Background and Objectives:Intravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. Methods:Patients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and Limitations:Responders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical Implications:Distinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2 ) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summary:In this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

Intravesical Gemcitabine/Docetaxel (GemDoce) is an effective therapy in patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle-invasive bladder cancer (NMIBC) with 50% response at 2 years. However, the genomic landscape of BCG-unresponsive NMIBC and whether distinct mutations are associated with response and resistance to sequential intravesical GemDoce is unknown. Our goal is to define mutational features of BCG-unresponsive NMIBC and nominate genomic drivers of response and resistance to GemDoce. We identified patients with BCG unresponsive NMIBC who subsequently received intravesical Gem/Doce. We performed whole-exome sequencing of BCG unresponsive bladder tumors (total tumors n=23; Tumor-normal pairs n=3; Tumor-only n=20) prior to GemDoce administration and classified patients in “responders” (recurrence free survival (RFS) > 18 mo) and “non-responders” (RFS < 18 mo). The Broad Institute’s CGA pipeline was used to account for mutation calls, ABSOLUTE was used to define copy number alterations (CNA) and PhylogicNDT was applied to model phylogenetic and evolutionary tumor trajectories. Median follow-up was 45 months. Median time to HG-recurrence and cystectomy were longer in the responder group (33 mo, 28 mo) in comparison to the non-responder group (3.5 mo, 8 mo). We identified alterations in known bladder cancer genes including TP53 (10/20 tumors), KDM6A (9/20 tumors) and FGFR3 (5/20 tumors) in both responders and non-responders. Most alterations in TP53 and KDM6A were predicted loss-of-function mutations, consistent with the known tumor suppressor roles for these genes. Mutations in two genes that control cell division and chromosomal stability, CREBBP and STAG2, were exclusively present in responders to GemDoce. Both responders and non-responders harbor CNA in CDKN2A that characterize NMIBC. However, FGFR3, E2F2 and MDM2 amplifications were exclusively present in non-responders. Phylogenic analysis showed BRCA1 clonal mutations and subclonal BRCA2 mutations only in responders. BCG unresponsive NMIBC harbor mutational features that biologically explain response to GemDoce. Mutations in CREBBP and STAG2, and clonal BRCA1 mutations may sensitize tumors to GemDoce resulting in long-term responses to intravesical chemotherapy. Future efforts should focus on determining the presence of CREBBP and STAG2 using immunohistochemistry prior to GemDoce to improve intravesical treatment response in NMIBC. Matias Vergara, Kendrick Yim, Kevin R. Melnick, Brendan Reardon, Timothy N. Clinton, Matthew Mossanen, Graeme S. Steele, Michelle S. Hirsch, Natalie M. Rizzo, Kent W. Mouw, Matthew F. Wszolek, Keyan Salari, Adam S. Feldman, Adam S. Kibel, Eliezer M. Van Allen, Mark A. Preston, Filipe LF. Carvalho. Dissecting genomic features of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical gemcitabine/docetaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6600.

You have accessJournal of UrologyProstate Cancer: Detection & Screening III (MP31)1 May 2024MP31-13 CLINICOPATHOLOGICAL DIFFERENCES BETWEEN ANTERIORLY LOCATED AND PERIPHERAL ZONE PROSTATIC LESIONS DETECTED ON PROSTATE MULTIPARAMETRIC MAGNETIC RESONANCE IMAGING Clemens An, Constantine Velmahos, Alexandra Hunter, Bahar Piroz, Alfred Barney, Aileen Feng, Douglas Dahl, Michelle Kim, Matthew Wszolek, Keyan Salari, Dimitar Zlatev, Mukesh Harisinghani, Shulin Wu, Chin-Lee Wu, and Adam Feldman Clemens AnClemens An , Constantine VelmahosConstantine Velmahos , Alexandra HunterAlexandra Hunter , Bahar PirozBahar Piroz , Alfred BarneyAlfred Barney , Aileen FengAileen Feng , Douglas DahlDouglas Dahl , Michelle KimMichelle Kim , Matthew WszolekMatthew Wszolek , Keyan SalariKeyan Salari , Dimitar ZlatevDimitar Zlatev , Mukesh HarisinghaniMukesh Harisinghani , Shulin WuShulin Wu , Chin-Lee WuChin-Lee Wu , and Adam FeldmanAdam Feldman View All Author Informationhttps://doi.org/10.1097/01.JU.0001008936.35187.0b.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: With widespread utilization of multiparametric magnetic resonance imaging (mpMRI) of the prostate and MRI-ultrasound fusion prostate biopsy, there has been an improved detection and therefore increased incidence of anteriorly located prostate cancer. Our objective was to elucidate the differences in the oncological outcomes and biological features between anteriorly located (AN) and posteriorly located peripheral zone (PZ) prostate lesions. METHODS: Our database of patients who underwent mpMRI and transrectal ultrasound (TRUS) fusion biopsy between 2014 and 2022 at an academic, tertiary-care center were retrospectively reviewed. All biopsies with Grade Group≥2 were considered as clinically significant prostate cancer (csPCA). The Prostate Imaging Reporting and Data System (PI-RADS) score was also reported for each lesion. AN lesions were defined as those arising in the anterior fibromuscular stroma or transition zone. PZ lesions included only those arising from the peripheral zone. Laboratory findings and surgical pathology were also recorded. All continuous and categorical variable were analyzed by Student's T-Test and Chi-Squared, respectively. RESULTS: Of the 2143 patients in the database, 479 (22.3%) and 1554 (72.5%) patients had AN and PZ prostate lesions, respectively. The mean PSA and PSA density (PSAd) of AN lesions were significantly greater than those of PZ lesions (PSA: 9.4 vs 7.6, p<0.001; PSAd: 0.21 vs 0.17, p<0.001, AN vs. PZ respectively) (Table 1). Interestingly, AN lesions were more likely to be scored as PI-RADS 5 (41.5% vs 24.8%, p<0.001, AN vs. PZ respectively), however, less likely to have csPCA (32.4% vs 38.2%, p=0.023, AN vs. PZ respectively) (Table 1). Notably, no difference was found in the concordance of TRUS and surgical pathology between AN and PZ lesions (52.0% vs 55.3%, p=0.522, AN vs. PZ respectively) (Table 1). CONCLUSIONS: Anteriorly located prostate lesions present with a higher PSA and PSA density than lesions in the PZ. Although AZ lesions carried a higher rate of scoring PI-RADS 5, their rates of csPCA were lower than that of PZ lesions. Future studies will need to assess clinical outcomes in active surveillance and after active treatment to assess for potential biologic and oncologic differences. Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e509 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Clemens An More articles by this author Constantine Velmahos More articles by this author Alexandra Hunter More articles by this author Bahar Piroz More articles by this author Alfred Barney More articles by this author Aileen Feng More articles by this author Douglas Dahl More articles by this author Michelle Kim More articles by this author Matthew Wszolek More articles by this author Keyan Salari More articles by this author Dimitar Zlatev More articles by this author Mukesh Harisinghani More articles by this author Shulin Wu More articles by this author Chin-Lee Wu More articles by this author Adam Feldman More articles by this author Expand All Advertisement PDF downloadLoading ...

Purpose To analyze surgical and oncologic outcomes of patients undergoing open partial nephrectomy (OPN) versus laparoscopic partial nephrectomy (LPN) for treatment of renal cell carcinoma (RCC). Methods We retrospectively investigated our institutional RCC database for patients who underwent PN for RCC from 1997 to 2018. Decision for technique was at the discretion of the operating urologist, following practice patterns and training history. Outcomes analyzed included pre/peri/post-operative parameters, pathologic outcomes, and disease recurrence rates. Results 1088 patients underwent PN from 1997 to 2018. After exclusionary criteria, 631 patients who underwent 647 unique PNs for a total of 162 OPN and 485 LPN remained. Baseline, pre-op, and pathologic characteristics were not statistically different. Surgical time was lower in laparoscopic cases [185 vs. 205 min] ( p = 0.013). Margin involvement was not statistically different; LPN had lower estimated blood loss (EBL) [150 vs. 250 mL] ( p < 0.001) and longer ischemia time [21 vs. 19 min] ( p = 0.005). LPN had shorter length of stay [2 vs. 4 days] ( p < 0.001), fewer overall complications ( p < 0.001), and no significant difference in high-grade complications [2.89 vs. 4.32%] ( p = 0.379). Fewer LPN patients developed metastases [1.65 vs. 4.94%] ( p = 0.0499). Local recurrence rates were not statistically different [1.24 vs. 3.09%] ( p = 0.193). Renal function was equivalent between cohorts post-operatively. Conclusion Long-term oncologic outcomes were not significantly different between LPN versus OPN, with no statistical difference in patient and tumor characteristics. LPN was associated with lower EBL, shorter length of stay, and lower overall complication risk. Renal function was not significantly different between cohorts.

Introduction Prostate cancer is known to have a long natural history, with many men having an indolent form of disease that can be safely managed with active surveillance (AS). However, accurate and dynamic risk assessment of disease progression is critical to performing safe AS. Whereas standard survival analysis predicts a static probability of disease progression over time from diagnosis, conditional survival analysis accounts for how this probability dynamically changes over time. We aimed to examine the conditional survival of prostate cancer patients managed with AS. Methods We retrospectively reviewed our institutional AS database of men with localized prostate cancer from 1996 to 2016. Our AS protocol includes prostate-specific antigen and digital rectal exam every 4-6 months for 3 years, then annually. Mandatory confirmatory 12 core biopsy is done at 12-18 months. Multiparametric magnetic resonance imaging (mpMRI) or additional biopsies are done at the discretion of physician and patient. Patients were included in this analysis if on initial biopsy they had grade group 1-2 disease, up to 50% of cores positive, and up to 50% maximum core involvement. Primary outcome measures were biopsy progression-free survival and treatment-free survival. Biopsy progression was defined as subsequent biopsy with higher grade group, >50% of cores positive, or >50% core involvement. Standard static Kaplan-Meier analysis was performed, and then five-year conditional survival estimates were derived for both outcomes. Results 877 patients met inclusion criteria and were included in the final analysis. 415 (55.9%), 390 (44.5%), and 72 (8.2%) patients met criteria for NCCN very low-, low-, and favorable intermediate-risk categorization. Median follow-up time was 6.1 years (IQR 4.1 – 8.8). Median biopsy progression-free survival and treatment-free survival was significantly longer for very low-risk versus low-risk and favorable intermediate-risk patients. There was no significant difference between low-risk and favorable intermediate-risk for either outcome. At diagnosis, the overall 5-year risk of biopsy progression and progression to treatment was 36% (95% CI 32-39%) and 37% (95% CI 34-40%), respectively. The 5-year risk decreased over time for patients who survived additional years on AS (Figure 1). After 5 years on AS, the overall 5-year risk of biopsy progression and progression to treatment was 24% (95% CI 18-31%) and 24% (95% CI 19-30%), respectively. Conclusions Patients with NCCN very low-risk disease had significantly longer biopsy progression-free and treatment-free survival than patients with low-risk and favorable intermediate-risk disease. Furthermore, the probability of survival increases over time among patients who remain on AS longer. Future directions include creating a prospective dynamic risk calculator for men on AS that incorporates time survived on AS and other contemporary clinical factors including mpMRI.

Introduction Trimodality therapy (TMT) for muscle invasive bladder cancer (MIBC) has been included in our national guidelines as an alternative to radical cystectomy. While limited bladder-related quality of life (QOL) outcomes exist, there remains a need to understand objective secondary long-term TMT outcomes affecting QOL. Methods A retrospective review of our IRB approved, institutional database was conducted. Occurrence of bladder stones, gross hematuria (GH), recurrent urinary tract infection (rUTI) and ureteral stricture was evaluated. Bladder stone was defined as any report of calcification in the bladder following completion of TMT. Patients who presented at least once to the emergency department (ED) were counted as having GH. rUTI was defined as ³ 2 infections in 6 months or ³ 3 in 1 year and was evaluated only in patients who retained their bladder over follow up. Ureteral strictures that occurred following salvage cystectomy were not included. Results 271 patients were included. 227 (83.8%) retained their bladder at a median follow up of 51.8 months (mo) [interquartile range (IQR) 18.0-98.1]. 6 (2.2%) underwent cystectomy for benign causes including refractory lower urinary tract symptoms and poor bladder function (4, 1.5%), GH (1, 0.37%), and nonhealing fistula (1, 0.37%). Bladder stones occurred in 23 (8.5%) at a median time of 15.2 mo[IQR 8.3-23.6]. No treatment was needed in 10(43.5%). 1(4.4%) required cystolitholapaxy and 12 (53.2%) were removed endoscopically with forceps or irrigation. 49 (18.8%) patients experienced GH. 13 (26.5%) required no treatment, 12(24.5%) required catheter placement and hand irrigation, 14 (28.6%) needed continuous bladder irrigation, 5 (10.2%) required operative intervention and 5 (10.2%) required transfusion. 19 (8.4%) patients suffered from rUTI. 14 (5.3%) patients developed ureteral stricture at a median time of 27.8 mo [8.6-61.4] . 13 (92.9%) were managed with ureteral stents; 1 (7.1%) required percutaneous nephrostomy tube. Conclusions The rates of objective bladder related complications affecting QOL after TMT are relatively low. Similarly, the risk of developing an “end-stage bladder” requiring cystectomy and diversion is extremely low.; These data support good QOL outcomes after TMT for MIBC.

Distribution of ERCC2 mutations present in TCGA Bladder.

Radical cystectomy with urinary diversion, with or without cisplatin-based neoadjuvant chemotherapy, is the current standard of care for nonmetastatic muscle invasive bladder cancer 1. Orthotopic ileal neobladder is a type of continent urinary diversion that utilizes an intestinal segment as the anatomical and functional substitution of the urinary bladder (Supplemental Figure 1). Compared to ileal conduit, ileal neobladder has the advantage of achieving spontaneous voiding and urinary continence.

453 Background: Maintenance of renal function following treatment of bladder cancer presents an ongoing challenge. The decline following radical cystectomy is well documented. However, in patients undergoing trimodality bladder-sparing therapy consisting of transurethral resection (TURBT) and concurrent chemoradiation followed by adjuvant chemotherapy, renal function is poorly understood. Methods: We performed a retrospective review of 178 patients with muscle-invasive bladder cancer who underwent bladder-sparing therapy between 2001 and 2013 and collected nadir creatinine values in the month preceding TURBT and at 1, 3, 5, 7, and 9 years post treatment initiation. Wilcoxon signed-rank test and mixed effects analysis were performed to compare the pre-treatment and post-treatment levels of creatinine and EGFR and to analyze their temporal change. Results: Median follow-up was 48 months (range: 1 to 162 months). The mean pre-treatment creatinine and EGFR were 1.12 mg/dl and 71 mg/dl, respectively. Cr increased to 1.21 mg/dl and EGFR decreased to 65 mg/dl at 1 year following treatment initiation (p = 0.001, p = 0.002). All post-treatment values were also significantly different from pre-treatment values (all p values < 0.002), but there was no significant difference between the post-treatment values over time. Conclusions: Following bladder-sparing therapy for muscle invasive bladder cancer, renal function was generally well preserved in the long term. Although there was a modest yet statistically significant decrease in renal function that occurred during the first year, there was no further decline up to 9 years. While this initial decrease in function is of unknown clinical significance, the lack of further decline after 1 year is different from similar studies following cystectomy.

You have accessJournal of UrologyCME1 Apr 2023MP56-15 DEVELOPMENT AND OUTCOMES OF UPPER TRACT UROTHELIAL CARCINOMA FOLLOWING TRIMODALITY THERAPY FOR MUSCLE INVASIVE BLADDER CANCER Jillian Egan, Affan Zafar, Linda Nguyen, Matthew Wszolek, Niall Heney, Dimitar Zlatev, Richard Lee, Jason Efstathiou, and Adam Feldman Jillian EganJillian Egan More articles by this author , Affan ZafarAffan Zafar More articles by this author , Linda NguyenLinda Nguyen More articles by this author , Matthew WszolekMatthew Wszolek More articles by this author , Niall HeneyNiall Heney More articles by this author , Dimitar ZlatevDimitar Zlatev More articles by this author , Richard LeeRichard Lee More articles by this author , Jason EfstathiouJason Efstathiou More articles by this author , and Adam FeldmanAdam Feldman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003309.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Trimodality therapy (TMT) for muscle invasive bladder cancer (MIBC) is widely accepted as an alternative to radical cystectomy, as reflected by its inclusion in national guidelines.1,2 However, the development and outcomes of upper tract urothelial carcinoma (UTUC) after TMT have not been described in a contemporary cohort. METHODS: Our IRB approved, institutional database was retrospectively reviewed for all patients who underwent TMT for MIBC from 2000-2017. Upper tract recurrence was defined as detection of UTUC after the completion of TMT. Pathologic and follow-up data were recorded from review of the original pathology and clinical reports. Descriptive statistics were calculated, and Kaplan Meier time-to-event analysis was performed using STATA 17.0. RESULTS: 271 patients were included. Median follow up was 51.8 [interquartile range (IQR) 18.0-98.1] months (mo). 7 patients (2.6%) experienced upper tract recurrence at a median time of 46 [5-49] mo. Median upper tract recurrence free survival was not reached. There was one high grade (grade 3/3), two grade 2/3, and two low grade (Grade 1-2/3) tumors detected. 2 patients did not have pathology available. 2 patients were treated with nephroureterectomy, 3 were managed endoscopically and 2 received no treatment (1 due to comorbidities and 1 refused treatment). For those treated with nephroureterectomy, pathologic grade and stage were grade 2 pTaNx and grade 3 pT2Nx. Both had associated carcinoma in situ. Neither suffered complications. Of those who developed UTUC after TMT, 3 had ureteral stents placed for tumor or resection near or surrounding the ureteral orifice and no patients had hydronephrosis at the time of TMT for their bladder cancer. CONCLUSIONS: Upper tract recurrence after TMT is relatively rare, occurring in 2.6% of patients, consistent with prior data on upper tract recurrence following cystectomy for MIBC.3 The management of UTUC patients after TMT can proceed according to the standard of care for UTUC with no increased risk of complications or poorer outcomes. Source of Funding: None. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e780 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jillian Egan More articles by this author Affan Zafar More articles by this author Linda Nguyen More articles by this author Matthew Wszolek More articles by this author Niall Heney More articles by this author Dimitar Zlatev More articles by this author Richard Lee More articles by this author Jason Efstathiou More articles by this author Adam Feldman More articles by this author Expand All Advertisement PDF downloadLoading ...

Supplemental Figure 1. Gene set enrichment analysis. Supplemental Figure 2. TCF21 expression analysis. Supplemental Figure 3. TCF21 expression in cell lines. Supplemental Figure 4. Loss-of-function and gain-of-function studies of TCF21 Supplemental Figure 5. CD24 and CD44 expression in TCF21 OE UM-UC3 and UM-UC13 cells. Supplemental Figure 6. GSEA analysis of common pathways altered between the three cell lines. Supplemental Figure 7. Heatmap of hierarchical clustering of luminal markers showing differential expression after TCF21 upregulation in UC13 LN (A) and UC13 MET (B) cells.

Whole exome sequencing metrics for bladder tumor samples

GSC Subtype Signatures by ERCC2 mutation.

Comparison of Patient Eligibility based on select DNA Damage Response (DDR) gene mutations for the Alliance A031701, RETAIN-BLADDER Trials and by mBI-EFS Favorable/Unfavorable Outcomes following TMT.

AbstractPurpose: There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. Experimental Design: We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation. Results: With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06–0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15–0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells. Conclusions: Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.

Association of Alliance/RETAIN Trial DDR Genes with Clinical Outcomes following TMT

Supplemental Table 1. List of top 10 genes downregulated and 10 genes upregulated in LN metastasis samples. Supplemental Table 2. Hallmark pathways enriched in the metastasis samples. Supplemental Table 3. Hallmark pathways enriched in the primary tumor samples. Supplemental Table 4. List of genes altered by TCF21 overexpression in UC3. Supplemental Table 5. List of genes altered by TCF21 overexpression in LN cells isolated from UC13 xenografts. Supplemental Table 6. List of genes altered by TCF21 in distant metastasis cells isolated from UC13 xenografts.

Background: Surgical staplers and clip appliers are commonly used and have a potential to malfunction, which may result in serious injury or death. These events are self-reported to the Food and Drug Admin-istration and compiled in the Food and Drug Administration's Manufacturer and User Facility Device Experience database. This study characterizes mortality related to surgical stapler and clip applier failure reported in the Food and Drug Administration's Manufacturer and User Facility Device Experience database.Methods: The Food and Drug Administration's Manufacturer and User Facility Device Experience data-base was reviewed between 1992 and 2016 for medical device reports related to surgical staplers and clip appliers filed under the following product codes: GAG, FZP, GDO, GDW, KOG, and GCJ. Adverse events including death and the type of device failure were reviewed. Temporal trends in reported deaths related to device failure were analyzed and the Healthcare Cost and Utilization Project database was used to adjust for annual surgical case volume using linear regression analysis.Results: A total of 75,415 malfunctions, 21,115 injuries, and 676 deaths were associated with the use of surgical stapler and clip applier devices. Most deaths occurred postoperatively (N = 516, 76.3%) and were due to infection/sepsis (N = 89, 17.2%) or vascular injuries (N = 110, 21.3%). Intraoperative mortality (N = 79, 11.7%) was primarily due to vascular injuries (N = 73, 92.4%). Device failures resulting in death were noted both intraoperatively (N = 268, 39.6%) and postoperatively (N = 325, 48.1%). In post hoc root cause analysis, a surgical stapler and clip applier device problem was the most common attributed cause of death (N = 238, 65.4%). In the linear regression analysis, there was a significant increase in the mortality from device failure in the study period after adjusting for annual surgical volume (P < .01).Conclusion: Mortality related to the use of surgical staplers and clip appliers is increasing. Most deaths occurred postoperatively, and an increased awareness of potential life-threatening complications is warranted when these devices are used.(c) 2022 Elsevier Inc. All rights reserved.