bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency of pathogenic germline variants in cancer susceptibility genes in 841 renal cell carcinoma cases.
Authors: Li Mingwei , Qin Jiayue , Liang Xiayuan , Zhou Tao , Zhang Yanrui , Wang Huina , Cao Shanbo 
Published: June 2023

e16551 Background: Hereditary Renal cell carcinoma (RCC) syndrome accounts for approximately 5-10% of all kidney cancers. However, the genetic architecture of susceptibility to RCC is not well defined. In this study, we investigated the prevalence and spectrum of pathogenic/likely pathogenic germline variants of cancer susceptibility genes in unselected RCC patients in the real-world Chinese population. Methods: We retrospectively profiled the germline mutations of 841 unselected RCC patients using a next-generation sequencing panel consisting of 808 cancer-related genes. Interpretation of sequence variations was classified according to the American College of Medical Genetics and Genomics guidelines. Genomic alterations include single nucleotide variations (SNV), short insertions/deletions (INDEL) and copy number variations (CNV). Results: Within 841 unselected RCC patients included in this study, 132 germline pathogenic/likely pathogenic (P/LP) variants were identified in 125 patients (14.9%), of which 114 (13.6%) were mutations of SNV/INDEL and 11 (1.3%) were CNV. Overall, 46 patients (5.5%) carried mutations of hereditary RCC syndrome-associated genes such as VHL (13, 1.5%), FH (13, 1.5%) and FLCN (8, 1.0%). Interestingly, variants in other cancer-predisposition genes not traditionally associated with RCC occurred in 9.4% of the unselected series, including 55 (6.5%) patients carried mutations in DNA damage (DDR)-related genes (e.g., MUTYH, CHEK2 and BRCA1/2) and the other 24 (2.9%) had germline mutations of non-DDR-related genes (e.g., SPINK1 and APC). The median age of patients with mutations of RCC syndrome-associated genes was 38 (range 19-77), while the median age of patients with mutations of other cancer-predisposition genes was 52(range 22-82). Furthermore, in patients older than 46 years, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes were 1.9% and 6.7%, respectively. Notably, among 125 patients with identified germline mutations, nearly half (56, 44.8%) did not meet the recommended criteria for genetic testing. Conclusions: Our findings confirm a high prevalence of pathogenic germline variants in genes associated with both hereditary RCC and other cancer predispositions in the unselected Chinese RCC population. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing and expand the range of genes in RCC population with advanced age.
Phase 2 study of HDAC inhibitor tucidinostat in combination with anti-PD-1 antibody in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Liu Zhuowei , Jiang Lijuan , Li Xiangdong , Ye Yunlin , Wu Zhiming , An Xin , Shi Yanxia , Yao Kai 
Published: June 2023

e16563 Background: Tucidinostat (also known as chidamide), a novel histone deacetylase (HDAC) inhibitor, has been approved for treatment of patients (pts) with relapsed or refractory peripheral T-cell lymphoma and advanced hormone receptor-positive breast cancer in China. Tislelizumab (a PD-1 checkpoint inhibitor) is currently approved for pts with PD-L1-high locally advanced or metastatic urothelial carcinoma (UC) who progressed during/following platinum-containing therapy in China. However, the response rate of tislelizumab as monotherapy is limited in UC. The aim of this study was to evaluate the efficacy and safety of tucidinostat combined with tislelizumab in pts with locally advanced or metastatic UC. Methods: This study is an open-label, single-center, phase Ⅱ trial. Patients who previously failed systemic platinum-based chemotherapy with UC were included, regardless of PD-L1 status. Eligible pts received 30 mg oral tucidinostat twice weekly (BIW) in combination with 200 mg tislelizumab by intravenous drip every three weeks (Q3W). This is a Simon's two-stage design. All pts were treated until progression or unacceptable toxicity in two years. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), the safety and tolerability. Results: From Jan. 2021 to Sep. 2022, 26 pts were enrolled (median age 62 y, range 31-74y), of whom 24 were evaluable for response per RECIST 1.1 criteria. One pt was lost to follow-up and one withdrew the group due to sudden cerebral infarction. Complete response (CR) was observed in 2 pts, while partial response (PR) was observed in 8 pts, with an ORR of 41.7% (10/24). The DCR was 62.5%. The median PFS was 4.6 months. Most adverse events (AEs) were grade 1 or 2. The most common grade 3 AEs were neutropenia 11.5%, thrombocytopenia 11.5%, leukopenia 7.7%, anemia 7.7%, anorexia 7.7%, creatinine increased 3.8%. One pt experienced grade 4 immuno-pneumonia was permanently discontinued. One pt was on maintenance therapy of tucidinostat without immunotherapy because of interstitial pneumonia. Conclusions: The preliminary data indicate that tucidinostat combined with tislelizumab might be a potentially effective regimen with a manageable safety profile in UC. The study remains ongoing and updated results will be presented later. Clinical trial information: NCT04562311 .
Identification of prognostic biomarkers in plasma of patients with metastatic urothelial carcinoma (mUC).
Authors: Palacka Patrik , Svastova Eliska , Csaderova Lucia , Chovanec Michal , Rejlekova Katarina , Obertova Jana , Lesko Peter , Orszaghova Zuzana , De Angelis Valentina , Slopovsky Jan , Holickova Andrea , Roska Jan , Orasova Eveline , Nociar Boris , Mego Michal , Mardiak Jozef , Chovanec Miroslav 
Published: June 2023

e16564 Background: Performance status and visceral metastasis before first-line chemotherapy based on cisplatin (CDDP) predict survival of subjects with mUC. The objective of this study was to explore the prognostic value of selected plasma biomarkers. Methods: We have evaluated the samples from 86 mUC subjects (64.0% males). Performance status of ECOG 2 and visceral metastasis were present in 39.5% and 50.0% cases, respectively. The MILLIPLEX panels were used for determination of 51 biomarkers in plasma taken from patients before systemic therapy initiation. Study population was dichotomized into high and low groups by median for each parameter. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was carried out by the Cox regression model. Results: At median follow-up of 8.6 months (6.4-10.1), 95.3% of patients experienced disease progression and died. Better PFS was associated with low levels of nine biomarkers: IL-1RA (HR 0.65, P=0.0425), IL-6 (HR 0.52, P=0.002), IL-8 (HR 0.46, P=0.0002), IL-10 (HR 0.49, P=0.0004), IL-15 (HR 0.61, P=0.0198), IL-22 (HR 0.45, P=0.0043), MCP-1 (HR 0.59, P=0.0147), M-CSF (HR 0.59, P=0.0119), and VEGF-A (HR 0.64, P=0.0392). OS was significantly better in patients with low levels of G-CSF (HR 0.42, P=0.047), IL-1RA (HR 0.63, P=0.0314), IL-2 (HR 0.61, P=0.0249), IL-6 (HR 0.47, P=0.004), IL-8 (HR 0.44, P=0.0001), IL-10 (HR 0.43, P<0.0001), IL-15 (HR 0.53, P=0.0026), IL-22 (HR 0.47, P=0.0065), IL-27 (HR 0.63, P=0.0343), MCP-1 (HR 0.59, P=0.0134), M-CSF (HR 0.55, P=0.0042), TNFα (HR 0.53, P=0.0024), and VEGF-A (HR 0.59, P=0.0124). The independent prognostic values of IL-6, IL-10, MCP-1, M-CSF, and TNFα were confirmed in a multivariate analysis. Conclusions: In this study, we have proved that selected plasma biomarkers may have a prognostic value in mUC patients. Further research is required to understand their role as the biomarkers, but also potentially treatable pathogenic factors for mUC development. This research was funded by grant of the Integrated Infrastructure Operational Program, ITMS: 313011AFG5, co-financed by the European Regional Development Fund & OncoReSearch, Slovakia.
The impact of next generation sequencing on the management of urothelial cell carcinoma.
Authors: Abu-Hashish Hussein , Browne Rasheda , Zhu Xinhua 
Published: June 2023

e16576 Background: The urothelial carcinoma is commonly seen in urethra, bladder, ureter and renal pelvis. Targetable mutations included PD-L1, FGFR, PIK3CA, BRCA2, FBXW7, and Tumor mutation burden (TMB) greater than 10 Muts/Mb. Next genome sequencing is widely used to guide treatment of oncology patients; however, the efficacy of this practice is still not clear. Methods: Patients used in this study are from the Northwell Health Zuckerberg Cancer Center. This is a retrospective cohort study of patients with advanced urothelial carcinoma, who underwent next genome sequencing and received treatment based on targetable mutations. The primary objective for this study is to measure the response rate for patients with actionable gene aberrations on targetable treatment. Results: The RECIST 1.1 guidelines were used when identifying measurable lesions. Measurable lesions were identified as lymph nodes with a short axis ≥ 15 mm, or soft tissue lesions with a long axis ≥ 10 mm. Our sample size included 48 patients with urothelial carcinoma, these include bladder, ureter and renal pelvis cancers. Of these 48 patients, 21 received targetable treatment (16 males, 5 females), from those 21 only 20 had imaging before and after treatment. Most common mutations were TMB, PD-L1 and FGFR. 4 patients out of 20 had an overall response rate (20%), 3 had partial response (PR) and 1 had complete response (CR) to their respective targeted treatment. 11 patients had stable disease (SD). Thus disease control rate (DCR) was 15 out of 20 patients (75%) (when including PR, CR and SD out of 20 patients) had no progression of disease. Finally, 5 of the 20 patients had an overall progression of disease (PD). Conclusions: The results of our study indicate that next genome sequencing led to good treatment outcomes for patients previously heavily treated with advanced urothelial malignancy.
Upper tract urothelial cancer (UTUC): Role of sequencing, molecular subtyping and treatment outcomes.
Authors: Belay Sarah , Li Wenping , Aragon-Ching Jeanny B. 
Published: June 2023

e16578 Background: Upper tract urothelial cancers (UTUCs) are rare forms of urothelial cancer that behave in a more aggressive manner. Treatment response to immunotherapy may be less impactful in the adjuvant setting. Studies suggest molecular subtyping might predict survival outcomes. We seek to determine whether genomic sequencing, molecular subtype signatures can be used to predict patient response to chemotherapy in upper tract urothelial cancers. Methods: UTUC patients seen consecutively at a single institution during a 4-year period were evaluated with IRB approval. Analyses of NGS (next-generation sequencing) using Foundation Medicine or TEMPUS platforms were compiled. Decipher Bladder assay (research use only for UTUC) using a transcriptome microarray to characterize tumor specimens as luminal vs. non-luminal and 4 non-luminal subtypes. Retrospective and descriptive analyses were used to identify predictors of response and survival and therapeutic options patients (pts) underwent. Additional phenotypic factors such as initial staging, tumor location, response to neoadjuvant chemotherapy (NAC), and responses to treatment for localized or metastatic disease were determined. Results: UTUC patients whose clinical and demographic features were available for 23 patients (Male = 7; Female = 16); locally advanced = 9; metastatic = 14. Tumor samples were obtained with Decipher bladder assay (n=4); next-generation sequencing assay (n = 9). Neoadjuvant chemotherapy (NAC) was given in all pts with localized disease and for metastatic disease (n=11 pts). Platinum-based chemotherapy (PBC) resulted in median overall survival (mOS) of 36.6 mos compared to no chemotherapy 22.8 mos at the time of data cut-off. Decipher bladder assay showed basal subtype and mixed basal/claudin-low in 4 patients of whom one achieved stable disease though residual ypT3 after NAC and the 3 achieved progressive disease as best response, all with metastatic disease. NGS showed LOH - 21.01% and ATM truncation in 2 patients with prolonged responses to avelumab maintenance immunotherapy and 2 patients with CDK2A/2B loss with prolonged survival (mOS = 16.8 mos). Additionally, 5 patients were identified as having a TERT promoter variant, though this does not appear to have a significant relationship with survival or disease progression when compared to those without the variant. Conclusions: Results do not identify a specific NGS signature or subtype signature that predicts response to chemotherapy in the neoadjuvant or metastatic setting though receipt of chemotherapy appears to clinically affect outcomes in this small sample of UTUC patients. Further studies are needed to identify specific molecular signatures that would predict responses to therapy.
AI-based identification of FGFR3 mutation status from routine histology slides of muscle-invasive bladder cancer.
Authors: Saillard Charlie , Bannier Pierre-Antoine , Mann Philipp , Maussion Charles , Matek Christian , Hartmann Arndt , Eckstein Markus 
Published: June 2023

e16580 Background: Gain of function mutations of the FGFR3 gene have been reported to be important driver mutations in a subset of muscle-invasive bladder urothelial cancer (MIBC). Subsequently, gene specific kinase inhibitors (e.g., erdafitinib) have been developed to target FGFR3 mutant metastasized MIBC with promising clinical activity. FGFR3 mutational status testing is required for erdafitinib treatment, but FGFR3 mutations are rare in metastatic MIBC (10-15%). Thus, cheap and fast pre-screening tools such as artificial intelligence (AI) based image classifiers could help to reduce turnover times of FGFR3 mutational testing and save costs arising from universal mutational testing. Herein, we propose an AI-based approach to identify MIBC FGFR3 mutated patients on routine histological slides. Methods: Slides from 612 patients with MIBC from two different sources (CCC-EMN Erlangen cohort n = 239, mutant = 20; TCGA-BLCA n = 373, mutant = 50) were used. The CCC-EMN cohort was used as a discovery set while TCGA-BLCA was used as an independent validation set. A two-step AI model was used to 1) extract features from each slide and 2) predict FGFR3 status from these features. The AUC, sensitivity and specificity were used as metrics to assess the performance of our model. Most predictive regions of FGFR3 mutation were reviewed by an expert pathologist. Results: The model reached an AUC/Sensitivity/Specificity of 0.82 [0.76-0.87] / 0.90 [0.82-0.97] / 0.57 [0.53-0.62] on TCGA-BLCA, substantially improving upon results previously reported on the same cohort (Loeffler et al. 2021: AUC = 0.70). Most predictive regions of FGFR3 mutation revealed monomorphous conventional urothelial tumor morphology and low desmoplastic tumor stroma content, while least predictive regions contained pleomorphic tumor morphology and high amounts of desmoplastic tumor content. Conclusions: By ruling out 57% of MIBC FGFR3 wild type tumors with high sensitivity, our model is the first to reach valuable performance for clinical use. Consequently, this study paves the way for the development of FGFR3 pre-screening tools to ease the management of patients with MIBC.
Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).
Authors: Semaan Karl , El Zarif Talal , Saliby Renee Maria , Eid Marc , Saad Eddy , Labaki Chris , Kwak Lucia , Kaymakcalan Marina D. , Baca Sylvan , Berg Stephanie A. , Xie Wanling , Mantia Charlene , Choueiri Toni K. , McGregor Bradley Alexander , Bellmunt Joaquim 
Published: June 2023

e16585 Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with > 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]
Neutrophil-to-lymphocyte ratio as a predictor of immune checkpoint inhibitor therapy response in advanced bladder cancer.
Authors: Nair Monica , Dawsey Scott , Pramod Nikhil , Clemenceau Jean Rene , Gilligan Timothy D. , Ornstein Moshe Chaim , Wee Christopher Eing , Nizam Amanda , Almassi Nima , Weight Christopher J. , Gray Michi , Echle Jessica , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D. , Scott Jacob , Gupta Shilpa , Mian Omar Y. 
Published: June 2023

e16586 Background: Immune checkpoint inhibitor (ICI) therapy is a novel and promising agent for treating muscle invasive bladder cancer (MIBC). However, there is a need for further understanding of which patient factors or biological markers can be used to help identify patients who will have a successful response to ICI therapy. We hypothesized that Neutrophil-to-Lymphocyte Ratio (NLR) could be predictive of response to ICI therapy as this ratio has previously been reported to correlate with a higher number of myeloid derived suppressor cells. Methods: A retrospective cohort analysis was performed on patients with advanced or metastatic bladder cancer who were treated with ICI therapy at a single institution between 2015-2020. Information on survival, disease recurrence, and patient characteristics was gathered. Neutrophil and lymphocyte numbers were recorded at time of ICI administration and a ratio of neutrophils to lymphocytes was calculated. The median of these values was calculated and used to divide the cohort into low NLR and high NLR. Tissue samples from a subset of these patients were collected and sent for multiplex immunohistochemistry with a myeloid and T cell staining panel. Results: In a cohort of 115 patients with advanced bladder cancer treated with ICI, the mean time to last follow up or event (death or disease progression) was 375.78 days (SD 41). 35 patients (30%) had either a complete or partial response to ICI therapy. A Kaplan Meier survival analysis shows a significant difference in survival between the low and high NLR group, with lower NLR having a longer event free survival (Wilcoxon rank p = 0.0156). Multiplex IHC showed variable tumor and adjacent microenvironmental distributions of myeloid and lymphoid marker positive populations in ICI responders and non-responders. Conclusions: In an effort to better predict which patients may benefit from ICI therapy, we have studied NLR at the time of ICI administration and its association with event free survival. Our results suggest that a lower NLR could be associated with a longer event free survival. Further research is being conducted to study the immune microenvironment as it relates to bladder cancer response to ICI therapy.
Real world outcome of neuroendocrine carcinomas of the bladder compared to conventional tumors of the bladder.
Authors: Unlu Serhan , Ogbue Olisaemeka , Nanah Abdel Rahman , Sorathia Sharmeen , Almassi Nima , Lapinski James , Haddad Abdo S. , Daw Hamed 
Published: June 2023

e16591 Background: Platinum based neoadjuvant chemotherapy (NAC) has been shown to be a beneficial treatment strategy that increases overall survival (OS) in bladder cancer (BC) when compared to radical cystectomy (RC) alone, and the benefit was observed in multiple histologies associated with BC. Neuroendocrine carcinomas (NEC) of the bladder are a rare and aggressive BC subtype known to be chemotherapy sensitive, with improvement in oncological outcomes after NAC. However, due to inherent differences in natural progression of different BC histologies, higher chemosensitivity does not necessarily mean NEC has better outcomes compared to other BC histologies after NAC. We analyzed the outcomes of NEC patients and non-NEC BC patients to investigate the differences in benefit observed from NAC, and in oncological outcomes. Methods: Patients with BC that underwent cystectomy from 2000 to 2022 at the Cleveland Clinic Foundation were identified. Patients with NEC at transurethral resection (TUR) or cystectomy, and patients with BC with other pathologies (non-NEC) were selected. pCR was defined as downstaging from tumor presence in diagnostic resection to no residual tumor (pT0N0) after NAC. Survival outcomes of interest included recurrence-free survival (RFS) and OS. Results: A total of 562 cases of BC that underwent RC were identified. Of these, 50 patients included a diagnosis of NEC in their pathology report, either in TUR (n=42), or in RC (n=8) with 36% (18/50) of them with NEC without an associated conventional urothelial cell carcinoma (UCC), while 502 patients were diagnosed with UCC, with or without variant histologies and 10 patients with other histologies without UCC. Among patients with NEC, median age was 69 and M:F-45:5. When NEC patients were compared to non-NEC BC patients, they were more likely to present with muscle invasive bladder cancer (MIBC), (83% vs 60%; p=0.003) and receive NAC (86% vs 35%; p<0.001) Most common chemotherapy regimen used in NEC patients was combination platinum and etoposide (26/36), compared to platinum and gemcitabine in non-NEC BC patients (141/184). pCR rate was 36% (13/36) in NEC, compared to 20% (36/184) in non-NEC cohort. (p=0.046). In terms of survival outcomes, RFS and OS were similar between the two groups (log-rank p-values 0.08 and 0.14, respectively). Conclusions: NAC prior to RC is beneficial in NEC of the bladder as a higher proportion achieve pCR when compared to non-NEC BC. In our cohort, despite presenting with more advanced disease, oncologic outcomes after NAC with RC were similar between the two groups. [Table: see text]