bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravesical therapy and risk of cystectomy and bladder cancer death after BCG fails.
Authors: Wong Risa Liang , Holt Sarah K , Guo Amy , Gore John L. 
Published: May 2020

e17026 Background: Management of non-muscle-invasive bladder cancer (NMIBC) when BCG fails engages complex decision-making that incorporates consideration of radical cystectomy (RC) and several intravesical options. We sought to characterize trends in practice variation and health outcomes for patients receiving intravesical therapy and radical cystectomy for presumption of recurrent or progressive high-risk NMIBC that has failed BCG. Methods: We identified patients with high-risk NMIBC from SEER-Medicare diagnosed from 2004-2015 who completed a full dose of BCG treatment. We evaluated receipt of intravesical therapy after BCG fails based on a code for a transurethral resection of bladder tumor (TURBT) within 6 months of BCG treatment followed by a switch to a different intravesical agent, systemic therapy, or radical cystectomy. We constructed risk estimates for disease-specific survival and subsequent need for radical cystectomy and using the Kaplan-Meier method and multivariate Cox proportional-hazards models adjusted for competing risks of death and patient clinical/demographic factors. Results: Among high-risk NMIBC patients who received BCG in their first year of diagnosis (n = 14,369), 9.7% (n = 1,273) went on to receive intravesical therapy, 4.2% (n = 607) proceeded directly to cystectomy, 15.8% (n = 2,272) underwent re-induction with BCG, 7.0% (n = 1,009) initiated systemic chemotherapy and 4.4% died without receiving treatment after BCG. Median follow-up after the post-BCG recurrence was 29 months (IQR 42, 14-56). Those receiving intravesical therapy after BCG fails were older, had more comorbidities, resided in rural areas, and had higher proportion of clinical Ta cancers (p < 0.05 for all) compared with immediate RC patients. Intravesical agents after BCG fails are listed in the Figure. Among those undergoing intravesical therapy, 12.9% (n = 478) eventually underwent RC a median 13 months (IQR 20, 7-27) after treatment post-BCG (2-year cystectomy free survival 89.4% [95% CI 88.3-90.5%]). Actuarial 2-year and 5-year bladder cancer-specific survival was 84.0% (95% CI 82.3-85.7%) and 71.0% (95% CI 68.3-73.7%), respectively, after intravesical treatment post-BCG. Conclusions: The heterogeneity in treatments used for NMIBC that fails BCG indicates potential provider uncertainty in the management of this challenging clinical situation. The paucity of effective bladder-sparing therapies, which is reflected in a high 2-year risk of RC and bladder cancer-specific death, highlights the urgent need for new therapies in this patient population.
The role of HIF-1α in regulating NLRP3 inflammasome activation in bladder cancer.
Authors: Chen Yuan-Ru , Yeh Hsin-Chih , Chiu Fang-Yen , Wu Hsin-En , Fang Huei-Chen , Li Chia-Yang 
Published: May 2020

e17028 Background: Bladder cancer is one of the most common malignancies of urinary system with the forth incidence rate and the eighth leading mortality rate in male genitourinary tumors. Hypoxia environment activates the hypoxia‐signalling pathway, principally via hypoxia‐inducible transcription factors (HIF) to activate numerous target genes which mediate embryonic vascularization, metabolism, tumor angiogenesis and the other processes to supply tissues with blood and oxygen. Inflammasomes are multiprotein signal responsible for the maturation of proinflammatory cytokines IL-1β and IL-18 as well as trigger the inflammatory cell pyroptosis. Recent study showed that HIF-1α promotes NLRP3 inflammasome activation in bleomycin-induced acute lung injury. However, the role of HIF1α in regulating the progression of bladder cancer has not been examined so far. The present study aimed to investigate the effect of HIF-1α on NLRP3 inflammasome activation in urothelial carcinoma. Methods: In this research, urothelial carcinoma cell lines were treated with NLRP3 inflammasome inducers, LPS/ATP, to induce NLRP3 inflammasome activation. Results: Our preliminary results showed that both T24 and 5637 bladder cancer cells can be induced NLRP3 inflammasome activation and IL-1β secretion. In addition, hypoxia also induces the secretion of IL-1β in T24 cells. We further investigated the effect of NLRP3 inflammasome activation in modulating EMT-related protein levels, migration and invasion in bladder cancer T24 cells. Our results demonstrated that NLRP3 inflammasome activation promotes tumor growth and metastasis in bladder cancer cells. Furthermore, knockdown of HIF1α reduces both inflammatory response and migratory activity in bladder cancer. Conclusions: Collectively, these results suggest that targeting NLRP3 inflammasome might offer potential to treat hypoxic malignant tumor in bladder carcinoma.
Oncologic outcomes of complete transurethral resection prior to neoadjuvant chemotherapy for muscle-invasive bladder cancer.
Authors: Pak Jamie Sungmin , Haas Christopher R , Vila Reyes Helena , Anderson Christopher B. , DeCastro Guarionex Joel , Benson Mitchell C. , McKiernan James M. 
Published: May 2020

e17029 Background: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) is the standard of care for muscle-invasive bladder cancer (MIBC). Prior studies have shown that pT0 response at RC can be attributed to NAC and high-quality transurethral resections (TURBT) prior to NAC. Therefore, we sought to assess the association of completeness of pre-NAC TURBT with response and survival outcomes. Methods: This was a single-institution, retrospective review of patients who received NAC for clinically localized MIBC (≥cT2, N0) from 2000 to 2017. Exclusion criteria were receipt of non-cisplatin-based NAC or radiation (n = 15), and insufficient documentation of TURBT (n = 26). Complete TURBT (cTURBT) was defined as tumor resection in entirety and/or resection to normal appearing muscle in operative reports, or repeat pre-NAC TURBT revealing clinical T0 (cT0). After NAC, patients either underwent repeat TURBT or immediate RC, as per the treating physician. Patients refusing RC were placed on an active surveillance/delayed intervention (ASDI) protocol of cytology, cystoscopy, and imaging at 3-4 month intervals. Primary endpoint was durable complete response (dCR): pT0 at RC or remaining cT0 on ASDI for ≥1 year. Secondary endpoints included OS and durable down-staging (dDS): ≤pT1 at RC or remaining ≤cT1 on ASDI for ≥1 year. Results: Of a total 93 patients, 62 (67%) underwent pre-NAC cTURBT. Those with cTURBT had lower rates of variant histology (13% vs 32%, p = 0.03), hydronephrosis (15% vs 39%, p < 0.01), and more often pursued ASDI (60% vs 26%, p = 0.01). Patients with cTURBT were more likely to attain dCR (37% vs 13%, p = 0.01) and dDS (60% vs. 26%, p < 0.01). On multivariate (MV) analysis, cTURBT was a significant predictor of dCR and dDS; this remained true on subset analysis excluding 11 patients with ≥cT3 on restaging TURBT. On Kaplan-Meier analysis, patients with cTURBT had improved 5-year OS (78% vs. 46%, p < 0.01). On MV analysis controlling for variant histology, lymphovascular invasion, and hydronephrosis, cTURBT was the only significant predictor of OS, also on subset analysis excluding the 11 patients with ≥cT3 on restaging TURBT. Conclusions: A pre-NAC cTURBT is associated with improved oncologic outcomes and OS in this MIBC cohort. The extent to which cTURBT represents a selection criterion for having lower clinical stage or a therapeutic advantage in response to NAC is difficult to isolate from a retrospective study. However, this study suggests cTURBT should be pursued when feasible to potentially optimize outcomes after NAC.
Sarcomatoid urothelial carcinoma: Oncologic outcomes from a tertiary center and SEER-Medicare data.
Authors: Sekar Rishi Robert , Diamantopoulos Leonidas Nikolaos , Khaki Ali Raza , Vakar-Lopez Funda , Tretiakova Maria S. , Psutka Sarah P. , Holt Sarah K , Gore John L. , Schade George R. , Lin Daniel W. , Hsieh Andrew Caleb , Lee John Kyung , Yezefski Todd , Schweizer Michael Thomas , Cheng Heather H. , Yu Evan Y. , True Lawrence D. , Montgomery Robert B. , Grivas Petros , Wright Jonathan L. 
Published: May 2020

e17033 Background: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive bladder cancer variant with little evidence regarding prognostic characteristics and response to neoadjuvant chemotherapy (NAC). In this study, we delineate oncologic outcomes in patients with SUC after radical cystectomy (RC), presenting data from our institutional database and SEER-Medicare. Methods: We retrospectively queried our institutional database to identify consecutive patients with cT2-4 SUC and conventional (non-variant) UC (CUC) who underwent RC (2003-2018). SEER-Medicare database was also searched for patients with cT2-4 SUC (2004-2015). Clinicopathologic/treatment data were captured. Overall survival (OS – diagnosis to death) was estimated with the Kaplan-Meier method. T-test, χ2 test and log-rank test were used for group comparison analysis. Factors significant in univariate analysis for OS were included in the multivariate (MVA) Cox proportional hazards model. Results: Institutional RC database yielded 38 patients with SUC and 287 with CUC, while 190 patients with SUC were identified from SEER-Medicare [83 (44%) had RC]. Platinum-based NAC was given to 17/38 (45%), 162/287 (56%) and 26/83 (31%) patients, respectively. Institutional patients with SUC had significantly higher rates of pT3/4 disease at RC (66% vs. 35%, p < .001) and lower rates of complete pathologic response (ypT0N0) following NAC (6% vs 35%, p = .02). Median OS in patients who had RC was significantly inferior in our institutional SUC vs. CUC group (20 vs. 121 months, p < .001) and 21 months in the SEER-SUC cohort. No significant difference in OS was identified between NAC+RC vs. RC alone, both in the institutional (17 vs. 20 months, p = 0.66) and SEER-SUC cohort (24 vs. 20 months, p = 0.56). In MVA for the entire institutional cohort (SUC+CUC combined), SUC was independently associated with worse OS, when adjusted for advanced age, pT/N stage, performance status, NAC, lymphovascular invasion, surgical margins (HR, 95% CI: 2.3, 1.4 - 3.8, p = .001). Five patients had an abdomino-pelvic cystic recurrence, with median time to recurrence < 5 months. Conclusions: Patients with SUC treated with RC had high rates of extravesical extension, poor response to platinum-based NAC and worse OS compared to patients with CUC. Data from SEER showed a comparable OS to our SUC cohort. NAC was not associated with improved OS in any SUC cohort (institutional or SEER). A unique pattern of rapid abdomino-pelvic cystic recurrence, mimicking post-RC abdominal fluid collections, was also identified.
Magrolimab and gemcitabine-cisplatin combination enhance phagocytic elimination of bladder cancer.
Authors: Kiss Bernhard , Volkmer Anne Kathrin , Feng Dongdong , McKenna Kelly Marie , Mihardja Shirley , Chao Mark , Takimoto Chris H.M. , Liao Joseph C , Volkmer Jens-Peter , Weissman Irving L. 
Published: May 2020

e17035 Background: CD47 is an antiphagocytic signal and macrophage checkpoint that bladder and other cancer cells over-express to evade innate immunity. Magrolimab (Hu5F9-G4) a CD47 blocking antibody, promotes phagocytosis of cancer cells by macrophages and is being tested in several clinical trials (NCT02953509, NCT03248479, NCT02953782, NCT03558139). Chemotherapies synergize with magrolimab by increasing “eat me” signals on cancer cells, and thus enhancing phagocytosis. This synergy has been shown in MDS and AML, whereby magrolimab+azacitidine has shown encouraging efficacy in pre-clinical and clinical studies. This study aimed to investigate the effect of magrolimab as monotherapy and in combination with gemcitabine-cisplatin chemotherapy in bladder cancer. Methods: Phagocytosis of urothelial bladder cancer cells (639V) was evaluated in vitro with magrolimab alone and in combination with chemotherapy (gemcitabine + cisplatin). Treatment in vivo was evaluated in a xenograft mouse model. 639V cells were transplanted into NSG mice and upon confirmation of engraftment mice were randomized into 4 treatment cohorts: control (PBS), magrolimab, chemotherapy (cisplatin + gemcitabine), and magrolimab in combination with chemotherapy. In the first experimental setup treatment was started early in small tumors and in the second experimental setup treatment was started late after tumors have grown to large size. Tumor growth was monitored by in vivo bioluminescent imaging. Metastases were evaluated postmortem. Results: Chemotherapy increased calreticulin on bladder cancer cells. Magrolimab enhanced phagocytosis of bladder cancer cells in vitro and combination of magrolimab with chemotherapy further increased phagocytosis compared to either therapy alone. Magrolimab and chemotherapy, each alone decreased tumor growth in vivo but only combination of magrolimab with chemotherapy showed a strong inhibition of tumor growth, resulting in a significantly prolonged survival compared to all other treatment cohorts. This was shown for both, small tumors and large tumors. Metastases formation in liver and lungs was completely inhibited by treatment with magrolimab, whereas mice treated with chemotherapy alone or PBS control showed metastases in these organs. Conclusions: Magrolimab treatment in combination with chemotherapy was efficacious in preclinical in vitro and in vivo studies in bladder cancer and provides a novel treatment opportunity for patients with bladder cancer and other solid tumors.
The neural phenotype in invasive urothelial carcinoma patients: Alternative score detection and prognostic implication.
Authors: Zucali Paolo Andrea , Colombo Piergiuseppe , De Carlo Camilla , Giordano Laura , Hurle Rodolfo , Lazzeri Massimo , Elefante Grazia Maria , D'Antonio Federica , Regis Federica , Perrino Matteo , De Vincenzo Fabio , Guazzoni Giorgio Ferruccio , Roncalli Massimo , Santoro Armando 
Published: May 2020

e17037 Background: Recent molecular subtyping studies (NGS) identified a subset (5-15%) of muscle invasive urothelial carcinoma (MIBC) with transcriptomic patterns consistent with neuroendocrine (NE) differentiation in the absence of NE histology (NE-like), representing a potentially high risk subgroup of carcinoma which may require a different treatment strategy. We recently set an alternative immuno-phenotypical score (Piescore), to discriminate Luminal from Basal from Neural carcinoma. Aim of this study was to test the ability of Piescore in identifying NE-like cases in a mono-institutional cohort of patients treated with trans-urethral resection and radical cystectomy (RC) and to correlate them with clinical outcomes. Methods: Transurethral resection specimens harbored foci of HG pT2 (MIBC) UC from 116 pts who subsequently underwent RC have been submitted for immunohistochemical analysis, using relevant gene-expression-based markers for Basal type (CD44, CK5/6) and Luminal type (CK20 and pPARg). Piescore divided Basal and Luminal types when at least 3 of the 4 markers were consistent with a specific phenotype; Mixed if two luminal and two basal markers were present simultaneously; NE-like when all four markers were negative. Results: Overall, the Piescore identified Basal phenotypes in 49 patients (42,2%), Luminal in 38 (32,7%), and Mixed in 9 (7,8%). No expression was identified in 20 patients (17,2%): 7 cases with morphological NE differentiation and 13 cases with classical urothelial histology, all consistent with NE-like phenotype. Interestingly, in 10/13 patients the NE-like phenotype was only documented in the muscle invasive component of the tumor whereas in the non-invasive component they retained Luminal phenotype in 9 cases and Basal in one. With a median follow up of 188 months, the pathological stage of disease (pT2 versus ≥pT3 and/or N+) and the tumor vascular invasion (absent versus present) resulted prognostic (Stage: 5-years DFS rate 65% versus 30%, p = 0.038; 5-years OS rate 69% versus 32%, p = 0.017) (vascular invasion: 5-years DFS rate 47% versus 24%, p = 0.020; 5-years OS rate 54% versus 21%, p < 0.001) in all population. No statistically significant differences in terms of pathological stage of disease, vascular invasion, DFS, and OS were observed in NE-like cases compared with non-NE-like cases. Conclusions: The NE-like urothelial carcinoma identified by Piescore immunophenotyping (CD44, CK5/6, CK20 and pPARg) did not show any statistically significant association with worse prognosis.
Neoadjuvant cisplatin based therapy in bladder cancer: Is less enough?
Authors: Abbasi Saqib , Al-Jumayli Mohammed , Hildebrand Hannah , Wulff-Burchfield Elizabeth Marie , Lee Eugene K. , Taylor John A , Holzbeierlein Jeffrey , Martin Grace , Parikh Rahul Atul 
Published: May 2020

e17046 Background: Patients receiving neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) often are not able to complete three or four cycles of therapy which is standard of care. Pathological completed response (pCR) is a surrogate marker for long term survival. We set out to determine if pCR differed based on total tolerated cycles prior to surgery in those receiving cisplatin based NAC. Methods: Data was gathered at our institution on patients receiving neoadjuvant gemcitabine with cisplatin (GC), or dose dense methotrexate, vinblastin, adriamycin, cisplatin (ddMVAC)). The primary outcome was pCR, and secondary outcome was downstaging. pCR was compared between those who received 1-2, 3, and 4 cycles. Results: A total of 92 patients receiving NAC during the years of 2014 to 2019. 12 received 2 or less cycles, 22 received 3, and 57 completed 4. Age was not significantly different between groups (69.7, ≤ 2), (69.0, 3), (67.4, 4). Gender differences were noted: (41.7% female, ≤ 2), (22.7% female, 3), (12.3% female, 4), p = 0.05. The rates of pCr among the three groups were: (16.7%, ≤ 2), (22.7%, 3), (40.4%, 4), p = 0.14. Downstaging was seen in: (33.3%, ≤ 2), (59.1%, 3), (52.6%, 4), p = 0.35. Conclusions: While not statistically significant our study suggests a trend on pCR rates related to the total of cycles of neoadjuvant chemotherapy prior to surgery. Limitations include retrospective design and small sample size.
Panel-derived TMB and immune-related GEP are associated with the response to immune checkpoint inhibitors (ICIs) in urothelial cancers.
Authors: Tan Kien Thiam , Chen Shu-Jen , Hsieh Yi-Lin , Su Yu-Li , Jan Yi-hua , Cheng Jen Hao , Hsu An , Huang Wan-Ting , Zhuo De-Wei , Wang Woei-Fuh , Wei Datsen George 
Published: May 2020

e17047 Background: Tumor mutational burden (TMB) and gene expression profile (GEP) have emerged as potential biomarkers for the prediction of response to the immune checkpoint inhibitor (ICI) treatment. An interferon-g gene signature was shown recently to predict ICI response in a pan-cancer setting. For TMB, not only did TMB-high patients experience better clinical outcome with ICI, but panel-derived TMB was also shown to be comparable to the gold standard, TMB derived from whole exome sequencing. Here, we evaluate possible correlations between panel-derived TMB, as well as immune-related GEP, with ICI response in urothelial cancers. Methods: FFPE tumor tissues from 30 patients with urothelial cancers who had previously received ICI as monotherapies or combination with chemotherapies at Kaohsiung Chang Gung Memorial Hospital were retrospectively tested for targeted next-generation sequencing (ACTOnco) and quantitative PCR-based GEP (ACTTME), for the identification of nonsynonymous variants across 440 cancer-associated genes and expression levels of > 90 immune-related genes, respectively. TMB was calculated by using the sequenced regions of ACTOnco to estimate the number of somatic nonsynonymous mutations per megabase of all protein-coding genes. For ACTTME, Cq values were normalized to internal control before group analysis. RECIST criteria were used to categorize tumor response to the treatment. Results: Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST criteria. In the ICI monotherapy cohort, the responders (n = 8) had significantly higher TMB than non-responders (n = 15) (Median 16.2 muts/Mb vs. 6.5 muts/Mb, p= 0.0035). In contrast, for the cohort receiving ICI combination therapy, several genes implicated in hypoxia (HIF1A), suppressive cell types (Treg & MDSC) and immune checkpoint (PD-L2) were significantly elevated ( p< 0.05) in the non-responder group by 2 to 8 folds. Conclusions: Despite the fact that the cohort size is small, this study showed panel-derived TMB, as well as immune-related GEP, can potentially serve as predictive biomarkers to identify urothelial cancer patients for immune checkpoint inhibitor therapy.
Is it necessary to obtain a second review on outside pathology for patients referred with non-muscle invasive (NMI) bladder cancer?
Authors: Brown Jared , Hensel Caitlin , He Jiaxian , McDonald Megan , Newhall Philip , Riggs Stephen Boyd 
Published: May 2020

e17049 Background: Correct pathological staging is paramount in treatment recommendations for patients with non-muscle invasive disease. As a referral center, we sought to evaluate the quality of outside pathology determined by College of American Pathology (CAP) recommendation as well as discordance in AUA risk group stratification. Methods: We retrospectively reviewed our database of patients who originally underwent resection of bladder tumors at external facilities that were subsequently referred to our cancer institute between 2015 and 2018. 75 initial pathologies were overread by one of our GU pathologists all with non-muscle invasive bladder cancer. We evaluated the discordance rate between outside pathology reports and our overread using the CAP criteria for reporting. Additionally, we included the association in risk stratification category as well as the change in risk stratification group following overread. Cohen’s kappa (κ) statistics were used to evaluate concordance in pathology report between LCI and external facilities. Comparisons of risk stratification between LCI and external facilities were analyzed using Fisher’s exact test. Results: 5 criteria for quality were evaluated to assess reporting. A relatively high agreement in reporting tumor grade between LCI and external facilities (κ = 0.65, p < 0.001) and moderate agreement in microscopic extent (κ = 0.41, p < 0.001). LVI was not commented on in 58.7% of outside reports. 6/12 (50%) of patients were upstaged from Low Risk (LR) to Intermediate Risk (IR), 2/11 (18%) from IR to High Risk (HR), and 6/46 (13%) from HR to MIBC (Table). Conclusions: Initial pathology reports from outside facilities were often lacking minimum criteria as recommended by the CAP. Furthermore, a significant number of patients were upstaged after review, including 13% of HR patients being overread as muscle invasive disease. Second review of outside pathology should strongly be considered as re-review may have implications on treatment recommendations. [Table: see text]