Superficial fibromas with CTNNB1 mutation.

Superficial fibromas are a group of mesenchymal spindle cell lesions with pathomorphological heterogeneity and diverse molecular backgrounds. In part, they may be indicators of an underlying syndrome. Among the best-known entities of superficial fibromas is Gardner fibroma, a plaque-like benign tumor, which is associated with APC germline mutations and occurs in patients with familial adenomatosis polyposis (Gardner syndrome). Affected patients also have an increased risk to develop desmoid fibromatosis (DTF), a locally aggressive neoplasm of the deep soft tissue highly prone to local recurrences. Although a minority of DTFs occur in the syndromic context and harbor APC germline mutations, most frequently their underlying molecular aberration is a sporadic mutation in Exon 3 of the CTNNB1 gene. Up to date, a non-syndromic equivalent to Gardner fibroma carrying a CTNNB1 mutation has not been defined. Here, we present two cases of (sub-)cutaneous tumors with a hypocellular and collagen-rich Gardner fibroma-like appearance and pathogenic, somatic CTNNB1 mutations. We aim to differentiate these tumors from other fibromas according to their histological appearance, immunohistochemical staining profile and underlying somatic CTNNB1 mutations. Furthermore, we distinguish them from locally aggressive desmoid fibromatosis regarding their biological behavior, prognosis and indicated therapeutic strategies. Consequently, we call them CTNNB1-mutated superficial fibromas as a sporadic counterpart lesion to syndromic Gardner fibromas.

[Conventional epiphyseal chondrosarcoma of childhood and adolescence: a case report]. / Konventionelles epiphysäres Chondrosarkom des Kindes- und Jugendalters: ein Fallbericht.

INTRODUCTION: Conventional chondrosarcoma is the second most common primary malignant bone tumor and usually occurs at older adult ages. It is rare in childhood and adolescence. CASE HISTORY: This case report presents the treatment course of a 13-year-old boy with a symptomatic chondrogenic tumor of the right distal femur. Histopathologically, an epiphyseal intermediate-grade chondrosarcoma (G2) was diagnosed. DISCUSSION: Based on the following case, potential radiological and histopathological differential diagnoses, such as chondroblastoma or chondroblastic osteosarcoma, are discussed against the background of current standards in orthopedic oncology.

[Tumors with predominantly adipocytic morphology]. / Tumoren mit prädominant adipozytärer Morphologie.

More than 20% of soft-tissue tumors belong to the group of adipocytic neoplasms. Difficulties may occur in the differential diagnosis of lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas, in the distinction of dedifferentiated liposarcomas from other soft-tissue sarcoma entities and in the detailed subtyping of liposarcomas. Especially in biopsies, the correct diagnosis and grading may be hampered due to limited tissue. Because of the ever-increasing molecular-pathological knowledge of soft-tissue tumors and the rising distribution of molecular diagnostic assays in institutes of pathology, differential diagnosis has been facilitated, as more than 90% of adipocytic tumors carry more or less specific genomic alterations. In the following, the most important subtypes of adipocytic tumors are described morphologically and genomically.

[Ewing sarcomas and Ewing-like sarcomas : New aspects]. / Ewing-Sarkome und Ewing-artige Sarkome : Neue Aspekte.

Sarcomas of the Ewing family of tumors are aggressive neoplasms occurring in bone and soft tissue of mostly children and young adults. Classical Ewing sarcomas are pathognomonically characterized by fusions between a gene of the RNA-binding TET family (EWSR1 or FUS) with a gene of the ETS-transcription family (FLI1, ERG, ETV1, ETV4 or FEV). Less frequent cases designated as Ewing-like sarcomas show different genetic rearrangements between EWSR1 and non-ETS genes (NFATC2, POU5F1, SMARCA5, PATZ, ZSG, SP3). Moreover, new molecular alterations biologically unrelated to Ewing sarcomas have recently been described in the category of undifferentiated round cell sarcomas including CIC-DUX4 fusions or BCOR alterations, each carrying unique gene expression signatures. In contrast to classical Ewing sarcomas, the morphologic spectrum of these tumor entities is much broader and includes round cell areas as well as spindled and myxoid components. The immunohistochemical profile with inconsistent CD99 positivity makes diagnosis more difficult and requires the use of a broad spectrum of antibodies and elaborate molecular work-up. Further studies for future therapeutic decision making in these newly described round cell sarcomas as well as for molecular subclassification of undifferentiated round cell sarcomas are ongoing.

Coherent modulation up to 100 GBd 16QAM using silicon-organic hybrid (SOH) devices.

We demonstrate the generation of higher-order modulation formats using silicon-based inphase/quadrature (IQ) modulators at symbol rates of up to 100 GBd. Our devices exploit the advantages of silicon-organic hybrid (SOH) integration, which combines silicon-on-insulator waveguides with highly efficient organic electro-optic (EO) cladding materials to enable small drive voltages and sub-millimeter device lengths. In our experiments, we use an SOH IQ modulator with a π-voltage of 1.6 V to generate 100 GBd 16QAM signals. This is the first time that the 100 GBd mark is reached with an IQ modulator realized on a semiconductor substrate, leading to a single-polarization line rate of 400 Gbit/s. The peak-to-peak drive voltages amount to 1.5 Vpp, corresponding to an electrical energy dissipation in the modulator of only 25 fJ/bit.

Rhesus CE expression on patient red blood cells is an independent prognostic factor for adenocarcinoma of the lung.

OBJECTIVES: The influence of blood group antigens on cancerogenesis is shown for distinct tumor types, yet the impact of Rhesus blood group antigens in lung cancer is not clarified. MATERIALS AND METHODS: To investigate the impact of Rhesus blood groups a non-small cell lung cancer (NSCLC) collective (n = 1047) was analyzed retrospectively. Using a second cohort of n = 340 primarily operated stage I-III NSCLC patients, we evaluated immunohistochemistry of CD47-antibody stained tissue samples in correlation to histopathologic subtype and Rhesus blood group. RESULTS AND CONCLUSION: In 516 of 1047 patients blood group data were available. Seven different RhCE phenotypes were grouped as "··ee," "ccE·," and "C·E·." Adenocarcinoma patients with Rh "··ee" revealed improved overall survival (29 (21.2-36.8) m; HR 1.00 [index]) compared with Rh "ccE·" (19 (1.9-36.1) m; HR 1.76 [1.15-2.70]) and Rh "C·E·" (10 (7.4-12.6) m; HR 2.65 [1.70-4.12]) univariately (P < .001) and multivariately (P < .001). Rh "··ee" showed reduced incidence of CNS-metastasis (P = .014) and metastasis count (P = .032) in stage IV adenocarcinoma. Immunohistochemistry associated CD47-positivity with adenocarcinomas (n = 340, P = .048). In n = 51 cases blood group data were available. The prognostic effect of Rh "··ee" compared with Rh "ccE·" and Rh "C·E·" was stated (P = .001), foremost in CD47-positive adenocarcinomas (Rh "··ee" vs. Rh "ccE·" and Rh "C·E·," P = .008). Inversely Rh "ccE·" or Rh "C·E·" was found beneficial in CD47-negative non-adenocarcinomas (P = .046). Phenotypic RhCE expression may be an independent prognostic factor for overall survival in adeno-NSCLC. We hypothesize an erythrocytic-immunologic interaction with tumor tissue, possibly altered by RhCE and CD47, resulting in a metastatic prone condition.

An atlas of bloodstream-accessible bone marrow proteins for site-directed therapy of acute myeloid leukemia.

The concept of arming antibodies with bioactive payloads for a site-specific therapy of cancer has gained considerable interest in recent years. However, a successful antibody-based targeting approach critically relies on the availability of a tumor-associated target that is not only preferentially expressed in the tumor tissue but is also easily accessible for antibody therapeutics coming from the bloodstream. Here, we perfused the vasculature of healthy and acute myeloid leukemia (AML)-bearing rats with a reactive ester derivative of biotin and subsequently quantified the biotinylated proteins to identify AML-associated bone marrow (BM) antigens accessible from the bloodstream. In total, >1400 proteins were identified. Overall, 181 proteins were >100-fold overexpressed in AML as compared with normal BM. Eleven of the most differentially expressed proteins were further validated by immunohistochemistry and confocal microscopic analyses, including novel antigens highly expressed in AML cells (for example, adaptor-related protein complex 3 ß2) and in the leukemia-modified extracellular matrix (ECM) (for example, collagen-VI-α-1). The presented atlas of targetable AML-associated BM proteins provides a valuable basis for the development of monoclonal antibodies that could be used as carriers for a site-specific pharmacodelivery of cytotoxic drugs, cytokines or radionuclides to the BM in AML.

[Gastrointestinal stromal tumors of the stomach and precursor lesions]. / Gastrointestinale Stromatumoren des Magens und ihre Vorstufen.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract although they are much less frequent than epithelial tumors. In more than 60% of cases they occur in the stomach. Especially small lesions measuring ≤1 cm in diameter, so-called microscopic GIST can occur multifocally, frequently in the proximal stomach wall and sometimes as an incidental finding in a gastrectomy specimen resected for gastric cancer. The multicentricity of GIST alone is not proof of a metastatic behavior or a syndromal or hereditary disease. Multiple sporadic synchronous and metachronous GIST are characterized by different primary mutations mostly in the KIT or PDGFRA genes and are often less aggressive. It is speculative whether a field effect is responsible or whether still unknown GIST-promoting factors may facilitate the development of several independent lesions. If KIT or PDGFRA mutations are lacking, a succinate dehydrogenase (SDH) deficient GIST has to be considered, either hereditary as Carney-Stratakis syndrome or syndromal as part of a Carney triad.

Generation of 64 GBd 4ASK signals using a silicon-organic hybrid modulator at 80°C.

We demonstrate a silicon-organic hybrid (SOH) Mach-Zehnder modulator (MZM) generating four-level amplitude shift keying (4ASK) signals at symbol rates of up to 64 GBd both at room temperature and at an elevated temperature of 80°C. The measured line rate of 128 Gbit/s corresponds to the highest value demonstrated for silicon-based MZM so far. We report bit error ratios of 10-10 (64 GBd BPSK), 10-5 (36 GBd 4ASK), and 4 × 10-3 (64 GBd 4ASK) at room temperature. At 80 °C, the respective bit error ratios are 10-10, 10-4, and 1.3 × 10-2. The high-temperature experiments were performed in regular oxygen-rich ambient atmosphere.

Blood group antigen A type 3 expression is a favorable prognostic factor in advanced NSCLC.

OBJECTIVES: Several blood group-related carbohydrate antigens are prognosis-relevant markers of tumor tissues. A type 3 (repetitive A) is a blood group antigen specific for A1 erythrocytes. Its potential expression in tumor tissues has so far not been examined. MATERIAL AND METHODS: We have evaluated its expression in normal lung and in lung cancer using a novel antibody (A69-A/E8). For comparison an anti-A antibody specific to A types 1 and 2 was used, because its expression on lung cancer tissue has been previously reported to be of prognostic relevance. Resected tissue samples of 398 NSCLC patients were analyzed in immunohistochemistry using tissue microarrays. RESULTS AND CONCLUSIONS: Expression of A type 3 was not observed in non-malignant lung tissues. A type 3 was expressed on tumor cells of around half of NSCLC patients of blood group A1 (p<0.001). Whereas no prognostic effect for A type 1/2 antigen was observed (p=0.562), the expression of A type 3 by tumor cells indicated a highly significant favorable prognosis among advanced NSCLC patients (p=0.011) and in NSCLC patients with lymphatic spread (p=0.014). Univariate prognostic results were confirmed in a Cox proportional hazards model. In this study we present for the first time prognostic data for A type 3 antigen expression in lung cancer patients. Prospective studies should be performed to confirm the prognostic value of A type 3 expression for an improved risk stratification in NSCLC patients.

Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting.

At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.

New Short-Lived Isotope

Two short-lived isotopes ^{221}U and ^{222}U were produced as evaporation residues in the fusion reaction ^{50}Ti+^{176}Yb at the gas-filled recoil separator TASCA. An α decay with an energy of E_{α}=9.31(5) MeV and half-life T_{1/2}=4.7(7) µs was attributed to ^{222}U. The new isotope ^{221}U was identified in α-decay chains starting with E_{α}=9.71(5) MeV and T_{1/2}=0.66(14) µs leading to known daughters. Synthesis and detection of these unstable heavy nuclei and their descendants were achieved thanks to a fast data readout system. The evolution of the N=126 shell closure and its influence on the stability of uranium isotopes are discussed within the framework of α-decay reduced width.

Nuclear chemistry. Synthesis and detection of a seaborgium carbonyl complex.

Experimental investigations of transactinoide elements provide benchmark results for chemical theory and probe the predictive power of trends in the periodic table. So far, in gas-phase chemical reactions, simple inorganic compounds with the transactinoide in its highest oxidation state have been synthesized. Single-atom production rates, short half-lives, and harsh experimental conditions limited the number of experimentally accessible compounds. We applied a gas-phase carbonylation technique previously tested on short-lived molybdenum (Mo) and tungsten (W) isotopes to the preparation of a carbonyl complex of seaborgium, the 106th element. The volatile seaborgium complex showed the same volatility and reactivity with a silicon dioxide surface as those of the hexacarbonyl complexes of the lighter homologs Mo and W. Comparison of the product's adsorption enthalpy with theoretical predictions and data for the lighter congeners supported a Sg(CO)6 formulation.

48Ca+249Bk fusion reaction leading to element Z = 117: long-lived α-decaying 270Db and discovery of 266Lr.

The superheavy element with atomic number Z=117 was produced as an evaporation residue in the (48)Ca+(249)Bk fusion reaction at the gas-filled recoil separator TASCA at GSI Darmstadt, Germany. The radioactive decay of evaporation residues and their α-decay products was studied using a detection setup that allowed measuring decays of single atomic nuclei with half-lives between sub-µs and a few days. Two decay chains comprising seven α decays and a spontaneous fission each were identified and are assigned to the isotope (294)117 and its decay products. A hitherto unknown α-decay branch in (270)Db (Z = 105) was observed, which populated the new isotope (266)Lr (Z = 103). The identification of the long-lived (T(1/2) = 1.0(-0.4)(+1.9) h) α-emitter (270)Db marks an important step towards the observation of even more long-lived nuclei of superheavy elements located on an "island of stability."

SS18-SSX fusion protein-induced Wnt/ß-catenin signaling is a therapeutic target in synovial sarcoma.

Synovial sarcoma is a high-grade soft tissue malignancy characterized by a specific reciprocal translocation t(X;18), which leads to the fusion of the SS18 (SYT) gene to one of three SSX genes (SSX1, SSX2 or SSX4). The resulting chimeric SS18-SSX protein is suggested to act as an oncogenic transcriptional regulator. Despite multimodal therapeutic approaches, metastatic disease is often lethal and the development of novel targeted therapeutic strategies is required. Several expression-profiling studies identified distinct gene expression signatures, implying a consistent role of Wnt/ß-catenin signaling in synovial sarcoma tumorigenesis. Here we investigate the functional and therapeutic relevance of Wnt/ß-catenin pathway activation in vitro and in vivo. Immunohistochemical analyses of nuclear ß-catenin and Wnt downstream targets revealed activation of canonical Wnt signaling in a significant subset of 30 primary synovial sarcoma specimens. Functional aspects of Wnt signaling including dependence of Tcf/ß-catenin complex activity on the SS18-SSX fusion proteins were analyzed. Efficient SS18-SSX-dependent activation of the Tcf/ß-catenin transcriptional complex was confirmed by TOPflash reporter luciferase assays and immunoblotting. In five human synovial sarcoma cell lines, inhibition of the Tcf/ß-catenin protein-protein interaction significantly blocked the canonical Wnt/ß-catenin signaling cascade, accompanied by the effective downregulation of Wnt targets (AXIN2, CDC25A, c-MYC, DKK1, CyclinD1 and Survivin) and the specific suppression of cell viability associated with the induction of apoptosis. In SYO-1 synovial sarcoma xenografts, administration of small molecule Tcf/ß-catenin complex inhibitors significantly reduced tumor growth, associated with diminished AXIN2 protein levels. In summary, SS18-SSX-induced Wnt/ß-catenin signaling appears to be of crucial biological importance in synovial sarcoma tumorigenesis and progression, representing a potential molecular target for the development of novel therapeutic strategies.

Immunization with Brugia malayi Hsp70 protects mice against Litomosoides sigmodontis challenge infection.

More than 1·5 billion people are at risk of being infected with filarial nematodes worldwide. Therapy and control of transmission are mainly based on mass drug distribution. As these drugs have to be administered annually or biannually and might be loosing their efficacy, a vaccine against filariae is an alternative approach to chemotherapy. In the current study, we have analysed the potential of Brugia malayi heat shock protein 70 (BmHsp70) as a vaccine candidate in a murine helminth infection. Immunization of BALB/c mice with alum-precipitated recombinant BmHsp70 conferred partial protection against subsequent challenge infection with the rodent parasite Litomosoides sigmodontis. Immunization resulted in reduced numbers of larvae in the pleural cavity as well as reduced numbers of circulating microfilariae. Reduced parasite burden was associated with high titres of BmHsp70-specific antibodies and increased production of type I and II cytokines in response to L. sigmodontis antigen and BmHsp70. In summary, the immunization with BmHsp70 induced cellular and humoral immune responses and partially protected against L. sigmodontis in a challenge infection. Therefore, we hypothesize that BmHsp70 might be considered as a potential vaccine candidate for reduction in the incidence of B. malayi infections in future studies.

Absorption engineering of NbN nanowires deposited on silicon nitride nanophotonic circuits.

We investigate the absorption properties of U-shaped niobium nitride (NbN) nanowires atop nanophotonic circuits. Nanowires as narrow as 20nm are realized in direct contact with Si3N4 waveguides and their absorption properties are extracted through balanced measurements. We perform a full characterization of the absorption coefficient in dependence of length, width and separation of the fabricated nanowires, as well as for waveguides with different cross-section and etch depth. Our results show excellent agreement with finite-element analysis simulations for all considered parameters. The experimental data thus allows for optimizing absorption properties of emerging single-photon detectors co-integrated with telecom wavelength optical circuits.

Acute interventional recanalisation of vertebrobasilar stenoses by angioplasty: complications and 12 months follow up.

INTRODUCTION: In acute symptomatic vertebrobasilar artery stenosis, the use of mechanical recanalisation remains controversial. The complication rate of acute interventional recanalisation (aIR) has to be considered, as evidence from randomised trials is lacking. In a single centre retrospective case series, we here describe complications and outcome after aIR. METHODS: We retrospectively assessed aIR in a tertiary care centre and included the following parameters: indication for aIR, national institute of health stroke scale (NIHSS) score on admission, recanalisation by thrombolysis in myocardial infarction score (TIMI) grades, post-interventional complications, mortality, NIHSS and modified Rankin scale at follow-up and rate of restenosis. RESULTS: We identified 14 aIR (14 percutaneous transluminal angioplasty with or without stent implantation in 12 patients; 6/12 with thrombolysis; n = 6 vertebral artery, n = 8 basilar artery; 4 women, mean age 67 years). Mortality was 25 % (3/12) after 7 days and 42 % (5/12) after 12 months. In 12/14, interventions are complete (TIMI 3, 86 %), in 2/14, a partial recanalisation (TIMI 2, 14 %) was achieved. In one case, a peri-interventional fatal intracerebral haemorrhage occurred (1/12, 8 %). At late follow-up (mean 342 days), one re-occlusion (1/7, 14 %) and one recurrent stroke (1/12, 8 %) were observed. CONCLUSIONS: In our single centre series of vertebrobasilar aIR recanalisation rate was high. However, procedural safety and clinical outcome varied considerably. The results of aIR need to be assessed in multicentric registers to define the procedural risk and outcome in the clinical setting.