Rein-Jüri Palisaar

Prediction of 90-day Mortality After Radical Cystectomy for Bladder Cancer in a Prospective European Multicenter Cohort

BACKGROUND Despite recent improvements, radical cystectomy (RC) is still associated with adverse rates for 90-d mortality. OBJECTIVE To validate the performance of the Isbarn nomogram incorporating age and postoperative tumor characteristics for predicting 90-d RC mortality in a multicenter series and to generate a new nomogram based strictly on preoperative parameters. DESIGN, SETTING, AND PARTICIPANTS Data of 679 bladder cancer (BCa) patients treated with RC at 18 institutions in 2011 were prospectively collected, from which 597 patients were eligible for final analysis. INTERVENTION RC for BCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS An established prediction tool, the Isbarn nomogram, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver operating characteristics-derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities. Univariable and multivariable logistic regression models were fitted to assess the impact of preoperative characteristics on 90-d mortality. RESULTS AND LIMITATIONS The 30-, 60-, and 90-d mortality rates in the development cohort (n=597) were 2.7%, 6.7%, and 9.0%, respectively. The Isbarn nomogram predicted individual 90-d mortality with an accuracy of 68.6%. Our preoperative multivariable model identified age (odds ratio [OR]:1.052), American Society of Anesthesiologists score (OR: 2.274), hospital volume (OR: 0.982), clinically lymphatic metastases (OR: 4.111), and clinically distant metastases (OR: 7.788) (all p<0.05) as independent predictors of 90-d mortality (predictive accuracy: 78.8%). Our conclusions are limited by the lack of an external validation of the preoperative model. CONCLUSIONS The Isbarn nomogram was validated with moderate discrimination. Our newly developed model consisting of preoperative characteristics might outperform existing models. Our model might be particularly suitable for preoperative patient counseling. PATIENT SUMMARY The current report validated an established nomogram predicting 90-d mortality in patients with bladder cancer after radical cystectomy (RC). We developed a new prediction tool consisting of strictly preoperative parameters, thus allowing clinicians an optimal consultation for RC candidates.

MicroRNA-205, a novel regulator of the anti-apoptotic protein Bcl2, is downregulated in prostate cancer

Decreased expression of the microRNA miR-205 has been observed in multiple tumour types due to its role in the epithelial to mesenchymal transition, which promotes metastasis. We determined the expression of miR-205 in 111 archival samples of prostate carcinoma and found it to be strongly reduced in most samples, with a median expression level of 16% in comparison to benign tissue from the same patient. Lower miR-205 expression correlated significantly with tumour size and miR-205 levels decreased with increasing Gleason score from 7a=3+4 to 8=4+4. In addition, we describe the anti-apoptotic protein BCL2 as a target of miR-205, relevant for prostate cancer due to its role in prognosis of primary tumours and in the appearance of androgen independence. The repression of BCL2 by miR-205 was confirmed using reporter assays and western blotting. BCL2 mRNA expression in the same collective of prostate cancer tissue samples was associated with higher Gleason score and extracapsular extension of the tumour (pT3). Consistent with its anti-apoptotic target BCL2, miR-205 promoted apoptosis in prostate cancer cells in response to DNA damage by cisplatin and doxorubicin in the prostate cancer cell lines PC3 and LnCap. MiR-205 also inhibited proliferation in these cell lines.

Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells

Background: Soluble adenylyl cyclase (sAC) may be an alternative intracellular localized source of cAMP controlling proliferation. Results: sAC is overexpressed in prostate carcinoma, and inhibition of sAC leads to cell cycle arrest. Conclusion: sAC controls proliferation of prostate carcinoma cells. Significance: sAC represents a novel pathway promoting proliferation in cancer cells and is a promising target for prostate cancer treatment. cAMP signaling plays an essential role in modulating the proliferation of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In this study, significant overexpression of soluble adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma, and therefore, the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3. Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells, led to lactate dehydrogenase release, and induced apoptosis. Cell cycle analysis revealed a significant rise in the G2 phase population 12 h after sAC inhibition, which was accompanied by the down-regulation of cyclin B1 and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap1/B-Raf signaling pathway. In contrast, protein kinase A does not play a role. In conclusion, this study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells.

Fusion of Magnetic Resonance Imaging and Real-Time Elastography to Visualize Prostate Cancer: A Prospective Analysis using Whole Mount Sections after Radical Prostatectomy

PURPOSE To determine whether the fusion of multiparametric magnetic resonance imaging (MRI) with transrectal real-time elastography (RTE) improves the visualization of PCa lesions compared to MRI alone. MATERIALS AND METHODS In a prospective setting, 45 patients with biopsy-proven PCa received prostate MRI prior to radical prostatectomy (RP). T2 and diffusion-weighted imaging (T2WI/DW-MRI) and, if applicable, dynamic contrast-enhanced sequences (T2WI/DW/DCE-MRI) were used to perform MRI/RTE fusion. The probability of PCa on MRI was graded according to the PI-RADS score for 12 different prostate sectors per patient. MRI images were fused with RTE to stratify suspicious from non-suspicious sectors. Imaging results were compared to whole mount sections using nonparametrical receiver operating characteristic curves and the area under these curves (AUC). RESULTS 41 of 45 patients were eligible for final analyses. Histopathology confirmed PCa in 261 (53%) of 492 prostate sectors. MRI alone provided an AUC of 0.62 (T2WI/DW-MRI) and 0.65 (T2WI/DW/DCE-MRI) to predict PCa and was meaningfully enhanced to 0.75 (T2WI/DW-MRI) and 0.74 (T2WI/DW/DCE-MRI) using MRI/RTE fusion. Sole MRI showed a sensitivity and specificity of 57.9% and 61% with the best results for ventral prostate sectors whereas RTE was superior in dorsal and apical sectors. MRI/RTE fusion improved sensitivity and specificity to 65.9% and 75.3%, respectively. Additional use of DCE sequences showed a sensitivity and specificity of 65% and 55.7% for MRI and 72.1% and 66% for MRI/RTE fusion. CONCLUSION MRI/RTE fusion provides improved PCa visualization by combining the strength of both imaging techniques in regard to prostate zonal anatomy and thereby might improve future biopsy-guided PCa detection.

Effectiveness of Adjuvant Chemotherapy After Radical Cystectomy for Locally Advanced and/or Pelvic Lymph Node–Positive Muscle-invasive Urothelial Carcinoma of the Bladder: A Propensity Score–Weighted Competing Risks Analysis

BACKGROUND The benefit of adjuvant chemotherapy (AC) for muscle-invasive urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC) is controversial. OBJECTIVE To assess the effectiveness of AC after RC for muscle-invasive UCB in contemporary European routine practice. DESIGN, SETTING, AND PARTICIPANTS By using a prospectively collected European multicenter database, we compared survival outcomes between patients who received AC versus observation after RC for locally advanced (pT3/T4) and/or pelvic lymph node-positive (pN+) muscle-invasive UCB in 2011. INTERVENTION AC versus observation after RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Inverse probability of treatment weighting (IPTW)-adjusted Cox regression and competing risks analyses were performed to compare overall survival (OS) as well as cancer-specific and other-cause mortality between patients who received AC versus observation. RESULTS AND LIMITATIONS Overall, 224 patients who received AC (n = 84) versus observation (n = 140) were included. The rate of 3-yr OS in patients who received AC versus observation was 62.1% versus 40.9%, respectively (p = 0.014). In IPTW-adjusted Cox regression analysis, AC versus observation was associated with an OS benefit (hazard ratio: 0.47; 95% confidence interval [CI]: 0.25-0.86; p = 0.014). In IPTW-adjusted competing risks analysis, AC versus observation was associated with a decreased risk of cancer-specific mortality (subhazard ratio: 0.51; 95% CI: 0.26-0.98; p = 0.044) without any increased risk of other-cause mortality (subhazard ratio: 0.48; 95% CI: 0.14-1.60; p = 0.233). Limitations include the relatively small sample size as well as the potential presence of unmeasured confounders related to the observational study design. CONCLUSIONS We found that AC versus observation was associated with a survival benefit after RC in patients with pT3/T4 and/or pN+ UCB. These results should encourage physicians to deliver AC and researchers to pursue prospective or large observational investigations. PATIENT SUMMARY Overall survival and cancer-specific survival benefit was found in patients who received adjuvant chemotherapy relative to observation after radical cystectomy for locally advanced and/or pelvic lymph node-positive bladder cancer.

Effect of Hospital and Surgeon Case Volume on Perioperative Quality of Care and Short-term Outcomes After Radical Cystectomy for Muscle-invasive Bladder Cancer: Results From a European Tertiary Care Center Cohort

Micro‐Abstract This prospective multicenter study analyzed the effect of hospital and surgeon case volume on perioperative quality of care and short‐term complications and mortality in 479 patients undergoing radical cystectomy for bladder cancer. We found that hospital volume might represent an at least equally important factor regarding postoperative complications as the surgeon case volume itself at European tertiary care centers. Background: Case volume has been suggested to affect surgical outcomes in different arrays of procedures. We aimed to delineate the relationship between case volume and surgical outcomes and quality of care criteria of radical cystectomy (RC) in a prospectively collected multicenter cohort. Patients and Methods: This was a retrospective analysis of a prospectively collected European cohort of patients with bladder cancer treated with RC in 2011. We relied on 479 and 459 eligible patients with available information on hospital case volume and surgeon case volume, respectively. Hospital case volume was divided into tertiles, and surgeon volume was dichotomized according to the median annual number of surgeries performed. Binomial generalized estimating equations controlling for potential known confounders and inter‐hospital clustering assessed the independent association of case volume with short‐term complications and mortality, as well as the fulfillment of quality of care criteria. Results: The high‐volume threshold for hospitals was 45 RCs and, for high‐volume surgeons, was > 15 cases annually. In adjusted analyses, high hospital volume remained an independent predictor of fewer 30‐day (odds ratio, 0.34; P = .002) and 60‐ to 90‐day (odds ratio, 0.41; P = .03) major complications but not of fulfilling quality of care criteria or mortality. No difference between surgeon volume groups was noted for complications, quality of care criteria, or mortality after adjustments. Conclusion: The coordination of care at high‐volume hospitals might confer a similar important factor in postoperative outcomes as surgeon case volume in RC. This points to organizational elements in high‐volume hospitals that enable them to react more appropriately to adverse events after surgery.

Primary renal angiosarcoma. Uncommon manifestation of a rare malignancy

This article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.ZusammenfassungWir beschreiben mit dem primär renalen Angiosarkom eine seltene Tumorentität bei einem 59-jährigen Patienten. Die mittlere Überlebenszeit liegt bei wenigen Monaten, wenn die Diagnose bei klinischer Symptomatik erfolgt. Heilungschancen bestehen durch chirurgische Resektion kleinerer Zufallsbefunde. Bei fehlender Standardtherapie orientiert sich die systemische Behandlung an der Therapie anderer Weichteilsarkome. Der Stellenwert der adjuvanten Therapie bleibt unklar. Mit doxorubicinbasierten Chemotherapieregimen konnte bei Angiosarkomen ein Überlebensvorteil erreicht werden.AbstractThis article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.

De novo neurogenic bladder dysfunction after salvage lymph node dissection in patients with nodal recurrence of prostate cancer

To examine the impact of Salvage lymph node dissection (SLND) on bladder function and oncological outcome in hormone naïve patients with nodal recurrence of prostate cancer (PCa) after radical prostatectomy (RP).

Primär renales Angiosarkom@@@Primary renal angiosarcoma: Ungewöhnliche Manifestation eines seltenen Tumors@@@Uncommon manifestation of a rare malignancy

This article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.ZusammenfassungWir beschreiben mit dem primär renalen Angiosarkom eine seltene Tumorentität bei einem 59-jährigen Patienten. Die mittlere Überlebenszeit liegt bei wenigen Monaten, wenn die Diagnose bei klinischer Symptomatik erfolgt. Heilungschancen bestehen durch chirurgische Resektion kleinerer Zufallsbefunde. Bei fehlender Standardtherapie orientiert sich die systemische Behandlung an der Therapie anderer Weichteilsarkome. Der Stellenwert der adjuvanten Therapie bleibt unklar. Mit doxorubicinbasierten Chemotherapieregimen konnte bei Angiosarkomen ein Überlebensvorteil erreicht werden.AbstractThis article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.

Primär renales Angiosarkom

This article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.ZusammenfassungWir beschreiben mit dem primär renalen Angiosarkom eine seltene Tumorentität bei einem 59-jährigen Patienten. Die mittlere Überlebenszeit liegt bei wenigen Monaten, wenn die Diagnose bei klinischer Symptomatik erfolgt. Heilungschancen bestehen durch chirurgische Resektion kleinerer Zufallsbefunde. Bei fehlender Standardtherapie orientiert sich die systemische Behandlung an der Therapie anderer Weichteilsarkome. Der Stellenwert der adjuvanten Therapie bleibt unklar. Mit doxorubicinbasierten Chemotherapieregimen konnte bei Angiosarkomen ein Überlebensvorteil erreicht werden.AbstractThis article reports a case of primary renal angiosarcoma, a very rare and aggressive malignancy, in a 59-year-old male patient. The mean overall survival time is limited to a few months if the diagnosis is made when clinical symptoms are present but chances of a cure can be increased with surgical resection of smaller incidental findings. Due to the lack of a standard therapy, systemic treatment is based on the therapy of other soft tissue sarcomas. The role of adjuvant medical treatment particularly in angiosarcoma remains poorly studied but using a doxorubicin-based chemotherapy regimen, a survival benefit can be achieved.