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BackgroundPatients with locally advanced and high-risk prostate cancer (LAPC) are prone to experience biochemical recurrence despite radical prostatectomy (RP). We evaluated feasibility, safety and activity of a neoadjuvant chemohormonal therapy (NCHT) with 3-weekly full dose docetaxel and complete androgen blockade (CAB) in locally advanced and high-risk prostate cancer patients (LAPC) undergoing RP.MethodsPatients (n = 30) were selected by Kattans’ preoperative score and received trimestral buserelin 9,45 mg, bicalutamide 50 mg/day and 3 cycles docetaxel (75 mg/m2) followed by RP. Primary endpoints were biochemical (PSA) and local downstaging. Secondary endpoints included toxicity and operability assessments, pathological complete response (pCR), time to PSA progression, 5-year biochemical recurrence free survival (bRFS) and overall survival (OS).ResultsMedian baseline PSA was 25.8 ng/ml (2.1–293), and the predicted probability of 5-year bRFS was 10% (0–55). NCHT induced PSA-reduction was 97.3% (81.3-99.9%; p < 0.001) and post-RP 96.7% of patients were therapy responders, with undetectable PSA-values. Post- vs. pretreatment MRI indicated a median tumor volume reduction of 46.4% (−31.3-82.8; p < 0.001). A pathological downstaging was observed in 48.3%. Severe hematologic toxicities (≥CTC3) were frequent with 53.8% leucopenia, 90% neutropenia and 13.3% febrile neutropenia. RP was performed in all patients. While resectability was hindered in 26.7%, continence was achieved in 96.7%. Pathologic analyses revealed no pCR. Lymph node- and extracapsular involvement was observed in 36.7% and 56.7% with 33.3% positive surgical margins. After a median of 48.6 (19.9-87.8) months, 55.2% of therapy responders experienced PSA-recurrence. The estimated median time to PSA-progression was 38.6 months (95%CI 30.9-46.4) and 85.3 months (95%CI 39.3–131.3) for OS. The 5-year bRFS was improved to 40%, but limiting for interpretation adjuvant treatment was individualized.ConclusionsNCHT is feasible despite high hematotoxicity, with excellent functional results. Significant downstaging was observed without pCR. NCHT seems to improve the cohort adjusted 5-year bRFS, but clinical value needs further investigation in randomized trials.

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A histological grading system of chromophobe renal cell carcinoma (chRCC) is highly desirable to identify approximately 5-10% of tumors at risk for progression. Validation studies failed to demonstrate a correlation between the four-tiered WHO/ISUP grade and outcome. Previous proposals with threetiered chromophobe grading systems could not be validated. In this study, the presence of sarcomatoid differentiation, necrosis, and mitosis was analyzed in a Swiss cohort (n = 42), an Italian cohort (n = 103), a German cohort (n = 54), a Japanese cohort (n = 119), and The Cancer Genome Atlas cohort (n = 64). All 3 histological parameters were significantly associated with shorter time to tumor progression and overall survival in univariate analysis. Interobserver variability for identification of these parameters was measured by Krippendorff's alpha coefficient and showed high concordance for the identification of sarcomatoid differentiation and tumor necrosis, but only low to medium concordance for the identification of mitosis. Therefore, we tested a two-tiered tumor grading system (low versus high grade) based only on the presence of sarcomatoid differentiation and/or necrosis finding in the combined cohorts (n = 382). pT stage, patient's age (> 65 vs 65), lymph node and/or distant metastasis, and the twotiered grading system (low versus high grade) were significantly associated with overall survival and were independent prognostic parameters in multivariate analysis (Cox proportional hazard). This multiinstitutional evaluation of prognostic parameters suggests tumor necrosis and sarcomatoid differentiation as reproducible components of a two-tiered chromophobe tumor grading system.

Transurethral resection of urothelial carcinoma often results in tumor recurrence due to disseminated tumor cells. Therefore, new therapeutic strategies are urgently needed. The aim of this study was to establish an orthotopic human bladder carcinoma mouse model using the epidermal growth factor receptor (EGFR)-overexpressing bladder carcinoma cell line EJ28 and to compare therapeutic efficacy of intravesically instilled a-particle-emitting 213 Bi-anti-EGFR-monoclonal antibody (mAb) with mitomycin C. Methods: Female Swiss nu/nu mice were intravesically inoculated with luciferase-transfected EJ28 human bladder carcinoma cells after the induction of urothelial lesions by electrocautery. At different time points after cell inoculation, mice were treated intravesically with 213 Bi-anti-EGFR-mAb, mitomycin C, or unlabeled anti-EGFR-mAb. Tumor development and therapeutic response were evaluated via bioluminescence imaging. Results: Mice without therapy and those treated with unlabeled anti-EGFR-mAb reached a median survival of 41 d and 89 d, respectively. Mice that underwent therapy with 0.925 MBq of 213 Bi-anti-EGFR-mAb 1 h, 7 d, or 14 d after cell instillation survived more than 300 d in 90%, 80%, and 40% of the cases, respectively. Therapy with 0.37 MBq 1 h or 7 d after tumor cell inoculation resulted in survival of more than 300 d in 90% and 50% of mice, respectively. Mitomycin C treatment after 1 h and 7 d prolonged survival to more than 300 d in 40% and 50%, respectively; however, treatment turned out to be nephrotoxic. In contrast, no signs of nephrotoxicity could be observed after 213 Bi-anti-EGFR-mAb treatment. Conclusion: The study suggests that radioimmunotherapy using intravesically instilled 213 Bi-anti-EGFR-mAb is a promising option for treatment of bladder cancer in patients.

Intravesical instillation of Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of theBi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.

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Objectives: To retrospectively evaluate the value of CT for lymph node (LN) staging in bladder cancer. Methods: Two uroradiologists reviewed CT scans of 231 patients who underwent radical cystectomy and pelvic lymphadenectomy according to a predefined 12-field template. A 5-step model was used to grade the radiological likelihood of a LN to represent malignant spread based on size, configuration and structure as well as regional clustering. Statistical analyses were performed both on patient- and field-based levels. Results: LN metastases were found in 59 of 231 patients (25.5%). On a patient-based level, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were 52.6, 93.6, 73.2, 85.6 and 83.4%, respectively. Using the field-based approach, a total of 1,649 anatomical fields were evaluable, of which 114 fields showed malignancy (6.9%). On a field basis, sensitivity, specificity, PPV, NPV and accuracy were 30.2, 98, 51.5, 94.5 and 93.3%, respectively. Concerning local staging (pT category), the overall accuracy was 78%; overstaging occurred in 6% and understaging in 16%. Conclusions: In line with prior studies, the sensitivity of CT imaging for the detection of LN metastases was low, while high values for specificity were achieved. This was further underlined by analyzing standardized anatomical fields. Concerning local staging, postoperative changes after TURB-T rarely led to overstaging.