Introduction/ Background Automated high resolution scanning microscopes digitize large sets of histological samples and access the an anatomical features of cells and tissues from the mm range down to a resolution of .25mpp microns per pixel). The high quality of the scans allows for the collection of the quantitative morphotopological features of cells and tissues from different samples, which can be coupled to functional information through, e.g., concomitant immunostaining. The basis for robust and accurate quantification of structural and functional features is the segmentation of regions of interest (ROIs) which define different elements within the scans. Due to acquisition artifacts and the diversity and variance of possible tar- gets, the characterization and segmentation of ROIs in histological samples is difficult and challenging. In recent years, computational algebraic topology, a field of mathematics, has established a robust and versatile way to obtain qualitative information from data. The most fundamental qualitative description of an object is given by the study of its topology, how the object is connected, how many holes it has, and of what type. That allows characterizing data sets according to their structure, increasing our understanding of their properties. Aims We propose a method for the robust segmentation of hepatocyte nuclei based on the principles of persistent homology, a tool of algebraic topology. We show the application of our technique in histopathological, whole slide images obtained from liver sections of lipopolysaccharide (LPS)-treated mice. The robustness is achieved by the introduction of persistent homology to characterize the hepatocyte nuclei. Its stability proves the usefulness of persistent homology; variations in the properties of the ROIs induce small changes in the resulting characterization. By means of this representation for the hepatocyte nuclei, the resulting segmentation is less sensitive to acquisition artifacts and natural variations of the images across batches of slides. Methods The sample space of this study consists of 856 cropped images of 616x616 pixels each, obtained from three specimens. Each image was fragmented into connected components at different scales. Persistent homology is used to study the inclusion relations between connected components. The outcome of such process is a persistence diagram that provides a low-dimensional projection of the image structure. From that representation, it is possible to use conventional statistical methods for segmenting hepatocyte nuclei. After the segmentation, we assess the performance in comparison to a gold standard segmentation validated by experts. Results The computational topology approach proposed successfully detected hepatocyte cells under several natural variations. We evaluated on a per-pixel basis how the segmentation performs on: i) all nuclei in the images, ii) big round nuclei considered belonging to hepatocytes cells (accuracy 87.2%, recall 80.3%), and iii) nuclei regarded to non-parenchymal cells.

Though considerable efforts have been made in the development of new tools to study ovarian cancer, currently available models are either cell line- or mouse-based. We are developing an innovative human-based model of whole explant tissue culture using primary ovarian tumors.

Im Rahmen des Kongress der American Society for Clinical Oncology (ASCO) 2015 zeigt sich eindrucksvoll, wie effektiv die Immuntherapie bei definierten Patientenkollektiven ist. Besonders beachtlich erwies sich hierbei die Dauer der Responses bis hin zu Langzeitremissionen von metastasierten Erkrankungen.

Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2–68.2 months) vs 17.1 months (0.7–94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.

Preoperative treatment is nowadays standard for locally advanced esophagogastric cancer in Europe. Surprisingly, little attention has been paid to nonresponders so far. The aim of our retrospective exploratory study was the comparison of responder, nonresponder, and primary resected patients in respect of outcome considering the tumor entity.

ABSTRACT Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Colorectal cancer is one of the three most frequent malignancies in humans. Survival is mainly determined by local recurrence, lymphatic and hematogenous dissemination. Primary liver resection for metastases is possible in ~20-25% of patients with hepatic metastases and results in a 50% recurrence rate within 23 months. The five-year survival without treatment in patients with UICC stage IV is only 5%, the mean survival 6-9 months. As a result of promising developments in chemotherapy and targeted therapies in the last decade, the mean survival rate has significantly improved to over more than two years. Furthermore, the use of polychemotherapy in combination with anti-angiogenic and anti-proliferative biologicals has resulted in a significant increase of secondary resectability of liver metastases. Despite of a R0-resection (i.e. resection with clear margins) of liver metastases, only 30% of patients remain free of recurrence in the long-term. Prognostic scores are used for optimal patient selection, e.g. the Fong-Score. Resection is often limited by a high number of recurrences: intrahepatic micrometastases and disseminated tumor cells (DTC) are suspected as the cause of their development. In this connection the load of disseminated tumor cells correlates significantly with the survival and recurrence rate after resection. These micrometastases are targets in current adjuvant treatment studies (e.g. MT 201) by using anti-EpCam antibodies. The detection of DTC can supplement the previously used scores and represents the indication for an adjuvant antibody-based treatment (e.g. anti-EpCam) in the context of clinical trials.

Die prognostische Bedeutung tumorbefallener Lymphknoten (LK) beim M-Ca ist unumstritten. Für Patienten (Pat.) mit LK-Metastasen im prätherapeutischen Staging ist die neoadjuvante Chemotherapie an den meisten Zentren etabliert. Die Prognose bei befallenen LK zum Zeitpunkt der Resektion ist schlecht. Wir untersuchten die prognostische Relevanz der cN-, der pN-Kategorie (Kat.), des Lymphknotenquotienten (LK-Q) sowie der Anzahl resezierter LK. Zusätzlich wurde die Übereinstimmung des klinischen und pathologischen LK-Stagings analysiert.

The Co22.5Si77.5 (at.%) braze was used to bond porous Si3N4 ceramics. The effects of brazing temperature on microstructure and the bonding strength of the joint were studied. The results reveal that no visible reaction layer was observed. The corresponding joint strength was low. In order to improve the joint strength a carbon coated modification of the porous Si3N4 substrate was suggested. The impact of this modification on the joint properties was examined. It was established that a SiC reaction layer with a thickness from ∼15 μm to ∼65 μm was formed at the interface and SiC nanowires were observed when the temperature increased from 1280 °C to 1340 °C. The maximum shear strength of the carbon coated and uncoated joints were 115 MPa and 44 MPa, respectively. The significant improvement of the joint strength was attributed to the SiC reaction layer and a strengthening by the presence of SiC nanowires. .

97 formalin-fixed paraffin embedded biopsies of patients (66 males and 31 females, median age of 65 years) with RE (n=19), BE (n=24), LGD (n=17), HGD (n=16), or EAC (n=21) by immunohistochemistry. Protein expression of SOCS-2 was defined as strong positive, positive or negative if >50%, 20-50%, <20% of the epithelial cells were positive, respectively.Results: SOCS-2 mRNA expression was seen in all biopsy specimens.In patients with neoplasia, however, SOCS-2 expression was 3-5 fold lower compared to the expression levels in RE, BE, and healthy controls.No significant difference in SOCS-2 mRNA expression levels were seen in patients with LGD, HGD, and EAC.Strong positive SOCS-2 protein expression was found in 20% (11/54) of the specimens with neoplasia (LGD: 7/17, HGD: 0/16, EAC: 4/ 21) vs. 65% (28/43 p<0.001) of the specimens without neoplasia (RE: 10/19, BE: 18/24).Positive expression of SOCS-2 was detected in 28% (15/54) of the specimens with neoplasia (LGD: 2/17, HGD: 4/16, EAC: 9/21) vs. 23% (10/43) of the specimens without neoplasia (RE: 8/19, BE: 2/24), and SOCS-2 expression was negative in 52% (LGD: 8/17, HGD: 12/ 16, EAC: 8/21) vs. 12% (RE: 1/19, BE: 4/24, p<0.001), respectively.Conclusion: SOCS-2 expression is diminished in patients with BE-related neoplasia compared to patients with RE and BE, and healthy controls.This implies that SOCS-2 may serve as tumor suppressor gene in the esophagus.Although further exploration on the mechanism of SOCS-2 in BErelated neoplasia is needed, our data strongly suggest that SOCS-2 is an important target for anti-tumor therapy.

Hintergrund: Kationische Liposomen, in die Paclitaxel enkapsuliert ist (EndoTAG-1®), binden selektiv an die anionische Glykokalix neu entstehender Endothelzellen im Tumor und zerstören diese durch Induktion von Apoptose. Dies repräsentiert einen neuen innovativen anti-angiogenetischen Therapieansatz.

Accurate determination of carbon balances in heterogeneous ecosystems often requires the extrapolation of point based measurements. The ground resolution (pixel size) of the extrapolation base, e.g. a land-cover map, might thus influence the calculated carbon balance, in particular if biogeochemical hot spots are small in size. In this paper, we test the effects of varying ground resolution on the calculated carbon balance of a boreal peatland consisting of hummocks (dry), lawns (intermediate) and flarks (wet surfaces). The generalizations in lower resolution imagery led to biased area estimates for individual micro-site types. While areas of lawns and hummocks were stable below a threshold resolution of ~60 cm, the maximum of the flark area was located at resolutions below 25 cm and was then decreasing with coarsening resolution. Using a resolution of 100 cm instead of 6 cm led to an overestimation of total CO2 uptake of the studied peatland area (approximately 14 600 m2) of ~5% and an underestimation of total CH4 emission of ~6%. To accurately determine the surface area of scattered and small-sized micro-site types in heterogeneous ecosystems (e.g. flarks in peatlands), a minimum ground resolution appears necessary. In our case this leads to a recommended resolution of 25 cm, which can be derived by conventional airborne imagery. The usage of high resolution imagery from commercial satellites, e.g. Quickbird, however, is likely to underestimate the surface area of biogeochemical hot spots. It is important to note that the observed resolution effect on the carbon balance estimates can be much stronger for other ecosystems than for the investigated peatland. In the investigated peatland the relative hot spot area of the flarks is very small and their hot spot characteristics with respect to CH4 and CO2 fluxes is rather modest.

Nierenzellkarzinomassoziierte paraneoplastische Syndrome reichen von Veränderungen des Allgemeinzustands bis hin zu spezifischen metabolischen und biochemischen Veränderungen. Sie treten bei bis zu 40% der Patienten mit einem Nierenzellkarzinom im Krankheitsverlauf auf. Der vorliegende Beitrag erläutert die häufigsten beim Nierenzellkarzinom vorkommenden paraneoplastischen Veränderungen und beschreibt einige seltene Varianten sowie deren Manifestation und Therapie. Zusätzlich wird auf die vermuteten pathophysiologischen Mechanismen eingegangen. Die Bedeutung der nierenzellkarzinomassoziierten paraneoplastischen Manifestationen liegt u. a. in ihrer Rolle, ein möglicher Vorbote des Tumors oder seines Rezidivs zu sein. Dabei kennzeichnet ein solches paraneoplastisches Syndrom nicht zwingend eine schlechte Prognose oder das Vorliegen einer Metastasierung.

Immunotherapy in cancer relies on the identification and characterization of potential target antigens that can be recognized by effector cells of the immune system. Several strategies have been developed to identify such antigens, which then can be used for immunization strategies. Serological analysis of recombinant tumor cDN expression libraries (SEREX) identifies tumor antigens based on a spontaneous humoral immune response in cancer patients. SEREX is not limited to tumor types that can be grown in cell culture nor does it depend on T-cell clones that recognize the autologous tumor. SEREX-defined antigens need to be evaluated following an algorithm of several analytical steps before they become new target antigens for active immunotherapy: expression analysis to evaluate tumor association, serological analysis with sera from tumor patients and normal individuals to prove tumor-associated immunogenicity, identification of potential peptide epitopes for CD8 and CD4 T-cells, and evaluation in T-cell assays to demonstrate their potential use as vaccine targets. We recently identified a new breast cancer differentiation antigen designated as NY-BR-1 in an autologous breast cancer SEREX screening. The different steps of further evaluation are summarized in this chapter.