Search

Introduction:We sought to demonstrate how an implementation science framework can be used to increase rates of postoperative intravesical chemotherapy with gemcitabine in patients with low-...

Background Markers of stromal activation at future metastatic sites may have prognostic value and may allow clinicians to identify and abolish the pre-metastatic niche to prevent metastasis. In this study, we evaluate tenascin-C as a marker of pre-metastatic niche formation in bladder cancer patient lymph nodes. Methods Tenascin-C expression in benign lymph nodes was compared between metastatic (n = 20) and non-metastatic (n = 27) patients with muscle-invasive bladder cancer. Urinary extracellular vesicle (EV) cytokine levels were measured with an antibody array to examine potential correlation with lymph node inflammation. The ability of bladder cancer EVs to activate primary bladder fibroblasts was assessed in vitro. Results Lymph node tenascin-C expression was elevated in metastatic patients vs. non-metastatic patients, and high expression was associated with worse survival. Urinary EVs contained four cytokines that were positively correlated with lymph node tenascin-C expression. Bladder cancer EVs induced tenascin-C expression in fibroblasts in an NF-κB-dependent manner. Conclusions Tenascin-C expression in regional lymph nodes may be a good predictor of bladder cancer metastasis and an appropriate imaging target. It may be possible to interrupt pre-metastatic niche formation by targeting EV-borne tumour cytokines or by targeting tenascin-C directly.

BACKGROUND: Our goal is to review current literature regarding active surveillance (AS) of small renal masses (SRMs) and identify trends in survival outcomes, factors that predict the need for further intervention, and quality of life (QOL). METHODS: We performed a comprehensive literature search in PubMed and EMBASE and identified 194 articles. A narrative summary was performed in lieu of a meta-analysis due to the heterogeneity of selected studies. RESULTS: Seventeen articles were chosen to be featured in this review. Growth rate (GR) was not an accurate predictor of malignancy, although it was the characteristic most commonly used to trigger delayed intervention (DI). The mean 5-year overall survival (OS) of all studies was 73.6% ±1.7% for AS groups. The combined cancer specific survival (CSS) for AS is 97.1% ±0.6%, compared to 98.6% ±0.4% for the primary intervention (PI) groups, (p = 0.038). CONCLUSIONS: Short and intermediate-term data demonstrate that AS with the option for DI is a management approach whose efficacy (in terms of CSS) approaches that of PI at 5 years, is cost effective, and prevents overtreatment, especially in patients with significant comorbidities.

Purpose About 40% of men diagnosed with prostate cancer (Pca) are ≤65 years of age. This study evaluates the risk of second cancer among young Pca patients treated with surgery or radiation. Materials and methods This is a retrospective review of 150,915 men aged ≤65 years at Pca diagnosis treated with surgery or radiation registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2014. Incidence rates of second rectum/rectosigmoid junction (RJ), bladder, and lung cancer in each treatment group were reported with adjustment for potential confounders. Cumulative incidence functions were used to summarize the risk of second cancer after completing initial treatment. Results Men treated with external beam radiation (BEAM), brachytherapy (SEED), or combined radiation all exhibited a statistically significant increased incidence of second bladder cancer compared to men treated with surgery (adjusted incidence rate ratio [IRR]: 2.09, 1.91, and 2.04, respectively). Incidence of rectum/RJ cancer was also significantly increased in men receiving BEAM and combined radiation (adjusted IRR: 1.58 and 1.98, respectively). There were also significant differences in the cumulative incidence of second bladder cancer after receiving any form of radiation compared to surgery. Conclusion Pca survivors ≤65 years of age at Pca diagnosis had an increased risk of second bladder and rectum/RJ cancer after BEAM and combined radiation treatment after adjusting for confounding factors. Second bladder cancer incidence after either form of radiation treatment was increased even at 5 years after a Pca diagnosis.

Nonmuscle invasive bladder cancer (NMIBC) has an elevated risk of recurrence, and immediate postresection intravesical instillation of chemotherapy (IVC) significantly reduces the risk of recurrence. Questions remain about which subpopulation may maximally benefit from IVC. Our aim was to develop risk groups based on recurrence risk in NMIBC, and then evaluate the impact of a single, postoperative instillation of IVC on the subsequent risk of recurrence for each risk group.Using the SWOG S0337 trial cohort, we performed a posthoc analysis of 345 patients who were diagnosed with suspected low-grade NMIBC, underwent transurethral resection of the bladder tumor (TURBT), and received post-operative IVC (gemcitabine vs. saline). Using regression tree analysis, the regression tree stratified patients based on their risk of recurrence into low-risk - single tumor and aged57 years, intermediate-risk - single tumor and aged ≥ 57 years, and high-risk - multiple tumors. We used Cox proportional hazard models to test the impact of recurrence-free rate, and after adjustment to available covariates.Median age of the cohort was 66.5 (IQR: 59.7-75.8 years) with 85% of patients being males. Median overall follow-up time was 3.07 years (IQR: 0.75-4.01 years). When testing the impact of treatment in each risk group separately, we found that patients in the intermediate-risk treated with gemcitabine had a 24-month recurrence free rate of 77% (95% CI: 68%-86%) vs. 59% (95% CI: 49%-70%) in the saline group. This survival difference was confirmed on multivariable analysis (hazard ratio: 0.39, 95% CI: 23%-66%, P0.001). This group represented 53% of our cohort. Conversely, we did not observe a significant difference in recurrence-free survival among patients in the low- (P = 0.7) and high-risk (P = 0.4) groups.Our findings indicate that older patients with a single tumor of suspected low-grade NMIBC at TURBT maximally benefit from immediate postresection IVC (gemcitabine).

Systemic therapy is the mainstay of treatment for metastatic urothelial carcinoma (UC). Responses to first-line platinum-based therapy tend to be short-lived with potential toxicity. Despite the approval of checkpoint inhibitors, the long-term prognosis for patients with metastatic UC remains dismal. Herein we report the case of a patient with a solitary pulmonary metastatic lesion of urothelial origin as the only site of metastatic disease who remained free of disease for more than 2 years without systemic therapy after metastasectomy. We review the literature discussing the role of combined surgical and medical management of oligometastatic UC. As our case illustrates, a growing body of evidence suggests a potential role for a multimodal approach in patients with oligometastatic UC.

BACKGROUND: Surveillance regimens for non-muscle invasive bladder cancer (NMIBC) are disparate and controlled trials could inform guidelines. The feasibility of randomizing patients to variable frequency surveillance is unknown. OBJECTIVES: To determine patient willingness to randomization to high frequency (HF) versus low frequency (LF) surveillance regimen for NMIBC and compare patient comfort and healthcare costs across regimens. METHODS: A non-blinded, two-arm, randomized-controlled study of patients with low or low-intermediate risk NMIBC was conducted at two institutions where patients were offered randomization to HF vs. LF surveillance following initial tumor resection. The HF group underwent cystoscopy every three months for 2 years, then every 6 months for 2 years, then annually. The LF group underwent cystoscopy at 9 months following the 3-month cystoscopy, then annually. Assuming 75% of patients approached would agree to enrollment, a sample size of n = 35 patients per arm provided a one-sided 95% exact Clopper-Pearson confidence lower-limit of 60%. RESULTS: Of 70 patients approached, 45 (64.3%) agreed to participate and 25 (35.7%) declined enrollment due to preference for HF. Twelve biopsies were performed, including 4 (19%) of 21 patients in the HF group and 8 (33.3%) of 24 patients in the LF group. Disease recurrence (low grade Ta) was observed in 3 (14.3%) and 5 (20.8%) patients in the HF and LF groups, respectively. No patients experienced high grade recurrence or progression. Both groups had similar patient-reported procedure-related discomfort and quality of life measures over time. Patient out-of-pocket cost and healthcare systems costs were $383.80 more per patient annually in the HF group. CONCLUSIONS: Randomization to variable frequency surveillance is challenging as over a third of patients declined participation. However, these data provide important preliminary insights into the potential effects of surveillance frequency on oncologic and economic outcomes in patients with low and low-intermediate risk bladder cancer.

INTRODUCTION AND OBJECTIVE:Renal cell carcinoma (RCC) represents the sixth most frequently diagnosed cancer in men and the 10th in women worldwide, accounting for 5% and 3% of all oncological diagn...

INTRODUCTION AND OBJECTIVE:Extracellular vesicles (EV) comprise a diverse group of small vesicles secreted by almost all types of cells into the extracellular space. EV have been shown to play cruc...

INTRODUCTION AND OBJECTIVE:Upper tract urothelial carcinoma (UTUC) can be a multifocal disease and recurrence may involve the contralateral upper tract in 2-6% of cases. Intravesical mitomycin-C (M...

INTRODUCTION AND OBJECTIVE:Kidney cancer accounts for at least 3% of malignant diseases, and the incidence and mortality appear to be rising. Recent studies indicated that the estrogen receptor bet...

INTRODUCTION AND OBJECTIVE:Prostate cancer (PCa) remains one of the most prevalent male cancers in the United States, with over an estimated 26,000 cancer deaths annually. Presently, androgen depri...

INTRODUCTION AND OBJECTIVE:Kidney stone is a common disorder that poses a significant health care burden. The incidence of kidney stone disease is lower in premenopausal women than age-matched men,...

INTRODUCTION AND OBJECTIVE:Non-muscle invasive bladder cancer (NMIBC) exhibits a high recurrence rate and tumor multifocality, placing significant financial and psychological burden on patients. Ex...

Single center studies have shown that positive UroVysion® fluorescence in situ hybridization results were associated with recurrence of nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. Our goal was to validate these findings.We performed a prospective, multicenter diagnostic trial to determine whether the fluorescence in situ hybridization test could predict recurrence or progression in patients with primary high grade nonmuscle invasive bladder cancer who were scheduled to receive bacillus Calmette-Guérin. Fluorescence in situ hybridization testing was performed prior to the first bacillus Calmette-Guérin instillation, prior to the sixth instillation and at 3-month cystoscopy. The performance of fluorescence in situ hybridization was evaluated.A total of 150 patients were enrolled in analysis, including 68 with Ta disease, 41 with T1 disease, 26 with carcinoma in situ alone and 15 with papillary carcinoma plus carcinoma in situ. At 9 months of followup there were 46 events, including 37 recurrences and 9 progressions. For events with positive fluorescence in situ hybridization findings the HR was 2.59 (95% CI 1.42-4.73) for the baseline test, 1.94 (95% CI 1.04-3.59) for the 6-week test and 3.22 (95% CI 1.65-6.27) at 3 months. Patients with positive results at baseline, 6 weeks and 3 months had events 55% of the time and patients with negative results at each time point had no event 76% of the time.The study validated that a positive UroVysion fluorescence in situ hybridization test was associated with a 3.3-fold increased risk of recurrence. The test may be useful to risk stratify patients entering clinical trials in whom induction therapy fails. However, using the test to change management decisions is limited due to the discordance between results and outcomes as well as the variance of tests results with time.

While androgens may function via nuclear androgen receptor (nAR) to increase bladder cancer (BCa) progression, the impact of androgens on muscle invasive BCa, which contains nearly 80% nAR-negative cells, remains unclear. To dissect the androgens potential impacts on these nAR-negative muscle invasive BCa, we first found that the androgens, dihydrotestosterone (DHT) might function via a novel membrane AR (mAR-SLC39A9) to increase nAR-negative BCa cell migration and invasion. Mechanism dissection revealed that DHT/mAR-SLC39A9 might function by altering Gαi protein-mediated MAPK/MMP9 intracellular signaling to increase nAR-negative BCa cell migration and invasion. Preclinical studies using multiple in vitro nAR-negative BCa cell lines and an in vivo mouse model all demonstrated that targeting this newly identified DHT/mAR-SLC39A9/Gαi/MAPK/MMP9 signaling with small molecules mAR-SLC39A9-shRNA or Gαi-shRNA, and not the classic antiandrogens including enzalutamide, bicalutamide, or hydroxyflutamide, could suppress nAR-negative BCa cell invasion. Results from human clinical samples surveys also indicated the positive correlation of this newly identified DHT/mAR signaling with BCa progression and prognosis. Together, these results suggest that androgens may not only function via the classic nAR to increase the nAR-positive BCa cell invasion, they may also function via this newly identified mAR-SLC39A9 to increase the nAR-negative/mAR-positive BCa cell invasion.

PURPOSE To validate currently used recurrence prediction models for renal cell carcinoma (RCC) by using prospective data from the ASSURE (ECOG-ACRIN E2805; Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma) adjuvant trial. PATIENTS AND METHODS Eight RCC recurrence models (University of California at Los Angeles Integrated Staging System [UISS]; Stage, Size, Grade, and Necrosis [SSIGN]; Leibovich; Kattan; Memorial Sloan Kettering Cancer Center [MSKCC]; Yaycioglu; Karakiewicz; and Cindolo) were selected on the basis of their use in clinical practice and clinical trial designs. These models along with the TNM staging system were validated using 1,647 patients with resected localized high-grade or locally advanced disease (≥ pT1b grade 3 and 4/pTanyN1Mo) from the ASSURE cohort. The predictive performance of the model was quantified by assessing its discriminatory and calibration abilities. RESULTS Prospective validation of predictive and prognostic models for localized RCC showed a substantial decrease in each of the predictive abilities of the model compared with their original and externally validated discriminatory estimates. Among the models, the SSIGN score performed best (0.688; 95% CI, 0.686 to 0.689), and the UISS model performed worst (0.556; 95% CI, 0.555 to 0.557). Compared with the 2002 TNM staging system (C-index, 0.60), most models only marginally outperformed standard staging. Importantly, all models, including TNM, demonstrated statistically significant variability in their predictive ability over time and were most useful within the first 2 years after diagnosis. CONCLUSION In RCC, as in many other solid malignancies, clinicians rely on retrospective prediction tools to guide patient care and clinical trial selection and largely overestimate their predictive abilities. We used prospective collected adjuvant trial data to validate existing RCC prediction models and demonstrate a sharp decrease in the predictive ability of all models compared with their previous retrospective validations. Accordingly, we recommend prospective validation of any predictive model before implementing it into clinical practice and clinical trial design.

Background The current chemotherapy regimens may extend survival for patients with metastatic bladder cancer (BCa) for a few months, but eventually most patients succumb to disease because they develop resistance to their chemotherapy. Methods TCGA human clinical sample survey and urothelial tumor tissue microarrays (TMAs) were applied to investigate the expression of androgen receptor (AR) and NF-κB. Multiple BCa cell lines were used to test chemotherapy’s efficacy via multiple assays including XTT, flow cytometry, TUNEL, and BrdU incorporation. The effects of the AR degradation enhancer, ASC-J9®, combined with various chemotherapy reagents were examined both in vivo and in vitro. Results We unexpectedly found that in muscle-invasive BCa (miBCa) the signals of both the AR and NF-κB were increased via a TCGA sample survey. Results from multiple approaches revealed that targeting these two increased signals by combining various chemotherapeutic agents, including Cisplatin, Doxorubicin or Mitomycin C, with ASC-J9® led to increase the therapeutic efficacy. The combined therapy increases the expression of the pro-apoptosis BAX gene and cell cycle inhibitor p21 gene, yet suppresses the expression of the pro-survival BCL2 gene in miBCa cells. Preclinical studies using an in vivo mouse model with xenografted miBCa cells confirmed in vitro cell line data showing that treatment with ASC-J9® combined with Cisplatin can result in suppressing miBCa progression better than Cisplatin alone. Conclusions Together, these results support a novel therapeutic approach via combining Cisplatin with ASC-J9® to better suppress the progression of miBCa. Electronic supplementary material The online version of this article (10.1186/s13046-019-1258-0) contains supplementary material, which is available to authorized users.

Background Multiparametric magnetic resonance imaging (mpMRI) for prostate cancer detection without careful patient selection may lead to excessive resource utilization and costs. Objective To develop and validate a clinical tool for predicting the presence of high-risk lesions on mpMRI. Design, setting, and participants Four tertiary care centers were included in this retrospective and prospective study (BiRCH Study Collaborative). Statistical models were generated using 1269 biopsy-naive, prior negative biopsy, and active surveillance patients who underwent mpMRI. Using age, prostate-specific antigen, and prostate volume, a support vector machine model was developed for predicting the probability of harboring Prostate Imaging Reporting and Data System 4 or 5 lesions. The accuracy of future predictions was then prospectively assessed in 214 consecutive patients. Outcome measurements and statistical analysis Receiver operating characteristic, calibration, and decision curves were generated to assess model performance. Results and limitations For biopsy-naive and prior negative biopsy patients (n = 811), the area under the curve (AUC) was 0.730 on internal validation. Excellent calibration and high net clinical benefit were observed. On prospective external validation at two separate institutions (n = 88 and n = 126), the machine learning model discriminated with AUCs of 0.740 and 0.744, respectively. The final model was developed on the Microsoft Azure Machine Learning platform (birch.azurewebsites.net). This model requires a prostate volume measurement as input. Conclusions In patients who are naive to biopsy or those with a prior negative biopsy, BiRCH models can be used to select patients for mpMRI. Patient summary In this multicenter study, we developed and prospectively validated a calculator that can be used to predict prostate magnetic resonance imaging (MRI) results using patient age, prostate-specific antigen, and prostate volume as input. This tool can aid health care professionals and patients to make an informed decision regarding whether to get an MRI.

To provide a comprehensive overview and update of the Joint Societe Internationale d’Urologie–International Consultation on Urological Diseases (SIU–ICUD) Consultation on Bladder Cancer for muscle-invasive presumably node-negative bladder cancer (MIBC). Contemporary literature was analyzed for the latest evidence in treatment options, outcomes, including radical surgery, neoadjuvant and adjuvant treatment modalities, and bladder-sparing approaches. An international multi-disciplinary expert panel evaluated and graded the data according to guidelines from the Oxford Centre for Evidence-Based Medicine. Radical cystectomy (RC) is the standard of care for MIBC patients considered to be surgical candidates. While associated with substantial morbidity and mortality, this has been mitigated with improved technique, minimally invasive technology, and better perioperative care pathways (e.g., enhanced recovery after surgery). Neoadjuvant (NA) cisplatin-based combination chemotherapy improves overall survival and should be offered to eligible ≥ cT2N0 patients. Adjuvant (Adj) cisplatin-based combination chemotherapy may be considered, particularly for pT3–4 and/or pN+ disease without prior NA chemotherapy. Trimodal bladder-preserving treatment via maximum transurethral resection of bladder tumor followed by concurrent chemoradiation is safe and, when combined with early salvage RC for recurrence, offers long-term survival rates in selected patients comparable to RC. Immunotherapy is still experimental and is given either alone or in combination with chemotherapy and/or radiation. A multi-disciplinary approach is paramount to achieving optimal outcomes for MIBC patients, irrespective of their age, performance and nutritional status, fitness/frailty, renal and other organ function, or disease severity.

PURPOSE/OBJECTIVE(S) Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) near AGT associated with late hematuria following radiotherapy (RT) for prostate cancer. AGT encodes angiotensinogen and, in pre-clinical models, angiotensin pathway inhibition protects against late radiation toxicity in some tissues. Effects on the bladder have not been investigated. We tested the hypothesis that angiotensin converting enzyme inhibitors (ACEi) reduce risk of late hematuria following RT. We additionally investigated the effect of genetically-defined hypertension on hematuria. MATERIALS/METHODS Prostate cancer patients (N = 268) undergoing curative RT (alone or with surgery and/or androgen deprivation therapy) were enrolled from each of two cancer centers pre-RT and followed prospectively for development of hematuria for up to four years using patient reported outcome questionnaires. Hematuria was defined as gross bleeding or medication use for hematuria. Demographic, treatment, and medication data were abstracted from medical records. The cumulative probability of hematuria was estimated by Kaplan-Meier methods, and the log rank test assessed differences by ACEi/ARB, use stratified by enrollment center. Multivariable analyses used Cox models of time to onset of hematuria stratified by enrollment center. A polygenic risk score (PRS) comprising 882 SNPs previously associated with blood pressure was tested for association with time to onset of hematuria in our Radiogenomics Consortium GWAS cohorts (N = 3,608). RESULTS The cumulative probability of hematuria among all participants was 17.1% (N = 19) at four years (median follow-up of two years). Hematuria was seen in 1.4% of those taking vs 22.9% in those not taking ACEi (P = 0.01) at the start of RT, resulting in a hazard ratio (HR) of 0.11 (95% CI 0.01 to 0.83). The protective effect of ACEi on hematuria remained when adjusted for factors associated with ACEi use, including body mass index, hypertension, or diabetes. The protective effect also remained after stratifying by risk factors for hematuria, including prior transurethral prostate resection, smoking status, or prior prostatectomy. A blood pressure PRS was strongly associated with hypertension (odds ratio per standard deviation 1.40, 95% CI 1.30 to 1.50, P < 0.001) but not with hematuria (HR per standard deviation 0.97, 95% CI 0.87 to 1.07, P = 0.52). CONCLUSION Our study is the first to show a radioprotective effect of ACEi on bladder toxicity. This effect appears distinct from presence of hypertension, which is not itself a risk factor. These results point to a promising radioprotector readily available for testing in a randomized clinical trial. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects normal tissues to reduce RT toxicity.

Purpose/Objective(s) Pathological T2-4 N1 M0 prostate cancer (Pca) has a heterogeneous natural history. So far, only one randomized control trial has established the current standard of care of immediate androgen deprivation (ADT) after prostatectomy and lymph node dissection. The role of pelvic radiation (RT) for this cohort of patients remains unknown. The purpose of this study is to perform a retrospective review of our institutional experience to provide much-needed information that may improve the outcome of these very high-risk patients. Materials/Methods We identified patients with pT2-4 N1 M0 disease treated in our institution from 2006 to 2016. We reviewed ADT and RT records in addition to patient and disease characteristics. Kaplan-Meier analyses were utilized to evaluate overall survival (OS) and progression-free survival (PFS, defined as either biochemical or clinical evidence of disease recurrence). Results We identified a total of 94 patients with pT2-4N1M0 Pca with patient demographic and disease characteristics shown in the table. A total of 72 patients had postoperative RT with a median follow-up of 85.9 months (range 15 to 175 months). Among patients receiving RT, 54/72 (75%) received ADT concurrently (median duration of 24 months, range 4 -36 months). The median time from prostatectomy to RT initiation was 6 months (range 3-90 months). RT of 7 patients was initiated after PSA progression. For patients without RT, 15/22 (68%) received ADT (median duration of 24 months, range 3 to 96 months); the median follow-up was 91 months (range 9 to 164 months). The estimated 5-year OS for patients with RT and without RT were 100% and 85.7%, respectively (P = 0.04). The estimated 5-year PFS for patients with RT and without RT were 80.9% and 62.8%, respectively (P = 0.19). Among patients who received ADT, the estimated 5-year PFS was 82.3% with RT and 63.8% without RT, respectively (P = 0.26). Conclusion For a select group of patients with pT2-4N1M0 Pca, postoperative pelvic RT in combination with ADT appeared to have prolonged OS. Further investigation to stratify this group of patients, and ultimately prospective clinical trials to establish the effectiveness of combined pelvic RT and systemic treatment is needed for this cohort of high-risk patients.

Background Risk stratification for localized renal cell carcinoma (RCC) relies heavily on retrospective models, limiting their generalizability to contemporary cohorts. Objective To introduce a contemporary RCC prognostic model, developed using prospective, highly annotated data from a phase III adjuvant trial. Design, setting, and participants The model utilizes outcome data from the ECOG-ACRIN 2805 (ASSURE) RCC trial. Outcome measurements and statistical analysis The primary outcome for the model is disease-free survival (DFS), with overall survival (OS) and early disease progression (EDP) as secondary outcomes. Model performance was assessed using discrimination and calibration tests. Results and limitations A total of 1735 patients were included in the analysis, with 887 DFS events occurring over a median follow-up of 9.6 yr. Five common tumor variables (histology, size, grade, tumor necrosis, and nodal involvement) were included in each model. Tumor histology was the single most powerful predictor for each model outcome. The C-statistics at 1 yr were 78.4% and 81.9% for DFS and OS, respectively. Degradation of the DFS, DFS validation set, and OS model's discriminatory ability was seen over time, with a global c-index of 68.0% (95% confidence interval or CI [65.5, 70.4]), 68.6% [65.1%, 72.2%], and 69.4% (95% CI [66.9%, 71.9%], respectively. The EDP model had a c-index of 75.1% (95% CI [71.3, 79.0]). Conclusions We introduce a contemporary RCC recurrence model built and internally validated using prospective and highly annotated data from a clinical trial. Performance characteristics of the current model exceed available prognostic models with the added benefit of being histology inclusive and TNM agnostic. Patient summary Important decisions, including treatment protocols, clinical trial eligibility, and life planning, rest on our ability to predict cancer outcomes accurately. Here, we introduce a contemporary renal cell carcinoma prognostic model leveraging high-quality data from a clinical trial. The current model predicts three outcome measures commonly utilized in clinical practice and exceeds the predictive ability of available prognostic models.

Background Intermediate risk prostate cancer represents a largely heterogeneous group with diverse disease extent. We sought to establish rates of adverse pathological features important for radiation planning by analyzing surgical specimens from men with intermediate risk prostate cancer who underwent immediate radical prostatectomy, and to define clinical pathologic features that may predict adverse outcomes. Materials and methods A total of 1552 men diagnosed with intermediate risk prostate cancer who underwent immediate radical prostatectomy between 1/1/2005 and 12/31/2015 were reviewed. Inclusion criteria included available preoperative PSA level, pathology reports of transrectal ultrasound-guided prostate biopsy, and radical prostatectomy. Incidences of various pathological adverse features were evaluated. Patient characteristics and clinical disease features were analyzed for their predictive values. Results Fifty percent of men with high risk features (defined as PSA >10 but Conclusion Our findings underscore the importance of comprehensive staging beyond PSA level, prostate biopsy, and CT/bone scan for men with intermediate risk prostate cancer proceeding with radiation in the era of highly conformal treatment.

INTRODUCTION AND OBJECTIVE: High recurrence rates found in non-muscle invasive bladder cancer (NMIBC) pose a financial and psychological burden for patients. We demonstrated that bladder cancer (BC) cells release protein disulfide isomerase (PDI), a redox-regulated ER-resident protein, via extracellular vesicles (EVs) when experiencing high levels of ER stress for their own survival. Chronic exposure to PDI-enriched BC EVs induced malignant transformation in recipient non-transformed cells. We hypothesized that the dynamic redox state in BC cells determines PDI cellular localization and tumors with elevated PDI preferentially incorporate PDI into EVs for removal. Furthermore, PDI expression levels and subcellular localization in tumors from NMIBC patients may predict NMIBC recurrence. METHODS: Retrospective chart review identified 122 patients with newly diagnosed low-grade NMIBC classified into 2 groups: recurrent (N=55) and non-recurrent (N=67) during follow-up period. Formalin fixed paraffin embedded tumor specimens from index transurethral resection of bladder tumor (TURBT) were obtained and a tissue microarray (TMA) was constructed. Immunofluorescent staining of TMA sections was conducted using antibodies against PDI and BiP, an ER stress marker. Stained tissues were photographed and tumor regions in each field were manually masked and confirmed by a genitourinary pathologist. Within each tumor region, total antibody labeling was determined by measuring the mean pixel intensity values with NIH ImageJ/Fiji. Manders coefficient was used to assess the colocalization of epitopes using JACoP plugin in ImageJ. RESULTS: Tumor tissues from patients that recurred expressed significantly higher levels of PDI and BiP. Moreover, high PDI and BiP expression predicted worse recurrence-free survival. These data suggest that tissues under higher levels of ER stress—as indicated by higher levels of PDI and BiP expression—have a higher risk of recurrence. Significantly higher levels of PDI were detected in non-ER cytosol in recurrent cohort tumors. CONCLUSIONS: This study provides a novel mechanism for BC recurrence and valuable clinical predictive biomarkers for NMIBC recurrence and progression. Future clinical applications targeting this pathway may be an avenue to prevent NMIBC recurrence. Citation Format: Kit L. Yuen, Chia-Hao Wu, Christopher R. Silvers, Alexis R. Steinmetz, Hiroshi Miyamoto, Edward M. Messing, Yi-Fen Lee. Protein disulfide isomerase as a predictive biomarker for non-muscle invasive bladder cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 517.

BackgroundRadical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream.MethodsThe number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined.ResultsThe results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form.ConclusionCollectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.

INTRODUCTION AND OBJECTIVE:Increasing evidence suggests that inflammation and stromal activation at pre-metastatic sites constitute a niche that supports the colonization and outgrowth of dissemina...