Elevated Pre-Treatment Serum MMP-7 Levels Are Associated with the Presence of Metastasis and Poor Survival in Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making

Soluble Syndecan-1 Levels Are Associated with Survival in Platinum-Treated Bladder Cancer Patients

Cisplatin-containing chemotherapy represents the first-line treatment for patients with locally advanced or metastatic muscle-invasive bladder cancer. Recently, novel therapies have become available for cisplatin-ineligible or -resistant patients. Therefore, prediction of cisplatin response is required to optimize therapy decisions. Syndecan-1 (SDC1) tissue expression and serum concentration may be associated with cisplatin resistance. Thus, pre-treatment serum levels of SDC1 and its expression in chemo-naïve tissues were assessed in 121 muscle-invasive bladder cancer patients who underwent postoperative platinum-based chemotherapy. SDC1 concentrations were evaluated by ELISA in 52 baseline and 90 follow-up serum samples and tissue expressions were analyzed by immunohistochemistry in an independent cohort of 69 formalin-fixed paraffin-embedded tumor samples. Pre-treatment SDC1 serum levels were significantly higher in lymph node metastatic (p = 0.009) and female patients (p = 0.026). SDC1 tissue expression did not correlate with clinicopathological parameters. High pre-treatment SDC1 serum level and the presence of distant metastasis were independent risk factors for overall survival (Hazard ratio (HR): 1.439, 95% Confidence interval (CI): 1.003–2.065, p = 0.048; HR: 2.269, 95%CI: 1.053–4.887, p = 0.036). Our results demonstrate an independent association between high baseline serum SDC1 concentration and poor survival in platinum-treated patients. Analyzing baseline serum SDC1 levels may help to predict platinum-containing chemotherapy and could help to optimize therapeutic decision-making

MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity

High Serum PD-L1 Levels Are Associated with Poor Survival in Urothelial Cancer Patients Treated with Chemotherapy and Immune Checkpoint Inhibitor Therapy

SIMPLE SUMMARY: Advanced urothelial bladder cancer (BC) shows a heterogeneous response to both platinum and immune checkpoint inhibitor (ICI) therapies. The PD-1/PD-L1 signaling pathway represents an immune escape mechanism and tissue PD-L1 expression was shown to be associated with patients’ prognosis and therapy response in various solid tumors. In the present study, we found for the first time that higher pretreatment serum PD-L1 levels are associated with shorter survival in platinum- and ICI-treated BC patients. ABSTRACT: Serum PD-L1 (sPD-L1) levels are associated with prognosis in various tumors but has not yet been investigated in advanced bladder cancer. We assessed pretreatment serum samples from 83 BC patients who received platinum chemotherapy and from 12 patients who underwent immune checkpoint inhibitor (ICI) therapy. In addition, on-treatment samples from further therapy cycles were collected during chemotherapy (n = 58) and ICI therapy (n = 11). Serum PD-L1 levels were determined using ELISA. High baseline sPD-L1 levels were associated with worse ECOG status (p = 0.007) and shorter overall survival for both chemotherapy- and ICI-treated patients (p = 0.002 and p = 0.040, respectively). Multivariate analysis revealed high baseline sPD-L1 level as an independent predictor of poor survival for platinum-treated patients (p = 0.002). A correlation analysis between serum concentrations of PD-L1 and matrix metalloprotease-7 (MMP-7)—a protease which was recently found to cleave PD-L1—revealed a positive correlation (p = 0.001). No significant sPD-L1 changes were detected during chemotherapy, while in contrast we found a strong, 25-fold increase in sPD-L1 levels during atezolizumab treatment. In conclusion, our work demonstrates that pretreatment sPD-L1 levels are associated with a poor prognosis of BC patients undergoing platinum and ICI therapy. Future research should prospectively address the value of sPD-L1 in predicting treatment response

Is an Endorectal Balloon Beneficial for Rectal Sparing after Spacer Implantation in Prostate Cancer Patients Treated with Hypofractionated Intensity-Modulated Proton Beam Therapy? A Dosimetric and Radiobiological Comparison Study

Background: The aim of this study is to examine the dosimetric influence of endorectal balloons (ERB) on rectal sparing in prostate cancer patients with implanted hydrogel rectum spacers treated with dose-escalated or hypofractionated intensity-modulated proton beam therapy (IMPT). Methods: Ten patients with localized prostate cancer included in the ProRegPros study and treated at our center were investigated. All patients underwent placement of hydrogel rectum spacers before planning. Two planning CTs (with and without 120 cm3 fluid-filled ERB) were applied for each patient. Dose prescription was set according to the h strategy, with 72 Gray (Gy)/2.4 Gy/5× weekly to prostate + 1 cm of the seminal vesicle, and 60 Gy/2 Gy/5× weekly to prostate + 2 cm of the seminal vesicle. Planning with two laterally opposed IMPT beams was performed in both CTs. Rectal dosimetry values including dose-volume statistics and normal tissue complication probability (NTCP) were compared for both plans (non-ERB plans vs. ERB plans). Results: For ERB plans compared with non-ERB, the reductions were 8.51 ± 5.25 Gy (RBE) (p = 0.000) and 15.76 ± 11.11 Gy (p = 0.001) for the mean and the median rectal doses, respectively. No significant reductions in rectal volumes were found after high dose levels. The use of ERB resulted in significant reduction in rectal volume after receiving 50 Gy (RBE), 40 Gy (RBE), 30 Gy (RBE), 20 Gy (RBE), and 10 Gy (RBE) with p values of 0.034, 0.008, 0.003, 0.001, and 0.001, respectively. No differences between ERB and non-ERB plans for the anterior rectum were observed. ERB reduced posterior rectal volumes in patients who received 30 Gy (RBE), 20 Gy (RBE), or 10 Gy (RBE), with p values of 0.019, 0.003, and 0.001, respectively. According to the NTCP models, no significant reductions were observed in mean or median rectal toxicity (late rectal bleeding ≥ 2, necrosis or stenosis, and late rectal toxicity ≥ 3) when using the ERB. Conclusion: ERB reduced rectal volumes exposed to intermediate or low dose levels. However, no significant reduction in rectal volume was observed in patients receiving high or intermediate doses. There was no benefit and also no disadvantage associated with the use of ERB for late rectal toxicity, according to available NTCP models

Risk factors for ureteroenteric stricture after radical cystectomy and urinary diversion: A systematic review

ABSTRACTIntroduction Ureteroenteric stricture (UES) is the leading cause of renal function deterioration after radical cystectomy (RC) and urinary diversion (UD). The aim of the present review is to summarize studies that discussed the risk factors associated with UES development. Identifying the responsible factors is of importance to help surgeons to modify their treatment or follow-up strategies to reduce this serious complication.Materials and Methods A comprehensive search of the literature using the PubMed database was conducted. The target of the search was only studies that primarily aimed to identify risk factors of UES after RC and UD. References of searched papers were also checked for potential inclusion.Results The search originally yielded a total of 1357 articles, of which only 15 met our inclusion criteria, comprising 13, 481 patients. All the studies were observational, and retrospective published between 2013 and 2022. The natural history of UES and the reported risk factors varied widely across the studies. In 13 studies, a significant association between some risk factors and UES development was demonstrated. High body mass index (BMI) was the most frequently reported stricture risk factor, followed by perioperative urinary tract infection (UTI), robotic-assisted radical cystectomy (RARC), occurrence of post-operative Clavian grade ≥ 3 complications and urinary leakage. Otherwise, many other risk factors were reported only once.Conclusion The literature is still lacking well-designed prospective studies investigating predisposing factors of UES. The available data suggest that the high BMI, RARC and complicated postoperative course are the main risk factors for stricture formation

High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics

Purpose!#!To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [!##!Methods!#!Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [!##!Results!#!The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [!##!Conclusion!#!Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC