bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world treatment patterns among veterans with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Halwani Ahmad Sami , Patil Vikas , Morreall Deborah , Li Chunyang , Yong Christina , Appukkutan Sreevalsa , Partridge Jamie , Jhaveri Jay , Rasmussen Kelli Marie 
Published: June 2022

e17042 Background: Prostate cancer (PC) is the most common cancer diagnosed among U.S. Veterans. Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs in patients who, despite having received androgen deprivation therapy, experience a rising prostate-specific antigen (PSA) and castrate testosterone levels, with no evidence of metastatic disease on radiographic imaging. Given the recent approval of novel antiandrogens, the treatment landscape for nmCRPC has rapidly evolved. Although there have been numerous clinical trials examining the safety and efficacy of these treatments, few studies have identified real-world treatment patterns among nmCRPC patients. Methods: We conducted a retrospective observational study using patient information obtained from the Veterans Affairs (VA) Clinical Cancer Registry and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with PC at the VA, and later developed nmCRPC, defined as having: (1) evidence of rising PSA, i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) no evidence of metastatic disease on radiology reports. Treatments were extracted from CDW pharmacy dispensation records and were indexed at nmCRPC diagnosis. Results: A total of 12,549 patients were diagnosed with nmCRPC and treated in the VA from 2006 to 2020; of these, 7,239 (58%) were white, 3,386 (27%) were black, 784 (6%) were Hispanic, and 1,140 (9%) other. Median age at PC diagnosis was 69 years, with most patients residing in the South 4,817 (38%). Of the 7,659 (61%) patients receiving first-line (1L) nmCRPC therapy, 5,508 (72%) received bicalutamide, 621 (8%) ketoconazole, 563 (7%) abiraterone, 492 (6%) enzalutamide, and 242 (3%) flutamide. Although bicalutamide remained the most frequently used 1L nmCRPC therapy regardless of year, the adoption of abiraterone and enzalutamide beginning in 2012 resulted in a decline of 1L bicalutamide from 80% of patients in 2006 to 43% in 2020. Ketoconazole was the second most common 1L nmCRPC therapy and the most common second-line (2L) and third line (3L) nmCRPC therapy. Of patients receiving 1L therapy, 2,244 (31%) received 2L therapy, and of these, 708 (32%) received 3L therapy. Conclusions: To our knowledge, this is the largest real-world cohort of nmCRPC patients treated in a nationwide equal-access health care system. Despite the recent approval of several nmCRPC treatments (apalutamide, darolutamide, enzalutamide) which have demonstrated improved metastasis-free survival and treatment-related quality of life, our real-world findings suggest that older, first-generation antiandrogens remain the predominant 1L treatment for nmCRPC patients.
Unpacking low-value castration practices using behavior specification to guide de-implementation in prostate cancer care.
Authors: Skolarus Ted A. , Forman Jane , Sparks Jordan B. , Metreger Tabitha , Hawley Sarah T. , Caram Megan Veresh , Dossett Lesly Ann , Larkin Angela , Paniagua Cruz Alan , Makarov Danil V. , Leppert John T. , Shelton Jeremy B. , Stensland Kristian D. , Hollenbeck Brent K. , Shahinian Vahakn , Wittmann Daniela A. , Deolankar Varad , Sriram S. 
Published: June 2022

e17055 Background: Many men with prostate cancer will be exposed to ADT at some point during cancer survivorship. Unfortunately, ADT overuse in low-value scenarios is not uncommon (e.g., monotherapy in localized prostate cancer, biochemically-recurrent non-metastatic disease) resulting in more harms than benefits. We conducted an innovative survey study to unpack ADT overuse to inform behavior change and de-implementation strategies. Methods: Our survey used the Theoretical Domains Framework (TDF), and the Capability, Opportunity, Motivation – Behavior (COM-B) Model. The survey was fielded to the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on their likelihood of stopping ADT monotherapy in the case of a localized prostate cancer patient presenting to their office (yes/probably yes, probably no/no), and characterized Likert scale responses to 7 COM-B statements. We used multivariable logistic regression to identify associations between stopping ADT and COM-B responses across a dichotomized Likert scale of “strongly disagree/disagree/neutral” and “agree/strongly agree.”. Results: Our survey was completed by 84 respondents (13% response rate), with 27% indicating ‘probably no’/‘no’ to stopping low-value ADT monotherapy in the case of a localized prostate cancer patient presenting to their office. Our multivariable model identified 2 COM-B statements significantly associated with lower likelihood of stopping low-value ADT. Conclusions: Using an innovative, behavioral theory-informed survey, we identified that providers less likely to stop low-value ADT had greater concern about patient worry and were more interested in providing ADT recommendations consistent with peers, informing de-implementation strategy selection. Clinical trial information: MCT03579680. [Table: see text]
HPV E7 oncogene expression impairs Rb function and confers CDK4/6 inhibitor resistance in cervical cancer.
Authors: Xiong Yudi , Wang Yuan , Ou Haibin , Zhou Yunfeng 
Published: June 2022

e17504 Background: Malignant tumor proliferation is one of the important factors for poor prognosis. CDK4/6 inhibitors can delay tumor progression by inhibiting cell cycle and inducing apoptosis, so they are potentially effective broad-spectrum anti-tumor targeted drugs, but drug resistance limits their clinical applications. Our previous research found that the CDK4/6 inhibitor LEE011 has anti-tumor effects on cervical cancer C33A cells, but no anti-tumor activity against HeLa. The mechanism is not very clear, we speculate that it is related to HPV infection. In this research, our aim is to clarify the correlation between HPV and tumor drug sensitivity and explore the possible mechanisms. Methods: Two HPV positive human cervical cancer cell lines, SiHa and Caski were chosen to verify the sensitivity to LEE011 by cell morphology, cell cycle and apoptosis. The antitumor activity of CDK4/6 inhibitor LEE011 by E7 knockin C33A and E7 knock-down HeLa cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. Effects of LEE011 and E7 knock-down combination in vivo were studied by xenograft tumor regrowth delay, and tissue section immunohistochemistry. Results: SiHa and Caski were insensitive to LEE011 antitumor activity. Enhancement of drugsensitivity was lost in cell lines with HPV positive. After down-regulation of E7, LEE011 treatment increased the inhibition cell proliferation and pro-apoptosis of HeLa. Mechanistically, the loss of E7-induced Rb inactivation and LEE011 inhibited Rb phosphorylation, leading to cell-cycle arrest. In vivo, LEE011 inhibited tumor regrowth, with sustained inhibition of cyclin D-CDK4/6-Rb-E2F1 activity in E7 knock-down HeLa. However, up-regulation of E7 can reduce the ability of LEE011 to inhibit cell proliferation and pro-apoptosis of C33A. In summary, our study signifies inhibiting the CDK4/6 pathway by LEE011 in combination with down-regulation of E7 as a promising therapeutic strategy to treat cervical cancer. Conclusions: These findings suggested that HPV can affect Rb function by expressing oncoprotein E7 leading to resistance to targeted drug therapy, which means that HPV may be a biomarkers of drug therapy efficacy.
Prognostic analysis of doublet agent concurrent chemoradiotherapy in locally advanced cervical cancer: A propensity score analysis.
Authors: Wang Jingjing , Shan Minjie , Feng Yeqian , Wang Jinlei , Wu Lin , Liu Xianling , Zou Wen 
Published: June 2022

e17514 Background: Platinum-based concurrent chemoradiotherapy (CCRT) is the current standard treatment for patients with locally advanced cervical cancer (LACC). Previous reports showed that doublet agent CCRT can provide better prognosis than single agent CCRT. However, several controversies surround the doublet agent regimen. This retrospective study compared the efficacy and safety of cisplatin and nedaplatin in doublet agent CCRT by propensity score (PS) matching. Methods: Information on patients with stage IIB-IIIC2 cervical cancer who received doublet agent CCRT from January 2015 to December 2020 were collected. The chemotherapy regimen was docetaxel (75mg/m2) combined with carboplatin (AUC = 4-5) / cisplatin (50–70mg/m2) / nedaplatin (50-75mg/m2) once every 3 weeks. All patients underwent external-beam radiotherapy with intensity-modulated radiotherapy at a dose of 45–50 Gy/25fx to the pelvis with or without involving the para-aortic region and 60 Gy/25fx to gross disease in the lymph nodes, and 2-dimensional intracavitary brachytherapy with dose of 30 Gy/5fx to point A. Patients were classified into the cisplatin group and nedaplatin group. Treatment outcomes were compared between the two groups after 1:1 ratio PS matching adjusted for age, BMI, FIGO stage, pathology, tumor diameter, differentiation, complication, and cycles of chemotherapy. Categorical variables were compared using the χ2 test or Fisher's exact test. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. Results: There are 295 patients enrolled, median age 55 years (32–73 years). The median follow-up time was 38 months (5–77 months). The median number of chemotherapy cycle is 4 (1–6 cycles). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 82.5% and 80.4%, respectively. After PS matching, there were 83 patients each in the nedaplatin group and cisplatin group. All background factors between the two groups were well-balanced. There was no significant difference between the cisplatin and nedaplatin groups in terms of objective response rate (97.6% and 98.8%, p = 0.212), 5-year OS rate (96.5 vs.69.8, p = 0.066), and PFS rate (90.8 vs.72.4, p = 0.166). Also, there was no significant difference between the cisplatin and nedaplatin groups in terms of hematological toxicity (36.1% vs. 28.9%, p = 0.408), nausea and vomiting (19.3% vs. 20.4, p = 0.874), radiation proctitis (25.3% vs. 14.5%, p = 0.535), and radiation proctitis (12% vs.9.6%, p = 0.212). Conclusions: Doublet agent concurrent chemoradiotherapy is feasible, safe, and shows high efficacy in LACC patients. Here, the cisplatin group and nedaplatin group have similar prognosis and side effects, suggesting that nedaplatin and cisplatin are equivalent and can be replaced with each other for concurrent doublet agent CCRT.
Genomic characterization of primary cervical cancer and lung metastasis.
Authors: Tang Huarong , Yin Zhuomin , Lou Hanmei , Yu Yangyang , Song Yunjie , Xiao Mingzhe , Qi Chuang 
Published: June 2022

e17527 Background: Cervical cancer ranks fourth in incidence and mortality among female tumors in the world. Lung metastases are the most common metastatic foci of cervical cancer, which were associated with poor prognosis. Exploring the different genomic landscape between primary tumor and lung metastasis would help to understand the mechanism of cervical cancer lung metastasis. Methods: A total of 52 Chinese cervical cancer patients with lung metastasis were enrolled between 2016 and 2020. Among whom 37 patients had paired samples (primary tumor and lung metastasis), 6 had only primary tumor samples, and 9 had only lung metastasis samples. Lung metastasis samples were confirmed as cervical cancer metastasis via immunohistochemistry. All the formalin-fixed paraffin-embedded (FFPE) tumor samples and matched peripheral blood were collected and underwent whole-exome sequencing (WES). The Illumina NovaSeq 6000 (Illumina, San Diego, CA, USA) sequencing platform was used to perform 150-nt paired-end multiplex sequencing of DNA samples. The average coverage depth was 340× in FFPE samples and 170× in white blood cell controls. Normally distributed data were compared using the t-test and data with abnormal distribution were compared using the Mann–Whitney U test. Results: There were 4,212 and 6,341 somatic mutations in primary tumor and lung metastasis, respectively. The consistencies for SNVs/indels and CNVs were 41.22% (2.86%–76.11%) and 13.65% (3.69%–76.11%). The most frequently altered genes in primary tumor and lung metastasis were PIK3CA (23.26% vs. 36.96%; p = 0.26), TTN (23.26% vs. 39.96%; p = 0.18), MUC4 (16.28% vs. 39.96%; p = 0.03), ARMCX4 (25.58% vs. 26.09%; p = 1), and MUC16 (18.60% vs. 26.09%; p = 0.45). MUC4 had a significantly higher mutation frequency in lung metastasis than in primary tumor. To explore the mutation characteristics, co-mutations in primary tumor and lung metastasis were analyzed. EP300/MUC16 co-mutation (p < 0.01) was identified in primary tumor. KMT2D/MUC16 co-mutation (p < 0.01) was identified in lung metastasis. Among the paired samples, the Cosmic Signature analysis had shown that Signature 2, which was attributed to activity of the AID/APOBEC family of cytidine deaminases, was higher in lung metastasis than primary tumor (p = 0.042). Meanwhile, the amplification of 17q12 was more frequently observed in lung metastasis in contrast to primary tumor (p = 0.035). Furthermore, the GO/KEGG analysis had revealed that the mutant genes which only observed in lung metastasis were significantly enriched in ATPase activity and inositol phosphate metabolism. Conclusions: In summary, comprehensive genomic profiling of primary cervical cancer and lung metastasis can be of help to identify metastasis-specific features and understand the mechanism of cervical cancer lung metastasis.
Clinicopathological analysis of 285 cases of elderly patients with epithelial ovarian cancer.
Authors: Duan Yuanqiong , Zhang Mengpei , Yin Rutie , Han Jinbiao 
Published: June 2022

e17539 Background: Elderly patients with epithelial ovarian cancer often cannot receive standard treatment, and their survival time decreases with age, seriously threatening their lives. Elderly patients with epithelial ovarian cancer tend to have many complications and poor tolerance to surgery and chemotherapy, resulting in poor overall prognosis. Methods: The clinicopathological data of EOC patients aged ≥ 60 years old who were diagnosed and treated in our hospital from January 2013 to January 2018, with completed clinical and pathological data were collected for analysis and followed up through outpatient review, telephone, WeChat, QQ group, etc. to analyze the diagnosis and treatment plan and main prognostic factors. The deadline for follow-up was March 1, 2020. Results: Comparison of recurrence and the overall survival in different groups, the results respectively showed that the difference had statistically significant (χ2 = 255.027, p < 0.001) 、(χ2 = 314.443, p < 0.001). Analysis of the factors affecting the recurrence and death of patients showed that the results of single factor analysis showed age, BMI, Combined with cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, thrombus score, FIGO staging, pathological type, residual lesion size are the influencing factors of recurrence. Further multivariate analysis showed that combined cardiovascular and cerebrovascular diseases, pre-treatment CA125 value, FIGO stage, residual lesion size is an independent factor affecting relapse. The median survival time of relapse-free in the neoadjuvant chemotherapy group was 39.00 (30.67̃44.95) months; the median survival time of relapse-free in the directing surgery group was 36.00 (29.47̃42.53) months, statistical comparison showed no significant difference (χ2 = 2.426, p = 0.119). The total median survival time of the neoadjuvant chemotherapy group was 49.57 months; for the directing surgery group, the total median survival time was 47.07 months, and the statistical comparison showed no significant difference (χ2 = 0.166, p = 0.684). Conclusions: For the epithelial ovarian cancer in elderly patients the results showed that the standard treatment group was better than the non-standard treatment group, chemotherapy-only group, surgery-only group, and untreated group. Comparing with primary tumor debulking surgery (PDS),neoadjuvant chemotherapy-Interval debulking surgery (NACT-IDS) group could improve the intraoperative situation，reduce the amount of intraoperative bleeding, shorten the operation time, reduce the wound healing rate and the incidence of surgical complications, but it had no effect on the tumor removal rate, PFS and OS.
Connective tissue growth factor expression maintains the epithelial phenotype of ovarian cancer in early epithelial to mesenchymal transition.
Authors: Ramos Harry , Galoforo Sandra , You Yuan , Winer Ira Seth , Mor Gil , Alvero Ayesha , Gogoi Radhika 
Published: June 2022

e17544 Background: Epithelial to Mesenchymal Transition (EMT) is essential to the process of metastasis in ovarian cancer (OC). Early expressions of proteins and pathways during EMT essential for understanding mechanism and potential therapeutic targets in OC. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in OC. Methods: R182 and R2615 are well-characterized epithelial OC cell lines. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot. R182 and R2615 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and confirmed via PCR. Anoikis resistance and invasion assays were performed to characterize phenotypes of R182 and R2615 wild type (WT) and KO cells. For anoikis resistance, cells were plated in triplicate in an ultra-low adhesive (ULA) cell plate Promega CellTiter assay which measured cell viability quantified by absorbance at 450 nm at 0, 24, 48, and 72 hrs. For invasion assay, 3000 cells were suspended in 50% reduced growth factor Basement Membrane Extract. Human recombinant CTGF was added at 50 and 100 ng/mL concentrations. Cells were plated in tissue culture plate and placed in Cytation 5/Biospa and imaged at 4-hour interval for up to 6 days. Western blot evaluated expression of mesenchymal markers. Chemo-sensitivity was measured by half maximal inhibitory concentration (IC50) for Cisplatin between the WT and KO cells. RNA sequence analysis was performed for both R182 WT and KO cells and analyzed utilizing iPathway Guide. Results: CTGF is constitutively expressed in R182 and R2615 OC cells line as early as 6 hrs of culture and after 30 min of TGF-b treatment. Loss of CTGF promoted anoikis resistance. At 72 hr, R182 CTGF WT cells displayed 75% viability while R182 KO only have 10% viability. Further, we demonstrated that loss of CTGF increases invasion. Administration of exogeneous CTGF in KO cells suppresses invasion in a dose dependent manner demonstrated. Along with epithelial markers CK-18 and beta-catenin, the KO cells expressed the mesenchymal marker SNAIL. No difference in chemo-sensitivity to Cisplatin was seen between WT and KO in either cell line. RNA sequence analysis identified 1106 out of 14054 differentially expressed genes between the WT and KO cells. PI3KAkt, cell adhesion molecules and ECM receptor interaction were pathway that were most significantly regulated. Conclusions: CTGF expression maintains the epithelial phenotype of OC cells during EMT. Loss of CTGF allows anoikis resistance and invasion which are vital characteristics in the metastatic nature of OC. We suggest that loss of CTGF expression in OC cells could be a biomarker for more aggressive OC.
The value of a negative genetic result when triaging an adnexal mass.
Authors: Asulin Yitzhack , Dunton Charles J. , Haverbusch Victoria , Done James , Bullock Rowan , Ure Daniel , Debboli-Cop Marisa , Greenwood Jessica , Northrop Lesley 
Published: June 2022

e17553 Background: The baseline risk for ovarian cancer in the general population is 1.2%1. However, women with germline variants in ovarian cancer-associated genes can have a much higher baseline risk for ovarian cancer, up to 54%2. Such a difference in baseline risk presents a triaging challenging for physicians when evaluating adnexal masses. It is well known that identifying pathogenic variants in hereditary cancer syndrome genes often leads to changes in care. Less is known about the utility of negative genetic testing results, specifically in the context of adnexal mass assessment. Methods: An observational, prospective study was designed to examine the clinical impact of multivariate index assay (MIA) and germline genetic testing in patients with a known adnexal mass planned for surgery. Inclusion criteria were: female subjects aged 18-65, presence of an adnexal mass, receiving MIA, and consideration of germline genetic testing. Enrolled physicians selected patients under their care that met inclusion criteria and filled out a short survey describing how the results of each test impacted clinical management. This study was considered IRB-exempt as all information was de-identified. Results: 23 patients were enrolled that received both MIA and germline genetic testing. 21 cases had negative genetic testing and two had positive genetic testing. Both patients with positive genetic testing had low-risk MIA results. Both had risk-reduction surgery with benign findings. Three patients had high-risk MIA results with negative genetic results. All patients had a serial monitoring plan of care. Nine patients with low-risk MIA results and negative genetic results proceeded to surgery. No malignancies were reported. Of the 21 patients with negative genetic results, 17 were not immediately planned for surgery. Conclusions: While not reaching statistical significance, there is a strong association between a negative genetic result and non-immediate surgical intervention. While positive genetic testing results may lead to more aggressive, prophylactic surgical management, negative genetic results may support an expectant management approach. Effectively ruling out the most common hereditary cancer predisposition syndromes may provide physicians with useful insight into a patient's baseline risk. [Table: see text]