Th1-type immunity is considered to be required for efficient response to BCG in bladder cancer, although Th2 predisposition of BCG responders has recently been reported. The aim was to evaluate the relationship of Th1 and Th2 components in 23 patients undergoing BCG treatment. Peripheral blood, serum and urine samples were prospectively collected at baseline, during and after BCG. Th1 (neopterin, tryptophan, kynurenine, kynurenine-to-tryptophan ratio (KTR), IL-12, IFN-γ, soluble TNF-R75 and IL-2Rα) and Th2 (IL-4, IL-10) biomarkers as well as CD4 expression in T helper (Th), effector and regulatory T cells were determined. Local immune cell subsets were measured on formalin-fixed, paraffin-embedded cancer tissue by immunohistochemistry to examine expression of transcription factors that control Th1 (T-bet) and Th2-type (GATA3) immunity. We confirmed a Th2 predisposition with a mean GATA3/T-bet ratio of 5.51. BCG responders showed significantly higher levels of urinary (p = 0.003) and serum neopterin (p = 0.012), kynurenine (p = 0.015), KTR (p = 0.005), IFN-γ (p = 0.005) and IL-12 (p = 0.003) during therapy, whereas levels of IL-10 decreased significantly (p < 0.001) compared to non-responders. GATA3/T-bet ratio correlated positively with serum neopterin (p = 0.008), IFN-γ (p = 0.013) and KTR (p = 0.018) after the first BCG instillation. We observed a significant increase in CD4 expression in the Th cell population (p < 0.05), with only a modest tendency toward higher frequency in responders compared to non-responders (p = 0.303). The combined assessment of GATA3/T-bet ratio, neopterin and KTR may be a useful biomarker in predicting BCG response. Th2-promoting factors such as GATA3 may trigger Th1-type immune responses and thus contribute to the BCG success.

Nivolumab belongs to the standard therapy in the second‐line setting of metastatic renal cell carcinoma (mRCC). Although deep and long‐lasting responses are seen in some patients, the majority of patients will further progress. PD‐L1 is still under critical evaluation as a predictive biomarker. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO‐1, a negative immune‐regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO‐1 and other immune inhibitory molecules (PD‐L1, PD‐L2, FOXP3) as well as immune cell subsets (CD3, CD4 and CD8) were measured on formalin‐fixed, paraffin‐embedded sections of RCC specimens by immunohistochemistry. IDO‐1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO‐1 overexpression (>10%) could be detected more frequently in responders (100%, n = 6/6) compared to non‐responders (33.3%, n = 3/9; P = .028), resulting in a better progression‐free survival during immunotherapy (IDO‐1 ≤ 10% vs >10%, median: 3.5 vs not estimated (NE) months, P = .01 by log‐rank test). In addition, IDO‐1 was positively correlated with CD8⁺ T cell expression (r_s = .691, P = .006). PD‐L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs non‐responders: 83.3% vs 88.9%). No differences were noticed in the PD‐L1 expression on tumor‐infiltrating immune cells (PD‐L1 < 1% in 66.7% of both responders and non‐responders). In contrast to PD‐L1, these results suggest that IDO‐1 may be a more promising predictive biomarker for response to immune‐based cancer therapy in mRCC.

Renal cell carcinoma (RCC) with sarcomatoid differentiation belongs to the most aggressive clinicopathologic phenotypes of RCC. It is characterized by a high propensity for primary metastasis and limited therapeutic options due to its relative resistance to established systemic targeted therapy. Most trials report on a poor median overall survival of 5 to 12 months. Sarcomatoid RCC can show the typical features of epithelial-mesenchymal transition (EMT) and may contain epithelial and mesenchymal features on both the morphological and immunhistochemical level. On the molecular level, next-generation sequencing confirmed differences in driver mutations between sarcomatoid RCC and non-sarcomatoid RCC. In contrast, mutational profiles within the epithelial and sarcomatoid components of sarcomatoid RCC were shown to be identical, with TP53 being the most frequently altered gene. These data suggest that both epithelial and sarcomatoid components of RCC originate from the same progenitor cell, segregating primarily according to the underlying histologic epithelial subtype of RCC (clear cell, papillary or chromophobe). Current studies have shown that sarcomatoid RCC express programmed death 1 (PD-1) and its ligand (PD-L1) at a much higher level than non-sarcomatoid RCC, suggesting that blockade of the PD-1/PD-L1 axis may be an attractive new therapeutic strategy. Preliminary results of clinical trials evaluating checkpoint inhibitors in patients with sarcomatoid RCC showed encouraging survival data and objective response and complete response rates of up to 62% and 18%, respectively. These findings may establish a new standard of care in the management of patients with sarcomatoid RCC.

PD-L1 expression in bladder cancer and metastasis and its influence on oncologic outcome after cystectomy PD-L1 expression in bladder cancer and metastasis and its influence on oncologic outcome after cystectomy

Objective: The incidence of urethral injuries in children is rare due to the fact that the urethra is short, mobile and protected by the pubic bone. The management of urethral trauma in childhood remains controversial because of the limited expertise of most urologists. Material and Methods: We performed a literature review by searching the Medline database for articles published between 1975 and 2010 based on clinical relevance. Electronic searches were limited to the keywords ‘pediatric’, ‘urethral injury’, ‘trauma’ and ‘reconstruction’. Results: Retrograde urethrography is considered the gold standard for diagnosis of urethral injuries. The initial management should ensure drainage of the bladder either by suprapubic cystostomy or urethral realignment if possible: in complete anterior urethral disruption as well as in children with life-threatening pelvic and intra-abdominal injuries after posterior urethral injuries, a deferred repair after 3 months is necessary. Immediate primary suturing of disrupted and dislocated urethral ends should be avoided because of high complication rates. Primary repair, however, of the defect is possible in girls avoiding a 2-stage approach. Conclusion: The aim of therapy is minimizing remote damages such as urethrocutaneous fistulae, periurethral diverticulae, strictures, incontinence and impotence with different therapeutic management depending on classification of the injury and the presence of life-threatening injuries.