconductor ink that can be used to make patterned semiconductor-based optoelectronics in one step. The perovskite ink is formed via the dissolution of crystals of vacancy-ordered double perovskite Cs 2 TeX 6 (X = Cl - , Br - , I - ) in polar aprotic solvents, leading to the stabilization of isolated [TeX 6 ] 2- octahedral anions and free Cs + cations without the presence of ligands. The stabilization of the fundamental perovskite ionic octahedral building blocks in solution creates multifunctional inks with the ability to reversibly transform between the liquid ink and the solid-state perovskite crystalline system in air within minutes. These easily processable inks can be patterned onto various materials via dropcasting, spraying or painting, and stamping, highlighting the crucial role of solvated octahedral complexes toward the rapid formation of phase-pure perovskite structures in ambient conditions.

Purpose: WNT5A/ROR2 signaling pathway has been involved in many human cancers. Its role in pancreatic ductal adenocarcinoma (PDAC) has not been clarified yet. The purpose of this study was to determine the prognostic value of WNT5A expression in conjunction with the ROR2 expression in the same PDAC human tissues., Methods: We retrospectively analyzed by immunohistochemistry the WNT5A and ROR2 expression in117 paraffin-embedded PDAC specimens following surgical pancreatic resection. The prognostic value of WNT5A and ROR2 was assessed using Kaplan-Meier survival curves and multivariate Cox regression models., Results: High ROR2 expression was detected in 65.8% (77/117) of PDAC tumors, in 28.2% (33/117) in tumor-stroma, and in 71.1% (65/90) of normal pancreatic tissue. High WNT5A expression was found in 76.9% (90/117) of tumors, in 59.0% (69/117) of tumor-stroma, and in 83.0% (73/88) of normal pancreatic tissue. Spearman's correlation coefficiency demonstrated weak association between ROR2 and WNT5A expression in tumor (r=0.184; p=0.047), and no association in stroma (r=0.036; p=0.699). Multivariate analysis showed that regional lymph node invasion and differentiation were independent prognostic factors of survival, while ROR2- and WNT5A expression were not., Conclusions: Variable expression patterns for ROR2 and WNT5A were demonstrated in PDAC and normal pancreatic tissues suggesting a role for WNT5A/ROR2 signalling pathway, not only in PDAC but also in the normal pancreatic tissue during inflammation. The lack of prognostic significance for ROR2 and WNT5A expression in our cohort, either alone or in subgroup analysis, underlines the complexity of their role in PDAC, which is highly dependent on the different molecular receptor-ligand tissue contexts.

The metal halide ionic octahedron, [MX 6 ] (M = metal cation, X = halide anion), is considered to be the fundamental building block and functional unit of metal halide perovskites. By representing the metal halide ionic octahedron in halide perovskites as a super ion/atom, the halide perovskite can be described as an extended ionic octahedron network (ION) charge balanced by selected cations. This new perspective of halide perovskites based on ION enables the prediction of different packing and connectivity of the metal halide octahedra based on different solid-state lattices. In this work, a new halide perovskite Cs 8 Au 3.5 In 1.5 Cl 23 was discovered on the basis of a BaTiO 3 -lattice ION {[InCl 6 ][AuCl 5 ][Au/InCl 4 ] 3 } 8- , which is assembled from three different ionic octahedra [InCl 6 ], [AuCl 6 ], and [Au/InCl 6 ] and balanced by positively charged Cs cations. The success of this ION design concept in the discovery of Cs 8 Au 3.5 In 1.5 Cl 23 opens up a new venue for the rational design of new halide perovskite materials.

Purpose: Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC., Methods: Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition, HER2 gene expression was assessed using qPCR., Results: Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60 v 10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4; P < .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the HER2 amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a HER2 amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab., Conclusion: Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of HER2 expression and amplification levels may improve selection of patients for HER2-directed treatment., Competing Interests: Birgitta GeierOther Relationship: Biomax Informatics AG Dieter MaierOther Relationship: Biomax Informatics AG Albrecht KretzschmarHonoraria: Roche Pharma AG, Merck Serono, Shire, Amgen, Medac, SERVIER, Sanofi, MSD, Bristol-Myers Squibb, Bayer Schering Pharma, Aspen PharmaConsulting or Advisory Role: Roche Pharma AG, Shire, AmgenTravel, Accommodations, Expenses: PharmaMar, Merck Serono, Ipsen, Medac Ludwig Von WeikersthalHonoraria: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre Gabriele SieglerHonoraria: Medizinwelten services GmbH, Shire, Eisai, Roche, Janssen-Cilag, Aurikamed, Deutsche RöntgengesellschaftConsulting or Advisory Role: Janssen-Cilag, AstraZenecaResearch Funding: Servier, Beigene, Roche/Genentech, Roche, Celgene, Isofol Medical, Nutricia, Novartis, MOLOGEN, SanofiTravel, Accommodations, Expenses: Lilly Thomas DeckerConsulting or Advisory Role: Novartis Florian LordickHonoraria: Lilly, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Elsevier, BioNTech AG, SERVIER, Infomedica, Merck KGaA, Roche, MedscapeConsulting or Advisory Role: Lilly, Merck Sharp and Dohme, Bristol-Myers Squibb, Astellas Pharma, SERVIER, Zymeworks, Amgen, BeigeneResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: Bristol-Myers Squibb, LillyNo other potential conflicts of interest were reported.

Currently, colorectal cancer (CRC) is mainly identified via a visual assessment during colonoscopy, increasingly used artificial intelligence algorithms, or surgery. Subsequently, CRC is confirmed through a histopathological examination by a pathologist. Hyperspectral imaging (HSI), a non-invasive optical imaging technology, has shown promising results in the medical field. In the current study, we combined HSI with several artificial intelligence algorithms to discriminate CRC. Between July 2019 and May 2020, 54 consecutive patients undergoing colorectal resections for CRC were included. The tumor was imaged from the mucosal side with a hyperspectral camera. The image annotations were classified into three groups (cancer, CA; adenomatous margin around the central tumor, AD; and healthy mucosa, HM). Classification and visualization were performed based on a four-layer perceptron neural network. Based on a neural network, the classification of CA or AD resulted in a sensitivity of 86% and a specificity of 95%, by means of leave-one-patient-out cross-validation. Additionally, significant differences in terms of perfusion parameters (e.g., oxygen saturation) related to tumor staging and neoadjuvant therapy were observed. Hyperspectral imaging combined with automatic classification can be used to differentiate between CRC and healthy mucosa. Additionally, the biological changes induced by chemotherapy to the tissue are detectable with HSI.

Extra-adrenal, mediastinal paraganglioma are rare tumors that origin from sympathetic ganglia. Common diagnostic steps include CT, MRI and PET-Scan. We present a case where immunohistochemical staining was an essential step for final diagnosis in a patient without symptoms of endocrine activity and an uncommon location of this tumor entity. In combination with clinical particularities on the origin of the tumor and characteristic morphology, the immunohistochemical staining of tumor tissue is a necessary diagnostic tool for paraganglioma., Competing Interests: None., (© 2020 The Author(s).)

Because of the toxicity of lead, searching for a lead-free halide perovskite semiconducting material with comparable optical and electronic properties is of great interest. Rare-earth-based halide perovskite represents a promising class of materials for this purpose. In this work, we demonstrate the solution-phase synthesis of single-crystalline CsEuCl 3 nanocrystals with a uniform size distribution centered around 15 nm. The CsEuCl 3 nanocrystals have photoluminescence emission centered at 435 nm, with a full width at half-maximum of 19 nm. Furthermore, CsEuCl 3 nanocrystals can be embedded in a polymer matrix that provides enhanced stability under continuous laser irradiation. Lead-free rare-earth cesium europium halide perovskite nanocrystals represent a promising candidate to replace lead halide perovskites.

In the original article, the title of the article is "Restoration of MARCK enhances chemosensitivity in cancer". The authors would like to change the article title to "Restoration of MARCKS enhances chemosensitivity in cancer" by adding a letter "S" to the word MARCK.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Purpose: Increased ATP-binding-cassette (ABC) transporter activity is a major cause of chemotherapy resistance in cancer. The ABC transporter family member ABCB1 is often overexpressed in colorectal cancer (CRC). Phosphatidylinositol-4,5-bisphosphat (PI(4,5)P 2 )-dependent pathways are involved in the regulation of ABCB1 function. The protein Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) is a pivotal regulator of PI(4,5)P 2 and inactivated in many CRC cancers via genetic deletion or hyperphosphorylation. Therefore, MARCKS may critically impact ABCB1., Methods: CRC samples as well as CRC cell lines were tested for a connection between MARCKS and ABCB1 via immunofluorescence and Western-blot analysis. ABCB1 function was studied via calcein influx assay under treatment with known ABCB1 inhibitors (verapamil, tariquidar) as well as the kinase inhibitor bosutinib. ABCB1 internalization and MARCKS translocation was analyzed via confocal microscopy exploiting the endocytosis inhibitors chlorpromazine and dynasore. Abundance of PI(4,5)P 2 was monitored by intramolecular fluorescence resonance energy transfer (FRET). Reproductive cell survival was studied via colorimetric WST-1 and clonogenic assays in combination with exposure to the chemotherapeutics doxorubicin and 5-fuorouracil (5-FU)., Results: We found increased ABCB1 expression in MARCKS negative CRC patient tumor samples and established CRC cell lines. Mechanistically, the reconstitution of MARCKS function via recombinant expression or the pharmacological inhibition of MARCKS phosphorylation led to a substantial decrease in ABCB1 activity. In CRC cells, bosutinib treatment resulted in a MARCKS translocation from the cytosol to the plasma membrane, while simultaneously, ABCB1 was relocated to intracellular compartments. Inhibition of MARCKS phosphorylation via bosutinib rendered cells more sensitive to the chemotherapeutics doxorubicin and 5-FU., Conclusions: Cells devoid of MARCKS function showed incomplete ABCB1 internalization, leading to higher ABCB1 activity enhancing chemoresistance. Vice versa our data suggest the prevention of MARCKS inhibition by reversing hyperphosphorylation or genomic restoration after deletion as two promising approaches to overcome tumor cell resistance towards chemotherapeutic ABCB1 substrates.

BACKGROUND Transplantation of the liver entails a state of altered recipient immunologic competence. There are only scarce data concerning the impact of host immunologic factors on the outcome of liver transplant recipients in the context of hepatocellular carcinoma (HCC). MATERIAL AND METHODS Our study focused on evaluating the presence of tumor necrosis and frequency levels of angiopoietins and monocytes/macrophages subtypes in the host liver prior to liver transplantation (LTX) and their association with recurrence, graft rejection, survival, and clinical prognosis after LTX. Formation of tumor necrosis and tissue densities of angiopoietins and cellular immunologic infiltrates - CD68⁺ and CD163⁺ macrophages (TAMs) and TIE2-expressing monocytes (TEMs) - were quantified in recipient HCC specimens. The densities were then matched with clinicopathologic variables and patient survival after LTX (n=88). Some patients were treated prior to LTX by neoadjuvant transarterial chemoembolization (TACE, n=55). RESULTS Recipient hepatic infiltration with TEMs and CD68⁺ TAMs was associated with decreased 1-, 3-, and 5-year survival, as well as metastatic and recurrent HCC after LTX (all p<0.05). TEMs and infiltrating monocytes/macrophages were associated with angiopoietin expression, metastatic, and recurrent HCC (all p<0.05). Furthermore, hepatic angiopoietin-2 expression was associated with graft rejection after LTX (p<0.05). After TACE and LTX, formation of tumor necrosis was associated with an increased presence of monocytes/macrophages and a reduced incidence of recurrent HCC in the graft (all p<0.05). CONCLUSIONS Infiltrating monocytes/macrophages subsets and related angiopoietin axis are associated with worse survival, tumor recurrence, and clinical outcome after LTX for HCC.

Background: Patients with intestinal cancer (colorectal, appendiceal, and small bowel) with peritoneal metastases (PM) have a poor prognosis. We assessed whether pressurized intraperitoneal aerosol chemotherapy (PIPAC) together with systemic chemotherapy is an effective treatment option for these entities in palliative intent., Methods: Between November 2015 and February 2018, prospective data registry was performed (NCT03100708). Thirteen patients with intestinal cancer (median age 61 years [range 49-77]) underwent 26 PIPAC procedures with a median number of 2 interventions per patient (range 1-6). A chemoaerosol consisting of cisplatin/doxorubicin was administered during standard laparoscopy., Results: The median peritoneal carcinomatosis index according to Sugarbaker before the first PIPAC was 14 (range 2-27), and the median ascites volume was 10 mL (range 0-6300 mL). Six patients who received 2 or more PIPAC procedures had decreased and stable ascites volumes, while only 1 patient displayed increased ascites. The median overall survival was 303 days (range 30-490) after the first PIPAC procedure., Conclusions: PIPAC offers a novel treatment option for patients with PM. Our data show that PIPAC is safe and well-tolerated. Ascites production can be controlled by PIPAC in patients with intestinal cancer. Further studies are required to document the significance of PIPAC within palliative therapy concepts., Trial Registration: NCT03100708.

Background: Tumor escape mechanisms mediated in the tumor microenvironment can significantly reduce the capacity of the anti-tumor function of the immune system. TIE2-expressing monocytes (TEMs), related angiopoietins, and tumor necrosis are considered to have a key role in this process. We aimed to investigate the abundance and clinical significance of these biomarkers in hepatocellular carcinoma (HCC)., Methods: In this retrospective study, 58 HCC patients received surgery with a curative intent. The abundance of TEMs, angiopoietin-1 and -2 were detected in tumor specimens of the HCC patients (n = 58), and together with the occurrence of histologic tumor necrosis, were associated with established clinicopathological characteristics and survival., Results: Patients with HCC characterized by necrosis and TEMs revealed reduced both overall survival and recurrence-free survival (all p < 0.05). Angiopoietins and TEMs were associated with metastatic and recurrent HCC. Furthermore, the formation of histologic tumor necrosis was associated with advanced tumor stage and density of TEMs (all p < 0.05)., Conclusions: Histologic tumor necrosis, TEMs, and related angiopoietins were associated with multiple HCC parameters and patient survival. The tumor necrosis-TEM-angiopoietin axis may offer a novel diagnostic modality to predict patient outcome after surgery for HCC.

Glass and glass-ceramic samples of metastable lithium thiophosphates with compositions of 70Li 2 S-30P 2 S 5 and Li 7 P 3 S 11 were controllably prepared by using a rapid assisted-microwave procedure in under 30 min. The rapid preparation times and weak coupling of the evacuated silica ampules with microwave radiation ensure minimal reactivity of the reactants and the container. The microwave-prepared samples display comparable conductivity values with more conventionally prepared (melt quenched) glass and glass-ceramic samples, on the order of 0.1 and 1 mS cm -1 at room temperature, respectively. Rietveld analysis of synchrotron X-ray diffraction data acquired with an internal standard quantitatively yields phase amounts of the glassy and amorphous components, establishing the tunable nature of the microwave preparation. X-ray photoelectron spectroscopy and Raman spectroscopy confirm the composition and the appropriate ratios of isolated and corner-sharing tetrahedra in these semicrystalline systems. Solid-state 7 Li nuclear magnetic resonance (NMR) spectroscopy resolves the seven crystallographic Li sites in the crystalline compound into three main environments. The diffusion behavior of these Li environments as obtained from pulsed-field gradient NMR methods can be separated into one slow and one fast component. The rapid and tunable approach to the preparation of high quality "Li 7 P 3 S 11 " samples presented here coupled with detailed structural and compositional analysis opens the door to new and promising metastable solid electrolytes.

Pulmonary edema (PE) is an issue widely noted in acute exposure to hypoxia as seen in high altitude climbers, yet the etiology of this is not defined. Previous studies in rats showed that both hypoxia and strong sympathetic activation may induce PE. As acute exposure to hypoxia is accompanied by sympathetic activation, we assume that this may impair pulmonary circulation and contribute to the development of hypoxic PE. The aim of the present study was to investigate the effects of adrenergic agonists and antagonists as models for overstimulation and suppression, respectively, of sympathetic activity on cardiovascular function and formation of PE in hypoxic rats. Norepinephrine or adrenergic blockers were infused to rats exposed to normobaric hypoxia with 10% O 2 over time intervals up to 24 h. Normoxic and hypoxic controls received 0.9% NaCl infusion. We evaluated hemodynamic function and lung histology. A significant decrease of left ventricular systolic function was observed after 6 h of hypoxia. This effect was less pronounced with α-adrenergic blockade but was more severe with combined α-plus β-adrenergic blockade. Norepinephrine delayed the onset of hypoxic left ventricular depression but did not reduce its degree. Significant PE developed after 16 h of hypoxia. It regressed under α- but not with β-adrenergic blockade, and was aggravated by combining hypoxia with norepinephrine. Almost half of the animals exposed to hypoxia over 16-24 h suffered cardiorespiratory arrest during the experiment and presented with signs of acute right ventricular failure. They had significantly elevated serum catecholamine concentrations and significantly stronger PE than the others. Notably, most of them had received norepinephrine or combined adrenergic blockade. Mild changes in serum catecholamine concentrations indicated that hypoxic sympathoadrenergic activation was only weak. Hence, it was not sufficient to prevent left ventricular depression. However, the results show that α-adrenergic mechanisms contribute to the formation of hypoxic PE. Adrenergic blockade but also sympathetic overactivity may induce pulmonary congestion, PE and acute right ventricular failure indicating that a fine balance of sympathetic activation under hypoxic conditions is crucial. This has important implications for climbers to high altitude as well as for patients suffering from hypoxia.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Anti-tumour immune competence has an impact in hepatocarcinogenesis and success of anti-cancer therapies. Tumour-infiltrating lymphocytes (TILs) and monocytes/macrophages (TAMs) are proposed to have significance in cancer. However, there is only limited data concerning their impact on patient outcome and survival in hepatocellular carcinoma (HCC)., Methods: Frequencies of CD68 + , CD163 + M2-polarized TAMs and TILs were measured in de novo HCC tumours in non-cirrhosis (n = 58) using immunohistology and correlated to patients' clinicopathological characteristics and survival rates., Results: Patients with tumours marked by appearance of TILs and CD68 + TAMs showed an improved 1-, 3- and 5-year recurrence-free survival (all p ≤ 0.05). CD68 + TAMs were associated with reduced incidence of recurrent and multifocal disease. Conversely, CD163 + TAMs were associated with multifocal HCC and lymphangiosis carcinomatosa (all p ≤ 0.05)., Conclusions: TILs and CD68 + TAMs are associated with multiple tumour characteristics and patient survival in HCC. However, there is only scarce data about the biology underlying their mechanistic involvement in human tumour progression. Thus, experimental data on functional links might help develop novel immunologic checkpoint inhibitor targets for liver cancer.

Introduction: Intraoperative pathologic findings during bariatric surgery are relatively rare. Gastrointestinal stromal tumors (GISTs) are commonly located in the stomach and account for < 1% of all neoplasms of the alimentary tract. Coincidental detection of GISTs during bariatric surgery has been reported around 0.8%. We analyzed the incidence of GISTs in bariatric patients and investigated whether simultaneous resection can be oncologically adequate., Material/methods: A single-center retrospective study of 707 morbidly obese patients, who underwent bariatric surgery (either Roux-en-Y gastric bypass (RYGB), One Anastomosis Gastric Bypass (OAGB), or sleeve resection (LSG) between January 2012 and August 2018). Intraoperative incidental GISTs were recorded and documented for tumor size, localization, immunoreactivity, and mitotic index., Results: Nine (1.27%) patients were identified with GISTs. Seven (78%) tumors were detected in women; mean age 55.6 (range 27-74), mean BMI 51.7 mg/m2 (range 38-71). GISTs were predominantly located in the stomach (78%) and two (22%) within the small bowel; six were found during RYGB vs. three during LSG. No abort of surgery or change of the intended procedure was necessary. All tumors (0.2-3.7 cm) were resected with disease-free surgical margins and displayed low malignancy. No adjuvant therapy was necessary., Conclusions: The incidence of incidental GISTs in our series was higher to what has already been reported. Risk of malignancy was low and resection as part of the bariatric procedure was considered as definitive treatment. Suspicious tumors should be removed and confirmed by histology. In case of GIST histology, tumor resection with negative margins may be weighed as complete oncological treatment if there is low risk of malignancy.

Introduction: The differential diagnosis and therapy of retroperitoneal masses suspicious for soft tissue tumors remains difficult and needs individual decisions as to the best management of patients. We report an unusual case of retroperitoneal schwannoma (RS)., Presentation of Case: We report on a 57-year-old female patient with a retroperitoneal space-occupying lesion with displacement, but no infiltration of surrounding vessels, especially the inferior vena cava. As presence of malignancy could not be completely excluded by imaging and biopsy, we performed an open resection of the tumor with plastic reconstruction of the right renal vein. Curative resection of the tumor could be achieved and benign RS verified., Discussion: Preoperative work-up, including a broad spectrum of differential diagnoses, and consecutive appropriate surgical resection are challenging. Characteristic features of the pre-therapeutic diagnostics of retroperitoneal schwannomas are discussed and differential diagnostic considerations as well as surgical therapeutic options are outlined., Conclusion: Deeper understanding of retroperitoneal schwannomas gained from preoperative radiologic diagnostics may serve to underline the need for targeted biopsy. This and its histopathological examination necessitate expert interventional radiologists and pathologists. Thus, even the pre-therapeutic diagnostic management should be performed in a specialized center. If doubts remain regarding the entity of the retroperitoneal lesion and findings are still controversial after thorough assessment, surgical oncologic resection represents the therapy of choice, if the surgical risk is adequate., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Gastric cancer (GC) patients with peritoneal metastasis (PM) have poor prognosis. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in combination with systemic chemotherapy is a novel treatment option for patients in stage IV of the disease., Materials and Methods: Between November 2015 and June 2018, prospective data collection was performed in 24 patients with GC and PM (median age, 57; range, 44-75 years). These patients underwent 46 PIPAC procedures with a median number of 2 interventions per patient (range, 1-6). A laparoscopic access was used and a combined therapy of cisplatin and doxorubicin aerosol was administered., Results: The median peritoneal carcinomatosis index before the 1st PIPAC was 14 (range, 2-36), and the median ascites volume in patients before the 1st PIPAC was 100 mL (range, 0-6 mL, 300 mL). Eleven patients, who received 2 or more PIPAC procedures, had decreased and stable volumes of ascites, while only 3 patients displayed increasing volume of ascites. The median overall survival was 121 days (range, 66-625 days) after the 1st PIPAC procedure, while 8 patients who received more than 3 PIPAC procedures had a median survival of 450 days (range, 206-481 days) (P=0.0376)., Conclusions: Our data show that PIPAC is safe and well tolerated, and that the production of ascites can be controlled by PIPAC in GC patients. Patients, who received 2 or more PIPAC procedures, reported a stable overall quality of life. Further studies are required to document the significance of PIPAC as a palliative multimodal therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT03100708., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported.

Reducing the diameter of silver nanowires has been proven to be an effective way to improve their optoelectronic performance by lessening light attenuation. The state-of-the-art silver nanowires are typically around 20 nm in diameter. Herein we report a modified polyol synthesis of silver nanowires with average diameters as thin as 13 nm and aspect ratios up to 3000. The success of this synthesis is based on the employment of benzoin-derived radicals in the polyol approach and does not require high-pressure conditions. The strong reducing power of radicals allows the reduction of silver precursors to occur at relatively low temperatures, wherein the lateral growth of silver nanowires is restrained because of efficient surface passivation. The optoelectronic performance of as-prepared 13 nm silver nanowires presents a sheet resistance of 28 Ω sq -1 at a transmittance of 95% with a haze factor of ∼1.2%, comparable to that of commercial indium tin oxide (ITO).

Background: Tumour angiogenesis is modulated on both an epigenetic and protein level and has potential implications for immune cell responses. However, the importance of related angiogenic biomarkers in cholangiocarcinoma (CCA) is unknown. This study assessed human CCA samples for the expression of angiogenesis-associated microRNAs, angiopoietins (Angs) and monocytes expressing the Ang-receptor, TIE2, with regards to prognostic significance after liver resection., Methods: Angiogenic miRNAs were analysed in frozen samples of intrahepatic CCA (iCC; n = 43) and hilar CCA (HC; n = 45). Ang-1 and Ang-2, as well as TIE2-expressing monocytes (TEMs), were detected in paraffin-embedded iCC sections (n = 88). MiRNA expression and the abundance of TEMs and Angs were correlated with clinicopathological characteristics and survival., Results: MiR-126 was downregulated in 76.7% of all CCA samples, with high relative expression associated with smaller tumours and reduced lymph node metastasis. High Ang-1 expression was associated with less lymphangiosis carcinomatosa and better histological grading (all p < 0.05). The absence of TEMs in iCC correlated with elevated CA19-9 levels. High relative miR-126 and low miR-128 levels were associated with improved survival in iCC and HC, respectively (all p < 0.05). High miR-126, low miR-128 and TEMs were independent prognostic factors for recurrence-free and overall survival (all p < 0.05)., Conclusions: These results suggest that angiogenic miRNAs, Angs and TEMs are of prognostic value in CCA. In addition to the possible functional links between angiogenic miRNA expression profiles, Angs and immune-cell responses by TEMs, these data have clinical implications as novel diagnostic tools., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interest.

Introduction: M2-polarized tumor-associated macrophages (TAMs) and TIE2-expressing monocytes (TEMs) are associated with angiogenesis and have been identified as a potential prognostic marker in several solid tumors, including hepatobiliary malignancies. However, little is known regarding their influence on tumor progression and patient survival in pancreatic ductal adenocarcinoma (PDAC)., Results: Patients with tumors characterized by the presence of CD163 + TAMs or TEMs in TCA or TIF, respectively, showed a significantly decreased 1-, 3- and 5-year overall and recurrence-free survival compared to patients without CD163 + TAMs or TEMs (all ρ < 0.05). Patients with TEMs in TCA showed a higher incidence of tumor recurrence ( ρ < 0.05). Furthermore, the presence of CD163 + TAMs was associated with a higher tumor MVD ( ρ < 0.05)., Conclusions: Presence of M2-polarized TAMs and TEMs is associated with a decreased overall and recurrence-free survival of patients with PDAC., Materials and Methods: The localization and density of CD163 + M2-polarized TAMs and TEMs were quantified in the tumor central area (TCA) and tumor-infiltrating front (TIF) in human PDAC tissue ( n = 106) and correlated to clinicopathological characteristics, tumor recurrence rates and patient survival. In parallel, tumor microvascular density (MVD) and the density of angiopoietin-positive tumor cells were quantified. Statistical analysis was performed using SPSS software., Competing Interests: CONFLICTS OF INTEREST The authors declare that they have no competing interests related to the work.

Background: Legacy data and new structured data can be stored in a standardized format as XML-based EHRs on XML databases. Querying documents on these databases is crucial for answering research questions. Instead of using free text searches, that lead to false positive results, the precision can be increased by constraining the search to certain parts of documents., Methods: A search ontology-based specification of queries on XML documents defines search concepts and relates them to parts in the XML document structure. Such query specification method is practically introduced and evaluated by applying concrete research questions formulated in natural language on a data collection for information retrieval purposes. The search is performed by search ontology-based XPath engineering that reuses ontologies and XML-related W3C standards., Results: The key result is that the specification of research questions can be supported by the usage of search ontology-based XPath engineering. A deeper recognition of entities and a semantic understanding of the content is necessary for a further improvement of precision and recall. Key limitation is that the application of the introduced process requires skills in ontology and software development. In future, the time consuming ontology development could be overcome by implementing a new clinical role: the clinical ontologist., Conclusion: The introduced Search Ontology XML extension connects Search Terms to certain parts in XML documents and enables an ontology-based definition of queries. Search ontology-based XPath engineering can support research question answering by the specification of complex XPath expressions without deep syntax knowledge about XPaths.

The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor., (© 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Lymphangioma circumscriptum (LC) is a rare, benign condition, predominantly characterized by the malformation of lymphatic skin vessels. Its onset may be congenital or due to secondary causes such as radiotherapy, infections, or surgical procedures. We present the case of a 55-year-old patient with a pathologic history of squamous cell carcinoma of the penis followed by radical penectomy. Due to metastasis to the locoregional lymph nodes, the entire affected area was subsequently treated with radiation therapy, receiving a total dose of 55.8 Gray. Eight years after this treatment, translucent vesicles filled with a clear liquid appeared on the scrotum. Histopathology confirmed the diagnosis of LC and therapy with CO2 laser was applied, resulting in a favorable outcome. LC of the scrotum may present a long-term radiotherapy-induced complication of this site. Our clinical experience showed that the CO2 laser was the therapy of choice as the vesicles entirely disappeared and healed as white scar-like lesions.

Background: Heterotopic gastric tissue can be found in the entire gastrointestinal tract. It is usually located in the upper intestine. Rarely, it can be found in the gallbladder. This study describes several clinically, imaging features as well as histopathology findings of heterotopic gastric tissue in gallbladder (HGM)., Methods: The radiologic database of 1 tertiary university hospital was retrospectively screened for HGM. Additionally, a systemic review of the Medline database was conducted to identify previously published cases reports. In all cases clinical, imaging as well as histopathology features were retrieved from the papers., Results: In our databases, 1 patient with HGM was identified. Additionally, the systemic review yielded 32 suitable papers with 34 patients. Clinically, most of the patients suffered from abdominal discomfort. Most of the lesions were located in the lower gallbladder, especially (n = 14, 40%) in the gallbladder neck. On sonography, in 20.7% a broad-based mass was described. In 10.3% a sessile polyp was identified. In 5 cases, the mass was characterized as hyperechoic (55.5%), as isoechoic in 3 (33.3%) cases, and hypoechoic in 1 (11.1%). On computed tomography (CT), the lesions were most frequently hyperdense and all of them showed a slightly enhancement after application of contrast medium. On histopathology, most cases revealed heterotopic gastric mucosa of body-fundic type (60%) with chief and parietal cells, followed by pyloric type glands (20%). Every patient was treated with cholecystectomy and all had an uneventful recovery., Conclusion: HGM is a rare disorder with several differential diagnoses. Typically features were described to identify HGM in clinical routine and rule out malignant diseases like gallbladder carcinoma.

Rapid preparation utilizing assisted microwave heating permits significantly shorter preparation times for magnetocaloric compounds in the (Mn,Fe) 2 (P,Si) family, specifically samples of (Mn,Fe) 2-δ P 0.5 Si 0.5 with starting compositions of δ = 0, 0.06, and 0.12. To fully understand the effects of processing and composition changes on structure and properties, these materials are characterized using synchrotron powder diffraction, neutron powder diffraction, electron microprobe analysis (EMPA), X-ray fluorescence (XRF), and magnetic measurements. The diffraction analysis reveals that increasing δ results in decreasing amounts of the common Heusler (Mn,Fe) 3 Si secondary phase. EMPA shows (Mn,Fe) 2 (P,Si) in all three samples to be Mn and P rich, whereas XRF demonstrates that the bulk material is Mn rich yet P deficient. Increasing δ brings the Mn/Fe and P/Si ratios closer to their starting values. Measurements of magnetic properties show an increase in saturation magnetization and ordering temperature with increasing δ, consistent with the increase in Fe and Si contents. Increasing δ also results in a decrease in thermal hysteresis and an increase in magnetic entropy change, the latter reaching values close to what have been previously reported on samples that take much longer to prepare.

Schwannomas are benign tumors derived from Schwann cells and their typical site of origin is the subcutaneous tissue of the extremities. Gastrointestinal localization of Schwannomas is extremely rare and the stomach is the prevalent site. Gastric schwannomas primarily occur in the gastric submucosa and are usually asymptomatic.We present a rare case of a solitary gastric schwannoma in a 51-year old male, which initially manifested with hematemesis by acute upper gastrointestinal (GI) bleeding. The upper GI-Endoscopy revealed a gastric submucosal tumor, 7 cm in size, located in the proximal corpus and fundus. In the endoscopical Ultrasound (EUS-Examination), the lesion appeared to arise from the fourth proper muscle layer (Muscularis propria). The fourth layer origin and the isoechogenicity, as compared to the normal muscle layer, are endoscopic ultrasonographic characteristics of gastric schwannomas and help in distinguishing them from gastrointestinal tumors (GIST). Because of the unclear histological identity, the patient underwent a "rendezvous" endoscopic-laparoscopic surgical resection of the tumor in toto. The histomorphological features of the lesion and the strong expression of S100 in combination with absence of DOG1 expression indicated the diagnosis of gastric schwannoma. There was no evidence of malignancy. The postoperative course was uncomplicated.This is a very rare manifestation of gastric schwannoma, representing a rare differenzial diagnosis in a case of acute upper GI-Bleeding. Only 14 % of gastric schwanommas are presented with gastrointestinal bleeding, including mainly melena rather than hematemesis. This case is considered to be worthy of presentation owing to the rare and unusual cause of upper GI bleeding implied in it., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background . Tumor necrosis as well as tumor-associated macrophages (TAMs) in the tumor invasive front (TIF) have been suggested to have a prognostic value in selected solid tumors, inclusive hilar cholangiocarcinoma. However, little is known regarding their influence on tumor progression and prognosis in intrahepatic cholangiocarcinoma (iCC). Methods . We analyzed surgically resected tumor specimens of human iCC (n = 88) for distribution and localization of TAMs, as defined by expression of CD68, formation of necrosis and extent of peritumoral fibrosis. Abundance of TAMs, tumor necrosis and grade of fibrosis were assessed immunohistochemically and histologically and correlated with clinicopathological characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software. Results . Patients with tumors characterized by low levels of TAMs in TIF or necrosis showed a significantly decreased 1-, 3- and 5-y recurrence-free survival and a significantly decreased overall survival, when compared with patients with tumors showing high levels of TAMs in TIF or no necrosis. Patients with high density of TAMs in TIF showed significantly lower incidence of tumor recurrence, as well ( p < 0.05). Absence of tumor necrosis and TAMs in TIF were confirmed as independent prognostic variables in the multivariate survival analysis (all p < 0.05). Conclusions . High levels of TAMs in TIF or absence of histologic tumor necrosis are associated with a significantly improved recurrence-free and overall survival of patients with iCC. These results suggest TAMs and necrosis as valuable prognostic markers in routine histopathologic evaluation, and might indicate more individualized therapeutic strategies.

Copper nanowire networks are considered a promising alternative to indium tin oxide as transparent conductors. The fast degradation of copper in ambient conditions, however, largely overshadows their practical applications. Here, we develop the synthesis of ultrathin Cu@Au core-shell nanowires using trioctylphosphine as a strong binding ligand to prevent galvanic replacement reactions. The epitaxial overgrowth of a gold shell with a few atomic layers on the surface of copper nanowires can greatly enhance their resistance to heat (80 °C), humidity (80%) and air for at least 700 h, while their optical and electrical performance remained similar to the original high-performance copper (e.g., sheet resistance 35 Ω sq -1 at transmittance of ∼89% with a haze factor <3%). The precise engineering of core-shell nanostructures demonstrated in this study offers huge potential to further explore the applications of copper nanowires in flexible and stretchable electronic and optoelectronic devices.

Early-late intermetallic phases have garnered increased attention recently for their catalytic properties. To achieve the high surface areas needed for industrially relevant applications, these phases must be synthesized as nanoparticles in a scalable fashion. Herein, Pt 3 Y-targeted as a prototypical example of an early-late intermetallic-has been synthesized as nanoparticles approximately 5-20 nm in diameter via a solution process and characterized by XRD, TEM, EDS, and XPS. The key development is the use of a molten borohydride (MEt 3 BH, M = Na, K) as both the reducing agent and reaction medium. Readily available halide precursors of the two metals are used. Accordingly, no organic ligands are necessary, as the resulting halide salt byproduct prevents sintering, which further permits dispersion of the nanoscale intermetallic onto a support. The versatility of this approach was validated by the synthesis of other intermetallic phases such as Pt 3 Sc, Pt 3 Lu, Pt 2 Na, and Au 2 Y.

Solid pancreatic lesions found on imaging procedures are suspicious for malignancy and, therefore, demand immediate diagnostic evaluation and therapy. In the case of indeterminate histology, a primary resection should be considered in order to preserve the possibility of curative surgery, although rare entities may be initially disregarded. We present here the case of a 48-year-old female patient with a hypoechoic lesion of the pancreatic head, which was clearly delineated from the surrounding pancreatic tissue. The challenging diagnosis of metastatic leiomyosarcoma could only be established by considering the long-term clinical history and former histology specimens., (© Georg Thieme Verlag KG Stuttgart · New York.)

In this work, we report a new, general synthetic approach that uses heat driven benzoin radicals to grow ultrathin copper nanowires with tunable diameters. This is the first time carbon organic radicals have been used as a reducing agent in metal nanowire synthesis. In-situ temperature dependent electron paramagnetic resonance (EPR) spectroscopic studies show that the active reducing agent is the free radicals produced by benzoins under elevated temperature. Furthermore, the reducing power of benzoin can be readily tuned by symmetrically decorating functional groups on the two benzene rings. When the aromatic rings are modified with electron donating (withdrawing) groups, the reducing power is promoted (suppressed). The controllable reactivity gives the carbon organic radical great potential as a versatile reducing agent that can be generalized in other metallic nanowire syntheses.

Background: Tumor necrosis and peritumoral fibrosis have both been suggested to have a prognostic value in selected solid tumors. However, little is known regarding their influence on tumor progression and prognosis in hilar cholangiocarcinoma (HC)., Methods: Surgically resected tumor specimens of HC (n = 47) were analyzed for formation of necrosis and extent of peritumoral fibrosis. Tumor necrosis and grade of fibrosis were assessed histologically and correlated with clinicopathological characteristics, tumor recurrence, and patients' survival. Univariate Kaplan-Meier analysis and a stepwise multivariable Cox regression model were applied., Results: Mild peritumoral fibrosis was evident in 12 tumor samples, moderate peritumoral fibrosis in 20, and high-grade fibrosis in 15. Necrosis was evident in 19 of 47 tumor samples. Patients with tumors characterized by necrosis showed a significantly decreased 5-year recurrence-free survival (37.9 vs. 25.7 %; p < .05) and a significantly decreased 5-year overall survival (42.6 vs. 12.4 %; p < .05), when compared with patients with tumors showing no necrosis. R status, tumor recurrence, and tumor necrosis were of prognostic value in the univariate analysis (all p < .05). Multivariate survival analysis confirmed tumor necrosis (p = .038) as the only independent prognostic variable., Conclusions: The assessment of tumor necrosis appears as a valuable additional prognostic tool in routine histopathological evaluation of HC. These observations might have implications for monitoring and more individualized multimodal therapeutic strategies.

A multitude of factors influence the state of tissue samples on their way from the biopsy site in the body to the pathologist's microscope. Some of these factors can be influenced by surgeons, while others are dealt with in pathology departments, but surgeons should know potential pitfalls and caveats and their influence on the pathohistological diagnosis. These factors influence diagnoses made on conventional stains, but even more so the results of immunohistochemical stains and molecular pathology examinations. Therefore, the work-up of tissue samples should be standardised. This is of utmost importance for biobank tissue samples, especially those for which a tissue treatment protocol is recommended., (Georg Thieme Verlag KG Stuttgart · New York.)

Background and Objectives: Angiopoietins (Angs) play a pivotal role in angiogenesis and inflammation, and are associated with prognosis in malignancies. Monocyte express Ang-receptor TIE2 and correlate with prognosis in cancer. We aimed to investigate the prognostic value of Angs and TIE2-expressing monocytes (TEMs) in cholangiocarcinoma., Methods: We analyzed surgically resected tumor specimens of hilar cholangiocarcinoma (n = 47) for distribution of Angs (Ang 1/Ang 2) and TEMs, as defined by co-expression of CD14 and Ang receptor TIE2. Ang expression and abundance of TEMs were correlated with clinicopathologic characteristics, tumor recurrence and patients' survival., Results: High Ang 1 expression correlated with reduced metastasis (P < 0.05). Patients characterized by invading Ang-receptor bearing TEMs in tumor showed lower tumor recurrence (P < 0.05). Furthermore, TEMs in tumor and tumor invasive front correlated with increased survival (P < 0.05). TEMs in tumor invasive front were confirmed as independent prognosticator in multivariate survival analysis (P < 0.05)., Conclusions: High Ang 1 expression in hilar cholangiocarcinoma and infiltration of TEMs defines a subgroup of patients with beneficial tumor characteristics and prolonged survival. Besides suggested functional links between Ang expression and recruitment of TEMs, our data have possible clinical implications as novel diagnostic tools. J. Surg. Oncol. 2016;114:91-98. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Copper nanowire (Cu NW) based transparent conductors are promising candidates to replace ITO (indium-tin-oxide) owing to the high electrical conductivity and low-cost of copper. However, the relatively low performance and poor stability of Cu NWs under ambient conditions limit the practical application of these devices. Here, we report a solution-based approach to wrap graphene oxide (GO) nanosheets on the surface of ultrathin copper nanowires. By mild thermal annealing, GO can be reduced and high quality Cu r-GO core-shell NWs can be obtained. High performance transparent conducting films were fabricated with these ultrathin core-shell nanowires and excellent optical and electric performance was achieved. The core-shell NW structure enables the production of highly stable conducting films (over 200 days stored in air), which have comparable performance to ITO and silver NW thin films (sheet resistance ∼28 Ω/sq, haze ∼2% at transmittance of ∼90%).

Colloidal metal nanowire based transparent conductors are excellent candidates to replace indium-tin-oxide (ITO) owing to their outstanding balance between transparency and conductivity, flexibility, and solution-processability. Copper stands out as a promising material candidate due to its high intrinsic conductivity and earth abundance. Here, we report a new synthetic approach, using tris(trimethylsilyl)silane as a mild reducing reagent, for synthesizing high-quality, ultrathin, and monodispersed copper nanowires, with an average diameter of 17.5 nm and a mean length of 17 μm. A study of the growth mechanism using high-resolution transmission electron microscopy reveals that the copper nanowires adopt a five-fold twinned structure and evolve from decahedral nanoseeds. Fabricated transparent conducting films exhibit excellent transparency and conductivity. An additional advantage of our nanowire transparent conductors is highlighted through reduced optical haze factors (forward light scattering) due to the small nanowire diameter.

Background: Tumor-associated macrophages (TAMs) promote tumor progression and have an effect on survival in human cancer. However, little is known regarding their influence on tumor progression and prognosis in human hilar cholangiocarcinoma., Methods: We analyzed surgically resected tumor specimens of hilar cholangiocarcinoma (n = 47) for distribution and localization of TAMs, as defined by expression of CD68. Abundance of TAMs was correlated with clinicopathologic characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software., Results: Patients with high density of TAMs in tumor invasive front (TIF) showed significantly higher local and overall tumor recurrence (both ρ < 0.05). Furthermore, high density of TAMs was associated with decreased overall (one-year 83.6% vs. 75.1%; three-year 61.3% vs. 42.4%; both ρ < 0.05) and recurrence-free survival (one-year 93.9% vs. 57.4%; three-year 59.8% vs. 26.2%; both ρ < 0.05). TAMs in TIF and tumor recurrence, were confirmed as the only independent prognostic variables in the multivariate survival analysis (all ρ < 0.05)., Conclusions: Overall survival and recurrence free survival of patients with hilar cholangiocarcinoma significantly improved in patients with low levels of TAMs in the area of TIF, when compared to those with a high density of TAMs. These observations suggest their utilization as valuable prognostic markers in routine histopathologic evaluation, and might indicate future therapeutic approaches by targeting TAMs.

The surgical reconstruction of ureteric defects is often associated with post-operative complications and requires additional medical care. Decellularized ureters originating from porcine donors could represent an alternative therapy. Our aim was to investigate the possibility of manufacturing decellularized ureters, the characteristics of the extracellular matrix (ECM) and the biocompatibility of these grafts in vitro/in vivo after treatment with different crosslinking agents. To achieve these goals, native ureters were obtained from pigs and were decellularized. The success of decellularization and the ECM composition were characterized by (immuno)histological staining methods and a DNA-assay. In vitro: scaffolds were crosslinked either with carbodiimide (CDI), genipin (GP), glutaraldehyde, left chemically untreated or were lyophilized. Scaffolds in each group were reseeded with Caco2, LS48, 3T3 cells, or native rat smooth muscle cells (SMC). After 2 weeks, the number of ingrown cells was quantified. In vivo: crosslinked scaffolds were implanted subcutaneously into rats and the type of infiltrating cells were determined after 1, 9, and 30 days. After decellularization, scaffold morphology and composition of ECM were maintained, all cellular components were removed, DNA destroyed and strongly reduced. In vitro: GP and CDI scaffolds revealed a higher number of ingrown 3T3 and SMC cells as compared to untreated scaffolds. In vivo: at day 30, implants were predominantly infiltrated by fibroblasts and M2 anti-inflammatory macrophages. A maximum of MMP3 was observed in the CDI group at day 30. TIMP1 was below the detection limit. In this study, we demonstrated the potential of decellularization to create biocompatible porcine ureteric grafts, whereas a CDI-crosslink may facilitate the remodeling process. The use of decellularized ureteric grafts may represent a novel therapeutic method in reconstruction of ureteric defects.

In some patients with tumors located in the pancreas or in the periampullary region, the decision to perform a surgical resection can be difficult. In patients with concomitant chronic pancreatitis this decision can be even more challenging, since a definitive preoperative differentiation between non-malignant and malignant tumors in many cases is not possible. Clinical symptoms or complications from the tumor often direct a rational treatment strategy. For therapeutic decisions, an interdisciplinary discussion of all diagnostic findings by experienced clinicians is needed. However, in rare cases, like the one presented here, an uncommon non-malignant entity like a periampullary hamartoma may be only diagnosed after surgical resection., (Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Previously, we reported a six-marker gene set, which allowed a molecular discrimination of benign and malignant thyroid tumours. Now, we evaluated these markers in fine-needle aspiration biopsies (FNAB) in a prospective, independent series of thyroid tumours with proven histological outcome., Methods: Quantitative RT-PCR was performed (ADM3, HGD1, LGALS3, PLAB, TFF3, TG) in the needle wash-out of 156 FNAB of follicular adenoma (FA), adenomatous nodules, follicular and papillary thyroid cancers (TC) and normal thyroid tissues (NT)., Results: Significant expression differences were found for TFF3, HGD1, ADM3 and LGALS3 in FNAB of TC compared with benign thyroid nodules and NT. Using two-marker gene sets, a specific FNAB distinction of benign and malignant tumours was achieved with negative predictive values (NPV) up to 0.78 and positive predictive values (PPV) up to 0.84. Two FNAB marker gene combinations (ADM3/TFF3; ADM3/ACTB) allowed the distinction of FA and malignant follicular neoplasia with NPV up to 0.94 and PPV up to 0.86., Conclusion: We demonstrate that molecular FNAB diagnosis of benign and malignant thyroid tumours including follicular neoplasia is possible with recently identified marker gene combinations. We propose multi-centre FNAB studies on these markers to bring this promising diagnostic tool closer to clinical practice.

Background/aims: Previously, we found that catecholamine (CA) infusion in rats induced pulmonary injury with edema and inflammation resembling acute lung injury in humans. Here, we examined effects of norepinephrine (NE) and of selective α- and β-adrenergic agonists on the remodeling of pulmonary extracellular matrix., Methods: Eighty rats were infused over 8-72 h with NE, phenylephrine (PE), isoproterenol (ISO) or NaCl solution. We investigated mRNA expression of collagen, matrix metalloproteinase (MMP)-2, its tissue inhibitor (TIMP-2) and transforming growth factor (TGF)-β isoforms in lung tissue. Additionally, lung histology, hemodynamic function and cardiac hypertrophy were evaluated., Results: After 72 h of infusion, lung histology showed beginning fibrosis and vascular hypertrophy. Collagen type I, MMP-2 and TIMP-2 mRNA expression were significantly elevated. All these effects were most pronounced with NE while PE and ISO induced weaker responses. TGF-β mRNA expression was also elevated after 72 h, predominantly after PE infusion. Cardiac hypertrophy was most pronounced after ISO infusion., Conclusion: CA infusion over 72 h may induce pulmonary remodeling. Mainly α-adrenergic but also β-adrenergic mechanisms contribute to these processes. In contrast, cardiac hypertrophy is predominantly mediated by β-adrenergic stimulation and hence, is considered to be a direct adrenergic effect rather than a consequence of pulmonary fibrosis., (Copyright © 2012 S. Karger AG, Basel.)

Most infants with long-gap esophageal atresia receive an esophageal replacement with tissue from stomach or colon, because the native esophagus is too short for true primary repair. Tissue-engineered esophageal conducts could present an attractive alternative. In this paper, circular decellularized porcine esophageal scaffold tissues were implanted subcutaneously into Sprague-Dawley rats. Depending on scaffold cross-linking with genipin, glutaraldehyde, and carbodiimide (untreated scaffolds : positive control; bovine pericardium : gold standard), the number of infiltrating fibroblasts, lymphocytes, macrophages, giant cells, and capillaries was determined to quantify the host response after 1, 9, and 30 days. Decellularized esophagus scaffolds were shown to maintain native matrix morphology and extracellular matrix composition. Typical inflammatory reactions were observed in all implants; however, the cellular infiltration was reduced in the genipin group. We conclude that genipin is the most efficient and best tolerated cross-linking agent to attenuate inflammation and to improve the integration of esophageal scaffolds into its surrounding tissue after implantation.

Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: A 59-year-old man presented for a follow-up, 6 years after surgery for a large pheochromocytoma. He had suffered from diabetes mellitus, hypertension and abdominal pain in the right flank region. Previous postoperative follow-up did not reveal tumor recurrence., Investigation: Measurement of plasma free metanephrine and normetanephrine by high-performance liquid chromatography and radioimmunoassay; 123I-metaiodobenzylguanidine (MIBG) scintigraphy; hybrid 123I-MIBG single-photon emission CT (SPECT)-CT; MRI; testing for plasma norepinephrine and epinephrine; intraoperative ultrasonography; histological staining for chromogranin A and synaptophysin; and postoperative 18F-dihydroxyphenylalanine (DOPA) PET scan., Diagnosis: Recurrent pheochromocytoma., Management: Laparotomy with tumor resection. Reduction of antihypertensive medications. Further follow-up by MRI, hybrid 123I-MIBG SPECT-CT and testing for plasma catecholamines and free metanephrines.

Aberrations in the control of apoptosis represent a central feature of thyroid carcinogenesis. However, little is known about the regulation of components of the intrinsic apoptosis pathway in the thyroid. Using a real-time PCR approach we investigated the mRNA expression levels of Caspase3, Caspase3 s, xIAP, Bad, and beta-actin in a panel of 79 thyroid tumours. Additionally, we assessed the activation status of Caspase3 by immunohistochemistry. In the present study, we provide first evidence for a deregulation of the intrinsic apoptosis pathway on the transcriptional and post-transcriptional level. Thus, malignant thyroid tumours revealed a significant downregulation of the proapoptotic Bad. In contrast Caspase3 s, an alternative splice variant of Caspase3 with anti-apoptotic characteristics, was upregulated in follicular and anaplastic cancers. Moreover, papillary thyroid tumours revealed a significant upregulation of Caspase3 mRNA. On the post-translational level, thyroid malignancies featured an impairment in the activation of Caspase3, since activated Caspase3 accumulated exclusively in the cytoplasm of thyroid cancer cells, whereas follicular adenoma and normal thyroid tissues showed no cytoplasmatic but nuclear Caspase3 distribution. Further knowledge on apoptosis-deregulation during thyroid carcinogenesis might confer diagnostic and therapeutic benefits in the management of thyroid cancer., ((c) Georg Thieme Verlag KG Stuttgart . New York.)