bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low energy amplitude modulated radiofrequency electromagnetic fields to show antitumor effect in combination with standard treatment or as monotherapy in patients with advanced hepatocellular carcinoma.
Authors: Setogute Yone De Camargo , Costa Frederico , Sousa Micelange Carvalho , Lima Pablo Diego , Carvalho Luciana , Santos Elizabeth , Gumz Brenda Pires , Azevedo Fernanda , Sabbaga Jorge , De Castria Tiago Biachi , Fontes Jardim Denis Leonardo , Freitas Daniela , Horvat Natally , Franca Regis , Testagrossa Leonardo , Zanesco Tatiana , Iemma Antonio Francisco , Tuszynski Jack 
Published: January 2021

332 Background: Exposure to amplitude-modulated radiofrequency electromagnetic fields (EMF) in immortalized hepatocellular carcinoma (HCC) cell cultures and xenograft models demonstrated anti-tumor effect. Patients with advanced HCC exposed to systemic EMF showed objective response with potential survival benefit. Methods: An open-label, single center, prospective clinical protocol was performed in advanced HCC patients as an initial, second or third treatment modality. Systemic exposure to EMF modulated at patient-specific frequencies was applied as an add-on strategy (combination) to systemic conventional treatment or as a single therapeutic modality. A spoon-shaped antenna placed in the oral cavity delivered EMF over 90 minutes with monthly repetitions until death or consent of withdrawal. The primary objective was overall survival (OS) in comparison with historical control group of 45 advanced patients HCC from the same institution. Retrospective radiological review was conducted by two independent radiologists for objective response (OR) using RECIST1.1 criterion. Results: From March 2018 to April 2020, 55 advanced HCC patients were submitted to 373 EMF exposures. 87% were male, median age of 67, 84% were BLCL-C, 16% were Child-Pugh B, 29% had extra-hepatic metastasis, 55% had failed previous treatment and 71% had documented radiological progression. 31(56%) patients received EMF in combination with systemic therapy (25 sorafenib, 3 lenvatinib, 3 nivolumab). 24 patients received EMF as single treatment modality. The median OS for the entire patient cohort was 11.5 months. The median OS for combination treatment was 12.0 month and the median OS for single modality was 11.3 months. The median OS for the historical control was 5.3 month. The median OS from the entire cohort and the historical control were significant different (p = 0.0026) but the median OS from combination and single modality were not (p = 0.3434). Radiological images were available from 38(69%) patients. There were 6/38 (16%) documented objective responses (1 CR and 5 PR) and 30/38 (79%) patients experienced disease control. 4/21 (19%) OR were in patients using TKIs + EMF and 2/17 (12%) OR were in patients using EMF alone. Conclusions: EMF showed objective anti-tumor effect in combination with TKI or as single modality in advanced HCC patients. EMF showed improvement in overall survival in comparison with the historical control group supporting future development as a novel systemic treatment modality in advanced HCC patients. Clinical trial information: NCT 01686412.
Comparative landscape of actionable somatic alterations in advanced cholangiocarcinoma from circulating tumor and tissue-based DNA profiling.
Authors: Kasi Pashtoon Murtaza , Le Alexander D , Barrett Alex 
Published: January 2021

342 Background: Cholangiocarcinoma (CCA) is a target-rich disease. Despite this, treatment guidelines lack recommendations for broad molecular profiling in CCA to identify potentially actionable targets. Furthermore, comparative data assessing similarities and differences in actionable ctDNA and tissue based genomic biomarkers remain limited. As such, we sought to broadly characterize the genomic alterations that are linked to targeted therapies that may facilitate a more personalized approach to therapy. Methods: We retrospectively analyzed NGS data obtained from 137 advanced cholangiocarcinoma patients via Tempus xT tissue biopsy assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations including single nucleotide variants, specific insertion/deletions, amplifications and gene fusions. Results: 110 patients were tested once and 27 patients had two or more tests available. Of the 174 genomic results, 113 were tissue-based NGS results, and 61 were liquid-based NGS results. The total number of unique alterations was found to be 296. Focusing on aberrations for which there are approved therapies in the same or other tumor types or inclusion in guidelines and/or active clinical trials, we found FGFR2 fusions (6.8%), IDH1/2 (8.4%), BRAF-V600E (2.5%), HER2 (3%), MET (0.7%), BRCA1/2/ATM (2%), PIK3CA (4.7%), and ERRFI1 (0.7%). This comprises ~30% (Table). Of note, within this bucket of actionable findings, if we focus on ctDNA liquid biopsy cohort, the proportion goes up to 33.1% vs. 23.2% for tissue based genomic testing. For example, comparison of liquid to tissue, FGFR2 fusion was noted in 11.3% vs. 3.4%, BRAF-V600E in 3% vs. 1% and HER2 0% vs. 3.8%, respectively. Also, no MSI-High patients but two (1.5%) had KRAS-G12C mutation. Notable differences in the prevalence of actionable somatic mutations in solid vs. liquid results were observed (Table). Conclusions: These data provide an updated benchmark for guiding the development of targeted therapies in molecularly profiled CCA and support the use of both solid and liquid biopsy molecular profiling to guide therapy selection in patients with advanced cholangiocarcinoma. Additionally, liquid biopsy molecular profiling can fill the void where tissue may not be readily available. [Table: see text]
Cost of treatment change among patients with neuroendocrine tumors (NET) treated originally with somatostatin analogs.
Authors: Tawfik Bernard , Ray David , Moynihan Meghan , Princic Nicole 
Published: January 2021

365 Background: Understanding the economic implications of changes in treatment among patients with NET will be important as treatment sequencing continues to evolve. This study describes treatment characteristics and healthcare costs prior to and following treatment change from somatostatin analog (SSA) monotherapy to another therapy among a privately-insured NET patient population in the U.S. Methods: Patients with newly diagnosed NET and treated with SSA monotherapy were extracted from IBM MarketScan claims databases in 1/1/2014-3/31/2019. NET treatment change was captured ≥30 days after SSA start date (earliest new treatment = index date). Healthcare costs (reimbursed amount in 2019 dollars) were reported for 1, 3, and 6 months pre- and post-index intervals. Results: A total of 1,122 NET patients with SSA monotherapy were identified; 305 had further treatment changes (mean age: 58 years; female: 52%; metastatic disease at NET diagnosis: 49%). The majority of patients started on octreotide (81%) vs lanreotide (19%). Common treatment changes included alternate SSA (38%), targeted therapy (everolimus or sunitinib) (30%) or chemotherapy (23%). Fewer than 10% of patients were treated with PRRT 177Lu-dotatate or telotristat and 1% with a combination. Total healthcare cost increased from $12,376 to $25,647 (mean difference = $13,272 ±$24,189, p<0.001) for 1 month before/after treatment change, from $36,395 to $59,324 ($22,929 ±$41,764, p<0.001) for 3 months before/after, and from $66,786 to $109,224 ($42,438 ±$98,875, p<0.001) for 6 months before/after. Patients changing to targeted therapy had the largest 1 month interval cost increase ($19,677 ±$19,023, p<0.001) compared with patients changing to alternate SSA ($10,240 ±$14,112, p<0.001) and to chemotherapy ($4,057 ±$20,566, p=0.155). The differences were driven by increases in outpatient services and pharmacy prescriptions. Conclusions: The setting of rising costs after treatment change from SSA indicates treatment costs as the key driver, rather than NET disease severity. Future studies should investigate the clinical effectiveness of switching from SSA relative to the economic burden imposed by treatment change.
Population-based, real-world prognostic factors related to survival among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Yu Kenneth H. , Cockrum Paul , Surinach Andy , Wang Shu , Chu Bong Chul 
Published: January 2021

389 Background: Pancreatic cancer is expected to be the third deadliest cancer in the US in 2020. Many real-world studies of pts with mPDAC are restricted to single centers, limiting the generalizability of the insights they generate. There is a need to understand prognostic factors of survival in a broader setting to aid in tailoring treatment strategies for pts. This study aimed to identify important population-based predictors related to survival among pts diagnosed with mPDAC. Methods: Data were extracted for pts diagnosed with mPDAC between Jan 2017 and Dec 2019 from the Flatiron Health database. Predictive models for overall survival from the start of each treatment were developed using multivariable Cox proportional hazards regression. Treatment specific predictive models were generated for pts treated with first line (1L) gemcitabine + nab-paclitaxel (GNP), 1L FOLFIRINOX, 1L gemcitabine monotherapy (gem-mono), and 2L liposomal irinotecan-based regimens. The holdout method was used for cross-validation, splitting the data into 70% training / 30% validation. Age at diagnosis, sex, body mass index, smoking status, and ECOG performance score (PS) were included in all models due to clinical importance. Demographic, clinical characteristics, hematological labs, liver function tests (LFTs), and serum bilirubin levels were assessed for inclusion into the models. Uno’s concordance statistic (c-statistic) was used to assess the predictive accuracy of the models. Results: Of the 3,572 pts included in the study, 44% (n = 1,557) received 1L GNP, 27% (n = 954) received 1L FOLFIRINOX, 7% (n = 265) received gem-mono, and 22% (n = 796) received other regimens. 38% (n = 1,345) pts received 2L and of those, 17% (n = 222) received liposomal irinotecan-based regimens. Among all 1L pts, the following were included in the final model: prior surgery, white blood cell (WBC) counts, serum albumin, LFTs (ALP and ALT), serum bilirubin, and ascites (c-statistic: 0.65). The model for pts treated with GNP differed from the overall model via the addition of neutrophil counts and removal of serum bilirubin and ascites (c-statistic: 0.67). Stage at initial diagnosis was included in the model only for pts treated with 1L FOLFIRINOX (c-statistic: 0.68). Among pts treated with gem-mono the LFTs were not included in the model (c-statistic: 0.78). ALP, serum albumin, and WBC counts were important predictors of survival among pts treated with 2L liposomal irinotecan-based regimens (c-statistic: 0.70). Across all regimens the strongest predictors of survival were ECOG PS, serum albumin, and ALP. Conclusions: In one of the largest contemporary real-world studies of patients with mPDAC to date, important population predictors of survival in pts receiving systemic treatment were identified. Further validation studies are needed to understand the generalizability of these results.
Serial cell-free DNA (cfDNA) sampling in advanced pancreatic ductal adenocarcinoma (PDAC) patients may predict therapeutic outcome.
Authors: Botrus Gehan , Fu Yu , Sonbol Mohamad Bassam , Drusbosky Leylah , Ahn Daniel H. , Borad Mitesh J. , Starr Jason S. , Jones Jeremy Clifton , Raman Puneet , Mody Kabir , Bekaii-Saab Tanios S. 
Published: January 2021

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.
Familial pancreatic cancer (FPC) status as a clinical biomarker in patients receiving platinum-based systemic therapy: A case-control analysis.
Authors: Kelly Deirdre , Borgida Ayelet , Perera Sheron , Denroche Robert Edward , Holter Spring , Liu Zhihui (Amy) , Liu Zijin , Zhang Amy , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Wilson Julie , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Grant Robert C , O'Kane Grainne M. 
Published: January 2021

430 Background: Familial pancreatic cancer (FPC) is broadly defined as kindreds with at least a pair of first-degree relatives with pancreatic ductal adenocarcinoma (PDA). The role of DNA damage response agents, including platinum has not been well studied in this patient population. Methods: In this retrospective analysis, treatment details and clinical outcomes were analyzed in pts with FPC with advanced, unresectable or recurrent disease enrolled in the Ontario Pancreatic Cancer Study database. The primary outcome, overall survival (OS) was calculated from the initial diagnosis of advanced disease until death. 179 non-FPC patients from the COMPASS trial [NCT02750657] served as a control cohort all of whom had full molecular profiling and family history documented. OS between pts that received platinum-based therapy, and those that did not was compared using multivariable Cox proportional hazards model adjusting for age, sex, diagnosis year and FPC status. Interaction between FPC status and platinum was evaluated. Results: A total of 205 FPC pts were identified, 71% of pts had full germline testing and 16 (8%) had germline pathogenic variants in BRCA1/2. 104 (51%) were female and 101 (49%) male. Median age was 63 years (20-93) and 58 (28%) received platinum-based chemotherapy. Within the control arm (n=179), 71 (40%) were female, and 108 (60%) male; the median age was 64 years (29-84) and 106 (59%) received platinum-based therapy. In univariable analysis, median OS in pts with FPC was 16.9 months compared to 9.6 months (HR 0.46 [95% CI 0.37-0.58]). FPC patients receiving platinum had a superior median OS of 19 months compared to 15.5 months without platinum. In a multivariable analysis, both FPC (HR 0.33 [95% CI 0.21-0.51]) and receipt of platinum HR 0.53 [95% CI 0.38-0.73]) were prognostic. No interaction was seen with FPC and receipt of platinum (p=0.15). Conclusions: FPC status is prognostic but not predictive of platinum response in this study. Further molecular profiling of this unique cohort of patients will provide insights into putative predisposing germline alterations, and novel treatment strategies.
Shared DNA-based copy number with divided methylation changes differentiate and clinically associate early stage pancreatic cancer tumors.
Authors: Chao Eva , Aung Kyaw Lwin , Xu Qi , Matsui William H. , Kowalski Jeanne 
Published: January 2021

434 Background: There is no known molecular taxonomy of pancreatic cancer that can guide therapeutic strategies. Understanding the fundamental molecular mechanism underlying pancreatic cancer biology remains an unmet need. We explore the extent to which combinations of DNA-based molecular changes in copy number (CN) and methylation separate early stage PAAD tumors and associated with survival outcomes. Methods: We performed genome-wide combined cluster analyses on DNA-based CN and methylation changes using TCGA data. We examined cluster associations with clinical outcomes by comparing in months (mos), Kaplan--Meier estimated overall survival (OS) and disease-free interval (DFI) using a log-rank test. We performed additional comparisons among CN-Methylation derived clusters with respect to PAAD phenotypes. Results: Using 78 early stage pancreatic cancer tumors from TCGA with CN, methylation and clinical outcomes data, we identified two patient clusters with distinct gene copy number signatures that when combined with three methylation signatures, resulted in three additional clusters. Thus, the same gene CN signature, when combined with different methylation signatures, further differentiated tumors into sub-clusters with varying levels of associations with clinical outcome. Among them, analogous to current gene-expression based subtypes, we also identified an immune-rich subtype that was associated with improved overall survival (n=21, median OS=16mos; DFI=16mos), and an extracellular matrix (ECM)-rich with worse survival (n=19, median OS=12mos; DFI=8mos). Unlike previous expression subtypes, we identified another metabolic-enriched subtype with the same worse median OS and DFI, differentiated by methylation with the ECM-rich subtype. The improved OS cluster had a signature of CN neutral and increased methylation, while the poor cluster had a signature of CN gains and increased methylation among a set of genes distinct from the improved cluster. No significant differences in age, site, microsatellite instability and KRAS status among clusters were noted. Notably, in a multivariable model that included gene expression-based subtypes, only our DNA-level subtypes remained significantly associated with overall survival. Conclusions: While RNA-level changes often display large variations, DNA-level changes are more robust. Copy number changes appear to separate tumors into poor and improved prognosis clusters, while methylation appears to inform on the further separation of poor prognosis into various levels. A DNA-based molecular taxonomy for early stage pancreatic cancer could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for clinical trial monitoring of tumor responses.
Exploring cancer clinical trial participation in the new normal of COVID-19: The patient perspective.
Authors: Raymond Martha Ann , Simonetta Margaret-Ann 
Published: January 2021

461 Background: The impact of coronavirus (COVID-19) has significantly affected cancer patients seeking to enroll in a clinical trial. The pandemic has led to an unprecedented disruption across the cancer research community pausing trial operations. Data from the National Institute of Health and the National Library of Medicine indicates 988 cancer clinical trials were suspended from March  September 1, 2020, with 60% of institutions enrolling patients at a lower rate. Our research underscores the patient perspective of clinical trial participation amid COVID-19. Methods: July  September 2020 Nationwide eight-week online survey and interviews. Research goals: gain a better understanding of barriers and cultural attitudes of ethnically diverse communities regarding trial participation; learn the enhanced safety measures needed for patients to feel comfortable returning to the clinic; better understand the importance of effective patient-clinician communication. Results: 511 patient participants reported the following insights: 86% reported their healthcare team had not discussed trial participation; 99% reported being comfortable with telehealth visits for pre-screening and monitoring; 82% receive care at community-based hospitals. Barriers to enrollment and additional safety considerations include gaps in outreach and education services for ethnically diverse communities; absence of cultural sensitivity and disregard of historical perspective; financial insecurity and travel; and the need for increased COVID-19 testing, enhanced safety protocols and a proven vaccine. Participants identified their ethnicity as 38% Caucasian; 24% Black/African American; 19% Hispanic/Latino; 16% Asian; 2% Native American/Pacific Islander. Conclusions: Clinical trials provide patients access to the newest treatments, and yet only 2%-3% of adult cancer patients enroll in a trial. Common barriers to trial participation have been widely researched, but now amongst the coronavirus pandemic, additional barriers are evident. Based on our research, our call to action is clear: work with key opinion leaders in ethnically diverse populations to help build trust and mutual respect when discussing research studies; and engage patients and clinicians to openly discuss clinical trial enrollment working toward patient-centered communication. The coronavirus pandemic is a devastating public health threat, and it will take a collective effort from the entire cancer community to minimize the effect of COVID-19 on cancer clinical trial participation.