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Purpose: To assess use of stereotactic body radiotherapy (SBRT) for stage I renal cell carcinoma (RCC) and compare outcomes with thermal ablation and partial nephrectomy (PN).Materials and Methods: The 2004-2015 National Cancer Database was investigated for histopathologically proven stage I RCC treated with PN, cryoablation, radiofrequency (RF) or microwave (MW) ablation, or SBRT. Patients were propensity score-matched to account for potential confounders, including patient age, sex, race, comorbidities, tumor size, histology, grade, tumor sequence, administration of systemic therapy, treatment in academic vs nonacademic centers, treatment location, and year of diagnosis. Overall survival (OS) was evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models.Results: A total of 91,965 patients were identified (SBRT, n = 174; PN, n = 82,913; cryoablation, n = 5,446; RF/MW ablation, n = 3,432). Stage I patients who received SBRT tended to be older women with few comorbidities treated at nonacademic centers in New England states. After propensity score matching, a cohort of 636 patients was obtained with well-balanced confounders between treatment groups. In the matched cohort, OS after SBRT was inferior to OS after PN and thermal ablation (PN vs SBRT, hazard ratio [HR] = 0.29, 95% confidence interval [CI] 0.19-0.46, P < .001; cryoablation vs SBRT, HR = 0.40, 95% CI 0.26-0.60, P < .001; RF/MW ablation vs SBRT, HR = 0.46, 95% CI 0.31-0.67, P < .001). Compared with PN, neither cryoablation nor RF/MW ablation showed significant difference in OS (cryoablation vs PN, HR = 1.35, 95% CI 0.80-2.28, P = .258; RF/MW ablation vs PN, HR = 0.64, 95% CI 0.95-2.55, P = .079).Conclusions: Current SBRT protocols show lower OS compared with thermal ablation and PN, whereas thermal ablation and PN demonstrate comparable outcomes. [ABSTRACT FROM AUTHOR]

Purpose We summarize the evidence on gender specific differences in disease-free, cancer specific and overall survival after radical cystectomy for bladder cancer. Materials and Methods We performed a systematic literature search of MEDLINE®, Embase® and the Cochrane Library in July 2017. Studies evaluating gender specific differences in disease-free, cancer specific or overall survival after radical cystectomy for bladder cancer were included in study. Analyses included random effect meta-analysis, subgroup analyses, meta-influence and cumulative meta-analyses. Funnel plots and the Egger test were used to assess publication bias. Results Of the 3,868 studies identified during the literature search 59 published between 1998 and 2017 were included in analysis. Of the studies 30 in a total of 38,321 patients evaluated disease-free survival, 44 in a total of 69,666 evaluated cancer specific survival and 26 in a total of 30,039 evaluated overall survival. Random effect meta-analyses revealed decreased disease-free, cancer specific survival and overall survival in female patients than in their male counterparts. Pooled estimates showed a HR of 1.16 (95% CI 1.06–1.27, p = 0.0018) for disease-free survival, 1.23 (95% CI 1.15–1.31, p <0.001) for cancer specific survival and 1.08 (95% CI 1.03–1.12, p = 0.0004) for overall survival. Subgroup analyses confirmed impaired disease-free, cancer specific and overall survival in female patients in all strata. Publication bias was evident only for studies of cancer specific survival (Egger test p = 0.0029). After adjusting for publication bias by the trim and fill method the corrected pooled estimated HR of cancer specific survival was 1.13 (95% CI 1.05–1.21, p = 0.0012). Conclusions Female patients who underwent radical cystectomy for bladder cancer demonstrated worse disease-free, cancer specific and overall survival than their male counterparts. The multifactorial etiology might include epidemiological differences, gender specific health care discrepancies and hormonal influences. [ABSTRACT FROM AUTHOR]

Deregulation of the insulin‐like growth factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development‐ and tissue‐dependent manner and has been implicated in a broad range of malignancies including prostate cancer (PCa). Loss of imprinting (LOI) usually results in bi‐allelic gene expression and increased levels of IGF2. However, the regulatory mechanisms and the pathophysiological impact of altered IGF2 expression in PCa remain elusive. Here, we show that in contrast to many other tumors, IGF2 mRNA and protein levels were decreased in 80% of PCa in comparison with non‐neoplastic adjacent prostate and were independent of LOI status. Instead, IGF2 expression in both tumors and adjacent prostate depended on preferential usage of the IGF2 promoters P3 and P4. Decreased IGF2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with IGF2 expression in the 20% of PCa where IGF2 was higher in tumors than in adjacent prostate. We conclude that IGF2 is downregulated in most PCa and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. PCa differs from other tumors in that IGF2 expression is mainly regulated through methylation of promoter‐specific and not by imprinting. Targeting of promoter‐specific regions may have relevance for the adjuvant treatment of PCa. [ABSTRACT FROM AUTHOR]

Abstract: Background: Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. Objectives: The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). Methods: This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21–79). Results: Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. Conclusions: After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients. [Copyright &y& Elsevier]

Purpose: Patients with stage pT3N0 urothelial bladder cancer vary in outcome after radical cystectomy. To improve prognosis estimation a model was recently developed that defines 3 risk groups for recurrence-free survival based on pT substaging, lymphovascular invasion and positive surgical margin. We present what is to our knowledge the first external validation of this risk model. Materials and Methods: Analogous to the risk model derivation cohort our study group comprised 472 patients with stage pT3, pN0, cM0 disease without perioperative chemotherapy and with a median followup of 42 months (IQR 20–75). The primary end point was recurrence-free survival. The effect of variables was determined by univariate and multivariate Cox regression analysis, and predictive accuracy was determined by ROC analysis. Results: Stage pT3aN0 and pT3bN0 cases showed significantly different recurrence-free survival after 5 years (51% vs 29%, p <0.001). In the multivariate Cox model pT3 substage (HR 1.86, p <0.001), lymphovascular invasion (HR 1.48, p = 0.002), positive surgical margins (HR 1.90, p = 0.030) and patient age with a dichotomy at 70 years (HR 1.51, p = 0.001) had an independent effect on recurrence-free survival. In the low (221 patients or 47%), intermediate (184 or 39%) and high (67 or 14%) risk groups the 5-year recurrence-free survival rate was 55%, 45% and 13%, respectively (p <0.001). The concordance index of the risk model to predict recurrence-free survival was 0.64 (95% CI 0.59–0.69). Conclusions: This user friendly risk model can be recommended to estimate prognosis in patients with stage pT3N0 after radical cystectomy. Patients at high risk showed clearly compromised recurrence-free survival and should be included in adjuvant therapy studies. [ABSTRACT FROM AUTHOR]

Purpose: We examined papillary renal cell carcinoma prognostic variables and validated the 2002 UICC TNM staging system in a multicenter analysis. Materials and Methods: From 10 urological institutions in Germany followup data were collected on a total of 675 patients with papillary renal cell carcinoma. Central pathological review was done to validate external histopathological diagnoses. The Kaplan-Meier method was used to derive cumulative cancer specific and overall survival, and the log rank test was used to compare the curves of 2 or more groups. For multivariate analysis of prognostic factors Cox regression analysis was done. All proportional hazard assumptions were systemically verified using the Grambsch-Therneau test. Results: Cancer specific survival was significantly related to TNM stage and histological grading on univariate and multivariate analyses. Five-year cancer specific survival in pT1b cases was significantly shorter than in pT1a cases (90.0% vs 98.3%, p = 0.017). No significant difference was found between pT1b and pT2 tumors. Patients with pT3 or greater disease were at high risk for metastasis (50.6%) while metastatic disease associated with pT2 or less tumors occurred in 7.8% (p <0.0001). After metastatic disease was present the prognosis was poor with 7.2% 5-year cancer specific survival. Age was associated with poor prognosis in the subgroup with pT3 or greater tumors on univariate analysis (p = 0.026) but not on multivariate analysis. Conclusions: In its current form the 2002 UICC TNM staging system is not applicable to papillary renal cell carcinoma. Clinical and radiological followup should be offered at frequent intervals to patients with venous thrombus and/or locally advanced disease. The role of age remains unclear but should not be underestimated in risk stratification after surgery. [Copyright &y& Elsevier]

Summary: There is an evidence that components of the insulin-like growth factor (IGF)–signaling pathway are involved in the development and progression of prostate cancer. The aim of the present study was to provide a comprehensive analysis of the expression levels of proteins of the IGF axis in prostate cancer. We studied expression of the ligands IGF-I and IGF-II, the inhibitory IGF binding protein–3, the type I IGF receptor (IGF-IR), and the downstream mediator insulin receptor substrate-1 by immunohistochemistry in 56 tissue specimens (28 low-grade and 28 high-grade prostate adenocarcinomas). Protein expression in tumor areas, prostatic intraepithelial neoplasias (PINs), and adjacent benign prostatic tissue were evaluated regarding staining intensity and fraction of positive cells. An immunoreactivity score was established from staining intensity and fraction of positive cells, and correlated with the prognostic clinicopathologic parameters prostate-specific antigen serum levels, Gleason score, and TNM stage. The expression levels of all proteins investigated, except IGF binding protein–3, were up-regulated in PIN and in cancer. IGF-I and IGF-II expression showed a higher expression in high-grade compared with low-grade tumor areas. IGF-I and IGF-II and insulin receptor substrate-1 immunoreactivity was higher in tumors from patients with preoperative prostate-specific antigen serum levels 10 ng/mL or greater, and IGF-II expression was correlated with Gleason score. The data indicate significant alterations in the IGF system as prostate cancer develops. Differential expression of growth-stimulating components of the IGF system may be associated with the malignant phenotype and more aggressive tumor behavior. Expression of IGFs, especially IGF-II, may be predictors of the outcome of prostate cancer. [Copyright &y& Elsevier]

Summary: Neuroendocrine (NE) tumor cells in prostatic carcinoma (PCa) may influence tumor proliferation by a paracrine stimulus. The role of NE tumor cells is discussed controversially. This study investigates the influence of NE tumor differentiation on proliferation in PCa. Neuroendocrine differentiation, Ki-67, and Polo-like kinase 1 were studied immunohistochemically in 73 consecutive prostatectomies. Polo-like kinase 1 (PLK1) expression was also studied by Western and Northern blot analysis. Tumors were classified as high NE (HNE) and low NE differentiated (LNE), and depending on the growth pattern, with solitary and clusters of NE tumor cells. Low NE differentiated tumors were defined as less than 30 and HNE as 30 or more NE tumor cells per hot spot. Patients were followed by serum prostate-specific antigen (PSA) analysis. Neuroendocrine differentiation was present at least focally in 70% of tumors; 57% were HNE and 43% LNE. Solitary NE tumor cells were more often found in low-grade PCa, whereas clusters of NE tumor cells were more frequent in high-grade PCa. PLK1 messenger RNA and protein as well as Ki-67 were overexpressed in tumor tissue compared with tumor-free tissue. A stronger proliferation as determined by Ki-67 and PLK1 expression was present in HNE tumors compared with LNE tumors and in tumors with clusters in contrast to tumors with solitary NE tumor cells. Analysis for PSA relapse-free survival showed an earlier progression in HNE than in LNE tumors and in PCa with clusters of NE tumor cells. A significant and clustered NE differentiation in PCa may lead to an increased proliferation and earlier tumor progression, whereas few and solitary NE tumor cells have no prognostic impact. [Copyright &y& Elsevier]