tbuckley/cabot-search huggingface dataset:
Turning on the lights in gastrointestinal oncology: How digital medicines reveal clinical insights on medication adherence and patient behaviors.
Authors: Paul Morales, Daniel Beiswenger, Won Chan Lee, Ellen Travis, Edward Greeno
Journal: Journal of Clinical Oncology (2019)

e15118 Background: Oral therapies in colorectal cancer (CRC) introduce unique complexities in care. Understanding adherence in patients using capecitabine can be challenging. The Discover Program, a novel digital medicine program (DMP), was integrated into the treatment of CRC patients at Fairview Health Services and University of Minnesota Health, the first ever DMP in the field of oncology. The DMP consists of DigiMeds (medications with ingestible sensors), a small wearable patch, and a mobile app, which enable collection of objective adherence data, alongside biometrics (e.g., steps, rest, resting heart rate) giving patients, caregivers, and providers the ability to confirm treatment start dates, address missed doses and observe changes in physical function. Methods: From September 2018 to December 2018, patients with CRC were enrolled in the DMP. Clinical pharmacists (CPs) monitored adherence data and patient metrics through a secure web portal to enhance regular follow-up, address barriers to adherence, reveal unreported Adverse Events (AE), provide coaching and education, and target therapy adjustments when appropriate. Qualitative data regarding pharmacists’ experiences with the DMP and their evolving interactions with patients were collected. Results: Seven patients were enrolled in the DMP (mean age: 62.1 ± 8.45 years (mean ± SD); 85.7% female; patch wear: 92.4% ± 6.8%; average adherence: 89.7%± 7.8%; average days on DMP: 55.6± 39.2 days). CPs reported that objective medication adherence data eliminated the challenge of navigating patient recall about their medication taking and health overall. The DMP allowed prompt and tailored interventions for patients struggling with adherence to prescribed regimens and/or AEs. These interventions were more focused, personalized, and clinically meaningful with improved shared decision-making, increased patient engagement/adherence, and more efficient/effective AE management. Conclusions: DMP data yielded significant insights that are not available in the absence of this novel technology. Future pragmatic, large real-world studies are recommended to assess the impact of DMP on adherence, AE management, and clinical and economic outcomes.
Determinants of concordance in clinically relevant genes (CRG) from synchronously acquired tumor biopsies (tBx) and ctDNA in metastatic breast cancer (MBC).
Authors: Mafalda Oliveira, Fiorella Ruiz-Pace, Judit Matito, Raquel Perez-Lopez, Anna Suñol, Meritxell Bellet, Santiago Escriva-de-Romani, Esther Zamora, Patricia Gomez, Laia Garrigós, Marta Capelán, Miriam Arumí, Carolina Ortiz, Fabiola Amair-Pinedo, Francesco M Mancuso, Martin Espinosa-Bravo, Paolo Nuciforo, Rodrigo Dienstmann, Ana Vivancos, Cristina Saura
Journal: Journal of Clinical Oncology (2019)

1075 Background: NGS in ctDNA from MBC is feasible and results may be informative for patients’ management, especially in non-luminal tumors (Oliveira et al, ASCO 2018). We aimed to study the determinants of concordance in CRG in a cohort of 60 MBC patients undergoing tBx and ctDNA collection. Methods: MiSeq Amplicon-based NGS (59 cancer-related genes) was performed in one single metastatic lesion per patient and compared with liquid biopsies taken at the same time point at disease progression to prior treatment. The concordance in CRG ( PIK3CA, AKT1, ERBB2, ESR1, PTEN, BRAF, FGFR1, HRAS, KRAS, and PIK3R1) in tBx vs ctDNA was determined at patient and at mutation (mut) level and correlated with mutant allele fraction (MAF), total disease volume (TDV), and clinical characteristics. True positive in plasma (TPP): patient with a mut detected both in ctDNA and tBx. TDV was defined as all metastasis volume assessed by CT scan (excluding sclerotic bone metastasis), and analyzed by an experienced radiologist using the 3DSlicer semiautomatic segmentation tool (TDV = pixel size x number of pixels). Results: Concordance in CRG at patient and mut level was 72% and 55%, respectively. Concordance for ERBB2 (1/1; 100%) and PIK3CA (17/22; 77%) was higher than for ESR1 (8/20; 40%) and AKT1 (2/6; 33%). ctDNA failed to detect 14 mut present in tBx ( ESR1 n = 5, PIK3CA n = 5, AKT1 n = 3, BRAF n = 1). Concordance was 100% for non-luminal and 60% for luminal cases (P = 0.01). In univariate analysis, concordance was not associated with MAF in tBx (P = 0.15), TDV (p = 0.86), number of prior lines of therapy (P = 0.57), number of metastatic sites (P = 0.56) or presence of visceral metastasis (P = 1.0). In patients with PIK3CA mut (N = 22), those with TPP had a numerically higher TDV than those where a PIK3CA mut was not detected in ctDNA (20.9cm 3 vs 5.1cm 3 , P = 0.28). Across all patients, in the multivariate logistic model adjusted for other factors, TDV was a determinant of TPP (OR 1.02, 95%CI 1.0-1.06; P = 0.059). For each increase of 1cm 3 in TDV, there was a 2% increase in the probability of detecting a mut in ctDNA. Conclusions: Our results suggest that liquid biopsy testing for the detection of actionable CRG is clinically valid in MBC, although its yield depends on several factors – tumor subtype, analyzed gene, and possibly tumor volume – that reflect both tumor heterogeneity and tumor shedding rate. Due to the potential clinical implications, the observation that mutation detection in ctDNA may correlate with tumor volume merits further study in a larger dataset.
Knowledge, attitude and practice in cancer pain management: A survey study among attending physicians, residents and nurses.
Authors: Ying Ning, Haritha Ackula, Vishal Jindal, Mu Li, Pengyang Li, Ahmad Daniyal Siddiqui
Journal: Journal of Clinical Oncology (2019)

e18278 Background: Our study used KAP model to evaluate differences of Knowledge, Attitude, and Practice regarding cancer pain management among care providers in a community teaching hospital. Methods: A 32-question KAP survey was designed with 3 demographic, 15 Knowledge, 9 Attitude and 5 Practice questions. It was administered randomly and anonymously to attending physicians of medicine, medical residents and medical nurses. 106 effective questionnaires (24 attending, 41 residents and 41 nurses) were analyzed and compared with percentage by Chi-Squared Test using SPSS 25. Results: Majority of all 3 groups believe only 50-60% of cancer pain can be effectively managed, while the actual effectiveness is close to 90% with proper management. Demographically, female predominates in nurses as expected, there is no statistical difference in previous pain/palliative education. Years of experience vary considerably (P &lt; 0.001). Attending perform best in Knowledge (60% correctness), but not statistically better (P = 0.361), a common area of weakness is low awareness of alternative management besides medication. Attending and nurses have more positive attitude compared to residents (P = 0.002). Nurses perform best in Practice mainly demonstrated by higher awareness and consistency in pain evaluation and documentation (P &lt; 0.001). Finally, overall performance is consistent with self-reported confidence. Conclusions: Knowledge is relatively easy to acquire since residents have comparable level to attending, although further education is indicated for all the providers. More care experience and a positive attitude better predicts practice performance. All 3 group seems to lack belief and confidence in effective cancer pain management, another area to be addressed for quality improvement. [Table: see text]
Contributing factors and outcomes of burn-associated cholestasis
Authors: Christian de Tymowski, François Dépret, Sabri Soussi, Moreno Nabila, Thomas Vauchel, Maité Chaussard, Mourad Benyamina, Axelle Ferry, Alexandru Cupaciu, Marion Jully, Haikel Oueslati, Alexandre Fratani, Maxime Coutrot, Philippe Sogni, Maurice Mimoun, Marc Chaouat, Anne-Marie Zagdanski, Eric De Kerviler, Alexandre Mebazaa, Richard Moreau, Vincent Mallet, Matthieu Legrand
Journal: Journal of Hepatology (2019)
Abstract 15077: Identification of Cd82-Positive Human Cardiomyocyte-Fated Progenitors in Human Pluripotent Stem Cell-Derived Cells
Authors: Masafumi Takeda, Jun K Yamashita
Journal: Circulation (2017)

Background: Cardiovascular progenitor cells (CPCs) with multi-differentiation potentials to cardiomyocytes (CMs) and non-CM population are reported. Although CPCs differentiate into CMs with high e...
Detection of targetable somatic alterations in glioblastoma (GBM) and clinical impact.
Authors: Michael Fusco, Robert J Macaulay, Peter A. J. Forsyth, Christine Marie Walko
Journal: Journal of Clinical Oncology (2019)

2058 Background: In GBM, molecular markers are utilized to establish an integrated diagnosis as described in the WHO 2016 guidelines and identify patients (pts) with molecular targets amenable to therapeutic intervention. Herein we review our experience at Moffitt Cancer Center. Methods: A retrospective chart review between 4/1/2013 and 11/1/2018 was performed to collect demographic, clinical, disease, treatment and outcome variables on 163 unique pts with GBM whose tumors underwent comprehensive genomic profiling by FoundationOne or CDx testing. Genomic data was analyzed for recurrent alterations and tumor mutational burden (TMB). Results: Median age was 58 years (range 19 to 85). 13% were IDH1 or 2-mutated. Among the 141 IDH-wild type (wt) pts, TERT promoter mutations occurred in 83% and CDKN2A/B co-deletion in 65%. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was seen in 33%. A median of 5 clinically relevant alterations were identified per tumor sample (range, 2 to 34) and a median of 2 mutations (range, 0 to 6) were found to be actionable after review by our molecular tumor board. The most commonly actionable alterations were found in EGFR, BRAF and genes associated with homologous recombination deficiency (HRD) (see table). Four pts were treated with EGFR-targeted therapy, one pt with an HRD alteration received a PARP inhibitor (progression free survival [PFS] of 34 weeks), and two pts with BRAF V600E received dabrafenib/trametinib combination therapy (treatment ongoing at 14 weeks and 38 months, respectively). Median TMB (n = 118) was 4 (range, 0 to 371 Muts/Mb). One pt who received 44 months of temozolomide exposure had a hypermutated tumor (371 Muts/Mb) and was treated on trial with pembrolizumab, but progressed after 2 months. Conclusions: Though limited in patients with GBM, clinically actionable alterations are found in a small subset and can translate into meaningful clinical benefit. [Table: see text]
Pembrolizumab versus the standard of care for cancer therapy: A meta-analysis of 12 KEYNOTE trials comparing overall survival.
Authors: Nathaniel Parker, Ammar Al-Obaidi, Quoc Van Truong, Robert Badgett
Journal: Journal of Clinical Oncology (2019)

e14159 Background: Pembrolizumab (P) is an antineoplastic agent approved for multiple different tumor origins as well as tumor agnostic based on MSI status. Thus understanding the tumor characteristics most predictive of response is essential. Living meta-analysis provides a method to continuously assimilate emerging trials. In this study, we created a living meta-analysis to compare the effect of P on overall survival (OS). Methods: Meta-analysis was conducted according to the PRISMA guidelines. PubMed and Cochrane databases, and conference abstracts (e.g. ASCO, ESMO), were searched for phase III KEYNOTE RCT’s that reported OS among cancer patients receiving P. Results: 12 phase III trials involving 7,319 patients (3,861 in P arms) treated for 6 different types of cancer were retrieved. Median follow up was 12.9 months [range: 0.1-35.5]. Treatment was P alone, SOC chemo, and P + chemo in 11 (40%), 13 (46%), and 4 (14%) arms, respectively. P significantly improved OS (HR 0.71, 95% CI: 0.59-0.85, p &lt;0.001, I 2 = 0%) when used in any cancer type, setting, or therapy for advanced refractory or chemo-naïve cancer patients. The mean median OS was 12.5 vs 11.1 months in the total populations for all P and control arms, respectively (Table). Conclusions: Among all trials, P was associated with improved OS. Additional meta-analysis will be performed with R software (version 3.3.3; R Fdn.). Random-effects models will be used to compare OS. Heterogeneity will be assessed with Cochrane Q -statistic and quantified with I 2 test via subgroup analyses for cancer type, setting, therapy, and PD-L1%. This meta-analysis is continuously updated at http://openmetaanalysis.github.io/checkpoint-inhibitors. [Table: see text]
A phase I study of the safety and immunogenicity of a multi-peptide personalized genomic vaccine in the adjuvant treatment of solid tumors and hematological malignancies.
Authors: Ana Blazquez, Alex Rubinsteyn, Julia Kodysh, John Patrick Finnigan, Thomas Urban Marron, Marcia Meseck, Timothy O'Donnell, Jeffrey Hammerbacher, Michael J. Donovan, Milind Mahajan, Brett A. Miles, Hanna Irie, Amy Tiersten, Ashutosh Tewari, Samir S. Parekh, Sujit Nair, Matt D. Galsky, Eric E. Schadt, Philip Adam Friedlander, Nina Bhardwaj
Journal: Journal of Clinical Oncology (2019)

e14307 Background: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations that occur during carcinogenesis and can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematological malignancies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens based on patient’s HLA profile (ClinicalTrials.gov: NCT02721043). Results: Patients who completed vaccination with PGV001_002 (head and neck squamous cell cancer) received 10 doses of vaccine comprising 10 long peptides (LP) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced T-cell responses were determined at weeks 0 and 27 (before and after treatment, respectively), ex vivo by interferon (IFN)-g enzyme-linked immunospot assay and after expansion by intracellular cytokine staining. Overlapping 15-mer peptides (OLPs) spanning the entirety of each LP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4 + and CD8 + T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-g, TNF-a, and/or IL-2) from either CD4 + or CD8 + T cells. Conclusions: The PGV001 vaccine in our first patient showed both safety and immunogenicity, eliciting CD4 + and CD8 + responses to the vaccine peptides. As we enroll additional patients in this clinical trial, and perform deeper phenotyping of their tumor-reactive T cells, we will learn the determinants necessary for the successful generation of MTA-based vaccines, while informing future immunotherapeutic approaches and rational combinations. Clinical trial information: NCT02721043.
Comprehensive genomic profiling in Chinese patients with lung squamous cell carcinoma.
Authors: Zuping Lian, Heng Li, Youming Lei, Lei Xian, Kunpeng Bu, Xiangping Wang, Zhonghai Chen, Honglin Guo, Xiaoqian Chen, Fei Guo, Lin Zhang
Journal: Journal of Clinical Oncology (2019)

8540 Background: Lung squamous cell carcinoma (LUSC) is a major histological subtype of non-small cell lung cancer (NSCLC) and accounts for 30% of NSCLC. Previous studies had revealed the genomic characterization of LUSC in Western patients (pts). However, the comprehensive genomic features of LUSC in Chinese pts have not been well understood. Methods: Deep sequencing targeting 450 cancer genes was performed on FFPE and matching blood samples collected from 311 LUSC pts. Genomic alterations (GAs) including single nucleotide variations, short and long insertions and deletions, copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Results: The median age of LUSC pts was 63 years old (range 57-68.5), of which 88% were male. The most frequently mutated genes were TP53 (88%), PIK3CA (34%), CDKN2A (33%), SOX2 (26%), LRP1B (22%), KLHL6 (21%), KMT2D (19%), PRKCI (19%), NFE2L2 (18%) and MAP3K13 (17%). Interestingly the mutation rates of PIK3CA (p = 1.93e-05) and CDKN2A (p = 2.48e-05) were significantly higher than that in TCGA cohort. Genomic alterations in eight druggable genes recommended by the NCCN guideline occurred in 32% of pts, and alterations to PI3K/mTOR signaling pathway related genes occurred in 52% of pts. One patient with PIK3CA amplification achieved stable disease for eight months after everolimus treatment. Moreover, variants in the homologous recombination (HR) pathway were identified in 17% of pts. The median TMB of LUSC pts was 10.8 Muts/MB (range 6.9-14.5 Muts/MB) which was higher than Western populations [PMID: 28420421]. The 1 st Quartile (TMB-L), median and 3 rd Quartile (TMB-H) TMB value was 6.9, 10.8 and 14.5 Muts/Mb respectively. Comparing with the TMB-L group, frequencies of CDKN2A (39% vs 19%, p= 0.005), LRP1B (45% vs 8%, p&lt; 0.001) and KMT2D (27% vs 8%, p= 0.002) were higher in TMB-H group. Conclusions: In summary, we characterized the genomic alteration profile of Chinese LUSC pts. Consistent with previous reports, high mutation rates of TP53, PIK3CA and CDKN2A are the most important genomic features of LUSC. However, the proportion of PIK3CA and CDKN2A mutations in Chinese LUSC pts is higher than that of Western populations. In addition, we also found targetable pathways (including PI3K/mTOR) along with gene related variations and high TMB in many pts, providing potential targeted therapy and immunotherapy options for LUSC pts.
Factors of local immunity in patients with rectal cancer after prolonged radiotherapy.
Authors: Oleg Ivanovich Kit, Aleksandr V. Snezhko, Elena Yu. Zlatnik, Inna A. Novikova, Nabil Al-haj, Elena S. Bondarenko, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e15164 Background: Immunological study of the blood and tumor tissues was performed in patients with rectal cancer receiving neoadjuvant chemoradiotherapy. Methods: 30 patients with rectal cancer (13 women and 17 men aged 37-68 years with stage II-III adenocarcinomas G1-G3) were divided into groups according to results of DNA cytometry and their response to neoadjuvant treatment. When tumor proliferative activity was stable for 4 weeks of treatment, patients received surgery on time (group 1), while patients with verified inhibition of tumor proliferation (the index decrease by 1.5 times and more) continued treatment for 6-8 weeks and then were operated on (group 2). The immune status of patients (T, B, NK, DN, Tregs) was assessed during treatment. Homogenates of tumor tissue samples obtained during surgery were studied for the levels of lymphocytes (flow cytometry) and cytokines TNF-α, IL-1ß, IL-1RA, IL-6, IL-8, IFN-α, IFN-γ (ELISA); tumor proliferation index was assessed by DNA cytometry. Results were analyzed by Statistica 10.0 program. Results: The dynamics of parameters of the cellular immunity was different in patients of two groups. In group 1, percentage of T lymphocytes in blood decreased (from 66.7±3.3 to 50.4±1.6%), as well as their main subsets (CD4+ and CD8+ cells: from 33.6±2.7 to 27.0±1.7% and from 26.7±2.4 to 20.7±1.7% respectively). Patients of group 2 developed an increase in levels of NK cells from 10.1±1.2 to 15.3±2.2%, and levels of CD3+, CD4+ and CD8+ cells were significantly higher than in group 1: 35.0±1.8% for CD4+ and 28.3±2.9% for CD8+ (p &lt; 0.05). The groups also differed in indices of local immunity: DN cells levels in group 2 were lower than in group 1 (5.8±1.0 vs. 18.4±5.4%) and CD4+ were higher (36.6±3.3 vs. 26.2±3.1%; p &lt; 0.05). Patients of group 2 showed lower levels of IL-1ß, IL-6, IL-10, while IFNγ was elevated by 5.4 times, indicating a more favorable local cytokine status of the patients, compared to group 1. Conclusions: In rectal cancer patients with effect confirmed by DNA cytometry, prolongation of chemoradiotherapy to 6-8 weeks provides the formation of a more favorable immunological microenvironment of the tumor, and in such cases it is considered appropriate.
RAS activation and CDKN2A deletion to predict prognosis in cancer of unknown primary.
Authors: Tilmann Bochtler, Anna Reiling, Volker Endris, Thomas Hielscher, Anna-Lena Volckmar, Olaf Neumann, Martina Kirchner, Jan Budczies, Lukas Heukamp, Jonas Leichsenring, Michael Allgäuer, Peter Schirmacher, Albrecht Stenzinger, Alwin Kraemer
Journal: Journal of Clinical Oncology (2019)

e13026 Background: Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Given the typically dismal response to empiric chemotherapy, the deciphering of molecular profiles holds a particular promise for targeted therapy. Here, we address the prognostic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Methods: We performed targeted panel sequencing in a series of 252 CUP patients. Median age was 60.3 years and 59.1% were female. 71.2% of patients had unfavorable CUP. Lymph nodes, bone marrow, lung, peritoneum and pleura were the most frequent metastatic sites. Among histologic subtypes, adeno- (74.7%) and squamous cell carcinomas (13.7%) prevailed. DNA was extracted from micro-dissected formalin-fixed, paraffin-embedded tissue samples. For library preparation mostly multiplex PCR-based Ion Torrent AmpliSeq technology (Life Technologies) with Oncomine comprehensive assays v1 and v3 was used. Results: The prevailing genetic alterations were deletions in tumor suppressor genes TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01) and PIK3CA activation in squamous cell carcinomas (p = 0.03). Regarding prognosis, male sex, high ECOG score, unfavorable CUP subtype, a higher number of involved organs as well as RAS activation predicted decreased event-free and overall survival in multivariate analysis. Deletions in CDKN2A were a poor prognostic factor regarding overall survival. Markedly, TP53 mutations did not significantly influence prognosis. Since July 2015, 17/198 (8.6%) patients received a recommendation for molecularly guided therapy. However, due to lack of coverage by insurers or rapid clinical deterioration only 7 of these patients (3.5%) actually received targeted treatment. Conclusions: Besides offering targets for therapy, targeted panel sequencing in CUP is prognostically relevant, with RAS activation and CDKNA2 deletion emerging as independent risk factors in a comprehensive assessment with clinical risk factors.