bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adverse effects and discontinuation of pembrolizumab in BCG refractory non-muscle invasive bladder cancer.
Authors: Golijanin Borivoj , Malshy Kamil , Bhatt Vikas , Lagos Galina , Amin Ali , De Souza Andre Luiz , Cheng Liang , Mega Anthony E. , Golijanin Dragan 
Published: January 2024

588 Background: Non-muscle invasive bladder cancer (NMIBC) is associated with high rates of recurrence and progression despite adequate intravesical treatment with Bacillus Calmette-Guerin (BCG). Pembrolizumab was found to be effective in treating BCG-refractory NMIBC in the KEYNOTE-057 trial with a 41% complete response after 3 months and minimal adverse effects. As a result it was approved by the FDA on January, 2020, for the treatment of high risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors in patients ineligible for or unwilling to undergo cystectomy. This study reports a single institution’s experience using pembrolizumab in BCG refractory patients with high-risk NMIBC. Methods: Records of NMIBC patients who commenced treatment with pembrolizumab between January 2020 and January 2023 at a single institution were retrospectively reviewed. Demographic and clinicopathologic information was collected. Kaplan-Meier curves were generated to calculate progression-free survival (PFS), and treatment-specific survival (TSS). The combined positive score (CPS) of PD-L1 was assessed for each case treated by pembrolizumab. Results: Out of 250 patients with NMIBC who were screened for the study, 18 met the inclusion criteria. The median age was 74.1 years (IQR=67.8 – 81.4), male to female ratio of 3.5:1. The median follow-up time was 17.5 months (IQR= 8.1–22.5). A previous history of CIS was present in all patients as well as second-line chemotherapy for BCG refractory disease. At the start of pembrolizumab, stage distribution was as follows: 1 (5.6%) cTa, 6 (33.3%) had CIS, and 11 (61.1%) cT1. After an average of 8.9 cycles, 72.2% (13/18) stopped treatment. 27.8% (5/18) are still undergoing treatment, with an average of 12.6 cycles (SD=10.4). 1 out of the 13 patients who stopped treatment had a complete response. The remaining reasons for termination of treatment are Grade 2 or higher immune-related adverse events in 53.8% (7/13), progression in 30.8% (4/13), and recurrence in 7.7% (1/13). Four patients ultimately required radical cystectomy which revealed 1 pTa, 1 pTis, 1 pT1, and 1 pT4. Only 1 patient had CPS of PD-L1 > 10. Conclusions: There were higher rates of toxicity from pembrolizumab for the treatment of BCG-refractory NMIBC than expected. More research is needed to better define the patients who are likely to benefit from this treatment. Pembrolizumab for BCG refractory NMIBC can have high rates of Grade 2 or higher adverse events leading to early withdrawal from treatment. Early discussion about radical surgery remains an important part of the treatment guidelines for BCG refractory NMIBC.
A real-world observational study characterizing patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with or without androgen receptor pathway inhibitors (ARPIs).
Authors: Kolinsky Michael Paul , O'Sullivan Dylan E. , Boyne Devon J. , Brenner Darren R , Shokar Simran , Cheung Winson Y. 
Published: January 2024

59 Background: mCSPC treatment is rapidly evolving with androgen deprivation therapy (ADT) plus ARPIs viewed as the standard of care for most pts. Data are needed to understand the real-world characteristics and treatment patterns of mCSPC (PC) pts in this dynamic field. This study aimed to define clinical features of mCSPC pts, estimate the proportion of pts receiving ARPIs, and evaluate clinical and demographic features associated with ARPI use. Methods: This retrospective cohort study used data from electronic health records and administrative databases in the province of Alberta, Canada. All newly diagnosed metastatic PC pts between 2017-2020 were identified. Pts were considered to have mCSPC if they initiated ADT within 30 days prior to, or at any time after diagnosis. ARPI exposure was defined as receiving ARPI within 180 days of initiating ADT. ARPI-naïve pts may have received ADT alone or other non-ARPI therapy (i.e., docetaxel) within 180 days of initiating ADT. Multivariable logistic regression was used to evaluate pt characteristics related to the receipt of ARPI. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact. Results: Of the 976 mCSPC pts identified, 33.5% received an ARPI. In ARPI exposed pts, the median time from ADT to ARPI start was 7.9 weeks and median time on ARPI was 13.1 months (mos). In multivariable analyses, ARPI use was associated with younger pt age, more recent diagnosis, fewer comorbidities, a higher metastatic burden, treatment centre, referral to a medical oncologist, and prior local therapy (all p<0.05). The median time to next therapy was 24.6 mos (95%CI=19.5-33.0) vs. 18.5 mos (95%CI+16.9-21.1), and median OS was 38.5 mos (95%CI=32.8-NA) vs. 34.2 mos (95%CI=33.3-38.8) for APRI exposed vs. ARPI-naive pts, respectively (p=0.03). Conclusions: This study identified factors associated with ARPI use in mCSPC, potentially allowing targeted efforts to improve ARPI uptake for pts in whom use is low. These findings are important as they reflect outcomes seen in real world pts.
Blue light cystoscopy versus white light cystoscopy for the detection of bladder cancer in China: An analysis of unpublished clinical trial and real-world data.
Authors: Li Hanzhong , Hu Hailong , Ma Lulin , Guo Jianming , Liu Xiuheng , Huang Jian , Guo Yonglian , Wen Jin , Zhang Shudong , Zhang Hongxian , Jiang Shuai , Liu Cheng , He Wang , Kang Xinli , Wang Fei 
Published: January 2024

593 Background: Blue light cystoscopy (BLC) is superior to white light cystoscopy (WLC) in detection of bladder cancer, but no multi-center studies have been conducted in China with modern 4K LED equipment. The objective of this post hoc analysis of a randomized controlled trial (RCT) and a real-world study (RWS) was to compare BLC with WLC in the detection of bladder cancer and to determine the similarity between the RCT and RWS. Methods: In RCT (NCT05600322), patients with known or suspected bladder cancer were enrolled at seven hospitals in China from November 2022 to June 2023. In the prospective RWS, patients with known or suspected bladder cancer were enrolled at Hainan General Hospital from December 2022 to July 2023. Patients received intravesical HAL (Hexvix, Photocure ASA) and underwent WLC before BLC (System blue, Richard Wolf GmbH). Some patients were randomized to WLC to avoid observational bias. The primary endpoint was the proportion of patients with histologically confirmed tumors (Ta, T1, or CIS) who have at least one such lesion found by BLC but not by WLC. Secondary endpoints included, detection of CIS, lesion specific detection rate, false positive rates, and adverse events (AE). Results: 158 patients were enrolled in RCT, in which 37 patients were training patients, six patients were randomized to not undergo BLC, one patient withdrew. 114 patients remained in the full analysis set. 19 patients were enrolled in RWS. In patients confirmed with Ta, T1, or CIS, 42/97 patients (43.3%) in RCT and 4/12 patients (33.3%) in RWS had at least one confirmed lesion found by BLC but not by WLC (all p<0.0001). 11/114 patients (9.6%) with CIS in RCT and 1/14 patients (7.1%) with CIS in RWS showed at least 1 additional confirmed CIS lesion found by BLC but not by WLC. In RCT, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 94.7%, 100%, 98.2% and 100% for BLC and NA, 42.1%, 76.1%, 91.2% and 100% for WLC, respectively. In RWS, detection rates for PUNLMP, CIS, Ta, T1 and T2-T4 tumors were NA, 100%, 100%, 100% and 100% for BLC and NA, 50%, 81%, 100% and 100% for WLC, respectively. The false-positive rate was 23.2% and 16.0% for BLC and WLC in RCT and was 25.0% and 15.4% in RWS, respectively. In RCT, 200 AEs were observed in 95 patients, all mild to moderate, of which 191 were classified as unrelated to HAL. In RWS, 16 AEs were observed in 15 patients, all mild and were all unrelated to HAL. Conclusions: Both RCT and RWS confirm the superiority of BLC based on innovative LED technology with HAL over WLC in detection of bladder cancer in Chinese populations, especially CIS, and HAL is well tolerated. Clinical trial information: NCT05600322 .
Sequential endoluminal gemcitabine and docetaxel versus bacillus Calmette–Guérin for the treatment of high-grade upper tract urothelial carcinoma.
Authors: McElree Ian M. , Mott Sarah L. , Packiam Vignesh T. , O'Donnell Michael A. , Steinberg Ryan L. 
Published: January 2024

613 Background: BCG is currently the only endoluminal treatment option for high-grade (HG) upper tract urothelial carcinoma (UTUC). Gemcitabine/Docetaxel (Gem/Doce) has shown promising efficacy as a treatment for HG UTUC, though a comparison to BCG is lacking. We report the outcomes of patients treated with endoluminal Gem/Doce versus BCG for non-invasive HG UTUC. Methods: A retrospective review of patients treated with Gem/Doce versus BCG for clinically non-invasive HG UTUC was performed. Treatment was instilled via nephrostomy or retrograde ureteral catheter. Induction instillations were performed weekly for 6 weeks. If disease free, maintenance therapy for Gem/Doce was monthly for 6 months and a single 3 week mini-cycle for BCG. Recurrence was defined as biopsy-proven disease or HG cytology. Progression was defined as development of muscle invasion, metastases, or death due to cancer. Results: The final cohort included 59 patients with 71 treated upper tract units; 36 received BCG and 35 received Gem/Doce. Median follow-up was 62 months in the BCG group and 29 months in the Gem/Doce group. Indication for treatment included a positive HG cytology in 78% and 89% of the BCG and Gem/Doce groups, respectively; the remaining patients in each group presented with pathologically-confirmed HG disease. The 2-year estimates for recurrence-free and nephroureterectomy-free survival were 57% and 87% for the BCG group and 56% and 100% for the Gem/Doce group, respectively (Table). Upon multivariable analysis, treatment with Gem/Doce was not associated with an increased risk of recurrence versus BCG (HR 0.78, 95%CI 0.33-1.85; p=0.57). In total, 19% of patients receiving BCG and 15% of patients receiving Gem/Doce experienced a grade 3+ adverse event. The development of any symptoms was not statistically different between treatment groups (p=0.28). There were two deaths recorded during the study period, one in each treatment group. Conclusions: Endoluminal Gem/Doce and BCG have similar oncological outcomes and major AE rates in the treatment of HG UTUC. Further prospective evaluation is warranted. [Table: see text]
Clinical outcomes of frontline GemFLP in advanced urachal and non-urachal adenocarcinomas of the urinary tract: The MD Anderson Cancer Center (MDACC) experience.
Authors: Moussa Mohammad Jad , Chen Adrienne H. , Grana Allison K. , Gao Jianjun , Shah Amishi Yogesh , Corn Paul Gettys , Tannir Nizar M. , Goswami Sangeeta , Wang Jianbo , Araujo John C. , Kamat Ashish M. , Navai Neema , Pettaway Curtis Alvin , Adibi Mehrad , Czerniak Bogdan , Guo Charles C. , Siefker-Radtke Arlene O. , Campbell Matthew T , Alhalabi Omar 
Published: January 2024

630 Background: Adenocarcinomas of the urinary tract, including urachal (UA) and non-urachal (NUA) subtypes, are rare tumors. Triplet regimens combining gemcitabine, a taxane or 5-fluorouracil (5-FU)/leucovorin (L), and cisplatin (P), have been developed. Methods: We retrospectively reviewed records of patients receiving frontline (1L)GemFLP (Gemcitabine 200 mg/m2 IV on days 1 and 5; 5-FU 200 mg/m2 IV on days 1, 2, 3, 4, 5; L 10mg/m2 IV on days 1, 2, 3, 4, 5; P 20mg/m2 IV on days 1, 2, 3, 4, 5) in advanced UA and NUA at MDACC between 2003 and 2023. Advanced disease is defined as Sheldon stages IVA/IVB in UA and TNM stage IV in NUA. Imaging-based best overall responses (BOR) were complete (CR), partial (PR), stable (SD), progressive (PD) or non-evaluable (NE). Overall response rate (ORR) covers CR + PR, while disease control rate (DCR) covers CR + PR + SD. We report overall survival (OS) and progression-free survival (PFS) from GemFLP start. Results: Baseline characteristics of UA (n=40) and NUA (n=28) are in Table. In UA, bladder dome was primary location in 39 (97.5%). NUA pts had either bladder (11, 39.3%) or urethral (17, 60.7%) origin. BOR in 1L GemFLP are shown in Table. In UA, ORR is 20% and DCR is 72.5%. Median OS (mOS) is 19.8 months (95% CI: 12.2 - 30.6) and median PFS (mPFS) is 5.3 mo (95% CI: 3.1 – 6.3). In UA, pts with CR, PR, or SD have a significantly longer mOS than pts with PD [26 mo (16.2 – 35.6) vs. 7.7 mo (2.67 – 11.9), log-rank p <0.0001]. Meanwhile, in NUA, ORR is 35.7% and DCR is 75%. mOS is 12.95 mo (95% CI: 7.1-20.2) and mPFS is 5.3 mo (1.93 – 7.6). A similar significant survival benefit is seen in NUA pts with disease control versus pts with PD [17.6 mo (12.6 – 25.9) vs. 5 mo (2.63 – 7.1), p <0.0001]. Surgical consolidation was offered for 6 UA pts (3 PR, 3 SD), 3 of whom were regional N+ only, and for 4 NUA pts (1 CR, 1 PR, 2 SD) who were all regional N+ only. All except one showed residual pathological disease. Conclusions: 1L GemFLP is an active regimen in advanced UA and NUA, with a DCR of >70%. Pts with disease control (CR, PR, or SD) have a clear survival benefit compared to non-responders. 1L GemFLP might offer chances at surgical consolidation after disease control for pts with regional node-positive only disease, with larger cohorts needed to confirm findings. [Table: see text]
Outcomes with enfortumab vedotin in patients with advanced urothelial carcinoma and histology variants: Analysis of the UNITE study.
Authors: Jindal Tanya , Jiang Cindy Y. , Alhalabi Omar , Nguyen Charles B , Nizam Amanda , Basu Arnab , Bilen Mehmet Asim , Zakharia Yousef , Milowsky Matthew I. , Brown Jason R , Kilari Deepak , Emamekhoo Hamid , Hoimes Christopher J. , Khaki Ali Raza , Gupta Shilpa , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram , Koshkin Vadim S 
Published: January 2024

652 Background: Enfortumab vedotin (EV) is approved for patients (pts) with advanced urothelial carcinoma (aUC) but outcomes in pts with histology variants (HV) have not been well described. We hypothesized that presence of HV would impact EV treatment outcomes. Methods: UNITE is a multi-site retrospective study of pts with aUC treated with targeted agents, including 650 pts treated with EV regimens. We compared outcomes to EV monotherapy in pts with pure UC (pUC) relative to pts with any HV and with specific HVs. In pts with scans after > 1 cycle of EV, observed response rate (ORR) was assessed using χ2 test and logistic regression. Median progression-free survival (PFS) and overall survival (OS) from EV start were measured using the Kaplan Meier method and Cox proportional hazard test. Results: A total of 566 pts (366 with pUC; 200 with HV) from 17 US sites were treated with EV monotherapy. Median age was 70 years, 71% men, 87% Caucasian, 74% with ECOG PS 0/1 and 28% with liver mets. Median follow up was 21 mos from EV start, ORR was 49%, mPFS and mOS were 5.8 mos (95% CI: 5.29-6.67) and 12.2 mos (95% CI: 11.5 – 13.8), respectively. Pts with pUC had more visceral mets (69% vs 60%, p = 0.04) and liver mets (32% vs 21%, p =0.003) than pts with HV. No significant difference in outcomes were seen between pUC and pts with HV component (1-100%). Pts with predominant HV (50-99%; N=35), had numerically lower ORR relative to pUC pts (36% vs 52% OR 0.31, p <0.09), but no difference in mPFS or mOS. Pts with pure HV (pHV) (100%: N=14) had inferior outcomes relative to pts with pUC (ORR 0% vs 52%, p<0.001; mOS HR: 2.96 (95% CI: 1.60 – 5.46), p <0.001; mPFS HR: 1.9 (95% CI: 1.06 – 3.39), p=0.03). ORRs for specific HV are listed in the table. No significant difference in treatment outcomes were seen in pts with pUC vs any specific HV, except for NE HV which had inferior ORR (0% vs 52%; p=0.003). Conclusions: Responses to EV are noted in some aUC pts with HV, except for NE (any component) and pHV. Certain HV notable for poor outcomes, such as sarcomatoid and plasmacytoid, demonstrated responses to EV. These hypothesis-generating findings require further validation in studies with adequate sample size for specific HV, and in particular pHV. Evaluation of biomarkers, including Nectin4 expression, in HV is paramount. [Table: see text]
Applying fragmentomics profiles of urinary cell-free DNA for bladder cancer detection.
Authors: Zhang Ruiyun , Dong Hang , Gan Shuang , Tang Haoran , Zang Jingyu , Du Pan , Jia Shidong , Zhuang Guanglei , Chen Haige 
Published: January 2024

671 Background: The liquid biopsy approach focusing on DNA molecules supports non-invasive diagnosis of bladder cancer. While utilizing cell-free DNA fragmentation characteristics for the cancer detection has shown potential in plasma, its applications in urine remained unexplored. Methods: We enrolled 70 patients with bladder cancer and 49 healthy individuals in this study. The urinary cell-free DNA (ucfDNA) was extracted and tested by PredicineSCORE, a low pass whole genome sequencing (LP-WGS) assay to identify tumor-specific features. The ucfDNA fragmentomics profiles including the coverage at specific region, length and end-motif of fragment was implemented. We also investigated the copy number variation and the inferred tumor fraction which was adjust by the Expectation-Maximum (EM) algorithm. Subsequently, an ensembled machine learning model were constructed for classification of bladder cancer and normal control. Results: We observed strong correlation between tumor fraction and specific features. The absolute correlation coefficient between tumor fraction with the LYL1 bonding sites relative depth, the insert size ratio of short reads, and the CCCA end motif were above 0.9, 0.75 and 0.7, respectively. To further assess the robustness of PredicineSCORE assay, we then diluted the tumor samples with tumor fraction ranging from 0.1% to 50% by manually mix reads from tumor samples into normal samples. By applied XGBoost algorithm, the performance (F1 score > 0.95) showed promising ability to distinguish tumor from normal samples. The limit of detection (LOD) was less than 1%, indicating heightened sensitivity compared to previously proposed models. Conclusions: The study suggests that urinary cell-free DNA fragmentomic profiling may enhance the precision of non-invasive bladder cancer detection.
Variant subtypes in bladder cancer and CA125-positive cancer cell state.
Authors: Yang Heiko , Song Hanbing , Allegakoen Paul , Lu Kevin L. , Gayle Janae , Stohr Bradley A. , Ding Chien-Kuang Cornelia , Chou Jonathan , Meng Maxwell , Porten Sima P. , Huang Franklin W. 
Published: January 2024

694 Background: Variant subtypes in bladder cancer are clinically aggressive tumors associated with poor prognosis. The rarity of these tumors has made molecular characterization elusive. The aim of this study was to identify cell states unique to variant subtypes using single cell RNA sequencing. Methods: Fresh tissue was collected from bladder cancer patients undergoing surgery at our institution and sequenced using a bead-based single-cell RNA sequencing platform (SEQWELL). Tissue from histologic variants and high grade pure urothelial tumors were analyzed together for comparison. Pathologic diagnoses were independently confirmed. Analysis was performed using Seurat. Immunostaining validation was performed on a separately banked cohort. Bulk RNA sequencing data and clinical data were extracted and analyzed from The Cancer Genome Atlas (TCGA) database. Results: We generated a single cell RNA sequencing atlas of 9 variants (micropapillary, nested, squamous differentiation, pleomorphic giant-cell like, plasmacytoid, small cell) with 3 pure urothelial tumors for comparison. Our analyses reveal a tumor cell state shared among multiple variants that is characterized by highly specific expression of MUC16 (CA125) , KRT24, and WISP2 (Fig. 1). This cell state has transcriptional hallmarks of epithelial-mesenchymal transition and luminal-basal plasticity, and its signature is associated with poor survival and resistance to chemotherapy. Immunohistochemistry in a validation cohort demonstrates that CA125+ cells are found only in tumors with variant histology and not in conventional high-grade and low-grade urothelial carcinomas. Within variants tumors, CA125+ cells are more enriched in metastatic sites compared to the primary tumors, consistent with a more aggressive phenotype. Conclusions: A CA125+ cell state in variant subtypes in bladder cancer is associated with aggressive molecular features. Further investigation of this cell state is needed to define its role in the pathogenesis of variant tumors.
Survival outcomes in patients (pts) with prostatic cancer (PCa) based on pathologically confirmed sites of metastasis.
Authors: Galarza Fortuna Gliceida , Nazari Shayan , Swami Umang , Elliott Andrew , Gebrael Georges , Bagrodia Aditya , Puri Dhruv , Nabhan Chadi , McKay Rana R. , Antonarakis Emmanuel S. , Agarwal Neeraj 
Published: January 2024

72 Background: In a meta-analysis of 9 phase III trials involving 8,820 pts with metastatic castration-resistant prostate cancer, overall survival progressively decreased from those with lymph node only disease to those with bone, lung, and liver metastases. Herein, we aimed to validate these results in a large real-world dataset based on pathologically confirmed site of metastasis. Methods: PCa tissue specimens derived from the primary Pca (PPCa) and metastatic sites were molecularly profiled by Caris Life Sciences (Phoenix, AZ). Overall survival (OS) was assessed using insurance claims data, with OS calculated from date of initial tumor diagnosis to death or lost to follow-up using Kaplan Meier estimates and log-rank test. Molecular and immunologic differences by specific metastatic site are presented in a companion abstract. All the analyses were done using CODEai. Results: 6,069 PCa specimens were included in the analysis [n= 3,411 prostate, n=1,634 non-visceral (bone and lymph node), n=1,029 visceral disease (lung, liver, peritoneum, brain, other.)]. PCa specimens (n=6,069) were stratified based on tumor biopsy site, including prostate (n= 3411), NV (bone and lymph node; n=1,631), and visceral (lung, liver, peritoneum, brain, other; n=1027) subgroups. The median OS from initial diagnosis was significantly longer for pts with PPCa compared to those with visceral metastatic PCa (median OS 70.2 vs 55.5 months; HR 1.42, 95% CI: 1.28-1.58, p<0.001) as well as non-visceral PCa (median OS 70.2 vs 63.9 months; HR 1.15, 95% CI: 1.05 – 1.27, p=0.004). The comparison of median OS by site of metastatic disease compared to bone metastasis is presented in the Table. Conclusions: We validate the results of prior studies in a real-world PCa population and show differential OS based on the site of metastases, with liver metastases associated with the shortest OS and lung metastases showing the longest OS. These data argue against combining liver and lung metastases into a single category of visceral metastases when visceral metastasis is used as stratification factor for randomized trials. [Table: see text]