bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enfortumab vedotin (EV) outcomes with and without immediate prior immune checkpoint inhibitor (ICI) in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Koshkin Vadim S , Henderson Nicholas , Kilari Deepak , Jindal Tanya , Alhalabi Omar , Freeman Dory , Basu Arnab , Barata Pedro C. , Bilen Mehmet Asim , Zakharia Yousef , Emamekhoo Hamid , Shah Sumit , Milowsky Matthew I. , Davis Nancy B. , Gupta Shilpa , Hoimes Christopher J. , Grivas Petros , Bellmunt Joaquim , Campbell Matthew T , Alva Ajjai Shivaram 
Published: March 2023

514 Background: EV is FDA-approved in pts with aUC and ≥1 prior therapy line. Data from EV-103 trial indicate robust response to first-line EV/pembrolizumab, suggesting potentially at least additive treatment effect with EV/ICI combination. Given the long half-life of ICIs, pts who start EV treatment immediately after ICI may potentially derive benefit from that therapy sequence. We hypothesized that the last systemic therapy prior to EV would impact outcomes, as pts treated with ICI immediately prior to EV would have superior outcomes relative to pts treated with chemotherapy (chemo). Methods: UNITE is a retrospective study of pts treated with EV at 16 US sites. Pt characteristics and outcomes were abstracted from EMR review at each site. Observed response was determined by investigators for evaluable pts with scans following ≥1 EV dose. Pts treated with EV monotherapy were divided into two groups based on whether they received chemo or ICI as the line of therapy immediately prior to EV, regardless of other therapy received. Chi-squared test was used to assess differences in pt characteristics and ORR while log-rank tests were used for OS and PFS measured from EV start. Results: Among 325 pts treated with EV monotherapy, 247 had chemo or ICI as immediate prior treatment, with 186 pts receiving ICI (Group A) and 61 pts receiving platinum-based chemo (Group B). In 247-pt cohort, ORR to EV was 52% and mPFS and mOS were 6 and 13 mos. Group B pts were younger, had more bone mets and higher Bellmunt risk factors, but were otherwise similar to Group A (Table). Most pts had both prior chemo and ICI in both group A (58%) and group B (84%). Group A pts had shorter time from last treatment (median 1.2 vs 3.2 mo, p<0.01), lower ORR to immediate prior treatment (16% vs 37%, p<0.01) and fewer prior therapy lines (mean 1.9 vs 2.6, p<0.01). Group A had superior ORR (58% vs 37%, p=0.02), mPFS (6.9 vs 4.8 mo, p=0.02) and mOS (15.2 vs 8.8 mo, p=0.01) from EV start vs Group B. Conclusions: Pts with aUC treated with EV had superior outcomes if they received ICI instead of chemo as immediate prior treatment, suggesting the hypothesis that this may represent an optimal therapy sequence or combination. These data need external validation as limitations include retrospective design, lack of randomization, and selection and confounding biases. [Table: see text]
Phase 2 open label study of durvalumab with neoadjuvant chemotherapy in variant histology bladder cancer.
Authors: Khaki Ali Raza , Fan Alice C. , Shah Sumit , Parikh Divya Ahuja , Chien Joanne , Moore Kaidi , Ruiz Shann Mika , Haas Denise , Fakhoury Laith , Del Toro Noël , Baker Paige , O'Brien Aidan , Srinivas Sandy 
Published: March 2023

524 Background: The immune-responsive nature of bladder cancer has made it an active area of interest for novel applications of immune checkpoint inhibitors (ICIs), with multiple ICI agents approved in the metastatic setting and ongoing perioperative trials. Variant histology urothelial carcinoma is a rare, heterogenous, and aggressive disease category associated with poor prognosis and response to standard therapies. This investigator-initiated phase 2 trial explored the addition of durvalumab to neoadjuvant chemotherapy (NAC) in the setting of variant histology MIBC. Methods: Patients with cT2-T4a, N0-N1, M0 histologically-confirmed bladder cancer of variant histology who were candidates for platinum-based NAC and radical cystectomy were eligible for the study. Enrolled patients received durvalumab with each cycle of investigator’s choice of platinum NAC (ddMVAC, cisplatin/gemcitabine, or carboplatin/gemcitabine). The primary objective was to determine the safety and tolerability of each study treatment as assessed by the total number of adverse events of grade 3 or higher, judged by the investigator as probably or definitely related to durvalumab. Secondary objective was to determine the percent of subjects post neoadjuvant chemo immunotherapy who achieve tumor stage of pT2N0M0 or better at cystectomy. Target accrual was 24 patients. Results: Six patients were enrolled (the study closed early due to low accrual). Median age was 72 years, 17% were women, 67% were white, 33% were Asian. 50% received ddMVAC and 50% received carboplatin/gemcitabine. All patients completed the planned cycles of NAC and durvalumab (4 cycles) and 5/6 proceeded to radical cystectomy (one patient declined cystectomy). Three patients experienced a Grade 3 AE that was assessed by the investigator to be related to treatment (table). One patient with sarcomatoid and glandular histology had pathological complete response and one patient with papillary and 10% squamous had pT2N0 at cystectomy. Conclusions: The addition of durvalumab to platinum NAC for patients with variant-histology muscle invasive bladder cancer demonstrates a reasonable safety and tolerability profile. Further investigation into this combination is warranted in larger scale trials. Clinical trial information: NCT03912818 . [Table: see text]
Clinical features and prognosis of patients who undergo renal transplant with urothelial carcinoma.
Authors: Li Juan , Yan Xieqiao , Tang Bixia , Li Siming , Zhou Li , Xu Huayan , Guo Jun , Sheng Xinan 
Published: March 2023

527 Background: Malignant tumor has been identified as one of the three major causes of death for kidney transplant recipients. This study collected the clinical data of UC patients after kidney transplantation in our center retrospectively, and explored the natural course of disease and response to systemic treatment of this special subgroup of patients. Methods: 1332 consecutive uc patients diagnosed pathologically in our department from 2012 to 2022 were collected, including 26 renal transplant pts. Data were collected, including gender, age, pathological grade, primary site, initial diagnosis stage, metastasis time, site, systemic treatment plan and response to treatment. Kaplan-Meier survival analysis was used to explore the survival and prognostic factors of uc patients after renal transplantation. Results: 1332 consecutive uc patients from Sep 2012 to Sep 2022 in our department were collected, including 26 pts (1.95%) after renal transplantation. 7 males (26.9%).，overall median age of diagnosis 59.0y (40-79y), 24 pathological high-grade (92.3%), 6 cases are with other differentiation (23%), 7 cases (63.65%) her2 IHC 2~3+ in 11 tested cases. Primary site includes 8 renal pelvis (30.8%), 7 ureter (26.9%), 3 bladder (11.5%) and 8 multiple (30.8%). T1, T2, T3, T4 and Tx accounted for 1 (3.8%), 8 (30.8%), 14 (53.8%), 0 and 3 (11.6%)，with lymph node metastasis in 2 (7.7%). Initial stage I, II, III and IV were 3.8%, 69.2%, 11.6% and 15.4% The median survival time of the four groups was 73.4, 38.0, 18.3 and 13.9 months respectively. The median disease-free survival time of 24 patients after radical surgery was 16.0 months (95% CI: 13.2-27.8m), and 11 patients (42.3%) relapsed within one year after surgery. Among systematic treatment, 24, 9 and 3 patients received the first-, second- and third line treatment. First-line includes nab-ptx+gem (7), ptx+gem+endo/bev (6), ptx+gem+cisplatin+endo/bev (4), gem+cisplatin (3), ADC (2 ), gem+carboplatin (1) and gem+oxa (1). Second-line includes nab-ptx based chemo (5), ADC (2), ptx+gem+cisplatin+endo (1) and ptx+sorafenib (1). Third-line includes nab-ptx +gem+cisplatin+bev (1), gem+cisplatin+sotan (1) and everolimus+cisplatin (1). The mPFS of first-, second-, and third-line were 6.5 months (95% CI: 6.4-17.7 m), 2.6 months (95% CI: 1.6-5.3 m) and 2.0 months (95% CI: 1.8-21 m). The mOS was 15.3 months (95% CI: 8.4-15.1 m), 11.6 months (95% CI: 5.0-16.3 m) and 8.0 months (95% CI: 1.6-13.0 m). The most common distant metastasis in late stage included lymph node in 16 cases (61.5%), lung in 12 cases (46.1%), bone in 7 cases (26.9%) and liver in 5 cases (19.2%). Conclusions: Urothelial carcinoma in renal transplant patients has higher degree of malignancy, nearly half of the patients have rapid recurrence and metastasis after operation. It seems these sub-group patients have higher her2 (IHC 2-3+) status.
Leptomeningeal metastases in prostate cancer: A systematic review.
Authors: Choe Sharon In Wha , Wang Jue 
Published: March 2023

53 Background: Leptomeningeal metastasis (LM) is a rare complication of prostate cancer (PCa) that involves spread of malignant disease to the meninges and carries a poor prognosis. This review aimed to assess the clinical findings, treatments, and outcomes of LM cases reported in the literature. Methods: We performed a literature search for case reports in PubMed, Scopus, and ScienceDirect from database inception to June 2022 using keywords “leptomeningeal carcinomatosis AND prostate cancer” and “leptomeningeal metastases AND prostate cancer.” The reference lists of previously published reviews were also searched to identify additional articles. Results: We included 41 patients with a mean age (±SD, range) at diagnosis of 67.5 (8.4, 46-87) years. The most common presenting symptoms were headache (32%), leg weakness (24%), nausea (22%), vomiting (20%), vision complaints (17%), sensory abnormalities (17%), back pain (12%), and confusion (12%). The median time from initial PCa to LM diagnosis was 36 months (range 0-252) and was reported in 37 patients (90%). The median time of survival from LM to death was 1.7 months (range 4 days – 14 months) and was reported in 28 patients (68%). Four patients (13%) were still alive when the reports were written, including one who was alive at 16 months and another at 252 months. The median serum PSA (±SD, range) at time of diagnosis was 137.5 (507.9, 3.1-1500) ng/mL. The most common diagnostic tests were a combination of neuroimaging and CSF analysis (41%), neuroimaging only (32%), and autopsy only (12%). The most common imaging modalities used to aid diagnosis were MRI (65%) and CT (32%). CSF cytology was positive for malignant cells in 55% of 22 cases (54%) that reported cytology results. Thirty-four cases (83%) reported treatments, and the most common treatments were radiation (56%), steroids (32%), surgery (26%), hormonal therapy (21%), and chemotherapy (21%). Conclusions: LM is expected to become more prevalent with the overall increasing incidence of PCa with therapeutic advancements, yet it remains difficult to diagnose and treat. The findings of this review suggest that neurological symptoms in patients with advanced PCa should prompt providers to obtain neuroimaging to investigate possible LM.
Gene signatures for predicting the response to immune checkpoint inhibitor by integrating bulk and single-cell sequence data in patients with bladder cancer.
Authors: Chang Hyun , Kim Yongho , Lee Jeong Won , Jung Jin-Woo , Yoon Byung Il 
Published: March 2023

535 Background: Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in bladder cancer (BC) therapy, only a limited fraction of patients benefit from it. Thus, we aim to establish gene signature (iGS) and develop a model that predicts the response of ICI for the patients with BC. Methods: We collected bulk RNA expression data from BC cohort (GSE176307) receiving ICI and single-cell sequencing data from patients with BC (GSE135337). Single-sample gene set enrichment (ssGSEA) analysis was used to develop predictive iGS. Clinical benefit of ICI was defined as a complete or partial response or stable disease at week 24. The gene ontology (GO) and pathway enrichment analysis were established through DAVID database. Logistic regression model was constructed with iGS and clinical factors. The final model was validated by the K-fold cross validation technique. Results: We integrated bulk RNA expression data and single-cell sequencing data, and identified subset of cells (N= 157) that were associated with the overall survival (OS) of patients receiving ICI. These cells were compared with all other cells, and 85 up-regulated differentially expressed genes (DEGs) were identified. DEGs were mainly enriched in 'antigen processing and presentation of exogenous peptide antigen via MHC class II', 'peptide antigen assembly with MHC class II protein complex' and 'immune response' in the biological process enrichment analysis. High iGS score, that was derived from ssGSEA, was significantly associated with longer OS in multivariate Cox regression analysis (Hazard ratio: 0.40, P = 0.02) Final prediction model for clinical benefit included iGS score [odds ratio (OR) = 3.89], tumor mutation burden (OR = 9.8) and age (OR = 0.93) with accuracy of 0.80 and an area under the receiver operator characteristic curve (AUROC) of 0.77. Conclusions: We showed the potential of iGS from bulk and single cell RNA sequencing for predicting clinical benefit of ICI in BC.
Antitumor immunity as the basis for durable disease-free, treatment-free survival (DDFTFS) in patients with metastatic urothelial cancer (mUC).
Authors: Anker Jonathan Forrest , Pal Sumanta Monty , Kim-Schulze Seunghee , Wang Huan , Halperin Rebecca , Uzilov Andrew , Saito Takuro , Hahn Noah M. , Patel Manishkumar , Qi Jingjing , Xie Hui , Bhardwaj Nina , Gnjatic Sacha , Galsky Matt D. 
Published: March 2023

536 Background: Cisplatin-based chemotherapy has been associated with functional cures (i.e., DDFTFS) in a small subset of patients with mUC. However, the mechanistic basis for this phenomenon has remained elusive. Immune checkpoint blockade may enhance the ability of cisplatin-based chemotherapy to cure mUC, particularly if the latter is achieved by promoting antitumor immunity. From a phase II trial evaluating a phased schedule of gemcitabine and cisplatin (GC) followed by GC plus Ipilimumab (Ipi) for mUC, 4/36 patients were treatment-free disease-free >7 years after initiation of treatment. We sought to identify the immunological mechanisms associated with functional cure of such patients. Methods: Whole exome sequencing was performed on pre-treatment archival tumor tissue. Neoantigen binding affinity was predicted using NetMHCcons. Neoantigen-specific T cell response was assessed via IFNγ ELISpot assays after co-culture of patient-derived peripheral blood CD4+ and CD8+ T cells with autologous neoantigen-pulsed antigen presenting B cells. Serum protein soluble analytes were measured using the Olink Target 96 Immuno-Oncology Panel at the pre-treatment, post-GC, and post-GC+Ipi timepoints. Results: CD4+ and CD8+ neoantigen-specific T cell reactivity was measured at serial timepoints in 2 patients achieving DDFTFS and 5 patients not achieving DDFTFS. Strikingly, peripheral blood CD4+ and CD8+ T cell reactivity to a predicted neoantigen emerged on cycle 6 day 1 (after 2 cycles of GC followed by 4 cycles of GC + Ipi) in 2/2 patients achieving DDFTFS (variant in TP53 or DHX9) but in 0/5 patients not achieving DDFTFS. Peripheral serum proteomic analysis at serial timepoints (n = 35 patients) revealed that pre-treatment, patients achieving DDFTFS demonstrated an immune activated phenotype with elevations in cytotoxic adaptive immunity markers and immune checkpoints (Table). After the addition of Ipi, patients achieving DDFTFS demonstrated decreased markers of tumor-promoting inflammation but increased markers of adaptive immunity, co-stimulation, and cytotoxicity. Conclusions: Anti-tumor immunity may underlie functional cures achieved in patients with mUC treated with cisplatin-based chemotherapy +/- immune checkpoint blockade. Probing the mechanistic basis for DDFTFS may facilitate the identification of pre- and on-treatment features, and therapeutic components and sequences, necessary to extend this ultimate therapeutic goal to a larger subset of patients. [Table: see text]
EphA2 on urinary extracellular vesicles as a novel diagnostic marker for bladder cancer and its effect on the invasiveness of bladder cancer.
Authors: Tomiyama Eisuke , Fujita Kazutoshi , Kato Taigo , Hatano Koji , Kawashima Atsunari , Nonomura Norio 
Published: March 2023

539 Background: An accurate and non-invasive test for diagnosing bladder cancer (BCa) is needed. Potential diagnostic markers include cancer-specific proteins in urinary extracellular vesicles (uEVs) secreted directly from BCa. In this study, we aimed to identify a uEV-based protein biomarker for the diagnosis of BCa and develop an ELISA for clinical application. In addition, we evaluated whether the identified EV protein exerts a cancer-promoting effect on BCa. Methods: Urinary EVs were isolated by ultracentrifugation with a sucrose cushion. Shotgun proteomics (TMT-labeled LC-MS/MS) was performed on uEVs from seven patients with BCa and four healthy individuals. Biomarker candidates were selected from the identified proteins and validated with targeted proteomics (SRM/MRM) of uEVs from 49 patients with BCa and 48 individuals without BCa. In addition, we developed an ELISA, without time-consuming ultracentrifugation, for quantifying the uEV-based protein biomarker and evaluated its diagnostic performance using urine samples from 46 patients with BCa and 46 individuals without BCa. The effect of the validated EV protein on BCa was also analyzed in vitro. Results: Shotgun proteomics identified 1960 proteins, of which 13 membrane proteins were significantly upregulated in the uEVs from patients with BCa. Among them, eight proteins were validated by target proteomics, and Ephrin type-A receptor 2 (EphA2) showed the best diagnostic performance (ROCAUC = 0.79). We developed EV-EphA2-CD9 ELISA as a simple assay for uEV-EphA2 measurement with clinical value, which showed good diagnostic performance (sensitivity: 60.9 %, specificity: 97.8%). Furthermore, the combination of EV-EphA2-CD9 ELISA and urine cytology improved the detection of BCa (sensitivity, 80.4 %; specificity, 97.8 %), which could reduce the frequency of cystoscopy at bladder cancer diagnosis and during follow-up. In addition, we demonstrated that EphA2 promotes the proliferation, invasion, and migration of BCa cells and that EV-EphA2 promotes the invasion of BCa cells. The invasion-promoting effect of EV-EphA2 was attenuated by knockdown of Ephrin-A1, the ligand of EphA2, on BCa cells or by prior exposure of Ephrin-A1 to EV-EphA2, suggesting that the signalling pathway via Ephrin-A1 toward BCa cells was involved in the cancer-promoting effect of EV-EphA2. Conclusions: We identified uEV-EphA2 as a novel diagnostic marker for BCa and established EV-EphA2-CD9 ELISA for uEV-EphA2 quantification, which enables the non-invasive early diagnosis of BCa in clinical practice. Furthermore, we revealed that exosomal EphA2 promotes the invasion of BCa via its ligand; Ephrin-A1 on BCa cells, suggesting that these may be potential therapeutic targets.
Performance characteristics of a tumor-informed circulating tumor DNA (ctDNA) minimal residual disease (MRD) assay in invasive bladder cancer in clinical practice.
Authors: Mehler Shoshana , Guilbeau Seth , Somer Shmuel , Reed Kevin , Greene Heather , Vaena Daniel A. , Grothey Axel , Somer Brad 
Published: March 2023

542 Background: Detection of minimal residual disease (MRD) is emerging as a potential risk stratification and surveillance tool in patients with resected bladder cancer to potentially direct adjuvant therapy and early intervention. Recently, the sensitivity of MRD testing for early detection of recurrence has been questioned. We sought to evaluate the real world diagnostic performance characteristics of the Signatera ctDNA assay in patients with stage 1-4 bladder cancer who either had transurethral resection of bladder tumor (TURBT) in addition to either chemoradiation or radical cystectomy. Methods: Patients with bladder cancer who underwent ctDNA MRD testing after resection for stage 1-4 disease from 03/2021 to 09/2022 were evaluated retrospectively. Both patients with single and serial ctDNA assays were included. Individual chart review was performed to collect demographic and clinical variables such as diagnosis, stage, pathology, imaging results, and treatment course. Results: MRD results from 19 patients were available, 9 of which had serial assays. 13/19 patients were found to have ctDNA positive results at any time point. The positivity rate at initial testing was associated with stage: Stage 1: 3/5 patients, of which 2 had TURBT and 1 Radical cystectomy, stage 2: 2/5, stage 3: 6/8, and stage 4: 0/1. Notably, of the 9 patients with serial assays, one patient’s result converted from negative to highly positive during surveillance, with subsequent decrease to low positive after adjuvant therapy. One patient had a result of 2 consecutive low positives initially, which was converted to negative after systemic therapy and radiation. 7/19 patients completed testing 3 or more times over a span of approximately 4-13 months, 2 of whom had negative results throughout. Most patients who were found to have positive ctDNA did demonstrate radiographic recurrence within 2-3 months of ctDNA detection. Conclusions: Positive ctDNA MRD after resection is common in bladder cancer. Tumor-informed ctDNA MRD testing has very high sensitivity, but a one-time negative test result does not exclude the presence of metastatic disease. The above data shows an association between cancer stage and positivity results, particularly for advanced stages. Stage I cases with positive results can likely be explained by inadequate resection. Increases in ctDNA may represent early recurrence and can potentially be salvaged with early systemic therapy reverting to negative ctDNA. Prospective randomized and non-randomized studies are evaluating the clinical utility of ctDNA MRD testing in bladder cancer, and analysis of Signatera ctDNA assays will largely contribute to these efforts.