bluuebunny/crossref_metadata_2025 huggingface dataset:
MEK-inhibitor (inh) and hydroxychloroquine (HCQ) in KRAS-mutated advanced pancreatic ductal adenocarcinoma (PDAC).
Authors: Mehdi Maahum , Thalji Samih Z , Shreenivas Aditya V. , Chakrabarti Sakti , Thomas James P. , Christians Kathleen K. , Evans Douglas B. , Hall William A. , Erickson Beth , Thapa Bicky , Ahmed Gulrayz , Yazdanpanah Omid , Kurzrock Razelle , Aldakkak Mohammed , Holden Mary Beth , George Ben , Tsai Susan , Oxencis Carolyn , McFall Thomas , Kamgar Mandana
Published: June 2022

e16260

Background: Therapeutic inhibition of constitutive signaling mediated by mutated KRAS in PDAC remains a challenge except for modest success reported with KRAS G12C inhibition. A combinatorial strategy utilizing simultaneous MEK and autophagy inhibition holds therapeutic promise based on mechanism of action and preclinical data. We described characteristics and outcomes of patients (pts) treated with MEK-inh and HCQ at our institution. Methods: Ten KRAS-mutated advanced PDAC pts were treated with trametinib-HCQ (n = 9) or cobimetinib-HCQ (n = 1) off label due to lack of standard treatment options or toxicity concerns with cytotoxic systemic therapy. Trametinib dose was 2 mg once daily orally, Cobimetinib dose was 20 mg BID orally for 3/4 weeks cycles. HCQ was started at 200 mg BID and up-titrated weekly to 600 mg BID. Description of baseline and treatment (tx) characteristics, safety and efficacy is provided. Results: Median age at diagnosis was 61.3 years, and 7 pts were female. The number of prior lines of tx were 0/1/2/3/4 in 3/2/1/2/2 pts, respectively. KRAS mutations were: G12R/G12D/G12V/Q61H in 6/2/1/1 pts. Median overall survival was 6.6 months (m) in all pts, and 6.6/1.7 m in KRAS G12R/other KRAS (p = 0.31). Median progression-free survival was 5.7/6.2/1.5 m in all/ KRAS G12R/other KRAS (p = 0.16). Among 8 pts with evaluable response, 1 (12%) had partial response ( KRAS G12R) and 4 (50%) stable disease (3/4 KRAS G12R) as best response with disease control rate of 63%/80%/33% in total/ KRAS G12R/other KRAS (p = 0.29). Toxicity data are summarized in table 1. Conclusions: MEK-inh-HCQ demonstrated modest efficacy and manageable toxicities among KRAS G12R PDAC pts. Unlike G12D and G12V mutations in the KRAS gene, G12R is defective of conductive interactions for both PI3Ka and NF1. This ultimately results in a weakened signal being shunted through MAPK cascade and provides a unique opportunity where MEK inh can ablate signaling without the alternate pathways and WT-RAS isoforms compensating. Furthermore, as activation of PI3Ka is known to suppress autophagy, its lack of activation by KRAS G12R further sensitizes cells to HCQ. The combination therapy MEK-inh-HCQ is therefore mechanistically-rationale and warrants the further investigation of KRAS G12R as an actionable biomarker.[Table: see text]
Genomic landscape and clonal evolution between adenocarcinoma and squamous components in adenosquamous carcinoma of the pancreas.
Authors: Wang Zheng , Guo Shiwei , Jiang Yina , WU Yinying , Wu Zheng , Ma Qingyong , Wang Yan , Zhang Liwen , You Dong
Published: June 2022

e16265

Background: Adenosquamous carcinoma of the pancreas (ASCP) is a rare histological subtype of pancreatic cancer with high metastasis rate and poor prognosis, which is characterized by a variable proportion of adenocarcinoma and squamous carcinoma components with at least 30% of the tumor showing squamous differentiation. To get further insight into the tumorigenesis and progression, we profiled the genetic characterization and explored the evolutionary model of this subtype. Methods: A total of 10 patients with ASCP were enrolled. For each sample, glandular and squamous carcinoma tissues were separated by microdissection. Whole exome sequencing for 20 samples with matched peri-carcinomatous tissues were performed by next-generation sequencing. Results: Genetic profiling revealed that top 5 mutated genes of adenocarcinoma and squamous components were highly consistent including TP53 (100% vs 100%), KRAS (100% vs 90%), CDKN2A (40% vs 40%), KDM6A (20% vs 20%) and LRP1B (20% vs 20%). KEGG pathway analysis showed that PI3K-Akt, MAPK and FoxO signaling pathways were the most frequently mutated pathways in adenocarcinoma. In contrast, Apelin and Rap1 signaling pathways were highly mutated in squamous components, advocating that these pathways may play important roles in the transformation of squamous carcinomas. A higher proportion of indels were identified in adenocarcinoma than squamous components (12.1% vs 3%). The chromosome regions of 3p21.3, 9p21.3, 11p15.5, 16p13.11 and 21q22.3 were the most commonly deleted regions in the adenocarcinoma components, while losses of 1p36.21, 3p25.3, 3q13.13, 6p22.3 and 11p15.5 had been observed in the squamous components. Some of these regions had important effects on development and progression of cancer. For example, 9p21.3 had well-established impact on cell proliferation and apoptosis containing two crucial tumor suppressor genes, CDKN2A and CDKN2B. Additionally, the C > T mutation was predominant among the 6 types of single nucleotide variations. Most common signatures were related to aging (Single base substitutions, SBS1), BRCA1/2 mutations and responders to platinum therapy (SBS3), and defective DNA mismatch repair (SBS6). Tumor evolution analysis showed that the glandular and squamous components shared a common origin. There were two evolutionary scenarios in the early stages of tumor evolution, with a third of nine patients ware parallel evolution and the remaining patients were linear evolution. KRAS (100%), TP53 (66.7%) and TTN (33.3%) were frequently identified as clonal mutations. Conclusions: This is the first study to elucidate the genomic alteration as well as the clonal evolution using whole-exome sequencing in ASCP patients. It provides evidence for more comprehensive understanding of pathophysiology of ASCP at genomic level, which could contribute to the amelioration for ASCP patients’ management.
Real-world data comparing FOLFIRINOX versus gemcitabine nab-paclitaxel as first-line treatment of metastatic pancreatic ductal adenocarcinoma patients in the United States.
Authors: Klein-Brill Avital , Amar-Farkash Shlomit , Lawrence Gabriella , Collisson Eric Andrew , Fisch Michael Jordan , Aran Dvir
Published: June 2022

e16271

Background: The common first-line therapies for metastatic adenocarcinoma of the pancreas (mPC) are FOLFIRINOX and gemcitabine plus nab-paclitaxel (Gem-Nab-P). However, these treatments have not been directly compared in a clinical trial and comparative real-world data analyses on their effectiveness are limited. Using real-world data, we evaluated the impact on overall survival and post-treatment hospitalizations of 1L FOLFIRINOX vs. Gem-Nab-P in individuals with mPC. Methods: We performed a retrospective cohort study of 1L treatment of patients with mPC between 1/2015 and 6/2020, utilizing administrative claims data from the Anthem Cancer Care Quality Program. Real-world overall survival (rwOS) was defined as time from diagnosis to death. Inverse probability of treatment weighting (IPTW) was used to adjust for age, ECOG, Socioeconomic index (SDI), comorbidity, metastatic sites and pre-treatment. Median rwOS was estimated using the weighted Kaplan-Meier method. Results: Our cohort included 1,102 1L mPC patients, 566 (51.4%) treated with FOLFIRINOX (F), and 536 (48.6%) treated with Gem-Nab-P (GNP). F-treated patients were generally younger, with better performance status (ECOG PS), fewer comorbidities and living in regions with higher socioeconomic index. Following adjustments, the Median rwOS was 9.28 and 6.82 months for F-initiated patients and GNP, respectively (p-value = 2.5e-07). This survival benefit of F was observed among all sub-groups, including different ECOG PS, ages, socioeconomic index and metastatic sites. F-treated patients also had fewer post-treatment hospitalizations (p-value=0.027) and lower post-treatment costs (p-value=0.00004). Conclusions: Our retrospective cohort study demonstrated that FOLFIRINOX is associated with improved survival of approximately 2 months over Gem-Nab-P and is also associated with fewer post-treatments complications. A randomized controlled trial comparing these first line treatments is warranted to test the survival and post-treatment complications benefit of FOLFIRINOX over Gem-Nab-P.[Table: see text]
Machine learning based detection of pancreatic tumors using the Dxcover cancer platform.
Authors: Baker Matthew , Sala Alexandra , Cameron James Munro , Christie Loren , Conn Justin , Palmer David
Published: June 2022

e16275

Background: Pancreatic cancer is the 7th most deadly cancer worldwide with over 460,000 victims per year. In the current diagnostic pathway, carbohydrate antigen (CA) 19-9 serum test is the blood assessment used for detection of pancreatic cancer; although, with poor positive predictive values reported, it is not specific for pancreatic tumors as its levels can be raised in symptomatic patients with other benign comorbidities and/or because of other tumors in the surrounding area. Attenuated total reflection–Fourier transform infrared spectroscopy (ATR-FTIR) has demonstrated exceptional potential in human blood serum analysis for cancer diagnostics and its implementation in the clinical environment could represent a significant step forward in the early detection of pancreatic cancer. This proof-of-concept study aimed to investigate the use of the Dxcover cancer liquid biopsy as a novel approach for pancreatic cancer detection. Methods: The study was focused on the discrimination between both cancer (n = 100) versus healthy control samples (n = 100), and cancer (n = 35) versus symptomatic non-malignant control samples (n = 35) from patients with comorbidities and/or confounding diseases. Various machine learning algorithms were applied to discriminate between the classes: random forest (RF), partial least squares-discriminant analysis (PLS-DA) and support vector machine (SVM). Receiver operating characteristic (ROC) analysis was also employed to evaluate the classes’ degree of diagnostic separability. Permutation tests were performed for each classification in order to ensure their statistical significance. Results: Cancer (n = 100) and healthy control samples (n = 100) were distinguished with excellent results, achieving results up to a sensitivity of 91.0 %, specificity of 87.6 %, and accuracy of 89.3 % with PLS-DA. Moreover, an area under the curve (AUC) equal to 0.954 was obtained through ROC analysis. When discriminating between cancer (n = 35) and symptomatic control samples (n = 35), accuracy values were recorded in the range between 70.6 and 77.3 % with ROC analysis showing a balanced sensitivity and specificity over 75 % with an AUC of 0.844. Both discriminations were proven statistically significant. Conclusions: Pancreatic cancer detection in early stages would be key in improving prognosis and survival rates of patients, through targeted earlier surgery and treatments. The Dxcover cancer liquid biopsy could represent a powerful tool in the clinical environment as an easy-to-use, minimally invasive and reliable spectroscopic blood test for detection of pancreatic cancer.
Efficacy and the safety of endoscopic ultrasound guided radiofrequency ablation of pancreatic cancer: A systematic review and meta-analysis.
Authors: Ehsan Hamid , Masood Adeel , Wahab Ahsan , Ahmed Zahoor , Franco Diana , Rafae Abdul , Yousaf Muhammad Nadeem
Published: June 2022

e16276

Background: Endoscopic ultrasound-guided RFA (EUS-RFA) is a minimally invasive emerging modality that may be an alternative to surgical resection for the management of unresectable pancreatic cancer (UPC). In this review, we highlighted the efficacy, clinical and technical success of the EUS-RFA for UPC. Methods: Studies were selected with a comprehensive search strategy for EUS-RFA and pancreatic cancer on PubMed, Google Scholar, and Embase databases as of October 2021. The primary outcomes were the technical (TS) and clinical success rate (CS) of the EUS-RFA procedure, while the secondary outcome was the adverse events (AEs) rate. Results: Twelve studies including 114 patients with 50% (57) females were included. Common pancreatic tumors were locally advanced pancreatic ductal adenocarcinoma (LAPDAC) 38.3% (49), followed by nonfunctional neuroendocrine tumor (NNET) 32% (41), pancreatic cystic neoplastic lesions 14.8% (19), insulinoma 12.5% (16) and others 2.3% (3). The most common site of the tumor was pancreatic head 45.7% (59) followed by body, neck, and tail 47.6% (61). The average number of ablation sessions per patient was 1.4 based on the total of 115 EUS-RFA sessions performed in 84 neoplastic lesions. The pooled TS rate of EUS-RFA calculated from the total number of procedures was 99.2% [95% CI = 0.90-0.98, I2 = 0%]. The pooled CS rate calculated from the total number of pancreatic lesions was 91.9% [95% CI = 0.77-0.92, I2 = 0%]. Clinical improvement in symptoms was reported in five studies whereas complete resolution or decrease in tumor size was reported in all studies. The pooled AEs rate was 24.6% [95% CI = 0.17-0.39, I2 = 30%]. Common AEs were abdominal pain 10.5% (12), and pancreatitis 3.5% (4). Conclusions: EUS-RFA is a promising and safe modality that can be used for the management of UPC in selected patients with a high TS (99.2%) and CS rates (91.9%). Large clinical trials are needed to identify safety, clinical outcomes, and overall survival benefits of EUS-RFA.[Table: see text]
Sensitive detection of pancreatic adenocarcinoma using plasma cell-free DNA methylomes.
Authors: Nie Peiyao , Lv Fang , He Shuying , Han Tiancheng , Yang Shunli , Suxing Li , Liu Dan , Yang Ying , LI Yulong , Huang Yu S. , Hong Yuanyuan , Chen Weizhi , Yu Jianing , Sun Yongkun
Published: June 2022

e16277

Background: Cell-free DNA (cfDNA) methylation, fragmentation patterns, chromosome instability, and chromatin accessiblity have been previously shown to be valid plasma biomarkers for non-invasive cancer detection. However, conventional whole-genome bisulfite sequencing (WGBS) is unable to simultaneously profile all these biomarkers due to bisulfite-induced DNA damages. Here we developed a machine learning approach to comprehensively integrate multiple types of cancer genomic markers from enzyme-conversion-based low-pass whole-methylome sequencing (WMS) of plasma cfDNA to non-invasively detect pancreatic adenocarcinoma. Methods: Plasma cfDNA sampels from 139 cancer patients and 568 healthy individuals were collected and were split into the discovery and independent testing cohort. The discovery cohort includes 99 cancer patients and 398 healthy individuals and the independent testing cohort includes 40 cancer patients and 170 healthy individuals. Whole methylome sequencing (WMS) libraries were generated from enzymatically converted cfDNA and were subsequently paired-end sequenced at ̃2X coverage. The genome-wide methylation density, fragmentation fingerprints, chromosome instability, and chromatin accessibility were extracted from the WMS data and individually modelled via machine learning methods such as SVM, LR, GBDT, random forest. The final predictive model is an ensemble model integrating all uni-modal models. All models were trained and fitted on the discovery cohort. Results: Data of different modalities provide complementary information in separating the cancer patients from the healthy individuals. Unsupervised clustering of the individuals showed clear separation between cancer patients and healthy individuals. The final predictive model achieved AUC =0.982 in the discovery cohort and AUC =0.986 in the independent testing cohort. Under a specificity of 96.23% (CI: 87% - 88%), sensitivity was 95% (CI: 93% - 96%) in the independent testing cohort. Separating the cancer patients into different stages, we found that the detection power is usuaul lower for early-stage cancer patients. Conclusions: These results demonstrate the first proof of principle on the feasibility of integrating multiple genomic cancer markers to non-invasively detect pancreatic adenocarcinoma from WMS plasma cell-free DNA. A large prospective cohort study is planned to further validate its clinical performance.
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]
Impact of site-specific metastases and clinical complications on outcomes of patients with metastatic renal cell carcinoma (mRCC).
Authors: Wang Jianbo , Zhang Ning , Giordano Sharon H. , Tannir Nizar M. , Gao Jianjun
Published: June 2022

e16527

Background: Prognostic models based on the heterogeneity of mRCC disease characteristics, including anemia, hypercalcemia, and neutrophilia, are routinely used in clinic. In an attempt to improve these models, we conducted a retrospective analysis of patients(pts) with mRCC to assess the association of overall outcomes with specific sites of metastasis (mets) and clinical complications. Methods: We extracted data from the SEER-Medicare database on pts diagnosed with RCC from 2004 to 2015. Study cohorts included patients who were > 65 years old and had at least 1 of following site-specific mets or complications: ascites, bone mets, brain mets, liver mets, lung mets, pancreatic mets, and hypercalcemia. To accurately delineate the relationship between site-specific/clinical complications and clinical outcomes, pts were stratified into 3 groups by the timing of site-specific mets and complications appearance : A1 (pts with a site-specific mets or complication at the initial diagnosis of mRCC); A2 (pts with a site-specific mets or complication any time after diagnosis of mRCC); and B (pts who have no site-specific mets or complication but have other mets or complications). Kaplan-Meier curves for overall survival(OS) were produced and median(m) OS were reported. Multivariable Cox modeling was performed to assess the association of individual mets or complications with OS between pre-specified subgroups(A1+A2 vs B, A1 vs A2+B and A1 vs B). Results: We identified 4640 RCC pts in the SEER-Medicare database who had at least 1 of the specified sites of mets or complications. At a median follow-up of 8 months(mons), ascites, brain mets and hypercalcemia were associated with worse mOS in all predefined subgroup analysis. In pts with liver mets, groups A1+A2 had shorter OS than B . In pts with lung mets, mOS in A1 was longer than in A2+B or B. bone mets did not show a statistically significant correlation with OS in any stratified analysis. Lastly, pancreatic mets was associated with longer mOS, but this did not reach statistical significance regardless of the comparison groups (table 1). Conclusions: Our data show that ascites, brain mets, hypercalcemia, and liver mets was associated with poor prognosis, and de novo lung mets was associated with better clinical outcome in patients with mRCC. Based on these findings, we are working on comparing the clinical outcome of mRCC pts treated with targeted therapy to that of pts treated with immunotherapy and building a new prognostic model.[Table: see text]
IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients (CI-MIBC) first-stage analysis NCT04046094.
Authors: Parikh Rahul Atul , Taylor John A. , Chen Qi , Woolbright Benjamin L. , Chen Ping , Wulff-Burchfield Elizabeth Marie , Holzbeierlein Jeffrey , Jensen Roy A. , Drisko Jeanne A.
Published: June 2022

e16540

Background: Neo-adjuvant cisplatin-based chemotherapy (NAC) is considered standard of care for patients with locally advanced disease. However, ̃40% of patients are cisplatin ineligible (CI) due to renal insufficiency, hearing loss or poor performance status. Gemcitabine and carboplatin (GCa) has limited success in this setting. Patients usually proceed directly to cystectomy without realizing the potential survival benefit afforded by NAC. Intravenous ascorbate (vitamin C) administration (IVC) has been shown to improve the efficacy of carboplatin and gemcitabine-based therapy in other models. This single-arm, Simon 2-stage, window of opportunity trial included IVC with single cycle GCa to evaluate pathologic downstaging. We report on the interim first stage analysis of 12 patients. Methods: Patients with newly diagnosed CI-MIBC were enrolled and received single cycle GCa and IVC titrated to peak plasma concentration of 350 to 400 mg/dL (̃20 mM) for 21 days followed by cystectomy at 4-6 weeks from initiation of treatment. The primary outcome is pathological stage at cystectomy. Patients are then followed per NCCN guidelines with standard of care bloodwork, physical exam and imaging studies until progression and/or death. QOL is being evaluated by Functional Assessment of Cancer Therapy-Bladder (FACT-Bl). Results: All 12 patients completed GCa/IVC with 11 having had a cystectomy and 1 pending surgery. Pathological downstaging (yp < T2) was noted in 4 patients with 3 CRs (ypT0N0Mx) and 1 with residual ypTisN0Mx only. Of note, 1 CR was seen in a patient with locally advanced plasmacytoid variant. Participants tolerated treatment well with minimal treatment related AE/SAEs. Conclusions: Interim analysis of GCa-IVC NAC shows good tolerability with > 36% rate of downstaging. Of those with a pathological response, 75% achieved a CR. Continuation criteria has been met for stage 2. FACT-BI analysis and clinical follow up is ongoing and will be reported at study completion. Clinical trial information: NCT04046094.
A novel approach to assessing the effects of smoking on treatment response rate in muscle-invasive bladder cancer.
Authors: Gotschall Jeromy , Major C. Kendall , Jacobs Linda A. , Pucci Donna A. , Blauch Abigail , Palmer Steven C. , Mamtani Ronac
Published: June 2022

e16554

Background: Cigarette smoking is the strongest modifiable risk factor for bladder cancer and has been implicated in mechanisms of chemotherapy resistance. Prior studies examining tobacco exposure on chemotherapy response were limited by use of retrospective design and self-report assessment of smoking status, potentially under-estimating the association and risking bias towards the null. Cotinine is the central metabolite of nicotine and can be detected in saliva for up to 4 days after tobacco use. In this prospective cohort study, we tested the association between salivary cotinine level and pathologic response to neoadjuvant chemotherapy, assessed post-chemotherapy at the time of cystectomy, among patients with muscle-invasive bladder cancer (MIBC). Methods: Thirty-one patients with MIBC were prospectively recruited and surveyed on their smoking habits. Salivary cotinine was measured during chemotherapy using NicAlert test strips with cotinine concentration > 10ng/mL indicating active smoking (cotinine = 1) and cotinine concentration < 10ng/mL indicating no evidence of active tobacco use (cotinine = 0). Primary outcome was pathologic response at cystectomy, defined as complete response (pT0) or residual disease (pT1-4 or node+). For patients with prior history of tobacco use, the association between pre-chemotherapy cotinine level and post-chemotherapy response at cystectomy was assessed using a chi-squared test and an odds ratio with a 95% confidence interval (CI) using the Baptista-Pike method. Results: Thirty-one patients had cotinine levels measured during chemotherapy and 25 reported prior history of smoking. Of these 25 patients, 17 patients denied active smoking, 2 of whom had cotinine levels = 1 during chemotherapy. Response to chemotherapy by cotinine level among patients with prior history of tobacco use are shown in table 1. One patient declined cystectomy and was excluded from the analysis. The odds ratio of a complete response at cystectomy for patients with cotinine = 0 vs. cotinine = 1 was 3.86 (95% CI: 0.54-22.05) (p = 0.148). The odds ratio of residual disease with cotinine = 0 vs. cotinine = 1 was 0.26 (95% CI: 0.045-1.86) (p = 0.148). Conclusions: Prior smokers with no evidence of active tobacco use during curative chemotherapy were more than three-times as likely to demonstrate a complete response at the time of cystectomy compared to those with evidence of current tobacco use based on salivary cotinine levels. While this study was limited by a small sample size, it highlights a novel approach to tobacco use monitoring and the importance of continued smoking cessation counseling in patients with bladder cancer even after the diagnosis of cancer is made.[Table: see text]