The addition of a sagittal image fusion improves the prostate cancer detection in a sensor-based MRI /ultrasound fusion guided targeted biopsy

Background To explore the diagnostic benefit of an additional image fusion of the sagittal plane in addition to the standard axial image fusion, using a sensor-based MRI/US fusion platform. Methods During July 2013 and September 2015, 251 patients with at least one suspicious lesion on mpMRI (rated by PI- RADS) were included into the analysis. All patients underwent MRI/US targeted biopsy (TB) in combination with a 10 core systematic prostate biopsy (SB). All biopsies were performed on a sensor-based fusion system. Group A included 162 men who received TB by an axial MRI/US image fusion. Group B comprised 89 men in whom the TB was performed with an additional sagittal image fusion. Results The median age in group A was 67 years (IQR 61–72) and in group B 68 years (IQR 60–71). The median PSA level in group A was 8.10 ng/ml (IQR 6.05–14) and in group B 8.59 ng/ml (IQR 5.65–12.32). In group A the proportion of patients with a suspicious digital rectal examination (DRE) (14 vs. 29%, p = 0.007) and the proportion of primary biopsies (33 vs 46%, p = 0.046) were significantly lower. The rate of PI-RADS 3 lesions were overrepresented in group A compared to group B (19 vs. 9%; p = 0.044). Classified according to PI-RADS 3, 4 and 5, the detection rates of TB were 42, 48, 75% in group A and 25, 74, 90% in group B. The rate of PCa with a Gleason score ≥7 missed by TB was 33% (18 cases) in group A and 9% (5 cases) in group B; p-value 0.072. An explorative multivariate binary logistic regression analysis revealed that PI-RADS, a suspicious DRE and performing an additional sagittal image fusion were significant predictors for PCa detection in TB. 9 PCa were only detected by TB with sagittal fusion (sTB) and sTB identified 10 additional clinically significant PCa (Gleason ≥7). Conclusion Performing an additional sagittal image fusion besides the standard axial fusion appears to improve the accuracy of the sensor-based MRI/US fusion platform

Down-regulation of the pro-apoptotic XIAP associated factor-1 (XAF1) during progression of clear-cell renal cancer

BACKGROUND: Decreased expression of the interferon-stimulated, putative tumour suppressor gene XAF1 has been shown to play a role during the onset, progression and treatment failure in various malignancies. However, little is yet known about its potential implication in the tumour biology of clear-cell renal cell cancer (ccRCC). METHODS: This study assessed the expression of XAF1 protein in tumour tissue obtained from 291 ccRCC patients and 68 normal renal tissue samples, utilizing immunohistochemistry on a tissue-micro-array. XAF1 expression was correlated to clinico-pathological tumour features and prognosis. RESULTS: Nuclear XAF1 expression was commonly detected in normal renal- (94.1%) and ccRCC (91.8%) samples, without significant differences of expression levels. Low XAF1 expression in ccRCC tissue, however, was associated with progression of tumour stage (p = 0.040) and grade (p < 0.001). Low XAF1 tumour levels were also prognostic of significantly shortened overall survival times in univariate analysis (p = 0.018), but did not provide independent prognostic information. CONCLUSION: These data suggest down-regulation of XAF1 expression to be implicated in ccRCC progression and implies that its re-induction may provide a therapeutic approach. Although the prognostic value of XAF1 in ccRCC appears to be limited, its predictive value remains to be determined, especially in patients with metastatic disease undergoing novel combination therapies of targeted agents with Interferon-alpha

Impact of hormonal therapy on the detection of promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1) in prostate cancer

BACKGROUND: In spite of excellent cure rates for prostate cancer patients with favorable tumor characteristics, patients with unfavorable characteristics after radical prostatectomy are still at a significantly increased risk of tumor progression. Early adjuvant hormonal therapy (AHT) has been shown to be of prognostic benefit in these patients. Unfortunately initiation and duration of early AHT in the individual patient is based on statistic data. PSA, as the standard prostate marker is neither able to reliably indicate minimal residual tumor disease in the early postoperative phase, nor can it be used for therapy monitoring due to the suppressive effect of hormonal therapy on PSA production. Promoter hypermethylation of the detoxifying glutathione-S-transferase P1 gene (GSTP1-HM) has been shown to be the most common DNA alteration of primary prostatic carcinoma which, when used as a marker, is supposed to be able to overcome some of the disadvantages of PSA. However until now information on the impact of hormonal therapy on the detection of GSTP1-HM is lacking. The purpose of our study was to assess the impact of endocrine therapy on the detection of GSTP1-HM by methylation-specific PCR (MSP) in prostate cancer. METHODS: Paraffin embedded tumor samples from the radical prostatectomy (RP) specimens from 15 patients after hormonal therapy (HT) (mean 8 months) were assessed by MSP. In 8 of the patients the GSTP-1 status of the tumors before HT was assessed on the corresponding initial diagnostic biopsies. RESULTS: Following HT MSP showed GSTP1-HM in 13/15 of the RP specimens. In two patients analysis of the RP specimens failed to show GSTP1-HM. All initial tumor samples (8/8 biopsy specimens) showed GSTP1-HM, including both patients negative for GSTP1 HM in the corresponding RP specimen. CONCLUSION: In most cases hormonal therapy appears to not alter GSTP1 HM detection. However the change from a positive to a negative GSTP1 HM status in a subset of the patients may point to an, at least partial androgen dependency. Further studies on a larger cohort of patients are necessary to assess its frequency and the exact hormonal interactions

correlation of histopathology and prognosis

Die derzeit eingesetzten Modelle zur Abschätzung der Prognose von Patienten mit einem Nierenzellkarzinom basieren vornehmlich auf der Integration histopathologischer, klinischer und laborchemischer Faktoren. Man geht jedoch davon aus, dass der zusätzliche Einschluss molekularer Parameter, die die individuelle Tumorbiologie besser widerspiegeln, die Vorhersagegenauigkeit dieser Modelle noch deutlich verbessern kann. Da einer Fehlregulation der Apoptose eine zentrale Bedeutung bei der Entstehung, Progression und Therapierefraktärität maligner Tumoren zukommt, haben die IAP (inhibitor of apoptosis)-Proteinfamilie und deren Antagonisten diesbezüglich möglicherweise großes Potential. Schwerpunkt meiner Arbeiten war es deshalb, erstmalig das Expressionsprofil der IAPFamilienmitglieder cIAP1, cIAP2 und Livin sowie das der IAP-Antagonisten Smac/DIABLO, Omi/HtrA2 und XAF1 im Nierenzellkarzinom zu untersuchen und auf mögliche Korrelationen mit der Aggressivität und Prognose dieser Tumoren hin zu überprüfen. Methodisch kamen im Rahmen dieser Studien die real-time RT-PCR, die quantitative methylierungsspezifische PCR, immunhistochemische Untersuchungen und Western Blot Analysen zum Einsatz. Im Rahmen unserer Untersuchungen zur Expression der Apoptoseinhibitoren cIAP1, cIAP2 und Livin in Nierenzellkarzinom- und korrespondierenden Normalgeweben konnten wir zeigen, dass die mRNA von cIAP1 und cIAP2 in den meisten Nierenzellkarzinomen verstärkt exprimiert wird. Im Falle von cIAP1 war diese Überexpression unabhängig vom T- und G-Stadium mit einer mit einer günstigen Prognose assoziiert, wobei der prognostische Effekt innerhalb der Gruppe der pT3 Tumoren besonders ausgeprägt war. Eine mRNA Expression der Livin Splicevarianten α und β ließ sich in ca. 40% der untersuchten Karzinome, nicht aber im normalen Nierenparenchym nachweisen. Dieses Ergebnis konnte mittels stichprobenartig durchgeführter Western Blot Analysen auf Proteinebene bestätigt werden. Signifikante Korrelation der Expression von Livin mit histopathologischen Parametern oder der Prognose fanden sich nicht. Die Untersuchung zur mRNA Expression der mitochondrialen IAP-Antagonisten Smac/DIABLO und Omi/HtrA2 im klarzelligen Nierenzellkarzinom war ausschließlich auf Tumorproben beschränkt. Smac/DIABLO und Omi/HtrA2 waren in nahezu allen 67 Tumorgeweben exprimiert, wobei die Expressionsniveaus beider Parameter eng miteinander korrelierten. Während in einer univariaten Analyse sowohl die niedrige Expression von Smac/DIABLO als auch die von Omi/HtrA2 mit einem verkürzten rezidivfreien- und tumorspezifischem Überleben vergesellschaftet war, konnte dieser Zusammenhang im multivariaten Modell nur für Smac/DIABLO bestätigt werden. Die Untersuchung zur transkriptionellen Expression und Promotormethylierung von XAF1 in Nierenzellkarzinomen erfolgte ebenfalls ausschließlich an Tumorgewebe. Eine niedrige mRNA Expression von XAF1 im Tumor vermochte unabhängig vom T-, G- und M-Stadium eine ungünstige Prognose vorherzusagen. Dieser prognostische Effekt war dabei, ähnlich wie für cIAP1 gezeigt, in der Gruppe von Patienten mit pT3 Tumoren besonders stark ausgeprägt. Eine Methylierung des XAF1 Promotors konnte nur in 10% der untersuchten Proben nachgewiesen werden, wobei die XAF1 Expression dieser Proben erwartungsgemäß invers mit der Stärke der Methylierung korrelierte. Aufgrund dieser vielversprechenden Ergebnisse untersuchten wir schließlich auch die Proteinexpression von XAF1 in einem größeren Kollektiv von Patienten mit klarzelligen Nierenzellkarzinomen und einigen unabhängigen normalen Nierenparenchymproben. Expressionsunterschiede zwischen Tumor- und Normalgewebe konnten nicht nachgewiesen werden. Eine niedrige XAF1 Expression im Tumor war aber signifikant mit einer Progression des T- und G-Stadiums und in der univariaten Analyse auch mit einer limitierten Prognose assoziiert. Als ein von diesen histopathologischen Parametern unabhängiger prognostischer Faktor konnte XAF1 in dieser Arbeit hingegen nicht identifiziert werden. Unsere Ergebnisse zeigen, dass unter den in diesen Arbeiten untersuchten IAPs wahrscheinlich nur cIAP1 Potential als Prognoseparameter im Nierenzellkarzinom besitzt. Livin stellt allerdings aufgrund seiner isolierten Expression im Tumor prinzipiell ein attraktives therapeutisches Ziel dar. Aus der Gruppe IAP-Antagonisten scheinen sowohl Smac/DIABLO als auch XAF1 einen prognostischen Stellenwert zu haben, den es nun in größeren, prospektiven Studien weiter zu untersuchen gilt.Currently applied models for the prediction of prognosis for patients with renal cell cancer are mainly based on the integration of histopathological, clinical and biochemical factors. However, it is commonly accepted that the incorporation of molecular markers, which reflect tumor biology to a greater extend, could significantly increase the accuracy of predictive models. Due to the central role of apoptotic dysregulation on the development, progression and therapeutic susceptibility of cancers, the IAP (inhibitor of apoptosis) protein family could have a great potential in this regard. Main focus of my work was to investigate the expression profile of the IAP family members cIAP1, cIAP2, and Livin as well as the IAP antagonists Smac/DIABLO, Omi/HtraA2 and XAF1 in renal cell cancer. Furthermore, the correlation of above mentioned markers with tumor aggressiveness and prognosis was explored. My laboratory work was mainly based on real-time RT-PCR, quantitative methylation-specific PCR, immunohistochemistry and Western blot analyses. We demonstrated that the mRNA of cIAP1 and cIAP2 was overexpression in the majority of renal cell cancers. For cIAP1 the overexpression was associated with a favorable prognosis, independent from tumor stage and grade which the greatest prognostic value for patients with pT3 tumors. The mRNA expression of Livin- splicing variants α and β was observed in approximately 40% of investigated cancers, but not in adjacent benign tissue. These results were confirmed on the protein level by Western blot analyses. There were no statistically significant associations of Livin expression levels with histopathological characteristics and prognosis. The investigation of mRNA expression of the IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear cell renal cancer was limited to tumor samples. Smac/DIABLO and Omi/HtrA2 were expressed in almost all tumor samples with very similar expression levels. Although a low expression level of Smac/DAIBLO and Omi/HtrA2 was associated with inferior recurrence-free and tumor-specific survival in univariate analysis, only Smac/DIABLO remained an independent prognosticator in multivariable analysis. The investigation of XAF1 expression and promethylation was similarly limited to cancerous renal tissue only. A lower mRNA expression of XAF1 was associated with a favorable prognosis independent from tumor stage, tumor grade, and metastatic status. Similar to the results for cIAP1, the prognostic value was specifically high in patients with pT3 tumors. Methylation of the XAF1 promoter in tumors was only observed in approximately 10% of the samples, with an inverse correlation of XAF1 expression and degree of methylation. These promising results encouraged us to investigate protein expression of XAF1 in an extended cohort of patients with clear cell renal cancer and samples of adjacent benign tissue. We did not find any difference s in expression levels between cancerous and benign tissue. However, a lower XAF1 expression of the tumor was statistically significant associated with the progression of tumor stage, tumor grade and patient prognosis in univariate analysis. When accounting for histopathological characteristics, XAF1 did not remain an independent prognostic predictor. Our results demonstrate that cIAP1 I the most promising prognostic marker of the investigated IAPs in renal cell cancer. However, Livin represents an attractive potential therapeutic target as it is exclusively expressed in cancerous but not in benign renal tissue. With regard to the IAP antagonists, both - Smac/DIABLO and SAF1 - seem to have a prognostic value in renal cell cancer. Future prospective studies aiming to further evaluate our promising initial findings in larger patient cohorts are warranted

Functional Epigenetic Analysis of Prostate Carcinoma: A Role for Seryl-tRNA Synthetase?

Transcriptional silencing, as a result of aberrant promoter hypermethylation, is a common mechanism through which genes in cancer cells become inactive. Functional epigenetic screens using demethylating agents to reexpress transcriptional silenced genes may identify such inactivated genes for needing further evaluation. We aimed to identify genes so far not known to be inactivated by promoter hypermethylation in prostate cancer. DU-145 and LNCaP cells were treated with the DNMT inhibitor zebularine. Expression changes of total RNA from treated and untreated cells were compared using an RNA expression microarray. Genes upregulated more than 2-fold were evaluated by RT-qPCR in 50 cases of paired normal and tumor tissues of prostate cancer patients. SARS was found to be downregulated in prostate cancer in 42/50 cases (84%). In addition, GADD45A and SPRY4 showed a remarkable diminished expression (88% and 74%, resp.). The gold standard for promoter hypermethylation-inactivated genes in prostate cancer (GSTP1) was repressed in 90% of our patient samples. ROC analyses reported statistically significant AUC curves in SARS, GADD45A, and GSTP1 and positive Spearman correlations were found between these genes. SARS was discovered to be a novel gene that is repressed in prostate cancer and could therefore be recommended for its involvement in prostate carcinogenesis

Matched comparison of robot-assisted, laparoscopic and open radical prostatectomy regarding pathologic and oncologic outcomes in obese patients

To investigate pathological and oncological outcomes of obese patients who underwent robot-assisted radical prostatectomy (RARP) compared with laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (RRP) since limited comparative data exist with regard to oncological and survival outcomes. A total of 869 patients with body mass index ≥ 30 from two academic centers were identified. A total of 194 patients who underwent RARP were propensity score (PS) matched 1:1 to LRP or RRP cases. PS-matching variables included prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, surgeon experience, and nerve-sparing technique. Predictors of positive surgical margins (PSMs) were analyzed using logistic regression. Predictors of recurrence-free survival (RFS) were analyzed within Cox regression models. Overall survival was compared with RFS using the log-rank test. Pathologic Gleason scores 7 were found in 24.2, 63.6, and 11.7 % of patients, respectively. There were no statistically significant differences related to pathologic stage or lymph node metastases between surgical techniques. PSM for pT2 disease were observed in 22.9, 17.4, and 19.3 % of patients undergoing RARP, LRP, and RRP, respectively (not significantly different). Preoperative PSA and clinical stage cT2 disease were independently associated with PSM. There were no significant differences in mean 3-year RFS for RARP, LRP, and RRP (87.4, 91.0, and 85.7 %). Biopsy Gleason score >7, PSM, and clinical stage two were independent predictors of decreased RFS. RARP demonstrates similar pathological and oncological results compared with LRP or RRP for obese patients