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Purpose Interleukin 6 (IL-6), Oncostatin M (OSM), and downstream effector STAT3 are pro-tumorigenic agents in pancreatic ductal adenocarcinoma (PDAC). Glycoprotein 130 (gp130) is a compound of the IL-6 and OSM receptor complex that triggers STAT3 signaling. SC144 is a small molecule gp130 inhibitor with anticancer activity. This study examines the gp130 expression in human PDAC specimens and the in vitro effects of SC144 in PDAC cell lines. Methods Tissue micro-arrays were constructed from 175 resected human PDAC. The gp130 expression in tumor epithelium and stroma was determined by immunohistochemistry, and survival analysis was performed. Growth inhibition by SC144 was assessed in vitro using BrdU and MTT assays. Western blotting was performed to evaluate the SC144 effect on IL-6 and OSM signaling. Results Gp130 was expressed in the epithelium of 78.8% and the stroma of 9.4% of the tumor samples. The median overall survival for patients with or without epithelial gp130 expression was 16.7 months and 15.9 months, respectively (p = 0.830). Patients with no stromal gp130 expression showed poorer survival than patients with stromal gp130 expression (median 16.2 and 22.9 months, respectively), but this difference did not reach significance (p = 0.144). SC144 inhibited cell proliferation and viability and suppressed IL-6- and OSM-stimulated STAT3Y705 phosphorylation in PDAC cells. Conclusion Gp130 is expressed in the epithelium of most human PDAC, but stromal expression is rare. The small molecule gp130 inhibitor SC144 potently inhibits PDAC progression in vitro and may abrogate IL-6 or OSM/gp130/STAT3 signaling. These results suggest gp130 as a novel drug target for pancreatic cancer therapy.

Acute intermittent porphyria (AIP) is a very rare (orphan) metabolic disorder of porphyrin biosynthesis which is characterized by elevated plasma and urine levels of 5-aminolevulinic acid (5-ALA) and porphobilinogen (PBG). Patients with this disorder which is caused by a germline mutation of the hydroxymethylbilan-synthase (HMBS)-gene have a high risk of primary liver cancer which may be determined by disease activity. The exact mechanism of carcinogenesis of this rare tumor is unknown, however.We analyzed paraffin-embedded formalin-fixed liver tumor and normal liver specimens of two female AIP patients treated at the Munich EPNET center. One patient had developed hepatocellular carcinoma (HCC), the other intrahepatic cholangiocarcinoma (CCA). Since biallelic inactivation of HMBS had been observed in one study, we used Sanger and next-generation sequencing with a 8 gene porphyria panel plus 6 potential modifier loci to search for mutations in DNA extractions.In the patient with the HCC, we found a second inactivating mutation in the HMBS gene in the tumor but not in the adjacent normal liver tissue. No mutation could be found in the liver tissues of the patient with CCA, however.Biallelic inactivation of HMBS or protoporphyrinogen-oxidase (PPOX), another enzyme of porphyrin biosynthesis, has been observed in patients with acute porphyrias and liver tumors. We could confirm this in our patient with HCC with a mutation in HMBS but not in the one with CCA. Since 5-ALA can be converted into carcinogenic substances such as 4,5-dioxovaleric acid (DOVA) or 3,6-dihydropyrazine-2,5-dipropanoic acid (= cyclic dimerization product of 5-ALA), local production of these metabolites in hepatic areas with complete loss of HMBS activity may contribute to liver carcinogenesis.

Objectives To investigate the differentiation of premalignant from benign colorectal polyps detected by CT colonography using deep learning. Methods In this retrospective analysis of an average risk colorectal cancer screening sample, polyps of all size categories and morphologies were manually segmented on supine and prone CT colonography images and classified as premalignant (adenoma) or benign (hyperplastic polyp or regular mucosa) according to histopathology. Two deep learning models SEG and noSEG were trained on 3D CT colonography image subvolumes to predict polyp class, and model SEG was additionally trained with polyp segmentation masks. Diagnostic performance was validated in an independent external multicentre test sample. Predictions were analysed with the visualisation technique Grad-CAM++. Results The training set consisted of 107 colorectal polyps in 63 patients (mean age: 63 ± 8 years, 40 men) comprising 169 polyp segmentations. The external test set included 77 polyps in 59 patients comprising 118 polyp segmentations. Model SEG achieved a ROC-AUC of 0.83 and 80% sensitivity at 69% specificity for differentiating premalignant from benign polyps. Model noSEG yielded a ROC-AUC of 0.75, 80% sensitivity at 44% specificity, and an average Grad-CAM++ heatmap score of ≥ 0.25 in 90% of polyp tissue. Conclusions In this proof-of-concept study, deep learning enabled the differentiation of premalignant from benign colorectal polyps detected with CT colonography and the visualisation of image regions important for predictions. The approach did not require polyp segmentation and thus has the potential to facilitate the identification of high-risk polyps as an automated second reader. Key Points • Non-invasive deep learning image analysis may differentiate premalignant from benign colorectal polyps found in CT colonography scans. • Deep learning autonomously learned to focus on polyp tissue for predictions without the need for prior polyp segmentation by experts. • Deep learning potentially improves the diagnostic accuracy of CT colonography in colorectal cancer screening by allowing for a more precise selection of patients who would benefit from endoscopic polypectomy, especially for patients with polyps of 6–9 mm size.

Conventional ultrasound is the main imaging modality in obstetrics for assessing the maternal and fetal status. Up to date, contrast-enhanced ultrasound (CEUS) has not found widespread use in gynecology and obstetrics, but recent studies demonstrate promising results. The aim of the present study is to assess safe and valuable application of CEUS during pregnancy to investigate non-obstetric conditions. Five pregnant patients on whom CEUS was performed between 2019 and 2020 were included in this retrospective single-center study. A total of six CEUS examinations were performed including one CEUS-guided biopsy (mean age: 31 years, mean weeks of pregnancy: 18 weeks). CEUS examinations were performed by a consultant radiologist (EFSUMB level 3). All included pregnant women safely underwent CEUS. Neither maternal nor fetal adverse effects were detected. CEUS critically helped in the diagnostic workup of a desmoid tumor of the abdominal wall, hepatic hemangioma, amebic hepatic abscess, uncomplicated renal cyst and post-inflammatory alteration of the renal cortex and for excluding active abdominal bleeding. In addition, CEUS-guided biopsy was performed to prevent intratumoral hemorrhage. Findings from CEUS prompted immediate treatment in two women, whereas in three women regular obstetric monitoring of the women could be conducted. Our results demonstrate safe and crucial application of off-label CEUS in pregnant women to assess different non-obstetric conditions allowing to prevent additional ionizing CT or application of (gadolinium-based) contrast agent in MRI. Hence, CEUS might add pivotal value for evaluating obstetric and non-obstetric conditions and thereby directing clinical management of pregnant women in the future.

Purpose There are controversial debates if patients with Hürthle cell carcinoma, also known as oxyphilic or oncocytic cell follicular thyroid carcinoma, have a poorer outcome. In this study, we systematically evaluated the clinical outcome in a large patient cohort following thyroidectomy and initial I-131 radioactive iodine therapy (RIT). Methods We retrospectively evaluated a total of 378 patients with diagnosed oncocytic follicular Hürthle cell carcinoma (OFTC) (N = 126) or with classical follicular thyroid carcinoma (FTC) (N = 252). Patients received thyroidectomy and complementary I-131 RIT. Clinical data regarding basic demographic characteristics, tumor grade, persistent disease and recurrence during follow-up, and disease-free, disease-specific, and overall survival were collected during follow-up of 6.9 years (interquartile range 3.7; 11.7 years). Univariate and multivariate analyses were used to identify factors associated with disease-related and overall survival. Results Before and after matching for risk factors, recurrence was significantly more frequently diagnosed in OFTC patients during follow-up (17% vs. 8%; p value 0.037). Likewise, OFTC patients presented with a reduced mean disease-free survival of 17.9 years (95% CI 16.0–19.8) vs. 20.1 years (95% CI 19.0–21.1) in FTC patients (p value 0.027). Multivariate analysis revealed OFTC (HR 0.502; 95% CI 0.309–0.816) as the only independent prognostic factor for disease-free survival. Distant metastases of OFTC patients were significantly less iodine-avid (p value 0.014). Mean disease-specific and overall survival did not differ significantly (p value 0.671 and 0.687) during follow-up of median 6.9 years (3.7; 11.7 years). Conclusions Our study suggests that recurrence is more often seen in OFTC patients. OFTC patients have a poorer prognosis for disease-free survival. Thus, OFTC and FTC behave differently and should be categorized separately. However, patients suffering from OFTC present with the same overall and disease-specific survival at the end of follow-up indifferent to FTC patients after initial RIT.

Soft tissue sarcomas (STSs) are heterogeneous cancers associated with poor prognosis due to high rates of local recurrence and metastasis. The programmed death receptor ligand 1 (PD-L1) is expressed in several cancers. PD-L1 interacts with its receptor, PD-1, on the surface of tumor-infiltrating lymphocytes (TILs), thereby attenuating anti-cancer immune response. Immune checkpoint inhibitors targeting this interaction have been established as effective anti-cancer drugs. However, studies on the PD-L1 and PD-1 expression status in STS are commonly limited by small sample size, analysis of single STS subtypes, or lack of combinatorial marker assessment. To overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the number of TILs, their PD-1 expression, and associations with clinicopathological parameters in a large and comprehensive cohort of 225 samples comprising six STS subtypes. We found that nearly all STS subtypes showed PD-L1 expression on the tumor cells, albeit with a broad range of positivity across subtypes (50% angiosarcomas to 3% synovial sarcomas). Co-expression and correlation analyses uncovered that PD-L1 expression was associated with more PD-1-positive TILs (P

Die radiologische sowie nuklearmedizinische Diagnostik nimmt einen bedeutenden Stellenwert im diagnostischen Algorithmus, insbesondere zur Diagnosefindung sowie auch zur Staging-Untersuchung von gastroenteropankreatischen neuroendokrinen Tumoren (GEP-NET) dar. Die sonographische – einschlieslich der kontrastverstarkten – Untersuchung stellt eine wichtige initiale Modalitat dar, um bei anamnestischem und klinischem Verdacht nach NET zu suchen. Der vorliegende Artikel beschreibt das sonomorphologische Verhalten von Ileum- sowie Pankreas-NET und von neuroendokrinen Lebermetastasen. Sonographische Evaluation von Dunndarm‑, Pankreas-NET sowie neuroendokriner Leberfiliae. Kontrastverstarkte Computertomographie (CT) oder Magnetresonanztomographie (MRT), native Sonographie. Kontrastverstarkter Ultraschall (CEUS). Der CEUS unterstutzt die native Sonographie bei der Suche nach NET und der Differenzialdiagnose fokaler Lasionen und ist sensitiver fur Lebermetastasen (Sensitivitat nach der Literatur 99 % vs. 68 %). Der CEUS bietet eine Suchmethode, um nach eventuellen Tumoren bei positiver Anamnese bzw. positiven klinischen Ergebnissen und Laborwerten zu suchen. Er erlaubt eine nahere Differenzierung zwischen Benignitat und Malignitat. Auf schnittbildgebende Verfahren kann jedoch bzgl. Staging-Diagnostik nicht verzichtet werden.

The role of estrogen receptor beta (ER-β) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-β may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-β, phosphorylated ER-β (pER-β), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. High nuclear expression of ER-β was found in 61.7% and pER-β in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-β expression was 29 months, whereas for patients with high pER-β expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-β expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029). Expression of pER-β constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.

Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene from IFITs family is one gene among hundreds of IFN-stimulated genes. The potential role of IFIT3 in cancer is scarcely understood. In addition, the clinical relevance of IFIT3 is not yet known in pancreatic ductal adenocarcinoma (PDAC). We evaluated the prognostic significance of this gene in PDAC patients. The expression of IFIT3 was analyzed in pancreatic cancer cell lines with different metastatic potential (FG and L3.6pl) and one established gemcitabine resistant cell variant-L3.6plGres. Second, we analyzed the protein expression in tissue microarrays (TMA) from specimens of 254 radically resected patients with pancreatic adenocarcinoma. The prognostic relevance of IFIT3 was evaluated by the Kaplan–Meier and Cox regression analysis. L3.6pl cells with an aggressive capacity showed a significant higher expression of IFIT3 as compared to FG cells. IFIT3 was accumulated in gemcitabine resistant cells. Overexpression of IFIT3 increased the resistance of apoptosis against gemcitabine treatment. Patients who had high expression of IFIT3 (32%) and received chemotherapy had a statistically significant reduced survival in multivariate analysis. High expression of IFIT3 enhances anti-apoptotic activity and chemotherapy resistance of PDAC cells. High expression of IFIT3 was independently correlated to shorter patients’ survival and may serve as a prognostic marker.

INTRODUCTION: Neuroendocrine Neoplasms are classified according to the new WHO classification in (1.) well differentiated neuroendocrine tumors G1 (NET G1, Ki67 \textless/= 2 or mitosis count \textless2) and (2.) well differentiated neuroendocrine tumors G2 (NET G2, Ki67 3-20 or mitosis count 2-20) and (3.) poorly differentiated neuroendocrine carcinomas G3 (NEC G3, Ki67 \textgreater 20 or mitosis count \textgreater20). MATERIAL AND METHODS: In this study 310 NENs of the Ludwig-Maximilians-University in Munich were reevaluated according to the new WHO classification. RESULTS: 7% of the analyzed NENs were presented as neoplasias of the stomach. In NENs of the stomach three distinct subtypes are recognized: (1) type 1 associated with autoimmune chronic atrophic gastritis (2) type 2, associated with multiple endocrine neoplasia (MEN1) and Zollinger-Ellison Syndrom; and (3) type 3, sporadic tumors. DISCUSSION: Precursor lesions (i. e. hyperplasia of the ECL cells) are found in patients with hypergastrinaemia (type 1 and 2). This article should provide insights into the diagnosis of NENs of the stomach with emphasis on the new international standard.

Background: Frequent disease relapse and a lack of effective therapies result in a very poor outcome in pancreatic ductal adenocarcinoma (PDAC) patients. Thus, identification of prognostic biomarkers and possible therapeutic targets is essential. Besides their function in cell–cell adhesion, desmogleins may play a role in tumour progression and invasion that has not been investigated in PDAC to date. This study evaluated desmoglein expression as a biomarker in PDAC. Methods: Using immunohistochemistry, we examined desmoglein 1 (DSG1), desmoglein 2 (DSG2) and desmoglein 3 (DSG3) expression in the tumour tissue of 165 resected PDAC cases. Expression levels were correlated to the patients' clinicopathological parameters and postoperative survival times. We confirmed these results in two independent gene expression data sets. Results: A total of 36% of the tumours showed high DSG3 expression that correlated significantly with shorter patient survival (P=0.011) and poor tumour differentiation (P

This study evaluates the diagnostic accuracy of SUV-based parameters derived from [18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in order to optimize non-invasive prediction of soft tissue tumour (STT) grade. One hundred and twenty-nine lesions from 123 patients who underwent FDG-PET for primary staging (n = 79) or assessment of recurrence (n = 44) of STT were analyzed retrospectively. Histopathology was the reference standard for tumour grading. Absolute values and tumour-to-liver ratios of several standardized uptake value (SUV) parameters were correlated with tumour grading. At primary diagnosis SUVmax, SUVpeak, SUVmax/SUVliver and SUVpeak/SUVliver showed good correlation with tumour grade. SUVpeak (area under the receiver-operating-characteristic, AUC-ROC: 0.82) and SUVpeak/SUVliver (AUC-ROC: 0.82) separated best between low grade (WHO intermediate, grade 1 sarcoma, and low risk gastrointestinal stromal tumours, GISTs) and high grade (grade 2/3 sarcoma and intermediate/high risk GISTs) lesions: optimal threshold for SUVpeak/SUVliver was 2.4, which resulted in a sensitivity of 79 % and a specificity of 81 %. At disease recurrence, the AUC-ROC was 2.4 had 79 % sensitivity and 81 % specificity for high grade lesions. • At recurrence, FDG PET does not reliably indicate high grade sarcomas.

Die Entwicklung von Medikamenten, die molekulare Alterationen blockieren, welche entscheidend sind fur die Tumorentstehung, ist derzeit eine extrem wichtige Herausforderung. Die erfolgreiche „GIST-Story“ (gastrointestinaler Stromatumor) gibt neue Impulse fur mogliche weitere Medikamente, die sogenannte aktivierende Mutationen oder auch Treibermutationen hemmen konnen. Tyrosinkinasen und Tyrosinkinaserezeptoren sind vielversprechende Angriffspunkte fur eine sogenannte zielgerichtete Therapie, neue Medikamente sind zurzeit in Phase-2- und -3-Studien. Wir haben in einem grosen Tumorkollektiv die Rezeptoren verschiedener Tyrosinkinaserezeptoren uberpruft und die Resultate mit den klinisch-pathologischen Parametern verglichen. Aus der Chirurgischen Klinik der Ludwigs-Maximilians-Universitat (LMU) Munchen wurden 275 Sarkome der letzten 20 Jahre erneut begutachtet und nach der neuen WHO Einteilung kategorisiert. Zusatzlich wurden einzelne Tyrosinkinasen, die Angriffspunkte fur zielgerichtete Therapien sind, immunhistologisch angefarbt. Einzelne Tumorentitaten zeigten unterschiedliche Uberlebenskurven in den Kaplan-Meier-Kurven. Zusatzlich konnte eine distinkte Expression verschiedener Tyrosinkinaserezeptoren bei den einzelnen Subentitaten gesehen werden. Die Rezeptoren der vaskularen endothelialen Wachstumsfaktoren zeigten bei hoher Expression eine Korrelation mit der Tumorprogression. Wenn alle Vascular Endothelial Growth Factor Receptors (VEGFRs) hoch exprimiert waren, zeigten die Patienten ein signifikant schlechteres Uberleben. Da nicht alle Patienten auf eine gezielte Tyrosinkinaseinhibitortherapie ansprechen, sollten die Angriffspunkte der Medikamente und sogenannte Proteinsignaturen, die fur verschiedene Signaltransduktionswege wichtig sind, vor der Therapie analysiert werden, um eine optimale personalisierte Therapie zu gewahrleisten.

Background: Aberrant activities of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). Transcription factors STAT3 and STAT1, both downstream effectors of interleukin (IL)-6 and its receptor, are involved in growth and developmental control of CRC cells. Constituents of the signalling network around IL-6 and STAT activation are discussed as potential biomarkers and therapeutic targets in CRC. Methods: By immunohistochemical analysis of a tissue microarray covering >400 CRC biopsies, the expression and activity status of STAT1, STAT3 as well as of IL-6 and the IL-6 receptor α-chain was determined. The outcome was correlated with clinical information and patients' survival data. Colorectal carcinoma biopsies were also analysed for specific DNA-binding activity of STATs. Results: Statistical analysis showed tendential associations between individual STATs, IL-6/IL-6 receptor-α and clinicopathological parameters. The study revealed a significant correlation of high STAT1 activity with longer patient overall survival. Surprisingly, strong STAT3 expression in surgical specimens was correlated with an increase in median overall survival by about 30 months. Statistical analysis revealed that high expression levels of STAT1 and STAT3 were associated. This finding was backed up by biochemical data that showed simultaneous STAT1 and STAT3 DNA-binding activity in randomly selected CRC biopsies. Conclusion: By multivariate data analysis, we could show that STAT3 expression and activity constitutes an independent favourable prognostic marker for CRC.

A 39-year-old inpatient at a tumor orthopedic department with a history of a chondrosarcoma in the scapula presented with a destructive tumorous lesion in the staging computed tomography (CT). After ambiguous results in CT-guided biopsy and an open biopsy, a surgical removal of a tumorous lesion was performed. The histological findings showed a lipoma of the spine. Intraosseous lipomas with predisposition to pathological fracture or compression of the spinal cord with neurological symptoms should be removed. We report a case in which the patient presented with complete paraplegia due to an edema in the spinal cord immediately after removal surgery. The necessity of resection of a spinal lipoma with postoperative spinal cord damage needs to be discussed. To our knowledge, this case is one of the first to demonstrate that the diagnosis of tumors of the vertebra should be carefully evaluated and possible spinal cord damage as a complication should be kept in mind upon deciding on further therapies and interventions.

Resection of colorectal liver or lung metastases is an established therapeutical concept at present. However, an affection of both these organs is frequently still regarded as incurable. All cancer patients are documented in our prospective cancer registry since 1995. Data of patients who underwent liver and lung resection for colorectal metastases were extracted and analysed. Sixty-five patients underwent surgery for liver and lung metastases. In 33 cases, the first distant metastasis was diagnosed synchronously to the primary tumour. For the remaining patients, median time interval between primary tumour and first distant metastasis was 18 months (5–69 months). Complete resection was achieved in 51 patients (79 %) and was less likely in patients with synchronous disease (p = 0.017). Negative margins (p = 0.002), the absence of pulmonary involvement in synchronous metastases (p = 0.0003) and single metastases in both organs (p = 0.036) were associated with a better prognosis. Five- and 10-year survival rates for all patients are 57 and 15 % from diagnosis of the primary tumour, 37 and 14 % from resection of the first metastasis and 20 and 15 % from resection of the second metastasis. After complete resection, 5- and 10-year survival rates increased to 61 and 18 %, 43 and 17 % as well as 25 and 19 %, respectively. Long-term survivors (≥10 years) were seen only after complete resection of both metastases. Patients with resectable liver and lung metastases of the colorectal primary should be considered for surgery after multidisciplinary evaluation regardless of the number or size of the metastases or the disease-free intervals. Clear resection margins are the strongest prognostic parameter.

Genomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial-mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data.Tissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2´-deoxycytide in five colon cancer cell lines.On protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test.Reduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells.

Background: Desmocollin 3 (DSC3), a member of the cadherin superfamily and integral component of desmosomes, is involved in carcinogenesis. However, the role of DSC3 in colorectal cancer (CRC) has not yet been established. Methods: Desmocollin 3 expression in CRC cell lines was analysed by RT–PCR and western blotting. Methylation status of DSC3 was examined by demethylation tests, methylation-specific PCR, and bisulphite sequencing (BS). The regulatory role of p53 was investigated by transfection. Results: Desmocollin 3 was downregulated in CRC cells at mRNA and protein levels. Desmocollin 3 expression was restored in five out of seven cell lines after 5-aza-2′-deoxycytidine (DAC) treatment. A heterogeneous methylation pattern was detected by BS in promoter region and exon 1 of DSC3. Methylation of DSC3 genomic sequences was found in 41% (41 out of 99) of primary CRC, being associated with poor prognosis (P=0.002). Transfection of p53 alone or in combination of DAC increased the DSC3 expression. Similarly, treatment with p53 inducer adriamycin alone or in combination with DAC enhanced DSC3 expression. Conclusions: DNA methylation contributes to downregulation of DSC3 in CRC cell lines. Methylation status of DSC3 DNA is a prognostic marker for CRC. P53 appears to have an important role in regulating DSC3 expression.

The Jena Institute of Pathology has been serving as a consultation and reference center for soft tissue tumors in Germany since 1978. The present study provides an overview of the clinicopathological data from a two-year period and an update on diagnostics and research. Retrospectively, 7043 cases sent to the institute in the years 2006 and 2007 were analyzed. The majority of cases (>77.7%) were soft tissue tumors, of which 49% were categorized as malignant, 11.4% as intermediate, 35% as benign and 4.6% as tumors of uncertain biological potential. Neoplasms with fibroblastic differentiation were the most frequent. The mean age of patients with a sarcoma was 63 years. The molecular pathological analysis of soft tissue tumors has attained a major role in diagnosis. This is further advanced at the Jena institute in the context of a German Federal Ministry of Education and Research (BMBF) project for molecular sarcoma diagnosis with the aim of developing and validating DNA probes for in situ hybridization detection of translocations and their associated chromosomal breaks on the one hand, and DNA chips for the detection of fusion transcripts on the other. Research projects relate to the analysis of specific biomarkers in large tumor collectives and the pathomechanisms in several sarcoma entities.

Weichteiltumoren mit einem Hamangioperizytom-artigen Gefasmuster sollten in 3 Gruppen eingeteilt werden: 1. solitare fibrose Tumoren mit ihren Varianten, 2. Tumoren, die eine myoide oder auch perizytische Liniendifferenzierung ihrer Zellen zeigen und als „echte“ perizytische (perivaskulare) Tumoren bezeichnet werden konnen (Myoperizytome und eine Subgruppe der sinonasalen Hamangioperizytome), und 3. distinkte Entitaten, die nur fokal ein Hamangioperizytom-artiges Gefasmuster aufweisen, wie z. B. Synovialsarkome, mesenchymale Chondrosarkome, Myofibromatosen. In dieser Arbeit werden 268 intrathorakale und extrathorakale solitare fibrose Tumoren des Konsultations- und Referenzzentrums fur Weichteiltumoren in Jena evaluiert und immunhistologisch mit den Antikorpern CD34, Bcl-2, CD99, SMA, S100, PanCK und Ki-67 analysiert. Die Tumoren wurden nach dem aktuell vorliegenden Vorschlag der internationalen Arbeitsgruppe fur Weichgewebstumoren in die fibrose Variante, die zellulare Variante (mehr als 90% Hyperzellularitat), die fettzellbildende Variante und die riesenzellige Variante eingeteilt.

Comparative genomic hybridization was used to screen colorectal carcinomas for chromosomal aberrations that are associated with the metastatic phenotype of the lung. Specimens of 13 lung metastases, 6 primary tumors, 1 lymph node metastasis, 1 liver metastasis, and 1 ovarian metastasis were investigated and added to our CGH colon cancer tumor collective, comprising 85 tumor specimens from 56 patients (see CGH online tumor database at http://amba.charite.de/cgh). Lung metastases showed more alterations than liver metastases, particularly more deletions at 1p, 3p, 9q, 12q, 17q, 19p and 22q and gains at 2q, 5p, and chromosome 6. Comparing lung metastases with their corresponding primary tumors, particularly more deletions at 3p, 8p, 12q, 17q, and 21q21 and gains at 5p were observed. Based on our results, we wish to suggest a metastatic progression model. Specific subpopulations of metastatic cells have a distinct metastatic potential, which is reflected by a non-random accumulation of chromosomal alterations. Distinct alterations already exist within the primary tumor and this "ready to go package" gives the cells the metastatic potential to achieve the complex series of events needed for metastasis.

Overexpression of the c-erbB-2 protein (also called HER-2/neu) is observed in a variety of malignancies including colorectal cancer (CRC). In this study we aimed to evaluate the rate of c-erbB-2 overexpression in our tumor collection and to clarify its correlation with the chromosomal status at the c-erbB-2 locus in CRC. Additionally we correlated the c-erbB-2 overexpression and the chromosomal gain of 17q with patient survival. Seventy-four specimens were analyzed immunohistochemically using a polyclonal c-erbB-2 antibody (DAKO) and the staining was scored according to the Clinical Trial Assay recommendations (0–3+). Of these, 45 cases were analyzed by comparative genomic hybridization (CGH) and immunohistochemistry (IHC). Overexpression was observed in 51% of the cases (score ≥2). Chromosomal gains at the c-erbB-2 locus were clearly correlated with overexpression of the gene (P=0.0009). Furthermore Kaplan–Meier analysis showed that overexpression of c-erbB-2 was significantly associated with poor survival and thus could serve as a prognostic marker. We conclude that c-erbB-2 is related with tumor progression in CRC which can be observed on protein level and reflects chromosomal gain at the locus at 17q.

There was an error in the original version of Fig. 7 representing the DNA imbalances of the 4 lung cancer subtypes as detected by conventional CGH. For large cell lung cancer (LCLC), the ideogram of chromosome 9 together with the histograms of DNA gains and losses was shown and not chromosome 8 harbouring the FGFR1 locus. The corrected version with the chromosome 8 histogram (see new figure), however, indicates an identical finding, i.e. that chromosome 8p is more often affected by deletions than DNA gains.

Nature 486, 266–270 (2012); doi:10.1038/nature11114 In this Letter, several authors from the Australian Pancreatic Cancer Genome Initiative were inadvertently omitted: Christopher J. Scarlett and Warren Kaplan from the The Kinghorn Cancer Centre; and Aldo Scarpa from the ARC-NET Center for Applied Research on Cancer.