bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer.
Authors: Zeng Tao , Deng Huanhuan , Zhao Rongsong , Huang Longwu , Gong Yun , Zhu Yuetian , Wang Qingping , Li Feng , Liu Lirong , Qi Yan , Wang Xianshu , Zou Hongzhi 
Published: June 2021

e16503 Background: For bladder cancer (BC), the 5-year survival rate for patients with localized tumors can reach as high as 92%, but only 45% for those with tumors spreading to nearby regions. Cystoscopy combined with tissue biopsy can miss 10-40% of the cancer cases due to multiple factors. Meanwhile, the method is invasive, causing physical discomfort and psychological trauma for the patients. Therefore, development of a noninvasive, sensitive, and specific diagnostic alternative is needed. By analyzing TCGA data and improving analytic technology currently available, we have developed an easy-to-use, convenient, and accurate detection approach for BC relying on a single methylation marker. Methods: We searched TCGA database and selected a total of 366 candidate markers including those that have been published for subsequent examination and analyzed 446 primer pairs and probe sets. Using quantitative methylight method, we narrowed the field down to top 5 performers for subsequent urine-based testing of 270 samples. Finally, two markers were selected for validation testing in a group of 530 urine samples, consisting of 161 bladder cancers, 244 normal controls, 80 renal carcinomas, and 45 carcinomas of renal pelvis and ureter. In addition, we detected the methylation level and mRNA expression of target gene in 8 bladder cancer cell lines and 1 normal bladder epithelial cell line by MSP, qMSP and qPCR. Results: Methylation marker DMRTA2 had a sensitivity of 85.7%, an AUC value of 0.924, and an accuracy of 90.6%. The specificity, from a control group consisting of patients with lithangiuria, prostatoplasia, and prostatitis as well as healthy individuals, is 93.9% (138/161). Notably, the methylation assay had the highest sensitivities for tumors at stages of T1 (94.4%) and T2 (96.6%) compared with T3 (80.0%), T4 (71.4%), and unknown stage (90.0%). While methylation was observed in 34/45 urine samples from patients with carcinomas of renal pelvis and ureter, a good sensitivity of 75.6%, it was detected at extremely low rate of 7.5% (6/80) in those with interfering cancers of kidney and prostate. Additionally, the assay specificity was significantly affected by the age of the cancer patients and selection of healthy controls, critical aspects to be carefully considered during the design and development phase of the methylation-specific testing. Compared with SV-HUC-1, the normal bladder epithelial cell line, DMRTA2 gene was hypermethylated in 8 bladder cancer cell lines, which is consistent with the results of MSP and qMSP. The mRNA levels of DMRTA2 were low in some bladder cancer cell lines, such as T24, J82, UM-UC-3 and RT4, however were fairly high levels in 5637, SCaBER, TCCSUP and SW780. Conclusions: Our data demonstrated that a single-target DNA methylation signature could be highly effective to detect bladder cancer via urine samples.
Role of adjuvant chemotherapy in the treatment of patients with node-positive bladder adenocarcinoma: An analysis of the National Cancer Database.
Authors: Reddy Akshay G , Sparks Andrew D , Whalen Michael Joseph 
Published: June 2021

e16504 Background: Given the rarity of bladder adenocarcinoma, there is a paucity of data examining the role of adjuvant chemotherapy (AC) in patients with regional lymph node positivity. This study aims to elucidate the oncologic and survival outcomes of patients with node-positive disease treated with or without AC. Methods: A retrospective cohort analysis of patients with node-positive primary bladder adenocarcinoma who had either received AC or did not receive AC after either radical (RC) or partial cystectomy (PC) was performed using the National Cancer Database from 2006 to 2016. Non-metastatic node-positive was defined as pT(any)N1-3 (pN+) disease. Demographic and clinicopathological variables were compared to adjust for confounding covariates in multivariable analysis to determine appropriate oncologic and surgical outcomes. Results: A total of 106 patients met inclusion criteria, of whom 38 received AC and 68 did not. Receipt of AC was significantly associated with improved survival relative to those who did not receive AC (overall survival: 29% vs 2.7%; adjusted hazards ratio = 0.43; p = 0.003) independent of extent of surgery. There was a trend toward higher receipt of adjuvant radiation along with AC, independent of surgical margin status. Receipt of AC additionally trended towards a significant association with decreased odds of 90-day mortality and 30-day unplanned readmission (Table). Conclusions: Based on the improved survival outcomes, positive nodal status may be a useful indicator of those who may benefit from AC, and potentially adjuvant radiation therapy, in bladder adenocarcinoma. Though compelling, larger studies will be required to make more conclusive statements regarding the most appropriate treatment course in these patients.[Table: see text]
Prognostic value of galectin-1 and galectin-3 expression in local urothelial bladder cancer.
Authors: Zhu Jason , Livasy Chad , Donahue Erin E , Symanowski James Thomas , Grigg Claud , Matulay Justin T. , Kearns James T , Raghavan Derek , Burgess Earle F , Clark Peter E 
Published: June 2021

e16520 Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins which regulate cellular adhesion, proliferation, and apoptosis in solid tumors . Prior studies have reported that Gal-3 expression is associated with non-muscle invasive UC progression to muscle invasive disease. Therefore, we assessed whether UC Gal-1 and Gal-3 protein expression in cystectomy specimens was prognostic for overall survival (OS) or recurrence free survival (RFS). Methods: Tissue microarrays (TMA) were generated from chemotherapy naïve cystectomy specimens. Biopsies included benign urothelium, noninvasive papillary UC (Ta), UC in situ (Tis), and invasive UC (p1-pT4: INV). Gal-1 and Gal-3 IHC expression was scored by intensity (0-3) and % of cells staining positive (0-100). An H-score (product of % and intensity) was utilized for analysis. Clinical data including pathologic T stage, N stage, surgical margins, tumor size, and Charlson Comorbidity Index (CCI) were included in multivariable analysis. Results: 656 biopsies were evaluated from 301 patients. 198 (30%) were from benign urothelium, 28 (4%) Ta, 178 (27%) Tis, and 252 (38%) were INV. With a median follow up of 64 months, median OS was 47.5 mo and median RFS was 38.4 mo. Gal-1 H-score was significantly higher in INV specimens than non-INV specimens, and the inverse relationship was found with Gal-3 (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, p < 0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, p < 0.01). In multivariable analysis, T stage, N stage, margins, tumor size, PCV pre-op and CCI score were prognostic of OS and RFS. Gal-1 and Gal-3 H-scores were not predictive of RFS (Gal-1: HR 1.0, p = 0.67, Gal-3: HR 1.0, p = 0.25) or OS (Gal-1: HR 1.0, p = 0.71, Gal-3: HR 1.0, p = 0.37). Intra-tumoral Gal-1 and Gal-3 expression heterogeneity was observed. 203 (67%) patients had 2 or more tissue specimens and of these, 99 (49%) had discordant H-scores at the same level of invasion. Conclusions: In this cohort, both Gal-1 and Gal-3 expression correlated with biopsy T stage; however, the highest intra-tumor H-score per specimen did not independently predict for RFS or OS. This result differs from prior observations from smaller cohorts that showed an association between Gal-3 expression and RFS, suggesting that intra-tumoral Gal-1/Gal-3 heterogeneity may confound the study of Gal-1 and Gal-3 as a potential biomarker in UC. The biological significance of intra-tumoral Gal heterogeneity in UC merits further investigation.
Bladder cancer in young adults: Disease and treatment characteristics of patients treated at tertiary cancer center.
Authors: Abu-Hijlih Ramiz Ahmad , Salah Samer , Al-Ibraheem Akram , Abuhijla Fawzi , Abu Serhan Hashem , Shahait Mohammed 
Published: June 2021

e16521 Background: The incidence of bladder cancer in the Middle East is increasing. The data on young population with urothelial carcinoma (UC) of urinary bladder in the region is scarce. We evaluated clinical and tumor characteristics, in addition to management details in patients younger than 45 years old. Methods: We reviewed of all patients presenting with UC of the urinary bladder from July 2006 to December 2019. Clinical characteristics including demographics, stage at presentation, and treatment outcomes were described. Results: Out of 1,272 new cases of bladder cancer, a total of 112 patients (8.8%) were ≤45 years old. Seven patients (6%) had non-urothelial histology and were excluded. The remaining 105 eligible patients with UC had a median age at presentation was 41 years (35-43). Ninety three patients (88.6%) were males. Tumor stage at presentation: non-muscle invasive disease (Ta-T1), locally advanced muscle invasive bladder cancer (MIBC) (T2-3), and metastatic disease were 14 cases (84.7%), 2.8%, and 12.5%, respectively. All patients with MIBC received neoadjuvant cisplatin-based chemotherapy. Radical cystectomy was performed in 8 cases (7.6%); 3 patients with MIBC and 5 with high volume non-MIBC. Neobladder reconstruction was done in 6 patients. A total of 13 patients with metastatic disease (93%) received palliative chemotherapy (Gemcitabine/Cisplatin), and one (7%) was candidate of best supportive care only. Conclusions: Bladder cancer is relatively rare in young population, though the incidence at our region is higher than other reports in the literature. Most of patients present with early disease. Early diagnosis and multidisciplinary approach are paramount for management of these patients.
Prognosis impact of serous metastases (SMs) in clear cell renal cell carcinoma patients in the GETUG-AFU-26 NIVOREN phase II trial.
Authors: Bardet Florian , Dalban Cécile , Chevreau Christine , Negrier Sylvie , Laguerre Brigitte , Gravis Gwenaelle , Gross-Goupil Marine , Oudard Stephane , Barthélémy Philippe , Ferrero Jean Marc , Thiery-Vuillemin Antoine , Mahammedi Hakim , Narciso Berangere , Geoffrois Lionnel , Tantot Florence , Escudier Bernard , Ladoire Sylvain , Albiges Laurence 
Published: June 2021

e16566 Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p<0.0001) were significantly lower in patients with SMs. The dismal prognostic impact was observed both with pleura and peritoneum SMs. These 2 sites were not significantly associated. Using multivariate Cox models, SMs remained significantly associated with poor survival, independently of IMDC category, gender, age, and number of previous lines of therapy. Objective response rate in patients with SMs was not significantly different from others patients (16.4 vs 22.1%; p=0.147). SMs were not statistically associated with known poor prognosis metastatic sites (cerebral, bone, and liver.) Conclusions: SMs are a strong independent prognostic impact in patients receiving N for metastatic ccRCC Poor prognostic metastatic sites should be considered when assessing the prognosis of patients with metastatic ccRCC
Hot clear cell renal cell carcinoma immune status: Illusion or reality?
Authors: Bi Xingang , Lu Yi , Bi Xinyu , Luo Zhiwen 
Published: June 2021

e16575 Background: High tumor mutation burden (TMB) and increased CD8+ T cells infiltration are associated with positive ICIs response in many solid cancers. But non-responsive clear cell renal cell carcinoma (ccRCC) features modest TMB, high CD8+ T-cell infiltration but poor survival. Costimulatory molecules confer immune cell activation within the immune response. Therefore, we aimed to investigate ccRCC’s unique immune environment related prognosis and ICIs’ sensitivity from the aspect of co-stimulation alteration. Methods: We analyzed the combined ccRCC cohort of 844 patients’ RNA sequencing data, from two sources: One ccRCC group (533 patients) was from The Cancer Genome Atlas KIRC (TCGA-KIRC), and the validation group (311 patients) was from an ICIs treated clinical trial. Univariate, LASSO, and multivariate Cox regression analyses were used to identify overall survival-related costimulatory genes, which were used to build an immune prognostic model (IPM) stratifying survival risk level in ccRCC. Comprehensive bioinformatics discovered the relationship between immune status, ICIs’ sensitivity with IPM’ prognosis risk. Results: The survival related co-stimulatory genes were identified in 533 ccRCC patients to construct an immune prognostic model (IPM) to differentiate patients with a low or high risk of poor survival (AUC = 0.75). Functional enrichment analysis showed T cell homeostasis represented the major function alteration related to IPM risk score ( P< 0.05). ICIs clinical trial cohort validated the IPM’s moderate prediction performance for the ICIs response ( P= 0.028), for IPM-high risk patients are more likely to be resistant to ICIs. The high-risk group had higher CD8 + T cell infiltration, higher TMB, and higher cytolytic activity, while such a hot immune status was an illusion concealing the T cells homeostasis alteration with the increased proportion of dysfunctional CD8+ and CD4+ T cells, immunosuppressive cells (i.e., iT-regs, nT-regs, and CAFs) in IPM-high risk, this kind of refractory ccRCC subtype. Conclusions: Baseline CD8 + T cell infiltration, TMB, and cytolytic activity could not predict response to ICI in the ccRCCs, and hot tumor immune status represented by CD8+T cells in resistant ccRCC is an illusion concealing T cells homeostasis alteration. T cells homeostasis could provide critical insights into immunogenomic mechanisms contributing to the immunotherapy sensitivity in ccRCC. Our five-gene based IPM tested easily by PCR, was clinically accessible, cheap and useful for indicating refractory ccRCCs to undergo ICIs.
Predicting benefit of radium 223 based on biochemical response and site of metastasis: A real life multicenter UK study.
Authors: Das Prantik , Davies Jessica , Sharma Anand , Nair Ajith , Vengalil Salil , Perna Carla , Branagan Jenny , Masters Benjamin , Goh Chee , Otter Sophie , Prakash Vineet , Singh Sadmeet 
Published: June 2021

e17034 Background: Studies have shown an improvement in overall survival (OS) and symptom control in metastatic castration-resistant prostate cancer (mCRPC) with Radium-223 treatment. However, there is little information about predicting outcomes using either PSA or Alkaline Phosphatase (ALP) response or comparing bone only disease to bone and lymph node (LN) involvement. Methods: 335 patients receiving Radium 223 at 6 UK centres between March 2014 and June 2020 were included. The primary endpoint was overall survival, secondary endpoints were toxicity, symptomatic benefit and skeletal-related events(SRE) Results: The median age was 75, with 71% having bone only metastases and 29% also having lymph node involvement. Those with PSA response (30%) had a statistically significant improvement in OS, compared to non-responders (18.2 vs 13.8 months, p = 0.026). They also showed highest rate of imaging response/stable disease (54% vs 34%). ALP response was seen in 82%. This did not translate to significantly improved OS, but did correlate with better symptomatic benefit (40% vs 29%). Those with bone only disease showed a survival benefit compared to those with LN involvement (19.4 vs 11.4 months, p = 0.046). Other than anaemia (23.5%), Grade 2 or above toxicities were uncommon including thrombocytopenia and neutropenia(5.5 and 6.2% respectively ) . 14% patients required at-least one blood transfusion. SRE were seen in 24% overall, but lower of in PSA responders(18%). Conclusions: Real life multicentre data suggests that PSA response and bone only disease could be predictors for better survival following Radium-223, whereas ALP response correlates better with symptomatic benefit.
Propensity score matching analysis of ovarian cancer patients with multiple primary malignant neoplasms using multicenter real-world data.
Authors: Gao Qing-lei , Jiao Xiaofei , Li Ruyuan , Zeng Shaoqing , Zhao Yingjun , Ma Guanchen , Huo Yabing , Li Ming , Liu Xingyu , Yu Yang , Liu Jiahao , Chi Jianhua , Dai Yun , Wang Ya , Chen Youguo , Yao Shuzhong , Wang Jing , Li Qingshui , Wang Li 
Published: June 2021

e17501 Background: Multiple primary malignant neoplasms (MPMNs) in patients with ovarian cancer is rare and has not attracted enough attention. It is unclear how the MPMNs affect the prognosis of ovarian cancer (OC) patients. Methods: This is a multicenter retrospective analysis of 5, 268 ovarian cancer patients from six centers who was diagnosed with ovarian cancer from January 1, 1989 to August 21, 2020. Propensity score matching was used to balance the baseline characteristics between patients with and without MPMNs. Cox regression analysis was utilized to analyze the influence of MPMNs on overall survival (OS). Results: After excluding unqualified medical record, totally 4, 848 patients were analyzed and 240 were concurrent at least one MPMNs other than OC. Ten patients had two MPMNs and one patient had three. The most common concurrent cancer was breast cancer (111/240, 46.25%), followed by endometrial cancer (37/240, 15.42%), and cervical cancer (30/240, 12.50%). Patients with MPMNs were elder than those without MPMNs (52 vs. 51, P = 0.03) when ovarian cancer was diagnosed. And the proportion of early-stage cases was lower in patients with MPMNs (25.8% vs. 27.2%, P < 0.001). Patients with breast cancer had a higher proportion of high-grade serous ovarian cancer (HGSOC) than those without MPMNs. After using the propensity score matching method adjusting age, pathological type, grade, and stage, concurrent MPMNs, including breast cancer, had no effect on OS of ovarian cancer patients. Among 240 patients with MPMNs, patients with breast cancer shared similar age and stage compared with the rest patients, while their proportion of HGSOC was higher than patients with other cancer (68.4% vs. 51.1%, P = 0.028). However, the median OS of those two groups were similar (27.3 m vs.27.1 m, P = 0.744). In addition, 94 patients were diagnosed with breast cancer prior to ovarian cancer, seven diagnosed posteriorly to ovarian cancer, four diagnosed simultaneously, and six had no precise diagnosed dates. There was no remarkable difference in clinical characteristics between the prior and posterior groups, however, the median OS of those seven patients was significantly longer than the prior group (76.0 m vs. 25.4 m, P = 0.002). Conclusions: The MPMNs showed no influence on the overall survival of ovarian cancer patients. The order of diagnosis of ovarian cancer and breast cancer might affect the prognosis.
Preliminary results of niraparib and brivanib dual therapy evaluation in recurrent, metastatic and persistent cervical cancer (CQGOG0101): An open-label, phase II clinical trial.
Authors: Wang Haixia , Shu Jin , Zou Dongling , Zhou Qi 
Published: June 2021

e17506 Background: Early-stage cervical cancer (CC) has a good long-term prognosis, with 5-year survival rate more than 90% for localized disease. However, once the CC relapsed, patients lack effective solutions and usually die in less than one year. In this study (CQGOG0101), we aimed to assess the efficacy and safety of niraparib combined with brivanib or toripalimab in patients with recurrent CC. Herein, we report the cohort 1 portion of the study (patients recieving Niraparib 200mg and Brivanib 400mg orally).Findings for the cohort 2 of patients receiving niraparib and toripalimab will be reported separately. Methods: The cohort 1 of CQGOG0101 trial was to evaluate the safety and activity of Niraparib combined with Brivanib in patients with recurrent, metastatic, or persistent cervical cancer. 10 patients were planned to be enrolled (Actually nine patients). Eligible patients were aged 18–70 years with measurable lesions and had an ECOG performance status of 0-2. Patients received oral niraparib 200 mg and brivanib 400 mg once daily until disease progression, intolerable toxicity, or withdrawal of consent. Primary endpoint was the objective response rate (ORR) assessed by RECIST version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and safety. Results: Between May 8th, 2020 and Jan 22nd, 2021, 9 patients (median age, 50 years old [28-73]) were enrolled. Patients had received a median of two (1-3) previous lines of platinum-based therapy. All of nine patients had distant metastatic lesions and had underwent at least one post-baseline tumor assessment (To deadline for submission), including 1 confirmed partial response, 4 with stable disease, 4 with progressive disease. Median duration of treatment was 3.8 months (3-8.2), three patients were still on treatment. No drug-related grade 3 or worse treatment-emergent adverse events were detected, the most common grade 1-2 adverse events (AEs) included: neutropenia (4 of 9 patients), anemia (2 of 9 patients), thrombocytopenia (1 of 9 patients), hypertension (2 of 9 patients), proteinuria(1 of 9 patients), fatigue (1 of 9 patients), and increased ALT/AST (1 of 9 patients). Conclusions: This combo seems to show a similar efficacy compared to other recurrent cervical cancer late-line therapies. We are planning to initiate the cohort 2 to explore niraparib combined with anti-PD-1 antibody (Toripalimab) in recurrent CC in our trial later. Clinical trial information: NCT04395612.