Uveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic... Show moreUveal melanoma (UM) is a rare ocular tumor. Up to 50% of the patients develop distant metastases predominantly targeting the liver. The median survival after diagnosis of patients with hepatic metastases is approximately 4-6 months and hardly increased in the past decades due to lack of novel effective therapeutic options. Within the scope of this thesis we investigated the signaling landscape of metastatic UM and searched for novel avenues of therapy. In Chapter 2 we demonstrate that combinations of the multitarget drug Trabectedin with either the CK2/Clk double-inhibitor Silmitasertib or with the c-MET/TAM receptor inhibitors show synergistic growth inhibitory effects and induce apoptosis of UM cells in vitro. Chapter 3 describes the application of a CRISPR-Cas9 synthetic lethality screen for identification of molecular targets whose inhibition synergistically enhances the effect of the mTOR inhibitor everolimus in UM cells. In Chapter 4 we show that the combination of genetic depletion YAP1/TAZ together with Mcl-1 inhibition resulted in a synergistic inhibitory effect on the viability of UM cell lines. In Chapter 5 we analyzed the phospho-proteome of two UM metastatic cell lines and a primary tumor cell line from the same individual, and studied the role of MARK3 in YAP1/TAZ signaling. Show less
Purpose The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively... Show morePurpose The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively pooling data from three centers.Materials and Methods Retrospective analysis including patients ( >= 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liverdominant or liver-only metastases from UM. Predictors for OS were assessed using uni- and multivariate analyses. Other study outcome measures were response rate, progression-free survival (PFS), liver progression-free survival (LPFS), overall survival (OS) and complications according to CTCAEv5.0.Results In total, 101 patients (47.5% males; median age 59.0 years) completed a minimum of one M-PHP. At a median follow-up time of 15.0 months, complete response (CR), partial response (PR), stable disease (SD) and progressive disease were seen in five (5.0%), 55 (54.5%), 30 (29.7%) and 11 (10.9%) patients, respectively, leading to a 89.1% disease control rate. Median PFS, LPFS and OS were 9.0, 11.0 and 20.0 months, respectively. Survival analyses stratified for radiological response demonstrated significant improved survival in patients with CR or PR and SD category. Treatment of the primary tumor with radiotherapy, >= 2 M-PHP and lactate dehydrogenase (LDH) < 248 U/L were correlated with improved OS. Thirty-day mortality was 1.1% (n = 2). Most common complication was hematological toxicity (self-limiting in most cases).Conclusion M-PHP is safe and effective in patients with UM liver metastases. Achieving CR, PR or SD is associated with improved survival. Primary tumor treatment with radiotherapy, normal baseline LDH and > 1 M-PHP cycles are associated with improved OS. Show less
Purpose To evaluate the role of side and location of the primary renal cell carcinoma (RCC) on the risk of lymph node invasion (LNI) and/or nodal progression (NP) during follow-up. Materials and... Show morePurpose To evaluate the role of side and location of the primary renal cell carcinoma (RCC) on the risk of lymph node invasion (LNI) and/or nodal progression (NP) during follow-up. Materials and methods We evaluated 2485 patients with unilateral RCC, surgically treated in a single tertiary care referral center. Outcomes were LNI at surgery and/or NP during follow-up. We studied if RCC side (left vs. right) and location (upper vs. middle vs. hilar vs. lower area vs. more than one area) affected the probability of LNI and/or NP at follow-up. Results Overall, 43 and 15% of patients underwent lymph node dissection and had LNI at surgery, respectively. During follow-up, 2.2% of patients had NP. Higher rates of LNI and NP were observed for patients with primary tumor located in more than one anatomical kidney area relative to patients with tumor in a single area (upper 11% vs. middle 10% vs. hilar 0%, vs. lower 12% vs. more than one area 26%, p < 0.01). cM1, cN1, pT2/pT3/pT4 disease and Fuhrman grade 3/4 were independent predictors of the study outcome (all p <= 0.01). Neither the RCC side nor the location reached the independent predictor status (all p > 0.1). Conclusions Patients with single-side and more than one anatomical kidney area affected by RCC have higher rate of LNI at surgery and/or NP at follow-up. Neither side nor location of primary RCC tumor is related to the risk of harboring LNI at surgery and/or developing NP at follow-up. Show less
Depreitere, B.; Ricciardi, F.; Arts, M.; Balabaud, L.; Buchowski, J.M.; Bunger, C.; ... ; Choi, D. 2018
Background: A recent study of a highly select cohort suggested a survival benefit when local treatment is delivered in patients with metastatic bladder cancer (BCa).Objective: We examined in... Show moreBackground: A recent study of a highly select cohort suggested a survival benefit when local treatment is delivered in patients with metastatic bladder cancer (BCa).Objective: We examined in-hospital mortality (IHM) rates according to the presence, absence, and location of metastatic disease in a similar highly select cohort of BCa patients treated with radical cystectomy (RC).Design, setting, and participants: We used data for 25 004 BCa patients included in the National Inpatients Sample (NIS) database between 1998 and 2013.Intervention: Radical cystectomy.Outcome measurements and statistical analysis: We tested postoperative IHM rates according to the presence of metastases and the location of metastatic disease (exclusive nodal vs distant metastases). Multivariable logistic regression analyses were adjusted for age, gender, race, comorbidities, length of hospitalization, hospital location, teaching status, hospital surgical volume, and bed size.Result and limitations: Among 25 004 BCa patients treated with RC, 3830 (14.4%) had nonregional lymph node metastases (NRNM), 693 (2.8%) had distant metastases (DM), and 19 965 (79.8%) had nonmetastatic disease. Virtually all patients with metastatic BCa had a single metastatic focus (n = 4020; 93.7%). In multivariable logistic regression analyses, DM (odds ratio [OR] 2.31, 95% confidence interval [CI] 1.57-3.28; p < 0.001) but not NRNM (OR 0.88, 95% CI 0.66-1.15; p = 0.4) was associated with higher risk of IHM. The absence of information on preoperative chemotherapy and the retrospective study design may limit our findings.Conclusion: The risk of IHM for highly select individuals with NRNM treated with RC is similar to that for patients with nonmetastatic BCa. Conversely, patients with DM are at higher risk of IHM compared to patients with NRNM.Patient summary: According to existing data, radical cystectomy in the metastatic bladder cancer setting should be limited to patients with nonregional lymph node metastases, if at all indicated. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved. Show less
Moschini, M.; Mattei, A.; Cornelius, J.; Shariat, S.F.; Dell'Oglio, P.; Zaffuto, E.; ... ; Gallina, A. 2018
Growing literature supports good survival expectancies in bladder cancer (BCa) patients affected by clinical node metastases (cN+) treated with multimodal therapy. We evaluated the role of adjuvant... Show moreGrowing literature supports good survival expectancies in bladder cancer (BCa) patients affected by clinical node metastases (cN+) treated with multimodal therapy. We evaluated the role of adjuvant chemotherapy in cN+BCa patients treated with radical cystectomy (RC) and pelvic lymph node dissection (PLND) without neoadjuvant chemotherapy (NAC).We evaluated a total of 192 patients with BCa and cN+. All patients were treated with RC and PLND without NAC between 2001 and 2013. Kaplan-Meier analyses and Cox regression analyses were used to assess the impact of adjuvant chemotherapy (ACT) on recurrence, cancer-specific mortality (CSM) and overall mortality (OM) after surgery.Overall, 99 patients (51.6%) were found without node metastases at RC, while 18 (9.4%), 58 (30.2%) and 17 (8.9%) patients were found pN1, pN2 and pN3, respectively. With a median follow-up of 48 months, in cN+ patients we recorded 5-year recurrence, CSM and OM of 55, 53 and 51%, respectively. Overall, 36 (18.8%) patients were treated with adjuvant chemotherapy. At univariable analyses, ACT was associated with improved overall survival [Hazard ratio (HR): 0.42, confidence interval (CI) 0.20-0.86, p = 0.02) in pN+ subgroup only. These results were confirmed at multivariable analyses, where ACT was associated with improved CSS (HR: 0.45, CI 0.21-0.89, p = 0.03) and OS (HR: 0.37, CI 0.17-0.81, p = 0.01).We report good survival outcomes in cN+ patients treated with RC. The use of ACT after surgery increases survival expectancies, especially in those patients with pathological node disease. Our data need to be further evaluated in prospective setting. Show less
Groenen, K.H.J.; Janssen, D.; Linden, Y.M. van der; Kooloos, J.G.M.; Homminga, J.; Verdonschot, N.; Tanck, E. 2018
