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Thomas Greither,1,* Kersten Fischer,2,* Gerit Theil,2 Marios Marcou,1,2 Hans-Juergen Holzhausen,3 Katrin Weigelt,4 Ginette Serrero,5,6 David Hicks,5 Binbin Yue,5 Paolo Fornara,2 Bernd Wullich,4 Helge Taubert,4 Sven Wach,4 Verena Lieb4 1Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, Halle, Germany; 2Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany; 3Department of Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany; 4Department of Urology and Pediatric Urology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 5A&G Pharmaceutical Inc., Columbia, Maryland, USA; 6Program in Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA *These authors contributed equally to this work Background: GP88/Progranulin is a well-recognized cell growth promoter in different cancers, and elevated serum GP88 levels have been described as negative prognostic factor in breast cancer. However, serum levels in prostate cancer (PCa) patients have not yet been studied. Material and Methods: We analyzed serum GP88 levels by enzyme immunosorbent assay and correlated them with clinicopathological parameters in PCa patients. PCa patients were separated into two groups based on the serum GP88 median level (low ≤44.56 ng/mL or high >44.56 ng/mL) and according to their median age (younger ≤66 years or elder patients >66 years). Results: Low serum GP88 levels were more often detected in younger patients and high levels in elder patients (P=0.018; Fisher’s exact test). PCa patients were separated into three groups, Gleason score (GS) ≤6; GS=7; and GS≥8. In receiver operating characteristic analyses, we could distinguish GS≤6 from GS=7 [area under the curve (AUC): 0.646; P=0.018] and GS≤6 from GS≥8 (AUC: 0.629; P=0.048) but not GS=7 from GS≥8. For survival analysis, GP88 levels were separated into two groups by an optimized cutoff value of 36.92 ng/mL. Using this GP88 stratification, all PCa patients and younger patients with a low serum GP88 level had a significantly better overall survival compared with patients with higher serum GP88 levels (log-rank test P=0.010 and P=0.024). Conclusion: Serum GP88 levels are significantly different depending on age and GS, and they are associated with the prognosis of PCa patients. Keywords: GP88, progranulin, prostate cancer, Gleason score

Background: Survivin, a member of the inhibitor of apoptosis-protein family suppresses apoptosis and regulates cell division. It is strongly overexpressed in the vast majority of cancers. We were interested if survivin detected by immunohistochemistry has prognostic relevance especially for patients of the two soft tissue sarcoma entities leiomyosarcoma and synovial sarcoma.Methods: Tumors of leiomyosarcoma (n = 24) and synovial sarcoma patients (n = 26) were investigated for their expression of survivin by immunohistochemistry. Survivin expression was assessed in the cytoplasm and the nucleus of tumor cells using an immunoreactive scoring system (IRS).Results: We detected a survivin expression (IRS > 2) in the cytoplasm of 20 leiomyosarcomas and 22 synovial sarcomas and in the nucleus of 12 leiomyosarcomas and 9 synovial sarcomas, respectively. There was no significant difference between leiomyosarcoma and synovial sarcoma samples in their cytoplasmic or nuclear expression of survivin. Next, all sarcoma patients were separated in four groups according to their survivin expression in the cytoplasm and in the nucleus: group 1: negative (IRS 0 to 2); group 2: weak (IRS 3 to 4); group 3: moderate (IRS 6 to 8); group 4: strong (IRS 9 to 12). In a multivariate Cox's regression hazard analysis survivin expression detected in the cytoplasm or in the nucleus was significantly associated with overall survival of patients in group 3 (RR = 5.7; P = 0.004 and RR = 5.7; P = 0.022, respectively) compared to group 2 (reference). Patients whose tumors showed both a moderate/strong expression of survivin in the cytoplasm and a moderate expression of survivin in the nucleus (in both compartments IRS > or = 6) possessed a 24.8-fold increased risk of tumor-related death (P = 0.003) compared to patients with a weak expression of survivin both in the cytoplasm and in the nucleus.Conclusion: Survivin protein expression in the cytoplasma and in the nucleus detected by immunohistochemistry is significantly associated with prognosis of leiomyosarcoma and synovial sarcoma patients. [ABSTRACT FROM AUTHOR]

Soft tissue sarcoma (STS) is a heterogeneous group of rare malignancies with a five-year survival rate of approximately 50%. Reliable molecular markers for risk stratification and subsequent therapy management are still needed. Therefore, we analyzed the prognostic potential of miR-155-5p and miR-203a-3p expression in a cohort of 79 STS patients. MiR-155-5p and miR-203a-3p expression was measured from tumor total RNA by qPCR and correlated with the demographic, clinicopathological, and prognostic data of the patients. Elevated miR-155-5p expression was significantly associated with increased tumor stage and hypoxia-associated mRNA/protein expression. High miR-155-5p expression and low miR-203a-3p expression, as well as a combination of high miR-155-5p and low miR-203a-3p expression, were significantly associated with poor disease-specific survival in STS patients in the Kaplan-Meier survival analyses ( p = 0.027, p = 0.001 and p = 0.0003, respectively) and in the univariate Cox regression analyses (RR = 1.96; p = 0.031; RR = 2.59; p = 0.002 and RR = 4.76; p = 0.001, respectively), but not in the multivariate Cox regression analyses. In conclusion, the oncomiR miR-155-5p and the tumor suppressor-miR miR-203a-3p exhibit an association with STS patient prognosis and are suggested as candidates for risk assessment.

In various tumors, the hypoxia inducible factor-1α ( HIF-1α ) and the epidermal growth factor-receptor ( EGFR ) have an impact on survival. Nevertheless, the prognostic impact of both markers for soft tissue sarcoma (STS) is not well studied. We examined 114 frozen tumor samples from adult soft tissue sarcoma patients and 19 frozen normal tissue samples. The mRNA levels of HIF-1α, EGFR, and the reference gene hypoxanthine phosphoribosyltransferase (HPRT) were quantified using a multiplex qPCR technique. In addition, levels of EGFR or HIF-1α protein were determined from 74 corresponding protein samples using ELISA techniques. Our analysis showed that a low level of HIF-1α or EGFR mRNA (respectively, relative risk (RR) = 2.8; p = 0.001 and RR = 1.9; p = 0.04; multivariate Cox´s regression analysis) is significantly associated with a poor prognosis in STS patients. The combination of both mRNAs in a multivariate Cox's regression analysis resulted in an increased risk of early tumor-specific death of patients (RR = 3.1, p = 0.003) when both mRNA levels in the tumors were low. The EGFR protein level had no association with the survival of the patient's cohort studied, and a higher level of HIF-1α protein associated only with a trend to significance (multivariate Cox's regression analysis) to a poor prognosis in STS patients (RR = 1.9, p = 0.09). However, patients with low levels of HIF-1α protein and a high content of EGFR protein in the tumor had a three-fold better survival compared to patients without such constellation regarding the protein level of HIF-1α and EGFR. In a bivariate two-sided Spearman's rank correlation, a significant correlation between the expression of HIF-1α mRNA and expression of EGFR mRNA ( p < 0.001) or EGFR protein ( p = 0.001) was found, additionally, EGFR mRNA correlated with EGFR protein level ( p < 0.001). Our results show that low levels of HIF-1α mRNA or EGFR mRNA are negative independent prognostic markers for STS patients, especially after combination of both parameters. The protein levels showed a different effect on the prognosis. In addition, our analysis suggests a possible association between HIF-1α and EGFR expression in STS.

We studied the association of the serum levels of the microRNA family members miR-320a/-b/-c with clinico-pathological data to assess their applicability as diagnostic biomarker in prostate cancer (PCa) patients. The levels of miR-320a/-b/-c in 3 groups were evaluated by qRT-PCR (145 patients with PCa, 31 patients with benign prostatic hyperplasia (BPH) and 19 healthy controls). The levels of the three family members of miR-320 were directly correlated within each group ( P < 0.001), but they differed significantly among the three groups ( P < 0.001). The serum levels of the miR-320 family members were significantly increased in older patients compared to younger patients (≤ 66 years vs. > 66 years, P ≤ 0.001). In addition, the levels of all three miR-320 family members were significantly different in patients with low tumor stage compared with those with high tumor stage (miR-320a: P = 0.034; miR-320b: P = 0.006; miR-320c: P = 0.007) and in patients with low serum PSA compared with those with high serum PSA (≤ 4 ng vs. > 4 ng; miR-320a: P = 0.003; miR-320b: P = 0.003; miR-320c: P = 0.006). The levels of these miRNAs were inversely correlated with serum PSA levels. Detection in the serum samples of PCa patients with or without PSA relapse revealed higher levels of miR-320a/-b/-c in the group without PSA relapse before/after radical prostatectomy than in that with PCa relapse. In summary, the differences among the PCa/BPH/healthy control groups with respect to miR-320a/-b/-c levels in conjunction with higher levels in patients without a PSA relapse than in those with a relapse suggest the diagnostic potential of these miRNA-320 family members in PCa patients., Competing Interests: CONFLICTS OF INTEREST All authors declare to have no conflicts of interest.

The capillary morphogenesis gene 2 (CMG2), also known as the anthrax toxin receptor 2 (ANTXR2), is a transmembrane protein putatively involved in extracellular matrix (ECM) adhesion and tissue remodeling. CMG2 promotes endothelial cell proliferation and exhibits angiogenic properties. Its downregulation is associated with a worsened survival of breast carcinoma patients. Aim of this study was to analyze the CMG2 mRNA and protein expression in soft tissue sarcoma and their association with patient outcome. CMG2 mRNA was measured in 121 tumor samples of soft tissue sarcoma patients using quantitative real-time PCR. CMG2 protein was evaluated in 52 tumor samples by ELISA. CMG2 mRNA was significantly correlated with the corresponding CMG2 protein expression (r s = 0.31; p = 0.027). CMG2 mRNA expression was associated with the mRNA expressions of several ECM and tissue remodeling enzymes, among them CD26 and components of the uPA system. Low CMG2 mRNA expression was correlated with a worsened patients' disease-specific survival in Kaplan-Meier analyses (mean patient survival was 25 vs. 96 months; p = 0.013), especially in high-stage tumors. A decreased CMG2 expression is a negative prognostic factor for soft tissue sarcoma patients. CMG2 may be an interesting candidate gene for the further exploration of soft tissue sarcoma genesis and progression., Competing Interests: The authors declare no conflict of interest.

The advent of new and acute headaches poses a diagnostic challenge. The differential diagnosis comprises numerous diseases and syndromes, the prevalence of which varies depending on the geographical region. Due to increased magnitudes in international migration, the usual differential diagnostic spectrum has to be enlarged in individual cases. The presented case illustrates this dilemma and shows that, for example, tuberculosis deserves to be taken into consideration., (© The Author(s) 2016.)

Tumor-associated immune cells have been discussed as an essential factor for the prediction of the outcome of tumor patients. Lymphocyte-specific genes are associated with a favorable prognosis in colorectal cancer but with poor survival in renal cell carcinoma (RCC). Flow cytometric analyses combined with immunohistochemistry were performed to study the phenotypic profiles of tumor infiltrating lymphocytes (TIL) and the frequency of T cells and macrophages in RCC lesions. Data were correlated with clinicopathological parameters and survival of patients. Comparing oncocytoma and clear cell (cc)RCC, T cell numbers as well as activation-associated T cell markers were higher in ccRCC, whereas the frequency of NK cells was higher in oncocytoma. An intratumoral increase of T cell numbers was found with higher tumor grades (G1:G2:G3/4 = 1:3:4). Tumor-associated macrophages slightly increased with dedifferentiation, although the macrophage-to-T cell ratio was highest in G1 tumor lesions. A high expression of CD57 was found in T cells of early tumor grades, whereas T cells in dedifferentiated RCC lesions expressed higher levels of CD69 and CTLA4. TIL composition did not differ between older (>70 y) and younger (<58 y) patients. Enhanced patients' survival was associated with a higher percentage of tumor infiltrating NK cells and Th1 markers, e.g. HLA-DR+ and CXCR3+ T cells, whereas a high number of T cells, especially with high CD69 expression correlated with a worse prognosis of patients. Our results suggest that immunomonitoring of RCC patients might represent a useful tool for the prediction of the outcome of RCC patients.

Objectives: The study investigated the impact of occupational workloads on disc surgery specimens. We report the relationship between workload and histological features., Methods: Specimens were collected prospectively from patients suffering from lumbar disc prolapse (n=90) or spinal osteochondrosis (n=19). Histomorphology and occupational workload data and histomorphological features were evaluated. Occupational data were collected in a structured, standardized patient interview assessing lifting and carrying loads. In this way the exposure was assessed for each test subject's entire working life up to surgery., Results: There was no association between cumulative workload and histological patterns. In a subgroup of patients with a workload period of 12 months prior to surgery a relevant formation of chondrocyte clusters (p=0.055) was apparent. Chondrocyte cluster formation was found in 83% (n=74) of the prolapse patients and in 58% (n=11) of the osteochondrosis patients (p=0.02). Fibrocyte mediated scar formation was found in 55% of the prolapse patients and in 45% of the spinal stenosis patients. Chondrocyte clusters and their de novo collagen matrix did not integrate biomechanically sufficient with collagen fibers of the disc. Disintegration of clusters from disc matrix and formation of intra-discal sequesters were observed., Conclusion: Matrix degeneration was common but displayed no relationship to occupational workload or other histological features. Scar formation was observed in every second specimen. Regenerative chondrocyte cluster proliferation was a common feature in disc specimens and tended to be associated in patients with a workload one year before surgery.

Sialic acids (Sia) are widely expressed as terminal monosaccharides on eukaryotic glycoconjugates. They are involved in many cellular functions, such as cell-cell interaction and signal recognition. The key enzyme of sialic acid biosynthesis is the bifunctional UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), which catalyses the first two steps of Sia biosynthesis in the cytosol. In this study we analysed sialylation of muscles in wild type (C57Bl/6 GNE (+/+)) and heterozygous GNE-deficient (C57Bl/6 GNE (+/-)) mice. We measured a significantly lower performance in the initial weeks of a treadmill exercise in C57Bl/6 GNE (+/-) mice compared to wild type C57Bl/6 GNE (+/+) animals. Membrane bound Sia of C57Bl/6 GNE (+/-) mice were reduced by 33-53% at week 24 and by 12-15% at week 80 in comparison to C57Bl/6 GNE (+/+) mice. Interestingly, membrane bound Sia concentration increased with age of the mice by 16-46% in C57Bl/6 GNE (+/+), but by 87-207% in C57Bl/6 GNE (+/-). Furthermore we could identify specific morphological changes in aged muscles. Here we propose that increased Sia concentrations in muscles are a characteristic feature of ageing and could be used as a marker for age-related changes in muscle.

Unlabelled: The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G0-G1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu(+) cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics., Implications: These data suggest that CREB affects tumor immunogenicity and is a potential target for cancer therapy., (©2013 AACR.)

Background: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer., Patients and Methods: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples., Results: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015)., Conclusions: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.

Background: As high percentage of mammographic densities complicates the assessment of imaging findings, mammographic density may influence the histopathological evaluation of core-biopsies of the breast. We measured the influence of mammographic density on the inter-observer variability of histopathological findings of breast biopsies., Methods: Histological slides of 695 women who underwent core biopsies of the breast at University of Halle between 2006 and 2008 were evaluated in a blinded fashion by two pathologists using the five levels of the B-categorization scheme (B1-B5). To quantify mammographic density, we used a computer-based threshold method (Madena). We calculated observed and chance-corrected agreements (weighted kappa) and 95% confidence intervals (95% CI) according to four categories of mammographic density (<10%, 10<25%, 25<50%, ≥50%)., Results: The weighted kappa decreased monotonically from 89.6% (95% CI: 85.8%, 93.3%) among women with less than 10% of mammographic density to 80.4% (95% CI: 69.9%, 90.9%) for women with more than 50% of mammographic density, respectively. Results of a kappa regression analysis showed that agreement of pathologists on clinically relevant categories (B1-B2 versus B3-B5) decreased with mammographic density., Conclusions: Mammographic density is a relevant modifier of the agreement between pathologists who assess breast biopsies using the B-categorization scheme. The influence of mammographic density on the inter-observer variability can be explained to some extent by varying prevalences of histological entities across B categories that have typically different inter-observer agreement. Women with high mammographic density are at higher risk of inter-observer variability compared to women with low mammographic density and should possibly undergo a second pathology review.

Background: Argonaute genes are essential for RNA interference, stem cell maintenance and differentiation. The Piwi-like genes, a subclass of the Argonaute genes, are expressed mainly in the germline. These genes may be re-expressed in tumors, and expression of the Piwi-like genes is associated with prognosis in several types of tumors., Methods: We measured the expression of Piwi-like mRNAs (Piwi-like 2-4) in 125 soft tissue sarcoma (STS) samples by qPCRs. Statistical tests were applied to study the correlation of expression levels with tumor-specific survival for STS patients., Results: In multivariate Cox's regression analyses, we showed that low Piwi-like 2 and Piwi-like 4 mRNA expression were significantly associated with a worse prognosis (RR = 1.87; p = 0.032 and RR = 1.82; p = 0.039). Low expression of both genes was associated with a 2.58-fold increased risk of tumor-related death (p = 0.01). Piwi-like 4 and combined Piwi-like 2 and 4 mRNA levels correlated significantly with prognosis (RR = 3.53; p = 0.002 and RR = 5.23; p = 0.004) only for female but not for male patients. However, combined low Piwi-like 2 and 3 transcript levels were associated with worse survival (RR = 5.90; p = 0.02) for male patients., Conclusions: In this study, we identified a significant association between the expression of Piwi-like 2 and 4 mRNAs and the tumor-specific survival of soft tissue sarcoma patients. Furthermore, a connection between sex and the impact of Piwi-like mRNA expressions on STS patients' prognosis was shown for the first time.

In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.

Rationale and Objectives: Most secondary intramammary tumors occur as metastatic involvement from the contralateral breast. Breast metastases (BM) from nonmammary malignancies are very rare. The aims of this study were to estimate retrospectively the prevalence of BM from nonmammary malignancies and to describe their radiologic appearance., Materials and Methods: BM were identified in 51 patients, including 43 women and eight men with a median age of 61 years (range, 24-84 years). Computed tomography of the thoracic region identified 108 lesions in 38 patients. Mammography was available for 37 patients (54 lesions). Ultrasound evaluation was performed in 43 patients (71 lesions). In 24 patients (93 lesions), magnetic resonance imaging of the breast was done. Images were reviewed in consensus by two radiologists according to the Breast Imaging Reporting and Data System lexicon., Results: The prevalence of BM in several tumors ranged from 0.12% to 4.92%. On computed tomography, most metastases were round or oval in shape with marked or moderate enhancement. On mammography, solitary or multiple round or oval masses with circumscribed margins were the most common pattern of BM. Ten percent showed microcalcifications. On ultrasound, most BM were hypoechoic, oval or round in shape, with microlobulated or circumscribed margins, and posterior acoustic enhancement. Doppler imaging showed hypervascularity in 39% of BM. On magnetic resonance imaging, most lesions demonstrated marked homogenous contrast enhancement. Type 1 kinetic curve was seen in 18%, type 2 in 52%, and type 3 in 30%., Conclusions: The radiologic features reported in this study should be taken into consideration in the differential diagnosis of breast lesions., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Unlabelled: The aim of this study was to investigate the late changes in the expression of tenascin-C (TN-C) in salivary glands (SG) following irradiation (IRR)., Materials and Methods: In 124 submandibular SG from 62 Wistar rats, the effect of IRR dose (fractionated IRR, 2 Gy per day, total dose of 20, 40, or 60 Gy), time since IRR (6 months vs. 12 months), and animal age (1 year vs. 1.5 years) on TN-C expression profile and its distribution pattern was investigated., Results: Expression of TN-C showed slight to moderate alterations in the irradiated specimens. The expression differed in frequency and degree among various tissue structures. The most striking finding was pronounced dose-dependent heterogeneity, with increases, decreases and fluctuations in staining., Conclusion: The staining of TN-C predominantly showed notable dose-dependent heterogeneity, persisting for up to 1 year after completion of IRR. Thus, these findings can be attributed to late radiation effects. The altered expression of tenascin-C may play at least a partial role in late radiogenic dysfunction of the submandibular SG.

Background: The urokinase plasminogen activator (uPA) system is one of the best-investigated protease systems, both under physiological and pathological conditions, including various types of cancer. However, effects of co-expression of members of the uPA system in soft-tissue sarcoma (STS) patients at the protein level in both tumour tissue and serum have not been investigated yet., Methods: We examined 82 STS patients for protein levels of uPA, PAI-1and uPAR in tumour tissue and serum by ELISA., Results: A significant correlation between high antigen levels of uPA, PAI-1 or uPAR in tumour tissue, and of uPAR in serum, with poor outcome of STS patients was found for the first time. Most strikingly, we observed an additive effect of combined uPA, PAI-1 or uPAR levels in tumour tissue extracts with uPAR levels in serum on patients' prognosis. High uPA/uPAR, PAI-1/uPAR and uPAR/uPAR antigen levels in tumour tissue/serum were associated with a 5.9-fold, 5.8-fold and 6.2-fold increased risk of tumour-related death (P=0.003, 0.001 and 0.002, respectively) compared with those patients who displayed low levels of the respective marker combination., Conclusion: As expression of members of the uPA system in tumour tissue and serum is additively correlated with prognosis of STS patients, our results suggest that combinations of these biomarkers can identify STS patients with a higher risk of tumour-related death.

Budd-Chiari syndrome and membranous obstruction of the inferior vena cava frequently result in the development of mostly benign hepatic lesions. In cases of membranous obstruction of the inferior vena cava, which is prevalent mostly in the East, these lesions often progress to hepatocellular carcinoma. In contrast, malignant transformation has not yet been recognised in patients with isolated hepatic vein thrombosis. We report the case of a 37-year-old male Caucasian who presented with acute Budd-Chiari syndrome without involvement of the inferior vena cava. Despite porto-caval shunting, a hepatocellular carcinoma developed within several months. Three hepatic lesions were treated by radiofrequency thermal ablation until liver transplantation was performed. This report emphasises the possibility of malignant transformation of regenerative nodules in patients with disturbed hepatic perfusion in general. Physicians must be aware of this when assessing regenerative nodules, especially as no unambiguous predictors for the development of hepatocellular carcinoma have been identified so far.

The p53 stress response is crucial for the prevention of tumor formation. The oncogene HDM2 is one of the key negative regulators of p53 and is a central node in the p53 pathway. P53 and HDM2 form an oscillating feedback loop. HDM2 expression is regulated by different promoters. To evaluate its clinical relevance, we determined the levels of HDM2 transcripts originating from the constitutive P1 and p53-sensitive P2 promoter in 133 soft tissue sarcomas and correlated the results with the age of diagnosis and the patients' outcome. We show that only high levels of the HDM2-P1 transcript but not the P2 transcript are associated with an 11-year earlier age of onset (50.5 years) compared with low P1 levels (61.5 years; P < 0.0001, t test). In addition, low P1 and P2 mRNA expression levels were independent predictors of poor outcome for patients with soft tissue sarcomas (low P1: relative risk, 3.7; P < 0.0001; low P2: relative risk, 2.5; P = 0.001). A change in the expression levels of the HDM2 transcripts originating from the two HDM2 promoters could disrupt the oscillating P53-HDM2 feedback loop in a way that elevated levels of HDM2-P1 transcript are associated with an earlier age of tumor onset and that reduced levels of HDM2-P1 or HDM2-P2 transcripts are correlated with poor prognosis of patients with soft tissue sarcomas.