Evaluation of Computed Tomography for Lymph Node Staging in Bladder Cancer Prior to Radical Cystectomy.

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.

Clinical prognosticators of survival in patients with urothelial carcinoma of the bladder and lymph node metastases after cystectomy with curative intent.

INTRODUCTION: Patients with lymph node-positive urothelial carcinoma of the bladder generally have a poor prognosis. Nevertheless, long-term survival in up to 30% of patients is reported. In the absence of established prognostic molecular markers, an assessment of the prognosis with clinical parameters is mandatory. PATIENTS AND METHODS: All patients from one high-volume center with a curatively intended cystectomy for lymph node-positive urothelial carcinoma were evaluated. Patients' overall and cancer-specific survival were correlated with clinicopathological parameters. Pathological lymph node staging was performed with both the 2002 and 2010 TNM classification of the AJCC. RESULTS: Lack of a perioperative chemotherapy (p < 0.001), higher numbers of positive nodes (p = 0.002), a higher lymph node density (p = 0.003), a higher pathological T stage (p = 0.006) and urinary diversion with an ileal conduit compared to an ileal neobladder (p = 0.023) were prognostic of a shorter overall survival while the number of removed lymph nodes showed no significant association with survival. Both with the 2002 and 2010 TNM classifications patients staged pN1 had a longer overall survival and time to cancer-specific death in comparison to patients with more extensive lymph node disease. According to the 2002 classification, there was a significant survival difference between patients with lymph node metastases in regional and distant lymph nodes. DISCUSSION: Patients with a low lymph node density and an early pT stage present with the best prognosis among LN positive patients. The value of perioperative chemotherapy is emphasized. Which lymph node metastases are to be considered regional or distant remains a matter of debate.

The method of GFR determination impacts the estimation of cisplatin eligibility in patients with advanced urothelial cancer.

OBJECTIVES: To determine GFR with different methods in patients with first-line chemotherapy for advanced urothelial cancer (UC) and to evaluate the impact of these methods on the estimation of cisplatin eligibility. METHODS: A database was built retrospectively containing all patients receiving first-line chemotherapy for UC between 2001 and 2012 in one German high-volume center. GFR was calculated with the methods by Cockcroft-Gault (CG), MDRD and CKD-EPI. Measurements of creatinine clearance with timed urine collections were registered. RESULTS: A total of 166 patients were included. All methods of renal function determination yielded consistent results in terms of cisplatin eligibility for 134 patients (80.7 %) and disagreeing results for 32 patients (19.3 %). Twenty-two of these 32 patients with borderline GFR received cisplatin-based chemotherapy. Fifteen of these 22 patients completed at least three cycles. The mean GFR in the mentioned 32 patients was 51.3, 56.2 and 54.2 ml/min with the method by CG, MDRD and CKD-EPI. Three, ten and four patients were estimated cisplatin-eligible with either method. There was a good correlation between MDRD and CKD-EPI (r (2) = 0.92). CG tended to underestimate GFR compared to both MDRD and CKD-EPI. Measurements of creatinine clearance showed a wide distribution in comparison with MDRD (r (2) = 0.002). CONCLUSIONS: The method used to determine GFR influences the estimation of cisplatin eligibility in a subset of UC patients. MDRD and CKD-EPI formulas seem most valuable, while CG tends to underestimate renal function. Using a strict cutoff of 60 ml/min may unnecessarily preclude cisplatin in some patients.

Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches.

Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff.

Long-term results of a phase II study with neoadjuvant docetaxel chemotherapy and complete androgen blockade in locally advanced and high-risk prostate cancer.

BACKGROUND: Patients 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. METHODS: Patients (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). RESULTS: Median 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. CONCLUSIONS: NCHT 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.

Presurgical treatment with sunitinib for renal cell carcinoma with a level III/IV vena cava tumour thrombus.

AIM: The feasibility and safety of a presurgical treatment approach with sunitinib for renal cell carcinoma (RCC) with level III/IV tumour thrombus in the inferior vena cava (IVC) were to be evaluated and its potential ability to reduce the surgical morbidity explored. PATIENTS AND METHODS: In our institution, we treated five consecutive patients with suspected RCC and a level III/IV IVC tumour thrombus with preoperative sunitinib (50 mg, 4 weeks on, 2 weeks off). Side dose effects were assessed and the effect on the tumour size and the dependent surgical approach documented with a computed tomographic scan before and after the treatment. The data were analyzed retrospectively. RESULTS: The overall tolerability to presurgical sunitinib was good. All procedures were carried out without perioperative complications. In four patients, a reduction in tumour size was observed, which resulted in avoidance of a bicavital surgical approach with cardiopulmonary bypass in one patient. This patient was diagnosed with papillary renal cancer; the other four patients had clear cell carcinomas. CONCLUSION: Presurgical treatment with sunitinib is able to ease surgery for RCC tumour thrombi regardless of the histological subtype in selected patients. In our series, surgery was possible without additional morbidity. Two courses of a presurgical therapy with sunitinib seems to be an appropriate duration. In accordance with previously published data, presurgical sunitinib treatment may become more widely used in RCC with level III/IV IVC tumour thrombi but administered with restraint in cases of level I/II thrombi. The effects on the risk of recurrence and survival remain to be evaluated prospectively.

Poor efficacy of BEP polychemotherapy in metastatic spermatocytic seminoma.

Metastatic spermatocytic seminoma is an extremely rare disease. No chemotherapeutic regimen is established and the use of adjuvant radiation therapy after orchiectomy as frequently performed for classical seminoma is unclear. We report the third case of proven spermatocytic seminoma metastatic in the literature and provide a review of the literature. Administering BEP polychemotherapy as in classical seminoma was poorly effective in reducing the retroperitoneal mass in a patient with spermatocytic seminoma. A review of the literature showed that all the three described patients developing metastatic disease did not receive adjuvant radiation therapy after orchiectomy, which might be considered in high-risk cases.

Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.

Impact of nerve sparing technique on patient self-assessed outcomes after radical perineal prostatectomy.

PURPOSE: We investigated the impact of nerve sparing technique on erectile function, urinary continence and health related quality of life after radical perineal prostatectomy using a validated self-assessment questionnaire. MATERIALS AND METHODS: The Expanded Prostate Cancer Index Composite questionnaire was administered preoperatively and at defined intervals after surgery to 265 patients who underwent radical perineal prostatectomy at 2 institutions between January 2001 and December 2004. Of these patients 153 (57.7%) and 112 (42.3%) underwent nonnerve sparing and nerve sparing approaches, respectively. Kaplan-Meier analysis was used to determine time to recovery of erectile function (erections firm enough for intercourse) and urinary continence (0 pads per day). RESULTS: Median patient age was 60.6 years. Median followup was 15 months. In multivariate analysis preoperative erectile function (p = 0.005) and preservation of the neurovascular bundle (p = 0.018) were independent predictors of earlier recovery of erectile function, with hazard ratios of 2.3 (95% CI 1.2-4.6) and 4.0 (95% CI 1.5-10.3), respectively. Median time to recovery of urinary continence was 4.8 months in the nerve sparing group and 6.1 months in the nonnerve sparing group (p = 0.001). In multivariate analysis nerve sparing technique (p = 0.001, HR 1.4, 95% CI 1.1-1.9) and age (p = 0.012, HR 1.7, 95% CI 1.3-2.2) were independent predictors of recovery of continence. CONCLUSIONS: This analysis suggests that nerve sparing radical perineal prostatectomy is associated with improved recovery of urinary continence and favorable health related quality of life scores and, therefore, should be considered a viable alternative to other nerve sparing approaches.

In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines.

BACKGROUND: The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145. METHODS: The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram. RESULTS: Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells. CONCLUSIONS: The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.