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Background: The prognostic significance of tumour budding (TB) and minimal cell nest size (MCNS) was shown in human papillomavirus (HPV)-negative head and neck squamous cell carcinomas (HNSCC). However, the optimisation of cutpoints, the prognostic impact in HPV-positive HNSCC, and the comparison with other histopathological grading systems are insufficiently investigated. Methods: TB and MCNS were analysed digitally in 1 and 10 high-power fields (HPF) of 331 HPV-positive and HPV-negative cases from TCGA. Optimising the cutpoints a new cellular dissociation grading (CDG) system was defined and compared to the WHO grading and the Brandwein–Gensler (BG) risk model. Results: The two-tiered CDG system based solely on TB yielded optimal prognostic stratification with shortened overall survival for CDG-high cases. Optimal cut-offs were two buds (1 HPF) and six buds (10 HPF), respectively. Analysing MCNS did not add prognostic significance to quantifying TB. CDG was a significant prognostic marker in HPV-negative and HPV-positive tumours and prognostically superior to the WHO and BG systems. High CDG was associated with clinically occult lymph-node metastases. Conclusions: The most comprehensive study of TB in HNSCC so far confirmed its prognostic impact in HPV-negative tumours and for the first time in HPV-positive tumours. Further studies are warranted to evaluate its applicability for therapy guidance in HNSCC. [ABSTRACT FROM AUTHOR]

Advanced stage colorectal cancer (CRC) is still associated with limited prognosis. For preclinical evaluation of novel therapeutic approaches, murine models with orthotopic tumor growth and distant metastases are required. However, these models usually require surgical procedures possibly influencing tumor immunogenicity and development. The aim of this study was to establish a minimal-invasive endoscopy-based murine orthotopic model of metastatic CRC. During colonoscopy of CD-1 nude and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, implantation of Caco-2 and HT-29 CRC cells was performed subcutaneously (s.c.) or orthotopic into the colonic submucosa. White light endoscopy (WLE) and fluorescence endoscopy (FE) were applied for tumor detection in vivo. Ex vivo, resected tumors were examined by fluorescence reflectance imaging (FRI), histology, gelatin zymography and immunohistochemistry. In CD-1 nude mice, marked tumor growth was observed within 14 days after subcutaneous implantation while submucosal implantation failed to induce CRC after 17 weeks. In contrast, in NOD/SCID mice submucosal injection of HT-29 cells resulted in pronounced tumor growth 12 days post injectionem. Subsequently, rapid tumor expansion occurred, occupying the entire colonic circumference. Importantly, post mortem histological analyses confirmed liver metastases in 28.6 % and peritoneal metastases in 14.3 % of all mice. FRI and gelatin zymography did not detect a significantly increased matrix metalloproteinases (MMPs) expression in s.c. implanted tumors while MMP-tracer uptake was significantly enhanced in orthotopic implanted tumors. Neither s.c. nor orthotopic Caco-2 cell implantation resulted in tumor development. We successfully established an endoscopy-based model of metastatic CRC in immunodeficient mice. [ABSTRACT FROM AUTHOR]

Prognostic multigene expression assays have become widely available to provide additional information to standard clinical parameters and to support clinicians in treatment decisions. In this study, we analyzed the impact of variations in tissue handling on the diagnostic EndoPredict test results. EndoPredict is a quantitative reverse transcription PCR assay conducted on RNA from formalin-fixed, paraffin-embedded (FFPE) tissue that predicts the likelihood of distant recurrence in patients with ER-positive/HER2-negative breast cancer. In this study, we performed a total of 138 EndoPredict assays to study the effects of preanalytical variables such as time to fixation, fixation time, tumor cell content, and section storage time on the EndoPredict test results. A time to fixation of up to 12 h and fixation of up to 5 days did not affect the results of the gene expression test. Paired samples of FFPE sections with tumor cell content ranging from 15 to 95 % and tumor-enriched samples showed a correlation coefficient of 0.97. Test results of tissue sections that have been stored for 12 months at +4 or +20 °C showed a correlation of 0.99 when compared to results of nonstored sections. In conclusion, preanalytical tissue handling is not a critical factor for diagnostic gene expression analysis with the EndoPredict assay. The test can therefore be easily integrated into the standard workflow of molecular pathology. [ABSTRACT FROM AUTHOR]

The goal of this analysis was to characterize the survival impact of angiogenesis in the patients with high-risk breast cancer, particularly the predictive impact on benefit from dose intensification of adjuvant chemotherapy. Formalin-fixed tissue sample of 152 patients treated as part of the WSG AM-01 trial by either high-dose or conventional dose-dense chemotherapy were analyzed. Angiogenic activity was measured using microvessel count and vascular surface area (VSA) determined by the expression of vascular markers CD31 ( n = 128) and CD105/endoglin ( n = 130). Protein molecular breast cancer subclasses were analyzed by k-means clustering ( k = 5). The univariate impact of factors on event-free (EFS) and overall survival (OS) was tested by log-rank statistics and quantified by univariate Cox analysis. Multivariate survival analysis included factors significant in univariate analysis, as well as interactions was performed for EFS. Both VSA/CD31 ( P = 0.004) and VSA/CD105 ( P = 0.003) were significantly higher among cases with increased Ki-67. A significant association with molecular subtypes was also found for VSA/CD105: in patients with basal-like/Her-2 subtypes, mean was 1.72 versus 1.24 in patients with other subtypes ( P < 0.001). Elevated VSA/CD105 was associated with both significantly decreased EFS ( P = 0.01) and OS ( P = 0.02). Increased tumor size and positive Her-2 status were also prognostic for poorer EFS. The benefit of dose intensification for EFS was seen in those low-VSA/CD105 patients. The result was evident both in univariate and in multivariate survival analysis including all factors that were significant at the univariate level. Expression of angiogenesis markers may mirror or confer resistance to chemotherapy in the patients with breast cancer, particularly within the context of dose intensified chemotherapy. Highly angiogenic tumors may not derive sufficient benefit from dose intensification of chemotherapy alone. Our findings may serve as a rationale for further exploring anti-angiogenic treatment options in the patients with such highly angiogenic tumor subtypes. [ABSTRACT FROM AUTHOR]

Copyright of Medizinische Klinik (Urban & Vogel) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Superficial soft tissue sarcomas (sSTS) are an important and frequent subtype of soft tissue sarcoma (STS). A wider knowledge of this tumor type may lead to better strategies in tumor therapy. An institutional review was performed on all patients with primary sSTS of the extremities and trunk operated on between 1990 and 2003. The medical records of 108 patients with sSTS were analyzed. The local recurrence rate was 11% after a median of 25 (mean 42) months. Metastases occurred in 21 patients (19%), and 79 patients lived without evidence of disease after a mean follow-up of 112 ± 42 months. Mean survival time was 89 months at a cumulative 5-year survival rate of 85%. R0 resection significantly enhanced cumulative survival ( p = .001), as did patient age < 60 years ( p = .002), tumor grading G1 and G2 compared to G3 ( p = .004), absence of positive lymph nodes ( p = .018), and no occurrence of metastases ( p = .001). Tumor size ≤ 5 cm reduced the local recurrence rate significantly ( p = .044). Significant multivariate risk factors for metastases were age ≥ 60 years ( p = .016) and tumor grade G3 ( p = .021). Patients with sSTS who are ≥60 years of age or who have G3 tumors have a high risk of distant metastases. Patients with T2 tumors have an elevated risk for local recurrence. Certainly all patients with sSTS should be in a tight after-care program to allow early diagnosis of local recurrence or distant metastases. Age < 60 years, tumor grade G1/2, no positive regional lymph nodes (N0), and a R0 resection are significant prognostic factors for survival. [ABSTRACT FROM AUTHOR]

The objective of this study was to identify genomic alterations in resectable pancreatic cancer (PCA). Chromosomal imbalances were correlated with histopathological and clinical data to verify their prognostic significance. Specimens of 33 PCA were investigated by comparative genomic hybridization. Microdissection was used for separation of PCA from the normal cells before isolation of DNA; nick-end labeling and hybridization were performed according to standard protocols. Aberrations were correlated with staging and grading using log-rank test and Cox regression. Survival rates were plotted using the Kaplan–Meier method. Twenty-eight (85%) PCA showed aberrations. Gains of chromosomal material were most frequently identified on 8q (42%), 13q (30%), 18p (21%), and 3q (18%). Genetic losses were frequently detected on 1p (45%), 22 (42%), 19 (36%), 17p (27%), 18q and 8p (15% each), and 3p (12%). Losses of 8p ( n = 5) and 3p ( n = 4) were only detected in stages III and IV ( P < 0.05). Median survival time of all patients was 13 months. Median survival time of patients with aberration of 8q ( n = 14) was 8.5 months compared to 16 months in patients without gain of 8q ( n = 19; P = 0.029). The chromosomal regions containing genetic alterations represent potential loci for new target genes in PCA. The significant correlation of gain of chromosome 8q with short survival time suggests that 8q may be a new marker to assess prognosis and malignant potential of resected PCA in the individual patient, thereby helping to identify patients at risk for recurrence that might profit from adjuvant therapy. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

As primary osseous metastasis is the main adverse prognostic factor in patients with Ewing tumours, a NOD/ scid mouse model for human Ewing tumour metastases has been established to examine the mechanisms of metastasis. The aim of this study was to evaluate the feasibility of diagnostic molecular imaging by small animal PET in this mouse model. Human Ewing tumour cells were transplanted into immune-deficient NOD/ scid mice via s.c injection ( n=17) or i.v. injection ( n=17). The animals (mean weight 23.2 g) were studied 2–7 weeks after transplantation using a submillimetre resolution animal PET scanner. To assess glucose utilisation and bone metabolism, mice were scanned after intravenous injection of 9.6 MBq (mean) 2-[18F]fluoro-2-deoxy- D-glucose (FDG) or 9.4 MBq (mean) [18F]fluoride. Whole-body PET images were analysed visually and semi-quantitatively [%ID/g, tumour to non-tumour ratio (T/NT)]. Foci of pathological uptake were identified with respect to the physiological organ uptake in corresponding regions. Subcutaneously transplanted Ewing tumours demonstrated a moderately increased glucose uptake (median %ID/g 2.5; median T/NT 2.2). After i.v. transplantation, the pattern of metastasis was similar to that in patients with metastases in lung, bone and soft tissue. These metastases showed an increased FDG uptake (median %ID/g 3.6; median T/NT 2.7). Osseous metastases were additionally visible on [18F]fluoride PET by virtue of decreased [18F]fluoride uptake (osteolysis; median %ID/g 8.4; median T/NT 0.59). Metastases were confirmed immunohistologically. Diagnostic molecular imaging of Ewing tumours and their small metastases in an in vivo NOD/ scid mouse model is feasible using a submillimetre resolution PET scanner. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the relationship between chromosomal instabilities and clinicopathological factors in synovial sarcoma (SS). Methods: Twenty-two fresh-frozen SS were analyzed by metaphase comparative genomic hybridization (CGH). Additional microarray CGH was performed in 13 cases. Results: Fourteen patients with SYT–SSX1 rearrangements and nine patients with biphasic tumor subtypes had better prognosis than the eight patients with SYT–SSX2 rearrangements and 13 patients with monophasic subtypes, respectively. Gains (average 3.0) were more frequent than losses (average 1.0). Frequent gains were identified on chromosomal regions 2, 6q, 7, 8q, 12, 17q, 18q, and 21q, whereas frequent losses were over-lapped on chromosomes 1p31–p35, 3p, 6q, 16, and 17p. High-level gains were observed on chromosomes 1q21–q31, 7, 8, 12, 17q, 18q, and 21q. Thirteen monophasic and nine biphasic tumors had an average of 5.1 and 2.8 aberrations, respectively. Patients with tumors harboring numerous aberrations (≥3) had a worse clinical course. Microarray CGH more specifically detected genetic imbalances including gains in MDM2, MSH2, KCNK12, DCC, CDK2, ERBB3, SAS, and CDK4 and losses in HRAS, RASSF1, and CCND1. Gain of SAS was an important prognostic factor of SS. Conclusion: We have identified several factors influencing the prognosis of SS patients by metaphase and microarray CGH. [ABSTRACT FROM AUTHOR]

Laser holographic interferometry is based on the superimposition of the holograms of different motional states of an object on a single holographic storing medium. Using a combination of holographic interferometry and endoscopic imaging, we tried to detect areas of focally disturbed tissue elasticity in gastric cancer preparations. By connecting a mobile electronic speckle pattern interferometry (ESPI) camera system (light source: double frequency Nd:YAG laser, lambda = 532 nm) to different types of endoscopes, ex vivo experiments were performed on ten formalin fixed human stomachs, nine containing adenocarcinomas and one with a gastric lymphoma. Linking the endoscopic ESPI camera complex to a fast image processing system, the method of double pulse exposure image subtraction was applied at a video frame rate of 12.5 Hz. Speckle correlation patterns and corresponding phase difference distributions resulting from gastric wall deformation by gentle touch with a guide wire were analyzed. Tumor-free gastric areas showed high-contrast concentric fringes around the point of stimulation. In contrast, fringe patterns and filtered phase difference distributions corresponding to the areas of malignancy in all the cases were characterized by largely parallel lines, indicating that stimulation of rigid tumor tissue primarily led to tilting. Our ex vivo investigations of malignant gastric tumors show that the application of dynamic holographic endoscopy makes it possible to distinguish areas of malignancy from surrounding healthy tissue based on the differences in tissue elasticity. [ABSTRACT FROM AUTHOR]

In all, 85%of Ewing's sarcoma family tumors (ESFT), a neoplasm of unknown histogenesis, express EWS-FLI1 transcription factor gene fusions. To characterize direct target genes avoiding artificial model systems, we cloned genomic DNA from ESFT chromatin precipitating with EWS-FLI1. We now present a comprehensive list of 99 putative transcription factor targets identified, for the first time, by a hypothesis-free approach based on physical interaction. Gene-derived chromatin fragments co-precipitating with EWS-FLI1 were nonrandomly distributed over the human genome and localized predominantly to the upstream region and the first two introns of the genes. At least 20%of putative direct EWS-FLI1 targets were neural genes. One-third of genes recovered showed a significant ESFT-specific expression pattern and were found to be altered upon RNAi-mediated knockdown of EWS-FLI1. Among them, MK-STYX, encoding a MAP kinase phosphatase-like protein, was consistently expressed in ESFT. EWS-FLI1 was found to drive MK-STYX expression by binding to a single ETS binding motif within the first gene intron. MK-STYX serves as precedence for successful recovery of direct EWS-FLI1 targets from the authentic ESFT cellular context, the most relevant system to study oncogenic mechanisms for the discovery of new therapeutic targets in this disease.Oncogene (2005) 24, 2512-2524. doi:10.1038/sj.onc.1208455 Published online 14 February 2005 [ABSTRACT FROM AUTHOR]

OBJECTIVES: A variety of imaging techniques are available to diagnose bile duct strictures; the most effective imaging technique, however, has not been established yet. In the present study, we compared the impact of endoscopic retrograde cholangiopancreatography (ERCP), intraductal ultrasonography (IDUS), and magnetic resonance cholangiopancreatography (MRCP) with regard to diagnosing bile duct strictures.METHODS: We prospectively examined 33 patients with jaundice due to bile duct strictures by ERCP plus IDUS and MRCP. The objectives were to assess diagnostic quality of imaging, complete presentation of the bile duct, and differentiation of malignant from benign lesions. Surgical and histopathological correlations, which were used as the gold standard, were available in all cases since all included patients underwent laparotomy.RESULTS: Diagnostic image quality for ERCP was 88% and 76% for MRCP (p>0.05). Comparing ERCP and MRCP, complete presentation of the biliary tract was achieved in 94% and 82%, respectively (p>0.05). ERCP and MRCP allowed correct differentiation of malignant from benign lesions in 76% and 58% (p= 0.057), respectively. By supplementing ERCP with IDUS, the accuracy of correct differentiation of malignant from benign lesions increased significantly to 88% (p= 0.0047).CONCLUSIONS: Comparing ERCP with MRCP, we found adequate presentation of bile duct strictures in high imaging quality for both techniques. ERCP supplemented by IDUS gives more reliable and precise information about differentiation of malignant and benign lesions than MRCP alone without additional imaging sequences.(Am J Gastroenterol 2004;99:1684-1689) [ABSTRACT FROM AUTHOR]

Purpose. The objective of this study was to evaluate breast carcinomas for the expression of cyclooxygenase-2 (Cox-2) using a tissue microarray (TMA) and to determine its clinical and prognostic relevance. Methods. We analyzed Cox-2 expression in 600 samples from 200 breast carcinomas immunohistochemically performing TMA technology and semiquantitative analysis. Results were correlated with various clinicopathological variables and follow-up data. Expression of estrogen receptor, progesterone receptor, Ki-67, and Her-2/neu-oncogene was analyzed and correlated with Cox-2 status. Results. We observed a moderate or strong cytoplasmic staining for Cox-2 in 78 (40.6%) of breast carcinomas. Increased Cox-2 expression corresponded to higher pT stage (P=0.038), amplification of Her-2/neu (P=0.032), lymphovascular invasion (P=0.006), a high MIB-1 labeling index (LI) (P<0.001), and histological grading (P=0.013). We also observed an inverse relationship between strong Cox-2 expression and estrogen and progesterone receptor content of tumors (P=0.037 and P=0.010). However, we could not demonstrate a significant association between Cox-2 staining and overall survival or disease free survival time. Conclusions. These results suggest that Cox-2 expression is significantly associated with less differentiated and more aggressive breast carcinomas and might therefore be a useful prognostic indicator as well as a target for therapy. [ABSTRACT FROM AUTHOR]

Copyright of Strahlentherapie und Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Presents a study that compared allelic imbalances in human and murine osteosarcomas to identify genetic changes critical for osteosarcomagenesis. Background on osteosarcoma; Comparison between the human and mouse syntenic regions; Information on the association of disturbances of developmental control genes with tumorigenesis.

Telomeres are crucial for chromosomal stability and cell viability. Activation of telomerase, a specialized reverse transcriptase, is the predominant mechanism for maintaining telomere length and function in yeasts and human cells. Telomere maintenance is regarded as a key element in the immortalization of cells and hence in oncogenesis. Although more than 90% of all malignant tumors display telomerase activity, there appear to be alternatives to this mechanism. Alternative lengthening of telomeres (ALT) in the absence of telomerase has been described in various organisms and recently also in immortalized and transformed human cells. This article will discuss how ALT is detected and how it affects telomere morphology. It will review the frequency and relevance of ALT in in vitro immortalized cell lines, tumor-derived cell lines, and primary tumors. We have only begun to link mechanisms by means of which ALT may act in immortalized human cells to the growing knowledge about telomeres, and we can look forward to further fascinating insights into telomere biology. Our review will also emphasize recent advances in our understanding of the induction and repression of ALT and the demonstration of ALT in cancer cells in the light of new treatment strategies targeted against telomere maintenance mechanisms. [ABSTRACT FROM AUTHOR]

GG-62 is a cell line previously thought to be derived from an atypical Ewing tumor (ET). Reverse-transcriptase polymerase chain reaction revealed an in-frame fusion between the Ewing sarcoma gene ( EWS) codon 325 and the activating transcription factor 1 gene ( ATF1) codon 65 which permits the production of chimeric EWS-ATF1 oncoproteins. We also identified the genomic breakpoint resulting from a reciprocal t(12;22)(q13;q12), which is the hallmark of malignant melanoma of soft parts (MMSP). We applied Affymetrix human cancer G110 arrays to compare the gene expression patterns of GG-62 and other cell lines derived from small blue round cell tumors of childhood. Hierarchical clustering of 463 differentially expressed genes distinguished GG-62 from the ETs, as well as the neuroblastomas, and revealed a cluster of 36 upregulated genes. Several of these genes are involved in signal transduction pathways that may be critical for maintaining cell transformation; some examples are avian erythroblastic leukemia viral oncogene homolog 3 ( ERBB3), neuregulin 1 ( NRG1), fibroblast growth factor 9 ( FGF9), and fibroblast growth factor receptor-1 ( FGFR1). Furthermore, genes near the chromosome-12q13 breakpoint exhibited increased expression of GG-62 including ERBB3, NR4A1 (nuclear receptor subfamily 4, group A, member 1), cyclin-dependent kinase 2 ( CDK2), and alpha 5 integrin ( ITGA5). Altogether our findings demonstrate the MMSP derivation of GG-62 and may shed light on the mechanisms of tumorigenesis in this rare disease. [ABSTRACT FROM AUTHOR]

Telomere maintenance is regarded as a key mechanism in overcoming cellular senescence in tumor cells and in most cases is achieved by the activation of telomerase. However there is at least one alternative mechanism of telomere lengthening (ALT) which is characterized by heterogeneous and elongated telomeres in the absence of telomerase activity (TA). We evaluated the prevalence of TA, gene expression of telomerase subunits and ALT in relation to telomere morphology and function in matrix producing bone tumors and in osteosarcoma cell lines and present evidence of a direct association of ALT with telomere dysfunction and chromosomal instability. Telomere fluorescence in situ hybridization (T-FISH) in ALT cells revealed elongated and shortened telomeres, partly in unusual configurations and loci, dicentric marker chromosomes and signal-free chromosome ends. Free ends give rise to end-to-end associations and may induce breakage-fusion-bridge cycles resulting in an increased number of complex chromosomal rearrangements, as detected by multiplex-FISH (M-FISH). We propose that ALT cannot be seen as an equivalent to telomerase activity in telomere maintenance. Its association with telomere dysfunction and chromosomal instability may have major implications for tumor progression. Oncogene (2001) 20, 3835–3844. [ABSTRACT FROM AUTHOR]