Martina Hager

Up-Regulation of Functional Chemokine Receptor CCR3 in Human Renal Cell Carcinoma

There is increasing evidence that chemokines and chemokine receptors are causally involved in tumorigenesis by facilitating tumor proliferation and metastasis. Little is known about the possible function of chemokine receptors in the development and progression of renal cell carcinoma (RCC). We, therefore, analyzed the expression of chemokine receptors in tumor specimens and adjacent healthy kidney tissues [normal kidney cell (NKC)] from 10 RCC patients. We also characterized the permanent RCC cell line A-498. CCR6, CXCR2, and CXCR3 were consistently expressed by both malignant cells and NKCs. A-498 displayed additional expression of CXCR4. Importantly, the expression of CCR3 was almost absent on NKCs but clearly enhanced in a substantial proportion of RCC specimens. The primary CCR3 ligand, eotaxin-1/CCL11, induced intracellular Ca2+ mobilization, receptor internalization, and proliferation in A-498 cells confirming signaling competence of RCC-associated CCR3. In addition, we screened tumor tissue sections of 219 patients and found that 28% (62 of 219) expressed the CCR3 receptor. The presence of CCR3 in tumor samples seemed to correlate with the grade of malignancy. Previous work has established that eotaxin-1 expression is induced by tumor necrosis factor-α, a cytokine known to be present in RCC tissue. Our data, therefore, supports a scenario in which eotaxin-1 as part of tumor-associated inflammation promotes progression and dissemination of CCR3-positive RCC.

Publication output in telemedicine during the period January 1964 to July 2003

The MEDLINE database was used to survey the period January 1964 to July 2003 for the number of publications relating to telemedicine (n = 5911), as well as their distribution by country (n = 42). Publications per million inhabitants were then correlated with each countrys population density, gross national product, human development index (HDI) and number of PCs per 1000 inhabitants. Telemedicine publications made up 0.05% of all medical publications cited in MEDLINE. American and European countries along with others classified as industrialized produced 97% of all telemedicine publications. In terms of publications per million inhabitants, Norway and Finland took the lead. There were significant correlations between telemedicine publications per capita and HDI (r = -0.60), number of PCs per 1000 inhabitants (r = 0.73) and gross national product per capita (r = 0.69), but not population density (r = -0.12).

Increased activated Akt expression in renal cell carcinomas and prognosis

Renal carcinogenesis is promoted by overexpression of the activated serine/threonine kinase Akt (p‐Akt) and supposedly a concomitant reduction in phosphatase and tensin homologue deleted on chromosome 10 tumour suppressor gene (PTEN), which normally inhibits the activation of Akt. Because promising anti‐cancer therapies increasingly focus on pathways involving p‐Akt and PTEN, the present study evaluated the expression of p‐Akt in renal cell carcinomas and compared it with prognosis. P‐Akt and PTEN expression were analysed in a tissue microarray (TMA) from renal cell carcinoma (n= 386) and adjacent uninvolved renal tissue (n= 32) specimens. Increased p‐Akt was found more often in the nucleus than in the cytoplasm, and PTEN was concomitantly reduced in about 50% of cases. Neither tumour grade nor stage influenced p‐Akt expression, whereas the clear cell and papillary subtypes showed increased p‐Akt more often than did the chromophobe or sarcomatoid types. Increased cytoplasmic and nuclear p‐Akt levels were independent prognostic factors for diminishing patient survival. The present study found significantly increased nuclear but also cytoplasmic p‐Akt expression in renal cell carcinoma subtypes. Increased nuclear and cytoplasmic p‐Akt was an independent prognostic factor for diminishing patient survival. The considerable number of high‐grade and high‐stage RCC showing increased p‐Akt and reduced PTEN would justify further evaluation of therapeutic concepts based on inhibitors of the PI3K/p‐Akt/mTOR pathway.

Laparoscopic Treatment of Intrinsic Endometriosis of the Urinary Tract and Proposal of a Treatment Scheme for Ureteral Endometriosis

OBJECTIVE To discuss the contemporary management of urinary tract endometriosis and report our experience concerning laparoscopic treatment of intrinsic urinary tract endometriosis. METHODS We performed a retrospective, multicenter study of data collected from March 2006 to March 2011. Ten women were referred from gynecology, seven with ureteral involvement and hydronephrosis and three with bladder involvement, for urologic management. Of the 7 women with hydronephrosis, 5 were symptomatic, with recurrent urinary tract infections or pain. All 3 women with bladder endometriosis had hematuria. All patients had previously undergone unsuccessful hormonal therapy. Ureteral endometriosis was extensively investigated and treated by laparoscopic excision of endometriotic plaques and excision of intrinsic endometriosis of the ureter. Bladder endometriosis was treated by partial cystectomy. Some patients also had endometriosis in other organs and underwent, for example, wedge resection of sigmoid colon and oophorectomy. RESULTS The median age of the patients was 30 years (range 25-44). Seven patients with intrinsic endometriosis of the ureter all had hydronephrosis and proximal hydroureter and underwent laparoscopic ureteral segment excision and either end-to-end, spatulated uretroureterostomy or ureteral reimplatation with psoas hitch. Three patients had hematuria, and cystoscopic biopsy of the bladder lesions confirmed intrinsic endometriosis. They were treated with laparoscopic partial cystectomy. One patient with bowel symptoms also underwent laparoscopic wedge resection of the sigmoid colon and another underwent oophorectomy for a chocolate cyst. Most patients also had peritoneal endometriotic plaques excised. We did not perform simple ureterolysis. No complications were encountered. The median follow-up was 26.5 months (range 4-53), with no return of symptoms or recurrence. The annual follow-up examinations included urinalysis and ultrasonography of the urinary tract. CONCLUSION Intrinsic endometriosis can be successfully managed with minimally invasive techniques to provide relief of symptoms, protect renal function, and prevent recurrence. We describe a classification of ureteral endometriosis determined from staging investigations.

The association between local atherosclerosis and prostate cancer.

To morphometrically compare local atherosclerotic changes in cancerous prostate with those in noncancerous prostate specimens, as epidemiological studies report a positive association between the prevalence of general atherosclerosis and prostate cancer.

PTEN, pAKT, and pmTOR Expression and Subcellular Distribution in Primary Renal Cell Carcinomas and Their Metastases

The present study evaluated pAKT, pmTOR, and PTEN expression in a tissue microarray of primary renal cell carcinomas (PRCCs), their metastases, and normal renal parenchyma (NRP) (N = 45) by means of immunohistochemistry. Metastases in most subcellular compartments showed comparable and stronger expression for pAKT, pmTOR, and PTEN than PRCC and NRP, which was even more pronounced in patients with high-risk Memorial Sloan-Kettering Cancer Center (MSKCC) score. Furthermore, most subcellular compartments showed no differences between lymphogenous, haematogenous, synchronous, and metachronous metastases, which is interesting with regard to sensitivity to mTOR inhibitor therapy in metastasized RCCs with alterations in the PI3K/AKT pathway.

pS6 Expression in Normal Renal Parenchyma, Primary Renal Cell Carcinomas and their Metastases

In cancer therapy novel concepts focus on phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) inhibitors. In this context, phosphorylated S6 protein of the 40S ribosomal subunit (pS6) overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study therefore evaluated pS6 expression in normal renal parenchyma (NRP), primary renal cell carcinomas (PRCC) and their metastases. pS6 and pmTOR expression was immunohistochemically analyzed in a tissue microarray (TMA) from localized primary renal cell carcinoma (lPRCC) (n = 35), metastasized primary renal cell carcinoma (mPRCC) (n = 45), their metastases (n = 45), and NRP (n = 45). pS6 expression was stronger in mPRCCs and metastases than in NRP and lPRCCs (p < 0.05). In mPRCCs high-grade and high-stage tumors showed higher pS6 levels. pS6 overexpression was more frequently found in metastases (40/45; 88.9%) than in mPRCC (24/45; 53.3%) (p < 0.05). Overexpression of pS6 in metastases without concomitant overexpression in their primary tumors was found in 16/45 (35.56%) cases. Patients with pS6 overexpression in mPRCCs but also in metastases showed a tendency to shorter overall survival. pS6 score and pmTOR score correlated positively in NRP and in tumorous tissue (mPRCC and metastases). In conclusion, the present study showed stronger pS6 expression and more frequent overexpression in metastases than in corresponding PRCCs. In approximately one-third of the cases pS6 overexpression was found exclusively in metastases, which is interesting with regard to the association between high pS6 expression and sensitivity to mTOR inhibitor therapy.

Acceptance of telemedicine and new media: a survey of Austrian medical students

Telemedicine and new media (e.g. the Internet, tele-teaching and tele-learning) are increasingly being used in medicine. We surveyed the awareness and acceptance of these developments on the part of medical students (n =750) at the University of Innsbruck. A 16-item questionnaire was handed out in randomly chosen medical classes and collected immediately after completion, which resulted in a response rate of 99.9%. Nearly all of the students used the Internet regularly (68%) or at least sometimes (30%). Telemedicine was already known to most of the students, mainly from articles in magazines and newspapers (41%), but the great majority of them (95%) reported that they did not know about the telemedicine lectures offered by the University of Innsbruck. Most students (75%) thought that they would benefit from tele-teaching or tele-learning. The survey suggested that medical schools should offer more special lectures, as well as undergraduate or postgraduate qualifications in telemedicine. The marketing of such opportunities needs to be improved.

The AR/NCOA1 signaling regulates prostate cancer migration by involvement of PRKD1

Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. ( 3 H)-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell lines AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

MP42-05 FLUORESCENCE - TARGETED LAPAROSCOPIC LYMPH NODE DISSECTION IN PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Recently we have introduced fluorescence by means of Indocyanin Green(ICG) in addition to radio-guided dissection using Technetium 99(Tc99) for laparoscopic pelvic sentinel node dissection (Urology 2012). Since ICG also visualizes the lymphatic vessels it allows to better understand the lymphatic drainage of the prostate. Hence we could show that ICG alone gave equal results compared to TC99. Also the handling of this substance was much easier. Since ICG visualizes the complete drainage system we have as an evolution now left the sentinel concept to completely remove this template. We herein present the first results. METHODS: 38 consecutive men with intermediate and high risk prostate cancer have undergone targeted Lymphnode dissection during laparoscopic radical prostatectomy. The previous transrectal TRUSguided Injection of 2ml ICG into each lobe is now replaced by a transperineal approach, which is more precise. After removal of the complete ICG visualize Lymphnode template of each side, a standard extended LN-dissection was added as control. The Equipment for ICG eVisualisation was provided by Storz. All Lymphnodes were evaluated by 250 micrometer sections and imunohistochemistry. Data were collected prospectively and analyzed retrospectively. RESULTS: Transperineal Injection allowed for precise deposit of the tracer within the peripheral zone without any periprostatic extravasation. Fluorescence stained (F+) nodes were found on both sides in all patients except one. In total 596 nodes (17,9 +-8,4/patient) were removed, of which 473 nodes (14,3 +8,51/pat.) were F+. LN Metastases(pN1) were found in 15 pat.(39,5%), of which 2 pat. (5,3 %) had a solitary micrometastasis. In additional 3 patients (7,9 %) Tumor Cell Cluster were found in lymphnodes. There was not a single patient where non-stained metastases were found in addition to F+ Metastases. In the one patient, where there was no staining at all, a solitary metastasis was found in the template of the extended PLND. Metastases outside the template of extended PLND occurred in 5 patients(27,8% of N+). Since we always perform extended PLND, when there is no Fluorescence staining at all, no metastases was overlooked with our concept. CONCLUSIONS: Fluorescence-targeted lymphnode dissection allows to identify the lymphatic drainage of the prostate with great reliability. It proved to be more precise than extended lymphnode dissection in patients with intermediate and high grade prostate cancer.