bluuebunny/crossref_metadata_2025_split huggingface dataset:
Planned and actual dose reduction of standard or modified FOLFIRINOX in metastatic pancreatic cancer: A systematic review and meta-analysis.
Authors: Jung Kwangrok , Choi Su Hyun , Kim Jaihwan , Hwang Jin-Hyeok , Lee Jong-chan 
Published: June 2022

e16279 Background: FOLFIRINOX showed high efficacy but also high toxicity in metastatic pancreatic cancer (MPC). To reduce toxicity and maintain efficacy, many kinds of studies on modified FOLFIRINOX have been conducted. However, these studies do not have unified pattern of dose-modification. In addition to the diversity of 'planned dose' in study design for modified FOLFIRINOX, the 'actually administered dose' for patients are much more diverse in the real world studies. We aimed to visualize 10 year trend of ‘planned’ and ‘actual’ dose of FOLFIRINOX in prospective and retrospective trials and investigate clinical outcomes according to dose modification. Methods: A systematic literature search of databases (Medline, Embase, and Scopus) between 1 January 2011 and 30 September 2021 was conducted. Eligible studies included patients treated with FOLFIRINOX as first-line treatment in MPC and reported any type of information in ‘planned’ and ‘actual’ dose of FOLFIRINOX. For evidence mapping sorted by four groups (table 1), a web-based and interactive bubble-plot program (www.RDI-map.com) was developed. For clinical outcome assessment, data on objective response rate (ORR) and hematologic toxicity rate were pooled with random-effect model and compared according to planned dose of FOLFIRINOX. Results: A total of 37 studies were identified for evidence mapping. In the mapping, ‘planned’ dose of FOLFIRINOX ranged with 75–100% for oxaliplatin, 75-100% for irinotecan, 0–100% for 5-fluorouracil (5FU)-push, and 75–133% for 5FU-continuous intravenous injection (CIV), respectively. The ‘actual’ dose of each agents went down to 54–96%, 61–88%, 0–92%, and 63–98%, respectively. In the pooled analysis with 27 studies including clinical outcome, the overall ORR was 30.9% (95% CI, 27.4-34.4%). Comparing planned ‘standard’ FOLFIRINOX with planned ‘modified’ regimen, the ORR was 28.2% [95% CI, 22.5-33.9%] and 33.8% [95% CI, 30.3-37.3%], respectively (P = 0.100). Febrile neutropenia was 11.6% [95% CI, 0-16.0%] and 5.5% [95% CI, 0-8.9%], respectively in the same order ( P = 0.030). Conclusions: The RDI-map.com effectively provided multifactorial evidence-mapping for the practical pattern of dose reduction in FOLFIRINOX, and it revealed a significant gap between ‘planned’ and ‘actual’ dose of FOLFIRINOX. Planned ‘modified’ FOLFIRINOX showed similar efficacy and reduced febrile neutropenia, compared to planned ‘standard’ regimen. This data can serve as a guidance in both prescribing FOLFIRINOX for clinicians and designing further studies for researchers in MPC. [Table: see text]
Neoadjuvant radiation case volume and associated with margin-negative resection rates in patients with pancreatic cancer.
Authors: Thalji Samih Z , Hall William A. , Erickson Beth , Kamgar Mandana , George Ben , Christians Kathleen K. , Clarke Callisia , Doucette Saryn , Miller James , Hunt Bryan , Giorgadze Tamara , Evans Douglas B. , Tsai Susan 
Published: June 2022

e16281 Background: High surgical case volume (SCV) is associated with improved outcomes. Whether radiation case volume (RCV) is associated with outcomes is unknown, but of potentially increased importance given the recent results of the PREOPANC trial. We examined the impact of RCV on pathologic outcomes among patients (pts) with pancreatic cancer (PC) receiving neoadjuvant therapy (NAT). Methods: Pts with PC who received any NAT between 2009-2018 were identified from the National Cancer Database. Institutions were defined by SCV (low: < 9, medium:9-35, high:≥36 pts/year) and by RCV (nil:none, low:1-6, high:≥7 pts/year). Pathologic outcomes were node (N0/N1) and margin (R0/R1) status. Results: In total, 10,893 pts received NAT at 890 institutions; 3,522 (32%) received radiation at 562 (63%) institutions. Among all 10,893 pts, 2,896 (26%) were treated at low-SCV, 5,421 (50%) at medium-SCV, and 2,576 (24%) at high-SCV institutions. Among all 10,893 pts, 904 (8%) were treated at nil-RCV institutions, 7,736 (71%) at low-RCV, and 2,253 (21%) at high-RCV institutions. N0 resections were accomplished in 1,210 (54%) of 2,253 pts at high-RCV institutions, 3,732 (48%) of 7,736 at low-RCV, and 339 (38%) of 904 at nil-RCV institutions ( p values < 0.001). Similarly, R0 margins were achieved in 1,979 (88%) of 2,253 pts at high-RCV, 6,380 (82%) of 7,736 at low-RCV, and 671 (74%) of 904 at nil-RCV institutions ( p values < 0.001). Among 3,522 pts that received radiation, N0 resections were not different by RCV: 769 (62%) of 1,241 at high-RCV institutions and 1,461 (64%) of 2,281 at low-RCV institutions ( p= 0.22). Pts treated with radiation at high-RCV institutions had higher proportions of R0 margins: 1,120 (90%) of 1,241 at high-RCV and 1,931 (85%) of 2,281 at low-RCV institutions ( p< 0.001). High-RCV and low-RCV institutions were each associated with N0 resections (Table) and were not different from each other ( p= 0.33). High-RCV and low-RCV institutions were each associated with R0 margins, however high-RCV was more strongly associated than low-RCV ( p< 0.001). Conclusions: Pts at high-RCV facilities had greater odds of R0 margins independent of surgical case volume. As radiation techniques evolve, the value of high-RCV experience is likely to become increasingly important.[Table: see text]
Improving understanding of pancreatic cancer among patients using an animated patient’s guide to benefit informed decisions and health outcomes.
Authors: Munigala Satish , O'Reilly Eileen Mary , Bakelman David E , Holt Jane , Ko Andrew H. , Searle Nicholas , Gelrud Andres 
Published: June 2022

e16282 Background: Pancreatic cancer (PC) outcomes continue to be dismal in the United States with an estimated 48,220 deaths in 2022. Patients have limited knowledge regarding their management options making informed decisions difficult. Health literacy (HL) is a major barrier confronting patient understanding and visual formats of learning have been shown to help overcome HL barriers to enable informed patient understanding. Effective PC learning resources can mitigate poor disease understanding, and reduce HL impediments essential to patient decisions and best outcomes. In this study, we evaluated patient knowledge improvement, engagement, and participation in decisions with their oncology providers using National Pancreas Foundation’s (NPF) ‘An Animated Patient’s Guide to Pancreatic Diseases (APG)’ . Methods: NPF introduced APG in 2013, as an educational resource to address patient needs, informed decisions, barriers to HL and gaps in understanding. Using visual formats of learning (animations, videos, slide shows), we monitored metrics and learner feedback from September, 2013 to September 2021 (8 years). We evaluated learner activity, number of views with highest retention in the US and globally. Results: We gathered learner data on APG from 4,551,079 learners from over 100 countries. Most learners (60%) were from the US with 54% being patients, 17% family/caregivers, 16% healthcare providers and 13% other. The top 3 animations “ Understanding Clinical Trials”, “ Pancreatic Cancer: Treatment and Outcomes”, and “ Pancreatic Cancer: Signs, Symptoms and Risk Factors” had 182,217; 82,585; and 64,970 viewings respectively. Top 3 expert videos viewed most were “ What are the different stages of pancreatic cancer?”, “ What are the symptoms of pancreatic cancer?”, and “ What is a “Placebo” in a clinical trial and is it always used?" with 15,357; 12,475; and 5,282 views respectively. Conclusions: Our study shows that visual formats of education provided by APG were effective in improving patient understanding, enabling informed decisions, and addressing needs of PC patients with poor understanding and HL. Pancreatic cancer education utilizing visual formats has great potential to provide effective learning for patients. Continued efforts should be made to address HL barriers, inform patients, and provide resources that address needs in PC to achieve best healthcare outcomes.
Detailed immunogenomic analysis of high dose IL-2 pharmacodynamic effects: A benchmark for next-generation IL-2-based immunotherapies.
Authors: Beebe Kirk , Eisner Joel Robert , Shibata Yoichiro , Davison James M , Guo John , Farhangfar Carol J. , Farhangfar Farhang , Uronis Joshua M. , Mooney Jill , Milburn Michael Vance , Foureau David , White Richard L. , Amin Asim , Milla Marcos E 
Published: June 2022

e16501 Background: High-dose interleukin-2 (HD IL-2) was the first approved immune-oncology (IO) agent based on proven clinical efficacy in renal cell carcinoma (RCC) and metastatic melanoma, but its use was limited due to significant toxicities. Multiple next-generation IL-2 agents designed to retain efficacy while improving tolerability are in development. Yet, understanding of genomic markers that define optimized target pharmacology is incomplete. Newer evaluation techniques not available at the time of previous HD IL-2 experience may allow for identification of pertinent genomic markers. In this retrospective study, we report for the first time, RNA sequencing (RNAseq) of peripheral blood mononuclear cell (PBMC) samples from metastatic (mRCC) patients before, during and after HD IL-2 treatment. Detailed immunogenomic responses to HD IL-2 treatment with insight into traditional flow cytometry (FC) are presented. Methods: PBMC samples were collected for n = 23 HD IL-2 treated mRCC patients between 2009 and 2015 on Day 1, 3 and 5. Patient samples underwent prior FC analysis described elsewhere (Foureau et al, 2014; Cancer Immunol. Immunother. 63(12)). RNAseq was performed using NovaSeq6000 (Illumina) paired end sequencing on bulk PBMC samples from immediately before (Day 1), during (Day 3) and post-treatment (Day 5) Cycle 1 and/or Cycle 2 of the first course of HD IL-2. Individual genes and signatures for immune and proliferation differences were analyzed. Results: RNAseq analysis of PBMC samples demonstrated that CD8+ T cells transiently decreased in the blood during treatment but recovered to baseline on Day 5, and CD4 Treg cells increased on Day 3 and Day 5, which confirmed prior FC findings. TCR clonality was unchanged which indicates that T cell recovery and expansion is widespread and not driven by a specific subset of T cells. Additional notable insights included increased monocytes at Day 3, with the opposite for NK and B cells (Day 3 decrease and Day 5 expansion). Using a novel GeneCentric proliferation signature, increased expression was noted on Day 3 and Day 5 vs. Day 1, reflecting pronounced IL-2 induced proliferation. Conclusions: Immunogenomics provided further detail regarding IL-2 activity in addition to recapitulating several parameters from FC. Expression analysis of minimally invasive PBMC samples demonstrates the importance of this novel genomic approach to understand the pharmacology of IL-2 and related derivatives.
Prognostic value of hematologic parameters in patients with muscle invasive bladder cancer.
Authors: Katiyar Vatsala , Sidhu Jasdeep , Do Quan , Wu Xiaoyong , Rai Shesh , Aijaz Talha , Tariq Anosha , Singh Vikas 
Published: June 2022

e16502 Background: Muscle invasive bladder cancers (MIBC) tend to have an increased risk of progression and recurrence despite optimal management. Since various blood cells affect tumor microenvironments, modulate tumor growth and treatment responses, we examined the impact of Platelet/Lymphocyte ratio (PLR) and systemic inflammation response index [(SIRI) = N×M/L), N- Neutrophil, M-monocyte, and L-Lymphocyte] at diagnosis of MIBC patients on overall prognosis. Methods: We performed a retrospective analysis of all muscle invasive bladder cancer patients treated at our institute from January 2015 to December 2020. Patients with Stage I and IV disease were excluded. Descriptive statistics were obtained for entire cohort. The optimal cutoff points for PLR and SIRI were accessed by the receiver operating characteristic curve (ROC) based on overall survival (OS) and Progression free survival (PFS). Kaplan-Meier curve was used to compare the OS and the PFS between the groups. Univariate and multivariate Cox regression analyses were used to evaluate the impact of PLR and SIRI on the OS. Results: In our cohort of 112 patients, median age at diagnosis was 65 years (95% CI: 62-68). Patients were predominantly males (74.1%), Caucasians (88.3%), smokers (71.4%), and 59.8% had a BMI above 24.9. The median duration of follow up was 18.7 months (mo). The median OS was 28.5 mo (95% CI: 19.8-55.4) and median PFS was 16.7 mo (95% CI: 11.7-30.0). 50 patients (44.6%) were stage II and 62 patients (55.4%) were Stage III. 34 patients (30.4%) received chemotherapy in neoadjuvant or adjuvant setting, 6 patients (5.4%) received radiotherapy, and majority of patients (total 75; 67.0%) were treated with surgical intervention. The optimal cutoff points on OS for PLR and SIRI were 304.04 and 1.83 respectively. On univariate analysis, SIRI did not affect OS (HR: 1.26, 95% CI: 0.73-2.19, p = 0.406). Patients with high PLR had worse OS on both univariate (HR: 1.003, 95% CI: 1.001-1.005, p = 0.003) and multivariate (HR: 1.002, 95% CI: 1.000-1.004, p = 0.028) analyses. Nodal staging, radiation treatment, and baseline hemoglobin level were other statistically significant factors associated with OS. Conclusions: Although the standard TNM staging system is helpful in predicting tumor behavior, there is marked heterogeneity in responses to treatment for MIBC. Our study suggests that PLR at diagnosis can be a novel prognostic marker for patients with MIBC.
Molecular analyses of metastatic collecting ducts renal cell carcinoma from the phase 2 prospective trial of cabozantinib as first-line treatment (BONSAI trial Meeturo 2).
Authors: Todoerti Katia , Sepe Pierangela , Andrea Devecchi , Busico Adele , Agnelli Luca , Perrone Federica , Gargiuli Chiara , Dugo Matteo , De Cecco Loris , Claps Melanie , Fotia Giuseppe , Guadalupi Valentina , Verzoni Elena , Procopio Giuseppe 
Published: June 2022

e16507 Background: The phase II BONSAI trial ( n = 25 ; NCT 03354884) met the primary endpoint demonstrating activity of cabozantinib in untreated metastatic collecting ducts carcinoma (mCDC), a rare and biologically poorly characterized disease. Here we report on molecular analyses of baseline tissue samples. Methods: Formalin-fixed paraffin-embedded (FFPE) samples from 18 mCDC patients enrolled in BONSAI were sequenced by TruSeq RNA Exome kit (Illumina). The data were mapped and quantified using STAR and htseq, respectively. Globaltest and edgeR packages in R were used to assess the correlation between transcriptional profiles and survival data. Nineteen samples underwent DNA Sequencing with the Oncomine Comprehensive Assay Plus (ThermoFisher Scientific). The reads were aligned to the human genome reference (hg19) and analyzed with Opencravat and IonReporter software. Germline variants were excluded based on 1000 Genomes, GnomAd and Exac databases, and Clinical annotation of somatic variants was performed using ClinVar. Results: The global expression levels of thirty-one genes have been found significantly associated with overall survival (OS). The natural grouping of the 18 tumor samples based on the 31-gene signature identified a main group of 11 cases, showing global higher expression levels in 22 out of the 31 genes. This group displayed overall a significant higher OS rate in comparison to the remaining 7 patients, carrying opposite expression trend and mostly undergoing to disease progression. The identified signature was enriched in biological processes like cell junction, cytoskeleton organization and methylation. FOS oncogene was among the 9 genes negatively associated to OS, showing common higher expression in the poorer survival rate group. Furthermore, a 22-gene signature was found significantly associated with progression-free survival (PFS), involving mainly genes associated to cell cycle regulation or recognized as components of Golgi apparatus. Only three genes were globally up-regulated in the group of 9 patients characterized by shorter PFS. Finally, heterogeneous pattern of somatic mutations was identified in 19 tumor samples, with at least 8 genes recurrently affected in more than three patients. Notably, mutated genes were mostly involved in DNA repair and chromatin modification processes. Conclusions: Our findings for the first time define specific molecular signatures that differentiate therapy-specific outcomes in first-line mCDC, warranting further investigation of their involvement in the tumor biology. Clinical trial information: NCT 03354884.
Bio-miR: A prognostic microRNA-based signature for localized clear cell renal cell carcinoma.
Authors: Pinto Alvaro , Trilla-Fuertes Lucía , Miranda Poma Jesus , Vasudev Naveen , García-Fernández Eugenia , Lopez Vacas Rocio , Miranda Natalia , Wilson Michelle , López-Camacho Elena , Pertejo Ana , Lumbreras-Herrera Maria Isabel , Brown Joanne C , Zapater-Moros Andrea , De Velasco Guillermo , Castellano Daniel E. , González-Peramato María Pilar , Espinosa Enrique , Banks Rosamonde , Fresno-Vara Juan Angel , Gámez-Pozo Angelo 
Published: June 2022

e16519 Background: Prognosis of localized clear cell renal cell carcinoma (ccRCC) patients is estimated by nomograms based on clinico-pathological factors. However, clinical guidelines do not recommend their use. Recently, pembrolizumab has demonstrated benefit in disease-free survival (DFS) in medium-high risk localized ccRCC, increasing the need for better patient stratification tools. In this study, we have defined and validated a molecular signature, Bio-miR, based on the expression of nine microRNAs, with prognostic value in ccRCC. Methods: The discovery and two validation cohorts (Leeds-UK and Spain) consisted of patients with resected localized (stage Ib-III) ccRCC and no adjuvant therapy. miRNA expression was analyzed using microarrays and validated using qPCR in FFPE nephrectomy tissues. Cox regression was used to define the best microRNAs combination to predict risk of relapse. Results: In the discovery cohort (n = 71), DFS at 5 years was 93.9% amongst Bio-miR-defined low-risk patients and 61.6% in high-risk patients (HR = 6.9 (3.4-42.9), p < 0.001). Cancer-specific survival at 5 years was 95.7% and 86.4% in low- and high-risk patients, respectively (HR = 7.7 (1.7-35.1), p < 0.01). Bio-miR compared favorably with different histopathological factors and UISS and Karakiewicz´s nomograms. In the Leeds validation cohort (n = 75/95 passing qPCR quality control), patients defined as low-risk had a 5-year DFS rate of 94% versus 62% in high-risk defined disease. In this cohort Bio-miR was able to divide the Leibovich intermediate-risk population into two groups with divergent five-year DFS rates (100% vs 71%). In the Spanish validation cohort (n = 180), DFS rates at 5 years were 82.9% in the low-risk group and 58.7% in the high-risk group (HR = 2.4 (1.4-4.4); p < 0.005). Applying the inclusion criteria from the phase III KEYNOTE-564 trial, Bio-miR identifies a small low-risk population who could be spared adjuvant treatment. Conversely, amongst patients excluded from the study due to low-risk features, Bio-miR defines a high-risk population (DFS at five years of 50%) who should be prioritized for adjuvant therapy. Conclusions: We define and validate a nine-microRNA based signature capable of dichotomizing patients with localized ccRCC into low- and high-risk groups based on risk of relapse. Importantly, Bio-miR acts independently of tumor stage and grade and could, therefore, help refine the selection of patients for adjuvant therapy as well as inform the design of future adjuvant ccRCC trials.
Disease-free and overall survival outcomes for localized RCC patients by disease stage.
Authors: Haas Naomi B. , Bhattacharya Rituparna , Ogbomo Adesuwa S. , Imai Kentaro , Gautam Santosh , Rogerio Jackie , Yu Rebekah , Chhabra Jatin , Sundaram Murali 
Published: June 2022

e16526 Background: Real world evidence (RWE) on patient outcomes among early-stage non-metastatic renal cell carcinoma (RCC) patients (pts) of different risk groups are limited. This RWE study evaluated disease free survival (DFS) and overall survival (OS) patterns and risk of OS among pts with non-metastatic RCC in the US. Methods: This retrospective analysis identified pts, age ≥18 years, with non-metastatic RCC diagnosis between 01/01/2012-12/31/2015, and surgical treatment for RCC prior to metastatic diagnosis. Pts were identified from the ConcertAI Oncology Dataset which draws electronic medical records from 100 community oncology clinics in the US and followed until 08/19/2021. Pts were stratified into intermediate (int)-high (pT2N0 high grade, pT3N0) or high risk (pT4N0, pTanyN1) RCC. Time to event outcomes (DFS, OS) were examined using Kaplan-Meier methods, and association of recurrence and 5yr OS was examined using Cox proportional hazard model, controlling for baseline and clinical characteristics. DFS was defined as time from initial nephrectomy to first recurrence or death, whichever occurred first. OS was defined as time from initial nephrectomy to death. Results: The study included 274 pts (87% int-high risk, N = 239; 13% high risk, N = 35). Overall, pts were 63.5 yrs (median age), 66% male, 78% White, and 73% had clear cell RCC. Median follow-up was 49.5 months (mths). 54% int-high and 69% high risk pts had recurrence. As seen in the table, median DFS ranged from 14.6-64.8 mths and 5yr DFS rates ranged from 10-61% across risk groups. Median OS was 83.4 mths for int-high and 78.4 mths for high risk pts; 5yr OS rate was 69% for int-high and 58% for high risk. Compared to patients without recurrence, pts with recurrence had shorter median OS (93.8 vs 69.6 mths) and lower 5yr OS rate (85% vs 57%). In pts with recurrence, 5yr OS rate was similar between int-high and high risk groups (58% and 57%). Pts with recurrence were 2.4 times (HR = 2.4; 95% CI = 1.5, 3.9) more likely to die 5 yrs post initial nephrectomy compared to pts without recurrence. Conclusions: This study confirms findings from our previous research with SEER data that pts with recurrence had an increased risk of death, compared to pts without. The DFS and OS rates observed in this RWE study are supportive of DFS and OS rates observed in the placebo arm of the KEYNOTE-564 trial. Additionally, poor DFS rates were observed within subgroups of int-high risk pts. The study results indicate the high real-world unmet need in post-nephrectomy int-high or high risk localized RCC pts, highlight the need for effective adjuvant treatments, and inform the design of future interventional trials in non-metastatic RCC pts.[Table: see text]