Bladder cancer (BC) is a frequent type of carcinoma with an estimated incidence of approximately 100,000 men and women each year in the European Union (EU) with an associated mortality of 30,000 of these patients. In more than 70% the disease is diagnosed in a non-muscle invasive stage with the chance of minimally invasive, local treatment only, which might be required repetitively due to high rate of recurrence. In contrast, muscle invasive or metastatic stages need multimodal treatment strategies including surgical treatment and chemotherapy (CTX) in neoadjuvant (NAC), adjuvant, or palliative settings. Therapy recommendations and guidelines mainly refer to the most common histological type of BC, pure urothelial carcinoma (UC). However, BC can be classified as urothelial and non-UC. Non-urothelial BC and variants of UC account for up to 25% of all BCs. Further discrimination can be made into epithelial and non-epithelial non-UC. Most of the non-UCs are of epithelial origin (approximately 90%) including squamous-cell carcinoma, adenocarcinoma and small-cell carcinoma. Non-epithelial tumors are rare and include variants as sarcoma, carcinosarcoma, paraganglioma, melanoma and lymphoma. Even though it is unclear whether the prognosis of non-urothelial cancer truly differs from that of UC, there is evidence that additional variant histology might prognosticate an impaired prognosis. Accordingly, aggressive behavior and often advanced stages at primary presentation are frequently observed in non-UC arguing for radical and sometimes different treatment strategies as compared to pure UC. This review aims to summarize the available data for the most common histological variants of non-urothelial BC.
The adapter protein metastasis suppressor 1 (MTSS1) is implicated as a tumor suppressor or tumor promoter, depending on the type of solid cancer. Here, we identified Mtss1 expression to be increased in AML subsets with favorable outcome, while suppressed in high risk AML patients. High expression of MTSS1 predicted better clinical outcome of patients with normal-karyotype AML. Mechanistically, MTSS1 expression was negatively regulated by FLT3-ITD signaling but enhanced by the AML1-ETO fusion protein. DNMT3B, a negative regulator of MTSS1, showed strong binding to the MTSS1 promoter in PML-RARA positive but not AML1-ETO positive cells, suggesting that AML1-ETO leads to derepression of MTSS1. Pharmacological treatment of AML cell lines carrying the FLT3-ITD mutation with the specific FLT3 inhibitor PKC-412 caused upregulation of MTSS1. Moreover, treatment of acute promyelocytic cells (APL) with all-trans retinoic acid (ATRA) increased MTSS1 mRNA levels. Taken together, our findings suggest that MTSS1 might have a context-dependent function and could act as a tumor suppressor, which is pharmacologically targetable in AML patients.
636 Background: Cabozantinib (C) is a tyrosin kinase inhibitor (TKI) specific for VEGFR, MET and AXL. The phase-3 registration trial METEOR showed that C significantly improved progression-free and overall survival compared to Everolimus in patients with advanced/metastatic renal cell carcinoma (RCC) after failure of at least one VEGFR TKI and C was granted approval. In METEOR, starting dose for C was 60 mg once daily and dose de-escalation to 40 or 20 mg or stopping of C was done based on toxicity. The median dose was 43 mg. The dose had to be reduced in 62% of patients. By packing insert of C the recommended starting dose is 60 mg. We assumed that starting with 40 mg of C and escalating to 60 mg after getting accustomed to side effects may lead to a higher median dose of C. Methods: We report 20 RCC patients all started with C 40 mg and escalated to 60 mg when possible. We calculated the median time on therapy and the median dose and determined the best response. Results: The median time on C was 77 days for the patients having stopped therapy (n = 9). The median dose of C for the whole cohort was 46.0 mg. For the patients still on therapy (n = 11), the median dose was 47.7 mg. Eleven (55%) patients could be escalated to 60 mg (10 (91%) remained on 60 mg) and only 5 (25%) of patients had to be de-escalated to 20 mg. C did not have to be stopped due to toxicity. For best response, 47% reached partial remission, 13% stable and 40% progressive disease. Conclusions: Starting with 40 mg of C and escalating to 60 mg when possible may lead to a higher median dose of C compared to standard vice versa and seems to achieve responses comparable with the METEOR trial. These findings are limited by the small number of patients but warrant a prospective trial directly comparing both the escalating and de-escalating dosing schemes.
e16507 Background: Enzalutamide (Enza) prolongs survival in men with mCRPC in pre- and post chemotherapy setting. Commonly used prostate-specific antigen (PSA) may lead to non-straightforward prognosis. This is especially true for bone mCRPC (bmCRPC) in which initial bone-flare may add to difficult decision making. During other therapies, bouncing of alkaline phosphatase (ALP-Bounce) was shown as a promising surrogate for survival outcome. The purpose of this study was to evaluate the prognostic ability of ALP-Bounce compared to standard PSA and lactate dehydrogenase (LDH) after initiation of Enza. Methods: Patients with bmCRPC were included and analyzed. PSA, LDH and ALP were monitored at 2, 4, 8 and 12 weeks under very early Enza treatment. ALP-Bounce vs. no Bounce was analyzed using Kaplan-Meier estimates and uni- and multivariate (UV/MV) cox-regression models. ALP-Bounce was defined as an increase of ALP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. Results: Eighty-nine men were evaluable for analysis. The median overall survival (OS) of men with ALP-Bounce was 19 months (95% confidence interval: 7.9-30.1) compared to 12 months (7.7-16.3) for no Bounce. Analysis of progression-free survival (PFS) showed similar results with 8 (0-16.3) vs. 3 months (1.9-4.1). In UV no ALP-Bounce (Hazard Ratio (HR): 1.9 (1.1-3.3); p = 0.02), no PSA-decline ≥50% (HR: 2.3 (1.5-3.7); p < 0.01) and no LDH-Normalization (HR: 2.5 (1.6-4.1); p < 0.01) were significantly associated with worse PFS. In MV only no ALP-Bounce showed a trend towards worse PFS (HR: 2.1 (0.9-4.5); p = 0.09). In UV no LDH-normalization was a significant prognosticator of poor OS (HR: 2.6 (1.6-4.2); p < 0.01) while ALP-Bounce and PSA decline ≥50% were non-prognostic. In MV no LDH-normalization remained an independent prognosticator of poor OS (HR: 2.0 (1.1.-3.5); p = 0.02). Conclusions: ALP-Bounce and LDH-Normalization may add to identification of bmCRPC-patients with favorable prognosis during early therapy with Enza. The early occurence of ALP-Bounce might be beneficial. These results have to be validated in a prospective trial.
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