bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of DNA polymerases family members in cancer: The pan-cancer perspective.
Authors: Luo Zhiwen , Bi Xinyu , Bi Xingang 
Published: January 2021

475 Background: DNA polymerases family (DNA pols) has a lengthy reported significant influence on the initiation, development, and progress of cancer. However, the pan-cancer value of whole family members was poorly done. Our study intends to demonstrate the expression pattern and clinical cancer value of DNA pols members as prognostic biomarkers and a therapeutic target of pan-cancer. Methods: Comprehensive bioinformatics analyses were done using data from TCGA and CCLE. MultiCox regression was done to select tumor prognosis-related members. Nomogram was constructed to predict the overall survival (OS) across cancer patients. Transcription factor, GO, IPA, and GSEA enrichments were done to explore regulatory mechanisms and functions. Results: A total of 22 DNA pols were identified to have a potential to diagnostic value, and 10 DNA pols have a pan-cancer prognostic value under various stages, and cancer type, among which overexpression of 6 DNA-pols (POLA2, POLD1, POLD2, POLE2, POLE4, and POLQ) was found to be significantly related to worse outcomes regarding OS, while 4 DNA-pols (POLH, POLL, POLN, and REV1) significantly related to better outcomes. A 5-DNA pols based risk score (POLQ, POLD2, POLL, POLH, and REV1) was generated by MultiCox regression with a nomogram validated an accurate predictive efficacy. MYB Proto-Oncogene Like 2 (MYBL2) was identified as transcription factors of prognostic DNA pols in pan-cancer, and IPA mimic experiment reveals inhibiting MYBL2 could be a drug target to recover and balance the dysregulated expression pattern of DNA pols in pan-cancer. GO, IPA, and GSEA enrichments revealed functions and pathways altered by DNA pols in cancer, and the results were supported by pan-cancer cell sequencing data. Conclusions: DNA pols have a pan-cancer clinical value and can work as potential prognostic biomarkers. Furthermore, MYBL2 could be a drug target for pan-cancer.
Education on reactive oxygen species to lay the foundation for understanding therapeutic advances in anticancer therapy.
Authors: Parikh Kinjal , Warren Charlotte , Caracio Richard 
Published: January 2021

478 Background: The disruption of redox balance is increasingly thought to be one of the most important underlying factors contributing to the development, progression, and metastasis of cancers in human cells. This imbalance in redox homeostasis has been shown to be induced by the generation of free radicals, predominantly reactive oxygen species (ROS). Emerging data have established ROS as a new potential therapeutic target. Understanding the mechanisms associated with tumorigenesis is important to integrate novel potential therapeutic targets and understand which tumors or patient populations may benefit from ongoing research. Shortcomings in oncologists’ knowledge and confidence can hamper the integration of new treatments into the care of patients with cancer. Methods: An online continuing education (CME) activity consisted of a multi-media 30-minute video panel of two panelists discussing the mechanism, pathophysiology, and the premises for novel anti-cancer therapies. Educational effect was assessed using a repeated paired pre-/post-assessment study design. A McNemar’s test was used to identify differences between pre- and post-assessment responses. Effect size was calculated using Cohen’s d test by determining the strength of the association between the activity and the outcomes (d < .20 is modest and d ≥ .80 is large). P values were calculated and those < .05 were considered statistically significant. The activity launched 5/14/2020 and data are represented through 8/6/2020. Results: A total of 1,033 learners, of which there are 656 physicians, participated in the activity. Participating in education resulted in statistically significant improvements and noticeable educational effect and data for oncologists that answered all pre- and post-assessment questions are represented below (n = 45, p < .001, Cohen’s d = .454). Percentages represent relative rates of improvement The role of ROS on cancer cell proliferation, cancer cell toxicity, and the tumor microenvironment (67%, p < .05) The interplay of antioxidants to aid in the development of therapies to induce DNA-damaged cell death (100%; p < .001) The potential biomarkers to aid in the development of therapies to induce DNA-damaged cell death (34%; p < .05). Conclusions: This online, interactive, expert-led, CME-certified educational activity resulted in significant gains in oncologist knowledge and confidence regarding the ROS pathway and associated clinical pipeline developments Upon completion of the initiative, only 11% of oncologists were able to answer all 3 matched pre/post questions correctly, signifying the need for further education The novelty of the information to many learners demonstrate the need to continue highlighting clinical advances and molecular pathways that may have potential implications in cancer therapy progress.
Predictors of uptake of aspirin (ASA) chemoprevention in Lynch syndrome (LS).
Authors: Hall Michael J. , Clapper Margie , Chang Wen-Chi J , Chertock Yana , Nguyen Minhhuyen J 
Published: January 2021

49 Background: Substantial data support efficacy of ASA in colorectal adenoma and cancer (CRC) chemoprevention. In 2011, the CaPP2 Phase 3 trial showed benefit of 600 mg ASA daily for prevention of LS-associated CRC (HR 0.41,p=0.02) in persons w/ASA adherence >2 yrs. Anecdotally, uptake of ASA by LS pts has been low, but few data exist. We examined uptake and predictors of ASA chemoprevention among LS pts receiving follow-up at our center since 2011. Methods: Pts evaluated by Fox Chase’s Risk Assessment Program receive in-person medical recommendations and written information about cancer (CA) prevention measures including ASA. Medical records of 127 LS pts were retrospectively reviewed. Demographics, gene affected, personal Hx of CA, ASA use, and ASA dose were collected. Majority (94.5%) of cohort had documentation of ongoing LS endoscopic screening at our center—only 3.2% had no recent follow-up (past 3 yrs) and 2.4% had recently died (past 3 yrs). Chi-square tests and multivariable logistic regression were used in analyses. Results: Overall 24.4% (31/127) of pts reported ASA use for chemoprevention (see Table). Nearly half (48.4%) of ASA users took 81 mg ASA daily, and only 22.6% reported taking >600 mg ASA daily. ASA use was associated with older age, MLH1/ MSH2+ vs MSH6/ PMS2+, and personal Hx of CRC. In the multivariable logistic model, older age (OR 2.80, p=0.04) and MLH1/ MSH2+ (OR 2.64,p=0.07) were significant and borderline significant, respectively. Adding race/ethnicity and gender strengthened the effect of age>60 (OR 3.11, p=0.03), and improved fit (pseudoR2=16.8%). Conclusions: Uptake of ASA chemoprevention by LS pts is overall modest, but older age is associated with ASA uptake for chemoprevention. Among ASA users, fewer than 1 in 4 take the 600 mg daily dose shown effective in CaPP2. Confirmatory trials as well as efforts to elucidate barriers to ASA chemoprevention in LS are needed. [Table: see text]
Development and clinical validation of a blood test for early detection of colorectal adenomas and cancer.
Authors: Friedland Shai , Pan Jennifer Y. , Watson Drew , Chen Yu , Nimgaonkar Ashish , Gulzar Zulfiqar , Gupta Pratyush , Atkins Alex , Lai Jr-Ming , Hsieh Ben , Su Stephen , Ciu Iris , Setthasap Ploy , Sninsky John , Mei Rui 
Published: January 2021

50 Background: Many of the 50,000 annual colorectal cancer (CRC) deaths can be attributed to 1/3 eligible Americans not following screening guidelines or approximately 1/2 of the population not adherent to the follow-up post-polypectomy guidelines. The new understanding of the natural history and shared etiology of adenomas and CRC inform integration of clinically relevant biomarkers. The two objectives of CRC screening and surveillance are early detection to improve survival and prevention of CRC through removal of adenomas using colonoscopy. Adenomas account for 98% of actionable colonoscopies. Stool tests have low sensitivity for advanced adenomas (AA, 24-42%). Methods: A prospective, blinded study was conducted at the VA Palo Alto Health Care System. Patients had blood drawn prior to colonoscopy. The test analyzes two biomarkers: circulating gastrointestinal epithelial cells and somatic mutations of cell-free DNA. The probability of advanced neoplasia was obtained by ordinal/nominal logistic regression methods together with SEER-incidence rate and prior history of AA on a training set of 346 subjects. The cutpoint for the quantitative score was fixed and the remaining 112 subjects were tested. Results: Interim results for 458 patients with no prior diagnosis of colorectal cancer (CRC) are presented. The cohort included both screening (239) and surveillance (219) subjects. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Balanced distribution of roughly 3/4th subjects in each disease category were randomly selected for training and algorithm development and the remaining 1/4th subjects were used for validation. A cutpoint was selected to obtain a test specificity (non-neoplastic finding or negative colonoscopy) of 90% resulting in a sensitivity of 100% and 80.0% for detection of CRC and advanced neoplasia (AN = CRC+AA), respectively, on the training subjects. The area under the ROC curve is 0.91. Validation using the fixed cutpoint and 112 test subjects achieved 91.4% specificity and 100% and 75.0% sensitivity for CRC and AN. Conclusions: This blood test has high sensitivity for colorectal advanced neoplasia while retaining high specificity. The quantitative nature of the score has the potential to enable stratification of patients for screening or post-polypectomy surveillance colonoscopy. [Table: see text]
Examining patterns of and reasons for delays to treatment in colon cancer.
Authors: Kalam Ali , Arientyl Vanessa , Schriner Jacob B , Kopp Adam , Friedmann Patricia , Qin Jiyue , In Haejin 
Published: January 2021

52 Background: Delays in colon cancer (CC) treatment can impact patient outcomes. Detailed examination into the patterns and reasons for delay in the diagnostic and pre-treatment work up are understudied, hindering the development of strategies to improve timeliness of care. Methods: CC patients diagnosed at an urban academic institution in 2018 were investigated. Chart review yielded presentation location, diagnostic-work up, treatment and patient characteristics. Time between presentation to the healthcare provider to treatment initiation of ≥ 60 days was considered a delay (Total_Delay). Total time further examined as 3 phases: presentation to diagnosis (PtoD), diagnosis to staging completion (DtoS), and staging completion to treatment (StoT). Delays for each phase was defined as ≥ 30 days. Total_Lt60d vs non-Total_Ge60d were compared. A logistic regression model was used to calculate odds ratio (OR) and 95% confidence intervals (CI) to identify associations with Total_Ge60d. Results: Among 121 CC patients, the median time and interquartile range (IQR) between presentation and treatment initiation was 29 (IQR 8, 53) days. Total_Delay occurred in 21% of patients. The median time between presentation and treatment and interquartile range (IQR) for Total_Delay was 106 (IQR 82, 162) and 16 (IQR 6, 39) for non-Total_Delay. Age, sex, race, and comorbidities were similar between Total_Delay and non-Total_Delay. Total_Delay patients were generally more functionally independent (92% vs 74%, p < .06), presented to locations other than the emergency department (64% vs 42%, p < .075) and were less likely to have hospital admission work-up (20% vs 60%, p < .001) compared to non-Total_Delay. The logistic model showed that Total_Delay is associated with non-hospital work-up (OR 8.3, 95% CI 1.9-45.3), adjusting for comorbidities, symptoms, functional status, cancer severity, and insurance. Delays similarly occurred in all three phases for Total_Delay patients; 48% had delay during PtoD, 60% during DtoS, and 48% during StoT. The most common reason for delay by phase was the following; in the PtoD phase, 5 of 11 (46%) was due to obtaining endoscopy, in DtoS and StoT, 6 of 15 (40%) and 5 of 11 (46%), respectively, was in getting outpatient specialty appointments. Delays due to patient factors (PtoD 18%, DtoS 27%, StoT 28%) were less frequent. Conclusions: Delays to treatment for CC are largely driven by health systems delays. Bundling of diagnostic evaluation and pre-treatment that mimics work-up during a hospital admission may overcome delays in cancer care.
Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.
Authors: Brooks Gabriel A. , Tapp Stephanie , Daly Allan T. , Busam Jonathan , Tosteson Anna N.A. 
Published: January 2021

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.
Short-course radiotherapy and subsequent CAPOX plus camrelizumab followed by delayed surgery for locally advanced rectal cancer:Short-term results of a phase II trial.
Authors: Lin Zhenyu , Cai Ming , Zhang Peng , Li Xin , Cai Kailin , Nie Xiu , Tao Kaixiong , Zhang Tao 
Published: January 2021

63 Background: Chemoradiotherapy followed by radical surgery is standard treatment for patients with locally advanced rectal cancer (LARC). Short-course radiotherapy (SCRT), either with immediate or delayed surgery, provides similar oncological results compared with long-course radiotherapy with delayed surgery. Delayed surgery with the addition of neoadjuvant immunotherapy may bring better downstaging effect and minimize the risk of distant relapse. We conducted this single-arm phase 2 trial to investigate the efficacy and safety of SCRT combined with subsequent capecitabine and oxaliplatin (CAPOX) plus Camrelizumab (anti-PD-1 antibody) followed by delayed surgery in patients with LARC. Methods: Patients with histologically confirmed T3–4N0M0 or T1-4N+M0 rectal cancer, previously untreated disease, and ECOG performance status of 0-1, received SCRT (5×5 Gy) with subsequent two 21-day cycles of CAPOX (oxaliplatin 130 mg/m2 ivgtt, d1; capecitabine 1000 mg/m2 po bid, d1-14) plus Camrelizumab (200 mg iv drip, d1) after 1 week, followed by radical surgery after 1 week. Adjuvant therapy was decided by the investigator. The primary endpoint was pathological complete response (pCR) rate, defined as the absence of viable tumor cells in the primary tumor and lymph nodes. The study is ongoing to follow up the survival outcomes and obtain the results of next generation sequencing and PD-L1 expression. The data cutoff date was September 8, 2020. Results: From November 2019 to September 2020, a targeted number of patients (n = 29) were enrolled and are expected to complete the surgery by November 2020. The median age was 57 (range 31-73) years, 55% (16/29) of patients had ECOG performance status of 1, and the median distance from tumor to the anal verge was 5 (range, 1.9-9) cm. At data cutoff, 10 patients had undergone the surgery, with R0 resection rate of 100%. The pCR rate was 60% (6/10), including 56% (5/9) for those with mismatch repair-proficient, and 100% (1/1) for those with mismatch repair-deficient. Of 4 patients without pCR, 2 only received one cycle of CAPOX plus Camrelizumab due to the outbreak of COVID-19 in Wuhan, and 1 had signet-ring cell rectal carcinoma. At data cutoff, 20 patients had received at least one dose of Camrelizumab. Immune-related adverse events (irAEs) were all grade 1-2, and the most common irAE was reactive cutaneous capillary endothelial proliferation in 10 (50%) of 20 patients. Postoperative bleeding and infection occurred in 1 (10%) and 2 (20%) of 10 patients, respectively. No treatment-related death was observed. Conclusions: SCRT combined with subsequent CAPOX plus Camrelizumab followed by delayed surgery showed promising pCR rate with good tolerance in patients with LARC, regardless of the mismatch repair status, suggesting a candidate strategy for the neoadjuvant therapy. Clinical trial information: NCT04231552.
A single-institution experience using total neoadjuvant therapy to treat locally advanced rectal cancer.
Authors: Friedrich Tyler , Glode Ashley Elizabeth , Lentz Robert William , Herter Whitney , Davis S. Lindsey , Leal Alexis Diane , Kim Sunnie S. , Purcell William T. , Ahrendt Steven Arthur , Birnbaum Elisa , McCarter Martin , Gleisner Ana , Schefter Tracey E. , Vogel Jon , Messersmith Wells A. , Lieu Christopher Hanyoung 
Published: January 2021

64 Background: The management of locally advanced rectal cancer has historically included preoperative chemoradiation followed by surgery and then adjuvant chemotherapy. Recently there has been an increasing utilization of preoperative chemotherapy in addition to standard chemoradiation, a strategy known as total neoadjuvant therapy (TNT). TNT has been offered to patients at the University of Colorado Cancer Center since 2015. Methods: Records of all patients presenting to the University of Colorado colorectal multidisciplinary clinic since 2015 were screened for treatment with TNT. Data collected on these patients included demographic information, diagnosis and initial staging, preoperative treatment received, and surgical outcomes including treatment response and pathological stage. TNT included preoperative chemotherapy with oxaliplatin combined with either 5-FU (FOLFOX) or capecitabine (CAPOX) as well as chemoradiation, generally given with concurrent capecitabine. Patients then underwent surgical resection; if a complete clinical response was achieved with TNT, non-operative management (NOM) was offered. Results: A total of 81 patients thus far have undergone TNT followed by resection or, if complete clinical response and preferred by the patient, NOM. The mean age of patients was 56 years, ranging from 23 to 87, and 60% of patients were male. The majority of patients (67) had stage III disease at presentation while 1 had stage 1 (T2N0) disease, 11 had stage II disease and 2 patients had oligometastatic disease. Ultimately 13 patients (16%) opted for non-operative management after being found to have a complete clinical response following TNT. Of the 68 patients who underwent surgical resection, 21 (31%) had a pathological complete response, with another 14 (21%) with near-complete response. 28 patients (41%) had a partial treatment response and 5 (7%) had no treatment response. In total, the rate of complete clinical or pathologic response was 42%. Treatment was overall well-tolerated with 90% of patients receiving the full planned dose of radiation and 98% of patients completing all planned cycles of chemotherapy, though most of them with typical dose reductions needed. Of the patients who underwent surgery, 49 (72%) had low anterior resection and 19 (28%) had an abdominoperineal resection. Of patients with temporary ileostomies, 85% of them had their ileostomy reversed within 10 weeks of surgery. Conclusions: Treatment of locally advanced rectal cancer by a total neoadjuvant approach is well-tolerated and results in a high rate of clinical and pathological complete response.