Evaluating Guideline Adherence for T1 Bladder Cancer Treatment and Surveillance: A Retrospective German Multicenter Observation.

INTRODUCTION: To mirror guideline-adherence for pT1 bladder cancer treatment in Northern Germany. MATERIALS AND METHODS: Overall, 111 patients with pT1 diagnosis were treated at 4 institutions. Guideline-adherence was defined as repeat resection, instillation, and quarterly cystoscopy. Patient characteristics and pathological parameters were assessed. We summarized patients using descriptive analyses and evaluated guideline-adherence within selected subgroups. We created a multivariable model to identify predictors of guideline-adherence. RESULTS: Median age was 75 years (range 39-94 years), multifocal tumors were found in 44.1%, early instillation was performed in 33.3%, and repeat resection was performed in 77.5%. Of 62.2% who underwent instillation, 59.4% received BCG, while 40.6% received Mitomycin C or other agents. Cystoscopic follow-up was performed in 81.8%. Guideline-adherence was met in 56.8%. Patients aged below the median met adherence metrics more often compared to those above the median (66.7 vs. 46.3%; p = 0.030). Men more frequently met adherence metrics compared to women (62.1 vs. 37.5%; p = 0.038). More patients with multifocal tumors met all 3 adherence metrics (69.4 vs. 48.0%; p = 0.050), as compared to those with unifocal lesions. In multivariable analyses, age-adjusted comorbidity (OR 0.75; 95% CI 0.59-0.94; p = 0.011) and multifocality (OR 2.62; 95% CI 1.09-6.27; p = 0.031) were predictors of guideline-adherence. CONCLUSIONS: We found non-adherence in more than one-third of patients and disparities among patients of different age and according to tumor focality. Larger samples and prospective studies are needed to delineate and eradicate treatment disadvantages in these high-risk patients.

Liquid Biopsy Using Whole Blood from Testis Tumor and Colon Cancer Patients-A New and Simple Way?

Tumor cells shed exosomes, which are released to the blood. Detecting tumor-derived exosomes containing RNA in plasma (liquid biopsy) is currently being investigated for early identification of occult metastases or relapses. Isolation of exosomes is laborious, resulting in low RNA yields. As a more robust (but less sensitive) alternative, the authors examined whether whole blood can be used as well. Tumor samples from nonmetastasized seminoma (n = 5) and colon cancer patients (n = 6) were taken during surgery. Whole-blood samples were taken before and 5-7 d after surgery. A whole genome mRNA microarray screening was performed. Candidate genes were selected based on two criteria: (1) gene expression in the presurgical whole-blood sample/tumor biopsy; and (2) a two-fold decrease in the copy number of candidate genes was expected in the postsurgical whole-blood sample 5-7 d after intervention, relative to the presurgical blood sample. The rationale behind this is the loss of tumor material in the body and the decline in the release of tumor-derived RNA in exosomes. For both tumor entities and for each patient, several hundred candidate genes could be identified. In a group-wise comparison, 20 candidate genes could be identified in the seminoma and 32 in the colon cancer group. These findings indicate that whole blood might be suitable for a liquid biopsy. However, this study identified the short period after surgery (5-7 d) as a possible confounder. The authors plan to add an additional time point several weeks after the operation to discriminate tumor candidate genes from genes induced by the surgery.

Retinal toxicity after cisplatin-based chemotherapy in patients with germ cell cancer.

PURPOSE: Visual impairment represents an infrequent form of cisplatin-induced neurotoxicity; however, visual deterioration has been reported in several studies. To evaluate potential morphological and functional retinal alterations in patients with germ cell cancer (GCC) treated with cisplatin-based chemotherapy (CBC). METHODS: Multi-disciplinary and multi-institutional study design. Examination of 28 eyes of 14 male GCC patients, who had received at least one cycle of CBC. A matched control group of healthy, untreated patients were included in this study. Subjects underwent a retinal nerve fiber thickness (RNFL) measurement, color vision, visual acuity testing, full-field electroretinograms (ff-ERG). To assess a correlation between cumulative cisplatin dose and measured RNFL and ff-ERG Pearson correlation coefficient analysis was performed. RESULTS: Both study groups (CBC recipients vs. healthy controls) consisted each of 14 participants with a median patient age of 30 years (interquartile range (IQR) 26-37 years). Tumor histology was seminoma in 6 of 14 patients (43%), and non-seminomatous GCC in 8 of 14 patients (57%). Median cumulative cisplatin dosis at examination was 627 mg/m2 (IQR 413-1013 mg/m2). Morphological assessment revealed reduced RNFL in 11 of 14 patients (78.6%). Reduction in RNFL was significantly correlated to the cumulative CBC dose received (rho = + 0.70; p = 0.004). ff-ERG showed significant differences between CBC recipients and the control group in 2 of 5 tested categories (all p values <0.001). CONCLUSION: This study represents first evidence of chronic subclinical retinal toxicity due to cisplatin-based chemotherapy in patients with GCC. The reduction of RNFL might become clinically relevant in upcoming age-related chronic degenerative disorders such as glaucoma.

[Effects of Speech Therapy in Hospitalized Patients with Post-Stroke Dysphagia: A Systematic Review of Observational Studies]. / Efeitos da Terapia da Fala em Pacientes Internados com Disfagia Pós-Acidente Cerebrovascular: Revisão Sistemática de Estudos Observacionais.

INTRODUCTION: Since dysphagia may be one of the brain post-stroke consequences, the objective of this study was to analyze the average recovery time of patients with cerebrovascular accident and dysphagia subjected to speech therapy in a hospital bed. MATERIAL AND METHODS: Systematic review performed following the 'Preferred Reporting Items is Systematic Reviews and MetaAnalyses' instructions. The search was performed in different electronic databases, without restriction of time and language. The studies were evaluated regarding their methodological quality. RESULTS: Of 5671 titles, five studies were included. 176 patients with stroke and dysphagia were obtained (aged between 22 and 91 years old - average: 68.95), with no preference regarding gender. Improvement occurred in 84.26% of the subjects and the recovery time was between one and ninety days (average: 22 days). Randomization, blinding, loss to follow-up and withdrawal were not performed with control group in any study. DISCUSSION: The success of rehabilitation of oropharyngeal dysphagia as a post-stroke sequela will depend on the extent, location of the neurological lesion and early intervention in the hospital bed. Despite the recognition of health professionals about the importance of swallowing rehabilitation for these patients, there is a lack of studies that support an evidence-based practice, although the results point to improvements in this regard. CONCLUSION: Speech therapy in hospital bed in post-stroke hospitalized patients with dysphagia seems to bring satisfactory results in the short-term, revealing the importance of diagnosis and early intervention in these cases.

Introdução: Como a disfagia pode ser uma das sequelas pós-acidente cerebrovascular encefálico, o objetivo deste estudo foi analisar o tempo médio de recuperação de doentes com acidente cerebrovascular encefálico e disfagia submetidos à terapia da fala na beira do leito hospitalar. Material e Métodos: Revisão sistemática realizada a partir do Preferred Reporting Items is Systematic Reviews and Meta-Analyses. A busca foi realizada em diferentes bancos de dados, sem restrição de tempo e idioma. Os estudos foram avaliados quanto à sua qualidade metodológica.Resultados: De 5671 registos rastreados, cinco estudos foram elegíveis. Obtiveram-se 176 doentes com acidente cerebrovascular encefálico e disfagia (idades entre 22 e 91 anos - média: 68,95), sem prevalência quanto ao género. A melhora no quadro da disfagia ocorreu em 84,26% dos sujeitos e o tempo de recuperação entre um e noventa dias (média: 22). Em nenhum estudo foi realizada a randomização, o cegamento, o manejo de perdas, desistências e realizado com grupo controlo. Discussão: O sucesso da reabilitação da disfagia orofaríngea como sequela pós-acidente vascular encefálico dependerá da extensão, da localização da lesão neurológica e da intervenção precoce no leito hospitalar. Apesar do reconhecimento dos profissionais da saúde sobre a importância da reabilitação da deglutição para esses doentes, há carência de estudos que suportem uma prática baseada em evidências, embora os resultados apontem melhoras neste sentido. Conclusão: A terapia da fala na beira do leito em doentes disfágicos pós- acidente cerebrovascular encefálico parece trazer resultados satisfatórios em curto período de tempo, revelando a importância do diagnóstico e da intervenção da terapia da fala precoces.

Impact of the Ki-67 labeling index and p53 expression status on disease-free survival in pT1 urothelial carcinoma of the bladder.

BACKGROUND: The identification of protein biomarkers to guide treatment decisions regarding adjuvant therapies for high-risk non-muscle-invasive bladder cancer (NMIBC) has been of increasing interest. Evidence of the impact of tumor suppressor gene product p53 and cell proliferation marker Ki-67 on oncologic outcomes in bladder cancer patients at highest risk of recurrence and progression is partially contradictory. We sought to mirror contemporary expression patterns of p53 and Ki-67 in a select cohort of patients with pT1 bladder cancer. METHODS: Patients from four Northern German institutions with a primary diagnosis of pT1 bladder cancer between 2009 and 2016 and complete data regarding p53 or Ki-67 expression status were included for final analyses. Baseline patient characteristics (age, gender, age-adjusted Charlson comorbidity index) and tumor characteristics [diagnostic sequence, tumor focality, concomitant carcinoma in situ, 1973 World Health Organization (WHO) grading, lymphovascular invasion, adjuvant instillation therapy] were abstracted by retrospective chart review. Immunohistochemistry for detection of p53 and Ki-67 expression was performed according to standardized protocols. Microscopic analyses were performed by central pathologic review. First, we compared patients with positive vs. negative p53 expression and Ki-67 labeling index [>40% vs. ≤40%; cutoffs based on best discriminative ability in univariable Cox regression analysis with disease-free survival (DFS) as endpoint] with regard to baseline and tumor characteristics. Second, we evaluated the effect of biomarker positivity on DFS by plotting univariable Kaplan-Meier curves and performing uni- and multivariable Cox regression analyses. RESULTS: Of 102 patients with complete information on p53 status, 44 (43.1%) were p53 positive, and they more often harbored concomitant carcinoma in situ (50.0% vs. 27.6%; P=0.032) and 1973 WHO grade 3 (97.7% vs. 69.0%; P=0.001) compared to their p53 negative counterparts. Of 79 patients with complete information on Ki-67 expression status, 30 (38.0%) had a labeling index >40%. Mean Ki-67 labeling index was higher in WHO grade 3 vs. grade 2 tumors (45.8 vs. 29.7; P=0.004). At a median follow-up of 51.0 months, 31/91 patients with complete follow-up information (34.1%) suffered from disease recurrence or progression. In univariable Kaplan-Meier analyses, no difference regarding DFS was found in p53 positive vs. negative (P=0.8) or Ki-67 labeling index >40% vs. ≤40% (P=0.078) patients. In multivariable analyses, Ki-67 labeling index >40% remained an independent predictor of DFS [hazard ratio (HR), 2.66; 95% confidence interval (CI), 1.02-6.95; P=0.046], after adjusting for p53 expression and lymphovascular invasion. However, p53 status was not associated with our endpoint (P=0.8). CONCLUSIONS: While we found an association of a Ki-67 labeling index >40% and shorter DFS in pT1 bladder cancer patients, this did not hold true for p53 positivity. Future research is needed to identify additional microscopic and molecular risk factors and biomarker panels to improve risk stratification and guide adjuvant therapies in those patients.

Expression and Localization of Lung Surfactant Proteins in Human Testis.

BACKGROUND: Surfactant proteins (SPs) have been described in various tissues and fluids including tissues of the nasolacrimal apparatus, airways and digestive tract. Human testis have a glandular function as a part of the reproductive and the endocrine system, but no data are available on SPs in human testis and prostate under healthy and pathologic conditions. OBJECTIVE: The aim of the study was the detection and characterization of the surfactant proteins A, B, C and D (SP-A, SP-B, SP-C, SP-D) in human testis. Additionally tissue samples affected by testicular cancer were investigated. RESULTS: Surfactant proteins A, B, C and D were detected using RT-PCR in healthy testis. By means of Western blot analysis, these SPs were detected at the protein level in normal testis, seminoma and seminal fluid, but not in spermatozoa. Expression of SPs was weaker in seminoma compared to normal testicular tissue. SPs were localized in combination with vimentin immunohistochemically in cells of Sertoli and Leydig. CONCLUSION: Surfactant proteins seem to be inherent part of the human testis. By means of physicochemical properties the proteins appear to play a role during immunological and rheological process of the testicular tissue. The presence of SP-B and SP-C in cells of Sertoli correlates with their function of fluid secretion and may support transportation of spermatozoa. In seminoma the expression of all SP's was generally weaker compared to normal germ cells. This could lead to a reduction of immunomodulatory and rheology processes in the germ cell tumor.

MALDI imaging-based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays.

OBJECTIVE: Although most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer. MATERIALS AND METHODS: We employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations. RESULTS: Analysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers. CONCLUSION: Our data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.

Reduced membranous MET expression is linked to bladder cancer progression.

The MET protein is involved in the malignant progression of different tumors. This study aimed to analyze the relationship of MET expression with tumor phenotype and clinical outcome in bladder cancer and the role of gene amplification for MET overexpression. A bladder cancer tissue microarray containing 686 bladder cancers was analyzed by immunohistochemistry and by fluorescence in situ hybridization. MET immunostaining was seen in normal urothelium and was recorded in 459 of 560 analyzable urothelial carcinomas (82.0%). Low MET staining was associated with a more unfavorable tumor phenotype. MET staining was seen in 89.8% of 266 pTa, 81.1% of 132 pT1, and 69.4% of 160 pT2-4 cancers (P < 0.0001). MET staining was detectable in 92.4% of 66 grade 1, 85.6% of 257 grade 2, and 75.1% of 237 grade 3 cancers (P = 0.001). MET expression status was not associated with overall or tumor-specific survival in muscle-invasive cancers (pT2-4), tumor progression in pT1 cancers, or recurrences in pTa tumors. Only four of the analyzed tumors (0.8%) showed amplification of the MET gene. We conclude that MET is not overexpressed in urothelial cancer but rather downregulated in a fraction of cancers. Accordingly, rare amplification of the genomic area including the MET gene was not associated with MET protein overexpression.

German second-opinion network for testicular cancer: sealing the leaky pipe between evidence and clinical practice.

In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project's effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson's χ2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.

Clinically apparent and occult metastasized seminoma: almost indistinguishable on the transcriptional level.

PURPOSE: The aim of the present study was to examine the biological differences between seminomas with occult and clinically apparent metastases at the time of diagnosis of the primary tumor to gain insight into the biology of these tumors and facilitate the identification of novel predictors of seminoma metastasis. MATERIALS AND METHODS: Total RNA including small RNAs was isolated from testicular tumors of patients with pure seminoma presenting with lymphogenic metastasis (n = 5, clinical stage IIb/c) and occult metastasis (n = 5, clinical stage I). The regulation of biological processes was examined (1) throughout the mRNA transcriptome (whole genome microarrays, 8×60 K Array, Agilent with 4 samples/group) and (2) the miRNA transcriptome employing small RNA next generation sequencing (SOLID, Life Technologies with 5 samples/group). Protein coding genes (mRNAs) and small RNAs showing a significant (≥2-fold) difference between the groups were identified. Finally (3), we examined 95 candidate miRNAs in 36 apparent metastasized and another 5 occult metastasized seminoma using logistic regression analysis. RESULTS: Among 19,596 genes, on average 12,894 mRNAs appeared expressed (65.8%, SD+/-2.4; range, 62.0-69.3%) and 16.99×106/13.94×106 small RNA reads were identified for apparent/occult metastasized seminoma. These reads on average convert into 9,901/9,675 small RNAs including 422/404 mature microRNAs. None of these mRNAs/small RNAs met our selection criteria for candidate genes. From 95 candidate miRNAs 44 appeared expressed, with 3 of them showing weak but significant (p = 0.05) differences among both groups. CONCLUSIONS: Occult and apparent metastasized seminomas are biologically almost indistinguishable and probably represent no separate tumor entities. These findings may simplify future research on seminoma metastasis.

Circulating tumor cells in patients with testicular germ cell tumors.

PURPOSE: Germ cell tumors (GCTs) represent the most frequent malignancies among young men, but little is known about circulating tumor cells (CTCs) in these tumors. Considering their heterogeneity, CTCs were investigated using two independent assays targeting germ cell tumor and epithelial cell-specific markers, and results were correlated with disease stage, histology, and serum tumor markers. EXPERIMENTAL DESIGN: CTCs were enriched from peripheral blood (n = 143 patients) and testicular vein blood (TVB, n = 19 patients) using Ficoll density gradient centrifugation. For CTC detection, a combination of germ cell tumor (anti-SALL4, anti-OCT3/4) and epithelial cell-specific (anti-keratin, anti-EpCAM) antibodies was used. In parallel, 122 corresponding peripheral blood samples were analyzed using the CellSearch system. RESULTS: In total, CTCs were detected in 25 of 143 (17.5%) peripheral blood samples, whereas only 11.5% of patients were CTC-positive when considering exclusively the CellSearch assay. The presence of CTCs in peripheral blood correlated with clinical stage (P < 0.001) with 41% of CTC positivity in patients with metastasized tumors and 100% in patients with relapsed and chemotherapy-refractory disease. Histologically, CTC-positive patients suffered more frequently from nonseminomatous primary tumors (P < 0.001), with higher percentage of yolk sac (P < 0.001) and teratoma (P = 0.004) components. Furthermore, CTC detection was associated with elevated serum levels of α-fetoprotein (AFP; P = 0.025), ß-human chorionic gonadotropin (ßHCG; P = 0.002), and lactate dehydrogenase (LDH; P = 0.002). Incidence and numbers of CTCs in TVB were much higher than in peripheral blood. CONCLUSIONS: The inclusion of germ cell tumor-specific markers improves CTC detection in GCTs. CTCs occur frequently in patients with more aggressive disease, and there is a gradient of CTCs with decreasing numbers from the tumor-draining vein to the periphery.

Small RNAs in the peripheral blood discriminate metastasized from non-metastasized seminoma.

BACKGROUND: We aimed to better discriminate metastasized (lymphogen/occult/both combined) from non-metastasized seminoma based on post-transcriptional changes examined in the peripheral blood. METHODS: Total RNAs including small RNAs were isolated from the peripheral blood of patients suffering from metastasized testicular tumours (lymphogen, n = 5, clinical stage IIb/c; occult, n = 5, clinical stage I) and non-metastasized patients (n = 5, clinical stage I). Small RNA next generation sequencing (SOLID, Life Technologies) was employed to examine post-transcriptional changes. We searched for small RNAs showing at least 50 reads and a significant ≥ 2-fold difference using peripheral blood small RNAs of non-metastasized tumours as the reference group. Candidate small RNAs were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines. RESULTS: On average 1.3 x 10(7), 1.2 x 10(7) and 1.2 x 10(7) small RNA reads were detectable in non-metastasized, lymphogen and occult metastasized seminoma, respectively of which 73-76% remained after trimming. From these between 80-82% represented annotated reads and 7.2-7.8% (1.6-1.7 x 10(4)) were annotated small RNA tags. Of them 137 small RNAs showed > 50 reads and a ≥ two-fold difference to the reference. In univariate analysis we detected 33-35 different small RNAs which significantly discriminated lymphogen/occult/combined metastasized from non-metastasized seminoma and among these different comparisons it were the same small RNAs in 44-79%. Many combinations of two of these small RNAs completely discriminated metastasized from non-metastasized seminoma irrespective of the metastasis subtype. CONCLUSIONS: Metastasized (either lymphogen or occult) seminoma can be completely discriminated from non-metastasized seminoma with a combination of two small RNAs measured in the peripheral blood.

Changes in epidemiologic features of testicular germ cell cancer: age at diagnosis and relative frequency of seminoma are constantly and significantly increasing.

OBJECTIVES: Testicular germ cell tumors (GCTs) have their incidence peak in the third and fourth decades of life. Histologically, GCTs comprise of seminoma and nonseminoma at almost equal proportions with a slight preponderance of nonseminoma in most of the major series. Since decades, there is a shift toward decreasing age at presentation. Recently, there are suggestions of a reversal of the age trend, and also, the histologic subtype ratio appears to shift toward seminoma. We retrospectively looked to our patient populations to verify these recent trends. METHODS: A total of 2,482 patients with histologically proven GCT diagnosed between 1976 and 2010 were retrospectively evaluated regarding the year of diagnosis, histology of primary tumor, and age at presentation. Patients were categorized according to the following time periods of treatment: before 1990, 1990 to 1994, 1995 to 1999, 2000 to 2004, and 2005 to 2010. Mean age and relative proportion of seminoma were compared among patient categories by employing the chi-square test and analysis of variance, respectively. RESULTS: The mean age significantly increased from 28 to 36 years. The age difference between the 2 histologic subtypes remained constant between 6 and 8 years during the entire observation period. The relative proportion of seminoma continuously increased from 30.9% to 56% (P <0.001). CONCLUSION: There is evidence of a significant shift toward older age at diagnosis of GCT. In addition, the proportion of seminoma is constantly increasing at the expense of nonseminoma. The reasons for these developments are obscure. However, 2 old theories regarding the pathogenesis of GCT may receive support from our results: first, the theory of divergent pathogenetic pathways of seminoma and nonseminoma and second, the involvement of postnatal environmental factors in the pathogenesis of GCTs.

Heavy Metal Content in Thoracic Tissue Samples from Patients with and without NSCLC.

Objectives. Environmental factors expose an individual to heavy metals that may stimulate cancer growth preclinically including non-small cell lung cancer (NSCLC) cells. Here, we examine the prevalence of four heavy metals present in postsurgical tissues from individuals with and without NSCLC. Materials and Methods. Thoracic tissue samples from two separate sample sets were analyzed for cadmium (Cd), arsenic (As), mercury (Hg), and lead (Pb) content. Results. In the first sample set, there was no significant measurable amount of Pb and Hg found in either NSCLC tissue or nonmalignant lung tissue samples. Cd was the most prevalent heavy metal and As was present in moderate amounts. In the second sample set, Cd was measurable across all tissue types taken from 28 NSCLC patients and significantly higher Cd was measurable in noncancer benign lung (n = 9). In the NSCLC samples, As was measurable in moderate amounts, while Hg and Pb amounts were negligible. Conclusion. Cd and As are present in lung tissues for patients with NSCLC. With existing preclinical evidence of their tumorigenecity, it is plausible that Cd and/or As may have an impact on NSCLC development. Additional studies examining the prevalence and association between smokers and nonsmokers are suggested.

PTEN deletions are related to disease progression and unfavourable prognosis in early bladder cancer.

AIMS: This study aimed to determine the prevalence and clinical significance of deletions of the tumour suppressor gene PTEN in bladder cancer. METHODS AND RESULTS: A tissue microarray with 686 bladder cancers was analysed for PTEN deletions by fluorescence in-situ hybridization. PTEN mutations were analysed in nine tumours with heterozygous PTEN deletion. Heterozygous PTEN deletions were present in 16.5% of tumours and were associated with grade (P = 0.0024) and p53 status (P = 0.0141), but not linked to stage (P = 0.0965). PTEN deletions were seen in 5.8% of pTaG1, 10.9% of pTaG2, 29.0% of pTaG3, 16.7% of pT1G2, 22.2% of pT1G3, 17.7% of pT2-4G2 and 20.9% of pT2-4G3 tumours (P = 0.0235). PTEN deletions were associated significantly with recurrences in pTa tumours (P = 0.0173), progression in pT1 tumours (P = 0.0016), but not with overall or cancer-specific survival in pT2 tumours. Multivariate analyses including grade and PTEN deletions revealed that PTEN deletions but not grade were associated independently with recurrence in pTa tumours (P = 0.0377) and progression in pT1 tumours (P = 0.0030). No inactivating PTEN mutations were found. CONCLUSIONS: PTEN is linked to aggressive tumour phenotype and to unfavourable outcome in early bladder cancer. Heterozygous PTEN loss, i.e. reduced PTEN gene dosage, might be sufficient to cause aggressive tumour behaviour in bladder cancer cells.

Results of thoracic drainages placed in air rescue.

INTRODUCTION: horax injuries are to be found in approximately 78% amongst all accident victims. Moreover, they implicate an increase in mortality rate. Consequently, an adequate contemporary treatment has to begin preclinically, even if the conditions are less comfortable than in a clinical setting. Emergency doctors need to be familiar with the placement of chest tubes. MATERIALS AND METHODS: From January 1, 2007 to December 31, 2010, emergency doctors of the rescue helicopter site Christoph 20 had to place chest tubes directly at the scene of an accident in 49 patients. These patients were now reidentified, and their clinical course was reevaluated. By means of apparative diagnostics, it was possible to analyze the location of the tubes tip. Following a comparison of the patient, outcome versus the quality of preclinical thoracic discharge could be made. RESULTS: The preclinical placement of a chest tube became necessary mainly because of a blunt thoracic trauma. This was predominantly related to victims of traffic accidents, whereas male victims clearly dominated. Forty-two of those patients received further treatment at the Klinikum Bayreuth hospital, enabling an analysis of the tubes location by CAT (computed axial tomography) scan. Six patients had been discharged on both sides, contributing to 48 tube tips that could be examined concerning their location. Of the 48 chest tubes, 46 had been placed from a lateral approach. The ventral access by Monaldi had only been chosen in two cases. Altogether, nine incorrect placements, mainly within the right interlobe gap, had been detected. CONCLUSIONS: The study collective showed a significant preference to the lateral approach when placing a chest tube at the emergency scene of an accident. In total, a prevalence of 19% incorrect placements could be revealed, meaning the chest tube had either been placed within the lung parenchyma, the interlobe gap, or extrathoracically. Concerning the patient outcome, no statistically significant difference regarding the clinical course after incorrect chest tube placement could be identified.

Reduced CD151 expression is related to advanced tumour stage in urothelial bladder cancer.

AIMS: CD151 belongs to the group of tetraspanins and is aberrantly expressed in different tumours and differential expression has been associated with prognosis. The aim of this study was to clarify the relationship of CD151 expression with tumour phenotype and clinical outcome in bladder cancer. METHODS: A bladder cancer tissue microarray containing samples from 686 urothelial bladder cancers was analysed by immunohistochemistry. RESULTS: Membranous CD151 immunostaining was recorded in 409 (66.0%) of 620 analysable cases. High CD151 expression was seen in normal urothelium and in most non-invasive tumours. Low CD151 expression levels were associated with a more unfavourable tumour phenotype. CD151 staining was seen in 71.5% of 284 pTa, 62.1% of 145 pT1 and 60.4% of 187 pT2-4 cancers (p = 0.0033). CD151 staining was detectable in 77.3% of 75 grade 1, 71.1% of 273 grade 2 and 57.7% of 272 grade 3 cancers (p < 0.0001). CD151 expression status was not associated with overall or tumour-specific survival in muscle-invasive cancers (pT2-4), tumour progression in pT1 and recurrences in pTa tumours. CONCLUSION: On the basis of our data we conclude that loss of CD151 may contribute to bladder cancer progression through attenuation of cell adhesion. In clinically defined subgroups CD151 expression does not provide additional prognostic information.

Predicting metastasized seminoma using gene expression.

UNLABELLED: Treatment options for testis cancer depend on the histological subtype as well as on the clinical stage. An accurate staging is essential for correct treatment. The 'golden standard' for staging purposes is CT, but occult metastasis cannot be detected with this method. Currently, parameters such as primary tumour size, vessel invasion or invasion of the rete testis are used for predicting occult metastasis. Last year the association of these parameters with metastasis could not be validated in a new independent cohort. Gene expression analysis in testis cancer allowed discrimination between the different histological subtypes (seminoma and non-seminoma) as well as testis cancer and normal testis tissue. In a two-stage study design we (i) screened the whole genome (using human whole genome microarrays) for candidate genes associated with the metastatic stage in seminoma and (ii) validated and quantified gene expression of our candidate genes (real-time quantitative polymerase chain reaction) on another independent group. Gene expression measurements of two of our candidate genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2]) examined in primary testis cancers made it possible to discriminate the metastasis status in seminoma. The discriminative ability of the genes exceeded the predictive significance of currently used histological/pathological parameters. Based on gene expression analysis the present study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance. OBJECTIVE: To evaluate the usefulness of gene expression profiling for predicting metastatic status in testicular seminoma at the time of first diagnosis compared with established clinical and pathological parameters. PATIENTS AND METHODS: Total RNA was isolated from testicular tumours of metastasized patients (12 patients, clinical stage IIa-III), non-metastasized patients (40, clinical stage I) and adjacent 'normal' tissue (n = 36). The RNA was then converted into cDNA and real-time quantitative polymerase chain reaction was run on 94 candidate genes selected from previous work. Normalised gene expression of these genes and histological variables, e.g. tumour size and rete testis infiltration, were analysed using logistic regression analysis. RESULTS: Expression of two genes (dopamine receptor D1 [DRD1] and family with sequence similarity 71, member F2 [FAM71F2], P = 0.005 and 0.024 in separate analysis and P = 0.004 and 0.016 when combining both genes, respectively) made it possible to significantly discriminate the metastasis status. Concordance increased from 77.9% (DRD1) and 72.3% (FAM71F2) in separate analysis and up to 87.7% when combining both genes in one model. Only primary tumour size in separate analysis (continuous or categorical with tumour size >6 cm) was significantly associated with metastasis (P = 0.039/P = 0.02), but concordance was lower (61%). When we combined tumour size with our two genes in one model there was no further statistical improvement or increased concordance. CONCLUSION: Based on gene expression analysis our study provides suggestions for improved individual decision making either in favour of early adjuvant therapy or increased surveillance.

Standards and interdisciplinary treatment of boxing injuries of the head in professional boxing on the basis of an IBF World Championship Fight.

BACKGROUND: Boxing injuries are well known in hobby boxing as well as in professional boxing. Especially in professional boxing it is of great importance to implement and follow prevention-, diagnosis- and therapy-standards in order to prevent or at least to minimize injuries of the athlete. The utmost aim would be to establish international prevention-, diagnosis- and therapy-standards for boxing injuries in professional boxing. However, this aim is on a short run unrealistic, as there are too many different professional boxing organisations with different regulations. A realistic short term aim would be to develop a national standard in order to unify the management and medical treatment of boxing injuries in professional boxing. CASE REPORT: We present the management and interdisciplinary treatment of a professional boxer with a bilateral open fracture of the mandible during a middle weight IBF World Championship Fight. On the basis of this case we want to present and discuss the possibilities of an interdisciplinary and successful medical treatment. CONCLUSIONS: In order to prevent or minimize boxing injuries of professional boxers, annual MRI-Scans of the head and neck have to be performed as prevention standard. Furthermore, neurocognitive tests must be performed on a regular basis. Boxing injuries in professional boxing need an interdisciplinary, unbiased and complex analysis directly at the boxing ring. The treatment of the injuries should be only performed in medical centres and thus under constant parameters. The needed qualifications must be learned in mandatory national licence courses of boxing physicians, referees and promoters.

Y chromosome loss is a frequent early event in urothelial bladder cancer.

AIMS: Y chromosome losses have been described in 10-40% of bladder cancers and were suggested to be age-related. The clinical significance of chromosome Y losses is largely unknown, since only small sets of male bladder cancer patients have been evaluated in previous studies. The aim of this study was to further clarify the potential relevance of Y chromosome losses in bladder cancer with respect to clinical outcome and patient age. METHODS: A pre-existing bladder cancer tissue microarray (TMA) with clinical follow-up data including 516 urothelial bladder cancers from male patients was utilised in this study. Y chromosome losses were analysed by multicolour fluorescence in situ hybridisation (FISH) using a centromere Y probe and a centromere X probe. p53 immunostaining data were available for all patients from a previous study. RESULTS: Y chromosome losses were seen in 23% of 477 interpretable cancers from male patients. There was no significant difference in patient age in tumours with (67.4 +/- 4.3 years) or without (67.3 +/- 2.3 years) Y chromosome losses (p = 0.9068). Y chromosome losses were equally frequent in tumours of all grades (p = 0.7831) and stages (p = 0.6140). There was also no association with p53 immunostaining (p = 0.4092). Y chromosome losses were not associated with survival in 224 invasive urothelial cancers (pT2-4; p = 0.2324), an increased risk for recurrences in 197 pTa tumours (p = 0.7649) or increased progression risk in 76 pT1 tumours (p = 0.4582). CONCLUSION: The data of this study show that Y chromosome losses are frequent in urothelial bladder cancer of all grades and stages, which could imply that loss of the Y chromosome is an early event in bladder cancer development. p53 mediated genomic instability is evidently not required for the development of Y chromosome losses. Since there was no correlation between Y chromosome losses and clinical outcome, detection of Y losses has no clinical relevance in urothelial bladder cancer.