bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sputum cell‐free DNA: Valued surrogate sample for the detection of EGFR exon 20 p.T790M mutation in patients with advanced lung adenocarcinoma and acquired resistance to EGFR‐TKIs
Authors: Wang Zheng , Li Xiaoguang , Zhang Lin , Xu Yan , Wang Mengzhao , Liang Li , Jiao Peng , Li Yuanming , He Shurong , Du Jun , He Lei , Tang Min , Sun Mingjun , Yang Li , Di Jing , Zhu Guanshan , Li Lin , Liu Dongge 
Published: May 2021

AbstractBackgroundSputum cell‐free DNA (cfDNA) is a valuable surrogate sample for assessing EGFR‐sensitizing mutations in patients with advanced lung adenocarcinoma. Detecting EGFR exon 20 p.T790 M (p.T790 M) is much more challenging due to its limited availability in tumor tissues. Exploring sputum cfDNA as an alternative for liquid‐based sample type in detecting p.T790 M requires potential improvement in clinical practice.MethodsA total of 34 patients with EGFR‐sensitive mutation‐positive lung adenocarcinoma and acquired resistance to the first generation of epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) were enrolled. The sputum samples, and paired tumors and/or plasma samples were tested for p.T790 M mutation and concordance of p.T790 M status among the three sample types was analyzed.ResultsThe overall concordance rate of p.T790 M mutation between sputum cfDNA and tumor tissue samples was 85.7%, with a sensitivity of 66.7% and a specificity of 100%. The sensitivity for detecting p.T790 M in sputum cfDNA was 100%, 66.7%, and 0% in the three sputum groups of malignant, satisfactory but no malignant cells, and unsatisfactory, respectively. The combined results of plasma cfDNA testing and sputum cfDNA testing further increased the sensitivity to 100% for p.T790 M detection in satisfactory but no malignant cells sputum group.ConclusionThese findings revealed that cfDNA from malignant or satisfied but no malignant cells sputum is considered suitable for detecting p.T790 M mutation in patients with acquired resistance to first or second‐generation EGFR‐TKIs. The sputum cytological pathological evaluation‐guided sputum cfDNA testing assists in significantly improving the sensitivity of p.T790 M detection, bringing significant value for the maximal application of third‐generation EGFR‐TKIs in second‐line treatment.
TNF‐α/NF‐κB signaling epigenetically represses PSD4 transcription to promote alcohol‐related hepatocellular carcinoma progression
Authors: Shi Jia’ning , Song Shupeng , Li Shuangxing , Zhang Kaili , Lan Yinghua , Li Yongguo 
Published: May 2021

AbstractBackgroundChronic alcohol consumption is more frequently associated with advanced, aggressive hepatocellular carcinoma (HCC) tumors. Alcohol adversely impacts ER/Golgi membrane trafficking and Golgi protein N‐glycosylation in hepatocytes; these effects have been attributed (in part) to dysregulated adenosine diphosphate‐ribosylation factor (ARF) GTPase signaling. Here, we investigated the role of the ARF GTPase guanine exchange factor PSD4 in HCC progression.MethodsR‐based bioinformatics analysis was performed on publicly available array data. Modulating gene expression was accomplished via lentiviral vectors. Gene expression was analyzed using quantitative real‐time PCR and immunoblotting. PSD4 promoter methylation was assessed using quantitative methylation‐specific PCR. Phospho‐p65(S276)/DNMT1 binding to the PSD4 promoter was analyzed via chromatin immunoprecipitation. We constructed ethanol/DEN‐induced and DEN only‐induced transgenic murine models of HCC.ResultsWe identified PSD4 as a hypermethylated, suppressed gene in alcohol‐related HCC tumors; however, PSD4 was not dysregulated in all‐cause HCC tumors. Certain HCC cell lines also displayed varying degrees of PSD4 downregulation. PSD4 overexpression or knockdown decreased and increased cell migration and invasiveness, respectively. Mechanistically, PSD4 transcription was repressed by TNF‐α‐induced phospho‐p65(S276)’s recruitment of DNA methyltransferase 1 (DNMT1), resulting in PSD4 promoter methylation. PSD4 inhibited pro‐EMT CDC42 activity, resulting in downregulation of E‐cadherin and upregulation of N‐cadherin and vimentin. Hepatocyte‐specific PSD4 overexpression reduced ethanol/DEN‐induced HCC tumor progression and EMT marker expression in vivo.ConclusionsPSD4 is a hypermethylated, suppressed gene in alcohol‐related HCC tumors that negatively modulated pro‐EMT CDC42 activity. Furthermore, we present a novel phospho‐NF‐κB p65(S276)/DNMT1‐mediated promoter methylation mechanism by which TNF‐α/NF‐κB signaling represses PSD4 transcription in HCC cells.
ONC201 induces the unfolded protein response (UPR) in high‐ and low‐grade ovarian carcinoma cell lines and leads to cell death regardless of platinum sensitivity
Authors: Rumman Marufa , Buck Steven , Polin Lisa , Dzinic Sijana , Boerner Julie , Winer Ira S. 
Published: May 2021

AbstractObjectivesTreatment of both platinum resistant high grade (HG) and low‐grade (LG) ovarian cancer (OVCA) poses significant challenges as neither respond well to conventional chemotherapy leading to morbidity and mortality. Identification of novel agents that can overcome chemoresistance is therefore critical. Previously, we have demonstrated that OVCA has basal upregulated unfolded protein response (UPR) and that targeting cellular processes leading to further and persistent upregulation of UPR leads to cell death. ONC201 is an orally bioavailable Dopamine Receptor D2 inhibitor demonstrating anticancer activity and was found to induce UPR. Given its unique properties, we hypothesized that ONC201 would overcome platinum resistance in OVCA.MethodsCisplatin sensitive and resistant HG OVCA and two primary LG OVCA cell lines were studied. Cell viability was determined using MTT assay. Cell migration was studied using wound healing assay. Apoptosis and mitochondrial membrane potential were investigated using flow cytometry. Analysis of pathway inhibition was performed by Western Blot. mRNA expression of UPR related genes were measured by qPCR. In vivo studies were completed utilizing axillary xenograft models. Co‐testing with conventional chemotherapy was performed to study synergy.ResultsONC201 significantly inhibited cell viability and migration in a dose dependent manner with IC50’s from 1‐20 µM for both cisplatin sensitive and resistant HG and LG‐OVCA cell lines. ONC201 lead to upregulation of the pro‐apoptotic arm of the UPR, specifically ATF‐4/CHOP/ATF3 and increased the intrinsic apoptosispathway. The compensatory, pro‐survival PI3K/AKT/mTOR pathway was downregulated. In vivo, weekly dosing of single agent ONC201 decreased xenograft tumor size by ~50% compared to vehicle. ONC201 also demonstrated significant synergy with paclitaxel in a highly platinum resistant OVCA cell‐line (OV433).ConclusionsOur findings demonstrate that ONC201 can effectively overcome chemoresistance in OVCA cells by blocking pro‐survival pathways and inducing the apoptotic arm of the UPR. This is a promising, orallybioavailable therapeutic agent to consider in clinical trials for patients with both HG and LG OVCA.
Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma
Authors: Iacoboni Gloria , Villacampa Guillermo , Martinez‐Cibrian Nuria , Bailén Rebeca , Lopez Corral Lucia , Sanchez Jose M. , Guerreiro Manuel , Caballero Ana Carolina , Mussetti Alberto , Sancho Juan‐Manuel , Hernani Rafael , Abrisqueta Pau , Solano Carlos , Sureda Anna , Briones Javier , Martin Garcia‐Sancho Alejandro , Kwon Mi , Reguera‐Ortega Juan Luis , Barba Pere ,   GETH, GELTAMO Spanish Groups
Published: May 2021

AbstractTisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.
Surgery shows survival benefit in patients with primary intestinal diffuse large B‐cell lymphoma: A population‐based study
Authors: Wang Moran , Ma Shengling , Shi Wei , Zhang Yuanyuan , Luo Shanshan , Hu Yu 
Published: May 2021

AbstractBackgroundThe clinical characteristics and prognosis of primary intestinal diffuse large B‐cell lymphoma (PI‐DLBCL) are rarely reported. We aimed to explore the role of surgery in patients with PI‐DLBCL.MethodsAdult PI‐DLBCL patients were included from the Surveillance, Epidemiology, and End Results database. The effect of surgery was evaluated by Kaplan–Meier and Cox proportional regression analyses. Propensity score matching (PSM) was used to reinforce our results. Lasso regression was utilized to determine independent risk factors of overall survival (OS) for a nomogram and a novel web‐based calculator. The performance of the model was measured via concordance index, receiver operating characteristic curve, and calibration plots in both cohorts.ResultsOverall, 1602 patients with PI‐DLBCL were analyzed. Surgery significantly improved survival in both univariate and multivariate analyses (p = 0.007, p < 0.001, respectively). Before PSM, local tumor destruction (LTD) displayed a survival advantage over resection in patients without chemotherapy (p = 0.034). After PSM, surgery was still identified as a beneficial factor for OS (p = 0.0015). However, there was no statistical difference between LTD and resection (p = 0.32). The nomogram for 3‐, 5‐, and 10‐year OS predictions exhibited dependable consistency between internal and external validation.ConclusionThis study approves the beneficial effect of surgery on clinical endpoints in PI‐DLBCL patients. For those who are not suitable for resection, LTD may also be a practical option. The predictive nomogram and the web‐based calculator could help clinicians individually evaluate the prognosis and optimize personalized treatment decisions for these patients.
BACH1 promotes the progression of esophageal squamous cell carcinoma by inducing the epithelial–mesenchymal transition and angiogenesis
Authors: Zhao Yan , Gao Jiajia , Xie Xiufeng , Nan Peng , Liu Fang , Sun Yulin , Zhao Xiaohang 
Published: May 2021

AbstractMetastasis to regional lymph nodes or distal organs predicts the progression of the disease and poor prognosis in esophageal squamous cell carcinoma (ESCC). Previous studies demonstrated that BTB and CNC homology 1 (BACH1) participates in various types of tumor metastasis. However, the function of BACH1 in ESCC was rarely reported. The present study demonstrated that BACH1 protein was overexpressed in ESCC tissues compared with paired esophageal epithelial tissues according to immunohistochemical staining (IHC). Higher levels of BACH1 mRNA were associated with decreased overall survival (OS) and shorter disease‐free survival (DFS) of ESCC patients based on an analysis of The Cancer Genome Atlas (TCGA) datasets. BACH1 significantly enhanced the migration and invasion of ESCC in vitro. Mechanistically, BACH1 promoted the epithelial–mesenchymal transition (EMT) by directly activating the transcription of CDH2, SNAI2, and VIM, as determined by chromatin immunoprecipitation‐quantitative polymerase chain reaction (ChIP‐qPCR). BACH1 overexpression significantly enhanced CDH2 promoter activity according to the results of a luciferase assay. The results of subsequent experiments indicated that BACH1 enhanced the growth of tumor xenografts. The density of CD31+ blood vessels and the expression of vascular endothelial growth factor C (VEGFC) in tumor xenografts were significantly associated with BACH1 levels according to the results of IHC and immunofluorescence (IF) analyses performed in vivo. Moreover, ChIP‐qPCR analysis demonstrated that the transcriptional activity of VEGFC was also upregulated by BACH1. Thus, BACH1 contributes to ESCC metastasis and tumorigenesis by partially facilitating the EMT and angiogenesis, and BACH1 may be a promising therapeutic target or molecular marker in ESCC.
Retroperitoneal or transperitoneal approach in robot‐assisted partial nephrectomy, which one is better?
Authors: Zhou Jing , Liu Zheng‐Huan , Cao De‐Hong , Peng Zhu‐Feng , Song Pan , Yang Luchen , Liu Liang‐Ren , Wei Qiang , Dong Qiang 
Published: May 2021

AbstractPurposeTo systematically assess the perioperative outcomes of retroperitoneal (RP) and transperitoneal (TP) approaches in robot‐assisted partial nephrectomy (RAPN), we conducted an updated meta‐analysis.MethodsA literature retrieval of multi‐database including PubMed, Web of Science, Embase, Cochrane Library, and CNKI was performed to identify eligible comparative studies from the inception dates to January 2021. Perioperative outcomes included operative time (OT), estimated blood loss (EBL), warm ischemia time (WIT), postoperative length of stay (PLOS), positive surgical margin (PSM), and complications (major complications and overall complications). Outcomes of data were pooled and analyzed with Review Manager 5.4.1.ResultsTwenty‐one studies involving a total of 2482 RP and 3423 TP approach RAPN patients met the inclusion criteria. Operating time (OT) (weighted mean difference [WMD] −16.60; 95% confidence interval [CI] −23.08, −10.12; p < 0.01) and PLOS (WMD −0.46 days; 95% CI −0.69, −0.23; p < 0.01) were shorter in RP‐RAPN. Besides, lower EBL (WMD −21.67; 95% CI −29.74, −13.60; p < 0.05) was also found in RP‐RAPN. Meanwhile, no significant differences were found in other outcomes.ConclusionsRP‐RARN was superior to TP‐RAPN in patients undergoing RAPN in terms of OT, PLOS, and estimated blood loss. Besides these two approaches have no significant differences in PSMs or perioperative complications.
Patient perspectives on chemotherapy de‐escalation in breast cancer
Authors: Rocque Gabrielle B. , Williams Courtney P. , Andrews Courtney , Childers Timothy C. , Wiseman Kimberly D. , Gallagher Kathleen , Tung Nadine , Balch Alan , Lawhon Valerie M , Ingram Stacey A , Brown Thelma , Kaufmann Tara , Smith Mary L. , DeMichele Angela , Wolff Antonio C. , Wagner Lynne 
Published: May 2021

AbstractBackgroundGiven excellent survival outcomes in breast cancer, there is interest in de‐escalating the amount of chemotherapy delivered to patients. This approach may be of even greater importance in the setting of the COVID‐19 pandemic.MethodsThis concurrent mixed methods study included (1) interviews with patients and patient advocates and (2) a cross‐sectional survey of women with breast cancer served by a charitable nonprofit organization. Questions evaluated interest in de‐escalation trial participation, perceived barriers/facilitators to participation, and language describing de‐escalation.ResultsSixteen patient advocates and 24 patients were interviewed. Key barriers to de‐escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for focus on less treatment. Facilitators included trust in physician recommendation, toxicity avoidance, monitoring for progression, perception of good prognosis, and impact on daily life. Participants reported that the COVID‐19 pandemic made them more likely to avoid chemotherapy if possible. Of 91 survey respondents, many (43%) patients would have been unwilling to participation in a de‐escalation clinical trial. The most commonly reported barrier to participation was fear of recurrence (85%). Few patients (19%) considered clinical trials themselves as a barrier to de‐escalation trial participation. The most popular terminology describing chemotherapy de‐escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de‐escalation.”ConclusionsFear of recurrence is a common concern among breast cancer survivors and patient advocates, contributing to resistance to de‐escalation clinical trial participation. Additional research is needed to understand how to engage patients in de‐escalation trials.
Expression and ERG regulation of PIM kinases in prostate cancer
Authors: Eerola Sini K. , Kohvakka Annika , Tammela Teuvo L. J. , Koskinen Päivi J. , Latonen Leena , Visakorpi Tapio 
Published: May 2021

AbstractThe three oncogenic PIM family kinases have been implicated in the development of prostate cancer (PCa). The aim of this study was to examine the mRNA and protein expression levels of PIM1, PIM2, and PIM3 in PCa and their associations with the MYC and ERG oncogenes. We utilized prostate tissue specimens of normal, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), untreated PCa, and castration‐resistant prostate cancer (CRPC) for immunohistochemical (IHC) analysis. In addition, we analyzed data from publicly available mRNA expression and chromatin immunoprecipitation sequencing (ChIP‐Seq) datasets. Our data demonstrated that PIM expression levels are significantly elevated in PCa compared to benign samples. Strikingly, the expression of both PIM1 and PIM2 was further increased in CRPC compared to PCa. We also demonstrated a significant association between upregulated PIM family members and both the ERG and MYC oncoproteins. Interestingly, ERG directly binds to the regulatory regions of all PIM genes and upregulates their expression. Furthermore, ERG suppression with siRNA reduced the expression of PIM in PCa cells. These results provide evidence for cooperation of PIM and the MYC and ERG oncoproteins in PCa development and progression and may help to stratify suitable patients for PIM‐targeted therapies.
Surgical strategies for hepatocellular carcinoma located in the left lateral lobe: A propensity score‐matched and prognostic nomogram study
Authors: Zou Jingwen , Li Shaohua , Wang Qiaoxuan , Mei Jie , Lu Lianghe , Lin Wenping , Wen Yuhua , Li Yuechao , Wei Wei , Guo Rongping 
Published: May 2021

AbstractPurposeFor hepatocellular carcinoma (HCC) located in the left lateral lobe, the optimal surgical procedure is still controversial. This study aimed to optimize surgical strategies and to construct a nomogram to predict the postoperative survival of patients with HCC.MethodsBetween 1 January 2005 and 30 September 2018, a total of 493 patients were enrolled. Propensity score matching (PSM) was performed between the left lateral lobectomy (LLL) and left hepatectomy (LH) groups (1:1). The study endpoints were overall survival (OS), recurrence‐free survival (RFS), and safety. A nomogram was generated using a multivariate Cox proportional hazards model. The discriminative ability and calibration of the nomogram were evaluated using C‐statistics and calibration plots.ResultsAfter matching, 87 pairs were included. The LH group had better 1‐, 3‐, and 5‐year OS rates than the LLL group (88%, 73%, and 69% vs. 73%, 57%, and 49%, respectively; p = 0.017). The 1‐, 3‐, and 5‐year RFS rates of the LH group were similar to those of the LLL group (64%, 49%, and 46% vs. 63%, 51%, and 42%, respectively; p = 0.652). There were no significant differences in postoperative complications. Eight factors were integrated into the nomogram and it had good discriminative ability and calibration.ConclusionOur data revealed that compared to LLL, LH may result in better OS and have similar postoperative complications for HCC. The nomogram may serve as a practical tool for the individual prognostic evaluation of patients with HCC.
Patient‐reported outcomes following neoadjuvant endocrine therapy, external beam radiation, and adjuvant continuous/intermittent endocrine therapy for locally advanced prostate cancer: A randomized phase III trial
Authors: Yokomizo Akira , Koga Hirofumi , Ito Kazuto , Takezawa Yutaka , Komiyama Motokiyo , Nishimura Kazuo , Yonese Junji , Hashine Katsuyoshi , Masumori Naoya , Arai Gaku , Saito Shiro , Shinohara Mitsuru , Shimizu Nobuaki , Yamauchi Atsushi , Satoh Takefumi , Tochigi Tatsuo , Kobayashi Mikio , Fujimoto Hiroyuki , Kakimoto Ken‐ichi , Fukui Iwao , Tsukamoto Taiji , Nozaki Miwako , Karasawa Katsuyuki , Hasumi Masaru , Ohtani Mikinobu , Ishiyama Hiromichi , Kuwahara Masaaki , Harada Masaoki , Ohashi Yasuo , Kotake Toshihiko , Kakizoe Tadao , Suzuki Kazuhiro , Naito Seiji , Yamanaka Hidetoshi ,   National Research Project on Endocrine‐Radiation Combination Therapy for Locally Advanced Prostate Cancer investigators
Published: May 2021

AbstractBackgroundWe evaluated patient‐reported outcomes (PRO) during neoadjuvant androgen deprivation therapy (ADT) plus external beam radiation therapy (EBRT) followed by either adjuvant continuous ADT (CADT) or intermittent ADT (IADT) for patients with locally advanced prostate cancer (Pca).MethodsA multicenter, randomized phase III trial enrolled 303 patients with locally advanced Pca. The patients were treated with 6 months (M) of ADT followed by 72 Gy of EBRT, and were randomly assigned to CADT or IADT after 14 M. The PROs were evaluated at sic points: baseline, 6 M, 8 M, 14 M, 20 M, and 38 M using FACT‐P questionnaires and EPIC urinary, bowel, and sexual bother subscales.ResultsThe FACT‐P total scores were significantly better (p < 0.05) in IADT versus CADT at 20 M (121.6 vs.115.4) and at 38 M (119.9 vs. 115.2). The physical well‐being scores (PWB) were significantly better (p < 0.05) in IADT versus CADT at 38 M (25.4 vs. 24.0). The functional scores were significantly better in IADT than those in CADT at 14 M (20.2 vs18.7, p < 0.05) and at 20 M (21.0 vs.18.9, p < 0.05).ConclusionThe PRO was significantly favorable in IADT on FACT‐P total score at 20 M and 38 M, PWB and functional scores at 38 M.