bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gasdermin C as a potential prognostic biomarker and its correlation with immune infiltration in pancreatic ductal adenocarcinoma.
Authors: Xia Xianghou , Yu Yang , Yang Hongjian , Zou Dehong , Wang Canming , Hu Jiejie , Mao Jiefei , Cai Xixi , Yin Wenjuan 
Published: June 2021

e16256 Background: Although pyroptosis is critical for macrophages against pathogen infection, its role in cancer cells remains elusive. GSDMC is a pyroptosis executioner newly identified in cancer cells and have been shown to facilitate inflammatory tumor death. However, the expression of GSDMC in Pancreatic Ductal Adenocarcinoma (PDAC), its prognostic significance and possible impact on reshaping tumor immune microenviroment in PDAC is still unknown. Methods: We investigated the expression level of GSDMC using TNM plotter with TCGA and GTEx databases, the prognostic value of GSDMC in PDAC using Kaplan-Meier plotter with TCGA, GTEx and TCGA databases. The correlations between GSDMC and immune infiltration in PDAC were calculated using TIMER2.0 and TIDE with TCGA database. We further validated the prognostic value of GSDMC with immunohistochemistry(IHC) staining on a tissue microarray of 172 cases of PDAC patients receiving treatment in our institution. Correlations between expression of GSDMC and tumor infiltration lymphacytes(TILs) cells were also analyzed on tissue samples of those 172 PDAC patients. Results: TNM plotter analysis shows that the expression of GSDMC in PDAC tumor tissue is 10.49 folds higher than it is in pancreatic normal tissues (p = 8.86*e-56). Results from Kaplan-Meier plotter analysis shows high expression of GSDMC is significantly correlated with poorer overall survival(OS), HR = 1.8(1.19−2.71) logrank P = 0.004 and shorter relapse free survival (RFS), HR = 4.6(1.94−10.88), Logrank P = 0.00014 in PDAC. Analysis with TIMER2.0 and TIDE platform shows that expression of GSDMC is positively correlated with immunosuppressive cells, Cancer Associated Fiberblast (CAF) and Meyloid Derived Tumor Suprresso Cells(MDTSC). IHC staining analysis results is also consistent with aformentioned bioinformatic analysis, showing that high GSDMC expression correlated with shorter OS and reduced Tils infiltration. Conclusions: Our findings suggest that high expression of GSDMC is related to poor prognosis and compromised immune cell infiltration in PDAC. GSDMC holds promise for serving as a valuable prognostic marker and therapeutic target in PDAC.
Association of FGFR alterations with FGFR 1-4 gene expression in TUR biopsies and matched NMP22 urine levels in early bladder cancer of the prospective real world clinico-pathological register trial: BRIDGister.
Authors: Wirtz Ralph M. , Friedersdorff Frank , Veltrup Elke , Kilic Ergin , Watts Richard , Kellner Ronny , Hake Roland , Eidt Sebastian , Roggisch Jenny , Koch Stefan , Ecke Thorsten 
Published: June 2021

e16533 Background: The objective of the present study was to identify molecular charactersitics associated with FGFR positive tumors in matched urine and TUR biopsy samples from patients being suspicious of bladder cancer and undergoing first TURB at the pilot center of the multicentric BRIDGister Real World Experience trial that are helpful for patient management and prognosis. Methods: For this pilot study paraffin fixed pretreatment tissue samples from the first TURB of 28 pts participating in the BRIDGister trial and matched urine samples were prospectively collected and analyzed. RNA from FFPE tissues were extracted by commercial kits and analyzed by Therascreen FGFR IVD kit (Qiagen GmbH, Hilden). Relative gene expression of subtyping markers (KRT5, KRT0) as well as FGFR1, FGFR2, FGFR3, FGFR4, ERBB2 was centrally tested by standardized test systems (STRATIFYER Molecular Pathology GmbH, Cologne). In addition urine samples were analyzed by commercially available urine tests (UBC Rapid, BTA stat, NMP22). Spearman correlation, Kruskal-Wallis, MannWhitney and Sensitivity/Specificity tests were done by JMP 9.0.0 (SAS software). Results: The pilot cohort of the BRIDGister trial consisted of 28 patients (median age: 73, male 71% vs female 29%) of diverse clinical stages (Benign lesions/no tumor 21%, pTa 32%, pT1 21%, pT2 21%) and WHO 1973 grade (G1 7%, G2 43%, G3 21%). Based on FFPE tissue testing using Therascreen FGFR IVD kit 9 out of 28 patients exhibited FGFR alterations (32%). FGFR positive tumors were associated with high expression of FGFR3 mRNA (r = 5.951, p = 0.0011) but low FGFR1 mRNA as well as FGFR4 mRNA (r = -0.3882, p = 0.0412 and r = -0.6305, p = 0.0004, respectively). Interestingly, FGFR alteration was positively associated with the basal marker KRT5 (r = 0.3929, p = 0.0386), but not with luminal KRT20 mRNA expression (r = -0.0208, p = 0.9179). Moreover FGFR3 altered bladder cancer was associated with elevated NMP22 levels in pretreatment urine (r = 0.3978, p = 0.0361). Conclusions: In early bladder cancer FGFR3 alterations are tightly associated with a characteristic FGFR mRNA signature. Mutation/Fusion of FGFR3 results in high FGFR3 but low FGFR1 and FGFR4 mRNA expression, which might be i.a. relevant for the response to FGFR inhibition and important to predict outcome of FGFR inhibitors. Morever FGFR alteration was associated with elevated NMP22 urine levels, which might be helpful for detecting and monitoring FGFR altered bladder cancer in a non invasive fashion. These results warrant further investigation and its impact on outcome prediction (BCG responsiveness, recurrence, proegression, etc) will be prospectively analyzed in the framework of the ongoing multicenter BRIDGister Real World Experience trial.
Comparative effectiveness of combination first-line therapies for metastatic renal cell carcinoma (mRCC).
Authors: Shay Rebecca C. , Nicklawsky Andrew , Lam Elaine Tat 
Published: June 2021

e16549 Background: Numerous immunotherapy (IO) and vascular endothelial growth factor receptor inhibitors (VEGFI) options are approved for first-line (1L) treatment of mRCC. We performed a systematic review and meta-analysis to compare the oncologic outcomes and adverse events of these therapies. Methods: We searched databases for randomized controlled trials (RCT) evaluating agents that are currently FDA-approved or on the NCCN compendium for 1L mRCC, with sunitinib (S) as a comparator. Primary outcomes were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade 3 and 4 (G3/G4) adverse events (AEs). We attempted network meta-analysis (NMA) to estimate relative effects of the comparative treatments. Survival outcomes were summarized using hazard ratios (HR). In the case that the HR was not reported but a Kaplan-Meier curve was available, the curve was digitized using Engauge Digitizer software. A frequentist fixed-effects NMA model was applied to each outcome. Results: 798 articles were identified, of which 47 were eligible for full text screening, and 8 were included for evidence synthesis. Eight RCTs recruiting a total of 5,565 pts with advanced or metastatic treatment-naïve RCC were included. The summary of all included studies is reported in Table 1. Ordered from the most to least effective, treatments with greatest mOS benefit include Nivolumab plus Cabozantinib (NC), Pembrolizumab plus Axitinib (PA), and Nivolumab plus Ipilimumab (NI); treatments with greatest mPFS benefit include Cabozantinib (C), NC, and Avelumab plus Axitinib (AA); treatments with the highest ORR include C, NC, and AA. Ordered from least to most toxic, treatments with G3/G4 AEs less frequent than sunitinib include Pazopanib (P), NI, and AA. Conclusions: OS generally favored IO-IO or IO-VEGFI combinations, while PFS and ORR favored single agent C or IO-VEGFI. The lowest risks of G3/G4 AE were seen with P or IO-IO. IO-VEGFI combinations had similar risks for G3/G4 AE. Longer real-world follow-up is needed. We recognize the limitations of cross-trial comparisons, but sought a summative view of the current data.[Table: see text]
Baseline neutrophil-to-eosinophil ratio (NER) and its association with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).
Authors: Ravindranathan Deepak , Liu Yuan , Martini Dylan J. , Brown Jacqueline T , Nazha Bassel , Russler Greta , Yantorni Lauren Beth , Caulfield Sarah , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim 
Published: June 2021

e16569 Background: Inflammatory markers have been studied as prognostic markers in patients with mRCC treated with CPIs. Recently, eosinophilia has been found to be associated with improved survival of patients with melanoma treated with CPIs. We reported baseline NER in patients with mRCC treated with CPIs and its association with clinical outcomes. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015-2018. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from CPI-initiation to date of death and radiographic or clinical progression, respectively. Patients with baseline NER were categorized into high or low; high defined as NER > 49.2 and low defined as NER < 49.2. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 184 patients were studied with a median follow up of 25.4 months. Median age was 63 years old with 72% male and 20% black. About 25% were in high NER group. The high NER patients had significantly shorter OS in both UVA (HR: 0.58, p-value=0.017) and MVA (HR: 0.62, p-value=0.046) (Table). There was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. Conclusions: High baseline NER was associated with worse OS in patients with mRCC treated with CPIs. Larger, prospective studies are warranted to validate this hypothesis generating data.[Table: see text]
Value of cabozantinib in the treatment of advanced metastatic clear cell renal cell carcinoma (ccRCC): Real-world data from a single Korean institution.
Authors: Lee Seoyoung , Kim Seul-Gi , Park Sejung , Lee Jeehyun , Beom Seung-Hoon , Shin Sang Joon , Rha Sun Young 
Published: June 2021

e16578 Background: Cabozantinib is a multitarget tyrosine kinase inhibitor and getting attention in these days through its combination with immune checkpoint inhibitors. In this article, we analyze the efficacy of cabozantinib in patients with metastatic ccRCC in Korean who had progression after 1 or more VEGFR TKI therapies. Methods: Seventy-five patients from Jan.2019 to Dec. 2021 at Yonsei Cancer Center who had received cabozantinib treatment in second to fourth line of therapy were retrospectively reviewed. The primary endpoint was PFS. The secondary outcomes were the response rate, disease control rate (DCR), and OS. The evaluable subjects for efficacy were those who had at least one response evaluation. Results: Among 75 patients, 57 (76.0%) were male and median age was 59 years (range 33-81). Median follow up time was 12.1 months. There were 22 (29.3%) patients of second line, 38 (50.7%) of third line and 15 (20.0%) of fourth line of treatment. Median PFS was 5.6 months (95% CI, 4.6-6.6). Median OS was 13.6 months (95% CI, 5.0-22.2). The PFS based on the line of treatment was 4.7 months for second line, 5.6 months for third line and 12.0 months for 4th line. Proportion of patients who were previously treated with ICI was different between treatment line groups and showed increasing trend toward later line; 13.6% of second line, 31.6% of third line, and 66.7% of fourth line, respectively. The objective response rate was 8.0% with 6 patients of partial response. The DCR was 69.3%. The major toxicities were similar with the western population and most of them were less than CTCAE grade 3. Most common grade 3 or 4 AEs were anemia, hand-foot syndrome, fatigue, and stomatitis. There were no grade 5 AEs. Conclusions: Our results demonstrate that cabozantinib is an effective treatment option after first line TKI in Korean ccRCC patients with manageable toxicities. Notably, its tolerability in the advanced line of treatment and synergy with ICIs are suggested in this study despite heterogeneous patients of real world setting. This is the first real world data with cabozantinib in Asian patients.
Clonal hematopoiesis in prostate cancer inferred from somatic tumor profiling.
Authors: Marshall Catherine Handy , Holler Albert E , Tsai Hua-Ling , Gondek Lukasz , Luo Jun , Antonarakis Emmanuel S. 
Published: June 2021

e17001 Background: Clonal hematopoiesis (CH) is a process associated with normal aging and may complicate the interpretation of liquid-biopsy genomic testing in oncology. Little is known about the prevalence of CH in prostate cancer as detected on somatic tumor profiling, or its association with clinical parameters and outcomes in prostate cancer. We sought to estimate the prevalence and clinical characteristics of patients with CH identified from tissue-based prostate cancer specimens. Methods: This was a retrospective study of men with prostate adenocarcinoma who underwent clinical somatic tissue-based next-generation sequencing using commercial platforms (n = 364). Patients with known hematologic malignancies (n = 7), and those with only liquid biopsies were excluded (n = 34), leaving 323 cases. Classical CH mutations were defined as those in DNMT3A, TET2 or ASXL1. Additional CH mutations included were defined as those in BCORL1, GNAS, SF3B1, JAK2 or PPM1D. Chi-squared tests were used to compare prevalence by categorical variables, Kruskal-Wallis tests to compare means across groups, and Cox proportional hazards were used for time-to-event analyses. Results: The prevalence of CH mutations in prostate cancer was 9% (30/323), and the prevalence of classical CH mutations was 7% (22/323)(Table). The most common mutations were in DNMT3A (n = 9), TET2 (n = 8) and ASXL1 (n = 5); other less common CH alterations were in GNAS and SF3B1 (n = 3 each), followed by CBL and JAK2 (n = 1 each). The most common site of tumor biopsy was the prostate (N = 266) followed by visceral (n = 19) and lymph node (N = 19) metastases. Men with any CH mutation were not significantly older at age of prostate cancer diagnosis (64 vs 62 years; p = 0.19) than those without; however, men with classical CH mutations were statistically older at diagnosis than those without (66 vs 62 years; p = 0.04). There was no difference in prevalence of CH mutations by Gleason sum (P = 0.67). Among men with localized disease at diagnosis, the median metastasis-free survival was 3.9 years in those with overall CH mutations and 6.6 years in those without CH mutations (HR [adjusted for age and Gleason] 1.3; 95% CI 0.7-2.3; p = 0.4). OS from the time of diagnosis to death was also numerically shorter in those with any CH mutation (median 9.7 years in those with and 14.2 years in those without CH mutations; HR 1.2, 95% CI 0.6-2.5; p = 0.6). Conclusions: CH can be detected in about 7-9% of prostate cancer patients from tissue-based tumor samples, is associated with older age, and may be linked to adverse oncological outcomes. The prognostic impact of CH in the context of specific systemic therapies (hormonal, chemotherapeutic) remains to be elucidated.[Table: see text]
Phase II study of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors (GCTs).
Authors: Mego Michal , Svetlovska Daniela , Reckova Maria , Kalavska Katarina , Obertova Jana , Palacka Patrik , Rejlekova Katarina , De Angelis Valentina , Sycova-Mila Zuzana , Chovanec Michal , Mardiak Jozef 
Published: June 2021

e17009 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP is overexpressed in GCTs compared to normal testis and PARP overexpression is early event in GCTs development. Gemcitabine and carboplatin showed activity in refractory GCTs. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and PARP inhibitor, veliparib, in patients with multiple relapsed/refractory GCTs. Methods: Fifteen patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from October 2016 to October 2020. All patients were pretreated with at least 2 cisplatin-based therapies (median 2, range 2 – 4); 3 tumors (20.0%) were absolutely refractory to cisplatin and 5 patients (33.3%) had visceral non-pulmonary metastases. Gemcitabine was administered at a dose 800mg/m2 day 1 and 8 every 3 weeks; carboplatin AUC = 4, day 1, every 3 weeks and veliparib 250mg bid day continuously. The primary end point was 12-months progression-free survival (PFS), if < 8 patients experienced 12-months PFS, the treatment will be considered ineffective. Results: Median age was 31 years (range: 22 – 48 months). Median number of treatment cycles was 4 (range 2 – 8). During a median follow-up period of 9.2 months (range: 1.9 – 23.8), all (100%) patients experienced disease progression and 14 patients (93.3%) died. Twelve-months PFS was achieved in 1 (6.7%) patient. Median PFS was 3.1 months, 95%CI (2.2 – 3.9) and median OS was 10.5 months, 95% CI (8.9 – 11.1). Partial remission was observed in 4 (26.7%) and disease stabilization in 5 (33.3%) of patients. Favorable response (complete or partial remission with negative serum tumor markers) experienced 3 (20%) patients. Treatment was well tolerated, however, 12 (80%) of patients experienced grade 3/4 neutropenia, 9 (60%) anemia, 14 (93.3%) thrombocytopenia and 2 (13.3%) febrile neutropenia. Conclusions: This study failed to achieve its primary end point and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib in multiple relapsed/refractory germ cell tumors. Clinical trial information: NCT02860819.
Schlafen 11 (SLFN11), a putative predictive biomarker of platinum/PARPi response, is frequently detected on circulating tumor cells (CTCs) in advanced prostate cancer.
Authors: Scher Howard I. , Fernandez Luisa , Cunningham Kate , Elphick Natalie , Barnett Ethan , Lee Jerry , Gilbertson Cole , Carbone Emily , Bourdon David , Blankfard Martin , Wang Eva , Jones Joshua Timothy , Tubbs Alisa , Anderson Amanda , Schonhoft Joseph D. , Wenstrup Rick 
Published: June 2021

e17039 Background: Schlafen 11 (SLFN11) is a DNA repair protein (DNA/RNA helicase homology) that is recruited to stressed replication forks and leads to cell death. Recent ph II trial data in Extensive Stage Small-Cell Lung Cancer (ES-SCLC) [Byers et al. JCO 2018 PMID: 29906251] and a retrospective analysis of Circulating Tumor Cells (CTCs) and tumor tissue in patients (Pts) with advanced prostate cancer [Conteduca et al. Mol Cancer Therapeutics 2020 PMID: 32127465] suggested that SLFN11 expression predicts sensitivity to DNA damage targeting agents. In both contexts, metastatic tumor biopsies may not provide adequate material for profiling. We assessed the frequency of SLFN11 expression in CTCs isolated from blood in men with progressing metastatic Castration Resistant Prostate Cancer (mCRPC) and related expression to Homologous Recombination Repair (HRR) alterations identified in metastatic tumor biopsies profiled by MSK-IMPACT. Methods: 95 patients with progressing mCRPC about to start a new systemic therapy who had undergone pre-treatment metastatic tumor profiling by MSK-IMPACT and a matched blood draw for CTC profiling were selected. Blood was sent overnight to Epic Sciences and processed onto glass pathology slides and bio-banked until analysis. Detected CTCs (cytokeratin (CK) positive and leukocyte (CD45) negative) were analyzed for SLFN11 protein expression by immunofluorescence and correlated to Homologous Recombination Repair (HRR) alterations in metastatic biopsy from the bone, lymph node, or visceral metastases (15 PROFOUND genes). A mean of 1.2 mL of blood was analyzed per patient. Results: CTCs with SLFN11 expression (DAPI+, CK+, CD45-, SLFN11+) were detected in 28.4% (27/95) of the patient sample analyzed. SLFN11 signal was found to overlap with the nuclear DAPI signal. Individual CTC expression of SLFN11 in a sample was heterogeneous and ranged from a minimum of 2.9% to 100%. Seven of 10 (70%) of patients with a BRCA1/2 or ATM alteration had a least one SLFN11 expressing CTC. In contrast, in patients with other HRR alterations, only 20% (1/5) had CTCs with SLFN11. Sequencing of single CTCs is ongoing. Conclusions: SLFN11 expression is detected with high frequency in CTCs in men with progressing mCRPC. In whom CTCs are detected, the majority of patients with BRCA1/2 or ATM altered tumors also had SLFN11 expressing CTCs. The results support the prospective evaluation of CTC SLFN11 expression as a predictive biomarker for PARPi or platinum agents.
Survival outcomes of primary mediastinal germ cell malignancies based on clinicopathological characteristics: A SEER database analysis.
Authors: Shrivastava Trilok , Baral Binav , Pudasaini Garima , Lingamaneni Prasanth , Batra Kunnal , Upadhyay Banskota Shristi Upadhyay , Shrestha Rohit 
Published: June 2021

e17055 Background: Primary mediastinal germ cell malignancies (PMGCM) account for up to 5% of all germ cell tumors. Different clinical and epidemiological factors have been known to have important prognostic implications as they contribute to a wide range of long term survival in individuals with PMGCM. Methods: We obtained data from the Surveillance, Epidemiology and End Results (SEER) database from years 1975-2016 to include cases with confirmed primary mediastinal germ cell tumors. After complete gathering of selected data, a total of 1,328 number of cohorts were obtained which were stratified by age, sex, race, type of malignancy, size of primary tumor, site, grade etc. and were analyzed by Cox regression using proportional hazard model. Kaplan Meier curves were also obtained to visualize all cause survival and stratified survival according to the types of malignancy. Results: In our study, we found the incidence of PMGCM to be 0.18 per 1,000 people with malignant cancer with a median age at diagnosis of 28 years, the age range being 21-50 years. 92.9% patients were males and 7.1% were females with more common occurrence in White patients (54.5%). Most common type of PMGCM was found to be Seminoma (23.4%) and 56.32% were poorly differentiated (Grade III), excluding unknown cases. About half (52%) of all was found to arise from the anterior mediastinum. 36% of all cases died from primary cancer. 42.7% underwent surgery, however there was no data for chemotherapy or radiotherapy. Mean survival time among all PMGCM was 37.5 months (p <0.05). A significant negative correlation was observed between survival time & age at diagnosis with Rp of 0.12 (p < 0.001). On survival analysis, age was a significant factor for decreased survival time with patients more than 50 years having a HR of 2 (p<0.001). Similarly, choriocarcinoma was associated with decreased survival time with HR 1.71 (p=0.03). Germinoma and seminoma were found to have higher survival time (HR 0.65 & 0.18; p=0.03 and <0.001 respectively). Patients with grade IV PMGCM had significantly lower survival time (HR 1.74, p<0.001). Patients who had undergone surgery had a better survival time compared to those who didn’t get surgery. There was no significant association of sex, race, tumor size or site with the survival time. Conclusions: Our study concludes that among PMGCM, seminomatous tumors have a favorable prognosis compared to non-seminomatous tumors with higher survival time. Age was found to be a significant contributing factor with ages over 50 having lower survival time. Surgical intervention was found to be associated with increased survival time, although it is important to recognize the lack of chemo-radiotherapeutics data.