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NOTCH2-inactivating antibody inhibited tumor progression in vitro and in vivo.

NOTCH2 silencing inhibited tumor progression through decreased cell proliferation and invasion.

NOTCH2-induced cell invasion was blocked by downstream inhibition of canonical NOTCH2 signaling.

Purpose: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1. Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer.Experimental design: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo.Results: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model.Conclusions: We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981–92. ©2016 AACR.

NOTCH2 overexpression promoted bladder cancer progression through increased proliferation and invasion.

The lists of antibodies, primers and patients characteristics and detailed information of methods were described in Supplementary Material and Methods.

Treatment of muscle invasive bladder cancer can be challenging since treatment is associated with significant side effects and complication rates-especially in patients who often present with relevant comorbidities. In the metastatic stage, the purpose of treatment is palliation, although the oligometastatic stage takes a distinct role. At this stage, treatment of the primary tumor can play a role, if metastasis can be treated locally in addition to systemic treatment, especially the evolving drug treatment landscape could also change long holding paradigms in the near future.This review focuses on the influence of definitive treatment of the primary tumor in patients with oligometastatic urothelial bladder cancer.Based on a literature search, the aim was to summarize data and give an overview on treatment of oligo-metastatic bladder cancer with focus on treatment of the primary tumor. Presented data derived mostly from retrospective studies and meta-analyses.Local treatment of the primary tumor in context of a multimodal therapy of lymph node metastatic or oligometastatic bladder cancer can have a positive influence on survival, quality of life and prevention of local complications in selected patients. The choice of local treatment should follow the same criteria as in non-metastatic bladder cancer.HINTERGRUND: Das muskelinvasive Blasenkarzinom stellt in seiner Behandlung eine besondere Herausforderung dar, da die Therapie mit signifikanten Nebenwirkungen und Komplikationsraten einhergeht, insbesondere bei Patienten mit relevanten Begleiterkrankungen. Im metastasierten Stadium besteht der Therapiezweck in der Palliation, wobei das Vorliegen einer Oligometastasierung eine gesonderte Rolle einnimmt. In diesem Stadium kann auch die Therapie des Primärtumors relevant sein, wenn die Metastasen neben einer systemischen Therapie ebenso lokal behandelt werden können – insbesondere auch in Hinblick auf die über die letzten Jahre die Therapielandschaft erweiternden neuen medikamentösen Möglichkeiten.In diesem Reviewartikel sollen die Einflüsse einer definitiven Therapie des Primärtumors bei Patienten mit oligometastasiertem Urothelkarzinom der Harnblase dargelegt werden.Basierend auf einer nicht-systemischen Literaturrecherche soll ein Überblick über bestehende Ergebnisse zur Therapie des oligometastasierten Blasenkarzinoms in Hinblick auf den Einfluss der Therapie des Primärtumors geben, wobei die Daten meist auf retrospektiven Studien und Metaanalysen bestehen.Eine Lokaltherapie des Primärtumors im Rahmen eines multimodalen Therapiekonzepts kann bei selektionierten Patienten mit lymphogen metastasiertem und oligometastasiertem Blasenkarzinom einen positiven Einfluss auf Überleben, Lebensqualität und Vermeidung von Lokalkomplikationen nehmen, wobei für die Wahl der lokalen Therapie dieselben Kriterien angewendet werden sollten wie im nicht-metastasierten Stadium.

Urothelial cancer (UC) is most commonly found in the urinary bladder, but can also appear in the upper urinary tract, where it is associated with several disease-specific challenges affecting its diagnosis, clinical staging, surgical management, and systemic therapy. A significant number of patients experience extra-vesical disease recurrence despite radical nephroureterectomy (RNU), leading to inevitable demise. Over the last years, the therapeutic armamentarium of UC has expanded with several systemic treatment options entering clinical care and deliver the potential to support a more individualized treatment in the near future. Currently, novel targeted therapies are emerging, accompanied with extensive biomarker research, which leads to a better understanding of the disease and therefore, reshaping the treatment landscape continuously and decisively. Though, systemic treatment of UTUC comes along with certain challenges that are specific to the disease, e.g., loss of renal function after RNU, which might result in ineligibility for a cisplatin-based chemotherapy. In this narrative review, the current standard of systemic treatment of UC in the perioperative and metastatic treatment setting are reported, with focus on UTUC. In addition, molecular aspects of UTUC, as well as future directions and specific implications for treatment of patients diagnosed with UTUC are discussed.

BACKGROUND To investigate the predictive and prognostic value of the preoperative modified Glasgow Prognostic Score (mGPS) in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). METHODS We conducted a retrospective analysis of an established multicenter database consisting of 4,335 patients who were treated with RC +/- adjuvant chemotherapy for UCB between 1979 and 2012. The mGPS of each patient was calculated on the basis of preoperative serum C-reactive protein and albumin. Uni- and multivariable logistic and Cox regression analyses were performed. The discriminatory ability of the models was assessed by calculating the area under receiver operating characteristics curves (AUC) and concordance-indices (C-Index). The additional clinical net-benefit was assessed using the decision curve analysis (DCA). RESULTS A mGPS of 0, 1, and 2 was observed in 3,158 (72.8%), 1,020 (23.5%), and 157 (3.6%) patients, respectively. On multivariable logistic regression analyses, mGPS of 1 or 2 were associated with an increased risk of pT3/4 disease at RC (OR 1.25, p=0.004 and OR 2.58, p

Simple Summary Seasonal variations in cancer diagnosis could already be demonstrated in prostate and breast cancer. The reasons for this observed seasonal pattern are still unclear. The health care system or other determinants such as the protective function of vitamin D3 in carcinogenesis could be assumed as one explanation. Testicular germ cell tumors are the most common developed malignancy among young men. The aim of our study was to investigate, for the first time, the seasonal variations in the clinical diagnosis of testicular germ cell tumors. We have been able to confirm that the frequency of monthly newly diagnosed cases of testicular cell tumors in Austria has a strong seasonality, with a significant reduction in the tumor incidence during the summer months and an increase during the winter months. Abstract We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr–Sep) and an increase during the winter months (Oct–Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct–Dec (p = 0.008) and Jan–Mar (p < 0.001) was significantly higher compared to the months of Jul–Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.