bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of Chinese early-onset renal cancer predisposed genetic features.
Authors: Gong Yu , Zhou Yifan , Zhang Bei , Bai Yuezong , Guo Jianming 
Published: May 2020

e17087 Background: The population of early-onset renal cancer patients is increasing in China and they need early genetic screening test to give risks management. In order to avoid the bias of focusing on the patients younger than 45 years old without comparing the genetic features of the patients over 45y and to find more biomarkers, we explored both germline and somatic variations of patients without age limitation. Methods: Ages at confirmed diagnoses and renal tissue samples were collected from 701 patients. The next generation sequencing (NGS) was performed using validated commercial panels containing over 300 genes or WES. Variations were classified into four groups: germline-MUT/ VLM (pathogenic or very like pathogenic mutations), germline-VOUS (variations of unknown significance), somatic-MUT/ VLM and somatic-VOUS. Statistical analysis was performed by t-test (single tail), and p≤ 0.05 was considered statistically significant. Results: In 701 renal cancer patients, with the median age of 55 (12, 86) years old, 114 (16.26%) patients confirmed diagnoses under 45y. The germline MUT/ VLM of 21 genes (FH, VHL, CHEK2, BRCA2, FLCN, ATM, TSC2, SDHB, MUTYH, SDHA, FANCA, RAD50, APC, BARD1, JAK2, LRP1B, TP53, FANCD2, PALB2, MSH6 and CDH1) were observed, more than previous studies. As two aggressive potential predisposed genes in early-onset renal cancer, VHL and FH were studied comprehensively. There were 29 (4.14%) and 369 (52.6%) patients carried FH variations and VHL variations (either germline or somatic), respectively. The median age of patients harbored VHL germline MUT/ VLM was 33.5 (23, 52), significantly lower than other groups (Table). Interestingly, in 6 patients harboring VHL germline MUT/ VLM, 3 of them carried large region deletion. The median age of FH germline-MUT/ VLM group was 33 (21, 59), significantly lower than patients carried germline VOUS (Table). In addition, germline variations or copy number variations of SDHB gene or germline variations of FLCN gene might be associated with early onset. However, the patients No. was small to give conclusion. Conclusions: Genetic test of FH and VHL genes might be necessary in early screening of renal cancer in China. The role of variations of SDHB and FLCN genes and large region deletion needs more explorations. [Table: see text]
Impact of treatment line on outcomes with salvage ipilimumab + nivolumab in metastatic renal cell carcinoma (mRCC).
Authors: Kotecha Ritesh , Lee Chung-Han , Knezevic Andrea , Shah Neil J. , Carlo Maria Isabel , Feldman Darren R. , Patil Sujata , Motzer Robert J. , Voss Martin H 
Published: May 2020

e17092 Background: With the approval of ipilimumab plus nivolumab (I+N) and other immune checkpoint blockade (ICB) based combinations in the first-line setting, the role of I+N for salvage is of high interest for treatment sequencing, yet data is limited. Methods: We conducted a retrospective review of mRCC patients (pts) treated with I+N in the second-line (2L) and beyond settings at MSKCC between 2013-2019. Pt demographics, treatment history and toxicity were compiled. IMDC-risk status was calculated at I+N therapy start. Time to treatment failure (TTF) was defined as earliest date of clinical progression, therapy change or death, and overall survival (OS) was estimated by Kaplan-Meier method. Results: 36 pts received I+N in the 2+L setting, including 31/36 with clear-cell histology. Evaluable IMDC-risk at I+N start was favorable in 1/35 and intermediate-poor in 34/35 pts. The most common 1L therapies were anti-VEGF (22/36) and VEGF + ICB (6/36). 11/36 pts had ICB treatment exposure prior to I+N therapy. I+N therapy in the 2L, 3L and 4L was in 21/36, 8/36 and 7/36 pts, respectively, and 7/36 pts continue I+N at data cut-off. 8/36 pts discontinued I+N due to toxicity, 20/36 pts discontinued therapy due to disease progression, and 1 pt discontinued per pt preference. Cohort median OS was 14.8 months (95%CI: 4.2-44). Overall median TTF was 5.0 months (95%CI: 2.9-14.4), and TTF per 2L, 3L and 4+L was 8.3, 8.9 and 2.5 months, respectively. The number of patients who completed all 4 I+N induction cycles in the 2L, 3L, and 4+L was 11/21 (52%), 5/8 (63%), and 1/7 (14%). The number of patients who subsequently received nivolumab maintenance therapy after induction was 16/21 (76%) in the 2L, 1/8 (13%) in the 3L, and 0/7 (0%) in 4+L. Conclusions: With emerging treatment options for mRCC, this study reveals activity and safety for I+N in 2+L settings. In this limited cohort, completion of induction ipilimumab and use of maintenance nivolumab decline in later-line settings, suggesting limitations as salvage therapy. [Table: see text]
Predictors of successful randomized phase III studies in the treatment metastatic renal cell carcinoma: A meta-analysis.
Authors: Lin Justin , Zhong Xiaobo , Galsky Matt D. , Oh William K. , Tsao Che-Kai 
Published: May 2020

e17105 Background: The success of randomized phase III therapeutic trials (RP3TT) to reach their primary endpoint is critical given the enormous resources required to conduct such studies. In an era of accelerated therapeutic development in advanced kidney cancer, we aim to identify factors in such studies associated with a positive endpoint (PE) to better understand how to optimize trial design. Methods: Using PubMed and ClinicalTrials.gov, we identified all published RP3TT in patients with metastatic renal cell carcinoma between 1/2007-9/2019. Studies were considered PE if the primary endpoint was reached, and negative endpoint (NE) if otherwise. Studies were categorized as either first line only (FLO) or second line and beyond (SLB), with adjuvant and consolidation therapy studies excluded. We collected components of study design and baseline patient characteristics and analyzed with multivariate logistic regression to evaluate the associations between each factor and PE RP3TT. Results: Of the 65 studies evaluated, only 22 RP3TT (14 FLO, 8 SLB) were found to have published data and were included, with 14 PE and 8 NE. For all studies, those with larger enrollment size (OR = 1.008, 95% CI [1.001-1.015], p = 0.021) and clear cell requirements (OR = 0.077, 95% CI [0.007-0.901], p = 0.041) were associated with PE. After adjusting for sample size, only larger enrollment size remained significant (OR = 1.007, 95% CI [1.001-1.014], p = 0.032). Other baseline patient demographic and clinical characteristic variables were not associated with PE RP3TT. Subgroup analysis of only FLO or SLB studies also did not yield any significant associations with PE RP3TT. Conclusions: Higher enrollment size was identified as factor associated with PE in RP3TT. Incomplete trial data reporting was evident, particularly in earlier studies. Further efforts are needed to better characterize factors in order to optimize clinical trial design in this disease. [Table: see text]
Dynamic changes in full blood count (FBC) occurring in patients treated with immune checkpoint inhibitors (ICIs) to predict responses in patients with metastatic renal cell carcinoma (mRCC).
Authors: Abu Ghanem Yasmin , Choy Julia , Jackson-Spence Francesca , Jovaisaite Agne , Grant Michael , Bex Axel , Powles Thomas , Szabados Bernadett 
Published: May 2020

e17110 Background: ICI transformed the treatment of 1L mRCC, yet early clinical predictors of response are still unknown. Methods: Retrospective database analysis from Barts Cancer Institute, London was carried out. Patients with treatment naïve mRCC were identified and grouped according to their 1L treatment: 1: VEGF inhibitor 2: IO/IO 3: IO/VEGF Data on hemoglobin, neutrophil-to-lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR) at baseline, 6weeks and 12weeks after treatment initiation was correlated with outcome. Results: Between Jan 2014 - Dec 2019; 28, 29 and 21 patients received 1L VEGF, IO/IO or IO/VEGF respectively. Patient receiving 1L VEGF inhibitors showed a decrease in Hb levels both in responding and non-responding groups (significant group effect: F(1,6) = 6.6, p = 0.04); significant time effect:F(2,12) = 12.4, p = 0.001). Group x time interaction was not significant. NLR levels decreased both in responding and non-responding groups over time (significant time effect: F(2,12) = 16.7, p = 0.001. PLR levels in non-responders increased over time, whereas in responding group, PLR levels steadily decreased over 6 and 12 weeks (significant time effect: F(2,12) = 0.3, 0.044). Patients receiving IO/IO combination therapy; within the non-responder group, Hb levels didn’t change significantly whereas in the responding group Hb levels increased significantly and overtook Hb levels of non-responding group (P = 0.001). NLR levels significantly decreased in the responding group (0.041) and a similar trend was observed at 12 weeks with a decrease in PLR among non-responders, with a significant group affect (F(1,5) = 0.18, 0.035). In patient treated with 1L IO/VEGF, among non-responders Hb levels increased slightly, only to return to baseline levels again at 12 weeks after treatment initiation. Whereas, Hb levels in the responding group increased significantly in both 6weeks and 12weeks after starting therapy. Significant time effect:F(2,20) = 3.65, p = 0.044. NLR levels in the responding group presented a steady decrease over time with a significant group and time effect. Both responders and non-responders experienced an increase in PLR over time. However, while PLR decreased at 12 weeks among responders, it continued to increase among non responders (significant time effect: F(2,20) = 0.3, 0.03), (significant group effect: F(1,10) = 0.05, 0.005) and significant interaction: F(2,20) = 0.1, 0.01) Conclusions: Close monitoring of FBC changes may predict response to ICI.
The effect of antibiotic use on immune-checkpoint inhibitor efficacy in patients with advanced urothelial carcinoma.
Authors: Khan Mohammad , Radakovich Nathan , Rini Brian I. , Mian Omar Y. , Ornstein Moshe Chaim , Gupta Shilpa 
Published: May 2020

e17116 Background: There is emerging evidence that antibiotic (Abx) use may be associated with poor response to immune-checkpoint inhibitors (ICIs) in patients (pts) with some solid tumors. However, this has not been studied in metastatic urothelial carcinoma (mUC). We examined the effect of Abx use on outcomes in pts receiving ICIs for mUC. Methods: We retrospectively reviewed adult pts receiving ICIs for mUC treated at Cleveland Clinic between 2015 and 2020. Pts included in the study received > / = 3 cycles of ICI therapy with either azetolizumab or pembrolizumab. Abx use was defined as at least 3 days of Abx in the 60 days preceding or following ICI initiation. PFS and OS were estimated using the Kaplan-Meier method and a Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CI). Results: A total of 69 pts with mUC receiving ICI therapy were included. The Abx-treated group consisted of 22 pts (32%) and the Abx-untreated group was 47 pts (68 %). 30 pts had Abx 60 days prior to ICI initiation and 20 patients had Abx within 60 days of ICI initiation. Abx use 60 days prior to ICI was not associated with PFS (HR = 0.91, 95% CI = 0.42-1.95) or OS (HR = 0.52, 95% CI = 0.33-1.68). Abx use during the first 60 days of ICI use was associated with decreased PFS (HR = 2.23, 95% CI = 1.03-4.86) but not OS (HR = 2.01, 95% CI = 0.89-4.53). Notably, there was no effect on response rates. The most commonly used Abx prior to treatment were: fluoroquinolones (30%); cephalosporins (26%); non-cephalosporin beta lactams (17%); and trimethoprim-sulfamethoxasole (13%). The most commonly used Abx after treatment initiation were: fluoroquinolones (17% of patients); cephalosporins (13%); non-cephalosporin beta lactams (12%); and trimethoprim-sulfamethoxasole (9%). Our study was insufficiently powered to address the effect of different antibiotic classes on outcomes. Conclusions: In our study, Abx use within first 60 days of treatment with ICIs was associated with decreased PFS and a trend toward decreased OS in pts with mUC but not in pts receiving Abx 60 days prior to ICI therapy. While the numbers are small, this is the first report exploring the effect of Abx on ICI response in mUC and further studies in larger databases are warranted.
Alternative inflammatory cytokines pathways in prostate cancer: In search of new therapeutic options.
Authors: Janiczek Marlena , Szylberg Łukasz , Antosik Paulina , Marszalek Andrzej 
Published: May 2020

e17504 Background: The inflammatory reaction pathways have impact on tumor cells development or anti-tumor responses. Both by the activity of the innate and acquired immune response signalling pathways. A proper acquired immune response is considered as anti-tumor. While inadequate innate or acquired stimulation of the immune system can cause chronic inflammation that can lead to oncogenesis. Numerous reports have revealed a relationship between chronic prostatitis and prostate cancer (PCa). The aim of the study is to retrospectively assess the histological material of PCa with the Gleason grading score. The histological material evaluated the level of inflammatory factors of pathways initiated by IL-17A and IL-17F. The evaluation of the expression of pro-inflammatory factors such as IL-17A, IL-17F, IL-17RA, IL-17RC, AKT1, EBPbeta, TRAF 6 and NF-kB made it possible to assess the influence of the inflammatory process on the progression of PCa. Methods: Studies were carried out on archival tissue material in the form of paraffin blocks of 40 men with PCa after radical prostatectomy. The control group of 10 men with benign prostatic hyperplasia (BPH). The material was obtained by the transurethral resection of the prostate (TURP). The immunohistochemistry was performed on the material prepared in this way using specific primary antibodies against IL-17A, IL-17F, IL-17RA, IL-17RC, ACT1, TRAF-6, C/EBPbeta and NF-kB. The expression of the antibody to be examined using the light microscopy and the Remmele Stegner score (IRS) in cancer staining were then evaluated. Statistical analysis was performed using the non-parametric Kruskal-Wallis test. Results: In statistical analysis, it was shown that the inflammatory pathway IL17A/IL-17RC/TRAF6/NF-kB occurs in both BPH and PCa. IL-17 RA did not show expression in any group of patients and in the control group. In addition, along with the increase in the grading of Gleason score, a decrease in the expression of the tested inflammatory parameters was demonstrated. Conclusions: The inflammatory process has an impact on the cancer of prostate cancer. There is a correlation between the grades according to Gleason score and the level of expression of inflammation parameters. Activation of the inflammatory pathway through IL17A/IL-17RC/TRAF6/NF-kB cascade could correlate PCa development on the base of BPH. Evaluation of the inflammatory pathway in PCa, the initiated IL-17, may become a starting point for further research on an attempt to use, for example, immunotherapy in PCa.
Germline mutation in multiple primary malignancies associated with prostate cancer.
Authors: Gong Yiming , Fan Liancheng , Zhu Yinjie , Pan Jiahua , Sha Jianjun , Dong Baijun , Xue Wei , Lei Jianqiang , Wang Jianfei 
Published: May 2020

e17505 Background: Multiple primary malignancies (MPM) are described as that one individual develop several malignancies that originate from different tissues at the same time or separated (different histology in different location). MPM are also considered as an indicator of germline mutation or hereditary disease. Here we performed next generation sequencing-based 642-gene panel test on the MPM patients to figure out the candidate germline mutation essential for multiple tumorigenesis. Methods: Blood samples from 27 patients diagnosed as MPM with prostate cancer and at least one additional primary cancer from 2018.12 to 2019.12 were collected to detect the germline variation of 642 gene panel. Meanwhile 25 blood samples from patients only diagnosed as prostate cancer were taken as control. After the sequencing results were obtained, the differences between the multiple primary and single primary cohorts were counted. Results: Statistical analysis of the mutations in the multi-primary and single-primary cohorts revealed that differences were concentrated in the following six genes: ESR1, PTPRB, CIC, ANKRD11, BRCA2, MLH1. It was found that the mutations of p.G145S and p.P146Q (frequency 18.5%) of ESR1 gene and p.G1150W (frequency 14.8%) of PTPRB gene which related to angiogenesis were only found in multiple primary cohort. And mutations of growth factor pathway gene CIC (frequency 22.2%), mutation of chromatin remodeling family gene ANKRD11, and two genes of DDR pathway (BRCA2, MLH1) appeared higher in multiple primary cohort, although there was no statistical difference. Conclusions: We found for the first time that the p.G145S and p.P146Q mutations of the estrogen receptor ESR1 gene and the p.G1150W mutation of the angiogenesis-related PTPRB gene may be the drivers of multiple primary prostate cancer, which need further study.
Circulating tumor cells with small nuclear size: A novel biomarker for survival and clinical outcomes in advanced prostate cancer.
Authors: Wang Jasmine Jiemei , Teng Pai-Chi , Jan Yu Jen , Chen Jie-Fu , Cook-Wiens Galen , Yao Nu , Chu Gina Chia-Yi , Chen Pin-Jung , Ho Hao , Lee Yi-Te , Huang Jiaoti , Li Ker-Chau , Chung Leland WK , Zhu Yazhen , Freeman Michael , Rogatko Andre , Yang Ju Dong , Tseng Hsian-Rong , Posadas Edwin Melencio 
Published: May 2020

e17512 Background: Very-small-nuclear circulating tumor cells (vsnCTCs) as a subset of CTCs with nuclear size < 8.5 μm associated with visceral metastases (VM) in advanced metastatic, castration-resistant prostate cancer (mCRPC). As VM predicts foreshortened survival, we hypothesized that vsnCTCs would be directly associated with poor overall survival (OS). Methods: Clinically annotated, blood samples from patients with mCRPC with survival follow-up within the Translational Oncology Program Blood & Biospecimen Bank were selected for analysis. CTCs were isolated and analyzed using the NanoVelcro assay. The nuclear size from all CTCs from each patient sample was compared to OS and progression-free survival (PFS) from the time of the blood draw. Results: A total of 76 patients had samples suitable for analysis. Sixty-six (87%) had CTCs; 49 (64%) were vsnCTC+ (≥1 vsnCTC). vsnCTCs were more common in mCRPC patients with previous androgen receptor signaling inhibitor (ARSI) therapy and/or 2 or more lines of treatment. OS was significantly shorter for vsnCTC+ than vsnCTC- patients (median 34 vs. 149 weeks; log-rank HR = 2.6; 95% CI = 1.5 to 4.5; P = 0.0006). Fifty patient samples were available for PFS analysis (i.e. drawn within 4 weeks of starting therapy). vsnCTC+ patients experienced more rapid progression than vsnCTC- patients (median 12 vs. 26 weeks, log-rank HR = 2.2, 95% CI = 1.3 to 4.0; P = 0.004). Multivariable Cox regression revealed that vsnCTC status was independently associated with OS and PFS. P-spline plot analysis showed that the HR of OS increased as the minimum CTC nuclear size decreased. The minimum CTC nuclear size was also independently associated with OS and PFS in a multivariable Cox regression analysis. Patients with prior use of androgen receptor signaling inhibitor (ARSI) therapy had significantly smaller minimum CTC nuclear size compared to those without prior use of ARSI. Average and median nuclear size did not strongly associate with OS or PFS. Conclusions: vsnCTC+ patients are at risk for more rapid clinical progression and have greater risk of death than vsnCTC-. We posit that the vsnCTC may be a biomarker of aggressive mCRPC with foreshortened survival. Interestingly, the CTCs with the smallest nuclei appear to best reflect the observed clinical behavior. This has potential importance in optimizing therapeutic choices and may point toward a unique biology relating nuclear size to aggressive molecular features. Our group continues to explore the biology underlying the vsnCTC.
Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.
Authors: Wei Yu , Zhu Yao , Wu Junlong , Ye Dingwei , Zeng Hao , Li Yonghong , Freedland Stephen J. , Zhou Fangjian , He Cai-Yun , Sun Guangxi , Zhu Sha , Zhao Jinge 
Published: May 2020

e17523 Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.