tbuckley/cabot-search huggingface dataset:
Molecular annotation of extramedullary acute myeloid leukemia to identify prevalence of targetable mutations.
Authors: Somedeb Ball, Todd C Knepper, Yehuda Ethan Deutsch, Chirag K Bhagat, Justin M. Watts, Terrence J Bradley, Wassim Samra, Onyee Chan, Mohammad Omar Hussaini, Kendra L Sweet, Chetasi Talati, Eric Padron, Rami S. Komrokji, Jeffrey E. Lancet, David Andrew Sallman
Journal: Journal of Clinical Oncology (2021)

7024 Background: Extramedullary (EM) involvement, including myeloid sarcoma (MS) and leukemia cutis (LC), is uncommon in patients with acute myeloid leukemia (AML). Mutational landscape of EM-AML is not well characterized, including concordance of sequencing data from EM vs. non-EM site (blood or bone marrow) and the potential for personalized targeted therapy in this patient cohort. Methods: In a multicenter retrospective study, clinical and genomic data were collected on EM-AML patients treated at Moffitt Cancer Center, Memorial Healthcare System, and University of Miami, as well as sequenced cases at a central laboratory. Next generation sequencing (NGS) data come from panels that interrogated 24- 406 genes, with 15 genes covered by all panels, including notably, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, and TP53. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox-regression were performed in SPSS (v.26). Results: Our study included 58 patients with EM-AML. Median age at diagnosis was 62 years; 55% of patients were males. In our cohort, 34 (59%) patients had MS, and 19 (33%) had LC. EM-AML was noted during relapse in 60% of evaluable patients (n=45), and 31% had isolated EM disease. Patients with LC had a significantly worse median overall survival (OS) than those with MS (5.7 months vs. 21.9 months, p= 0.008); Pattern of EM involvement (MS vs. LC) remained an independent prognostic factor for OS (p= 0.04) in a multivariate analysis including disease setting (new diagnosis vs. relapse) and ELN risk category. Results of NGS performed during EM presentation were available in 48 patients, 19 of which had NGS data from EM site. Most commonly mutated genes were NRAS on EM site NGS (37%) and NPM1 on non-EM site NGS (28%). Based on EM NGS, 52% patients had a targetable genomic alteration, with 37% mutations in IDH, 21% NPM1, 5% FLT3, and 11% MLL-PTD. Five (two with concurrent M+EM disease) out of nine evaluable patients had significant discordance in targetable mutations between EM and non-EM NGS at EM-AML. Three of four patients who received treatment with IDH1/2 inhibitors based on EM NGS achieved complete response. Conclusions: EM-AML has a distinct molecular architecture with an inferior OS in LC vs. MS patients. We conclude that EM site NGS is critical in patients with EM-AML, as 52% have potentially targetable mutations and could benefit from specific targeted therapies.[Table: see text]
CCND1 amplification profiling identifies a subtype of melanoma associated with poor survival and an immunosuppressive tumor microenvironment.
Authors: Yu Chen, Liu Jun, Jing Lin, Xuefeng Wang, Xiao-bin Zheng, Xuan Gao, Gang Chen, Jiani Xiong, Bin Lan, Chuan-ben Chen, Lu Si, Xuefeng Xia
Journal: Journal of Clinical Oncology (2021)

e21552 Background: Melanoma is generally regarded as an immunogenic type of tumor that will respond to immune checkpoint therapy. However, melanoma tumors with CCND1 amplification respond poorly to checkpoint therapy. Further understanding of how CCND1 amplification modifies the effect of checkpoint therapy is necessary to design future clinical trials. Methods: We used the data from the Geneplus Institute (n = 302), The Cancer Genome Atlas (TCGA) (n = 367),and the Memorial Sloan Kettering Cancer Center (MSKCC) (n = 350) to identify the incidence of CCND1 amplification and the relationship between CCND1 amplification and survival in melanoma patients and explored molecular mechanisms. Results: The frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations was low in these three cohorts. Data from TCGA did not show a statistically significant correlation between CCND1 amplification levels and prognosis of melanoma patients irrespective of immune checkpoint inhibitors (ICIs). In contrast, we found opposite results using the MSKCC cohort where CCND1 amplification was an unfavorable prognostic factor for melanoma patients. This was especially true for patients received ICIs who were harboring a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification were related to a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immunity boosting cells (follicular helper T-cells, naive B-cells, CD8+ T-cells). Furthermore, GSEA analysis from the TCGA database suggests that the signaling pathways such as oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we found that angiogenesis related molecules (HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) were remarkable decreased in a CCND1 High Amplification group from the TCGA database. Conclusions: Melanoma with CCND1 amplificationis an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Taken together, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, targeting oxidative and lipid metabolism pathway may be effective and promising therapeutic strategies for melanoma patients harboring CCND1 amplification.
Oncology trainees’ perceptions and knowledge of therapeutic cannabis use.
Authors: Poorva Bindal, Rushad Patell, Pavania Elavalakanar, Laura Dodge, Jason Freed, Deepa Rangachari, Mary K. Buss, Mara A. Schonberg, Ilana Braun
Journal: Journal of Clinical Oncology (2021)

11028 Background: Evidence shows that cancer patients are interested in learning about medicinal cannabis and frequently ask their oncologists for recommendations. To determine whether oncology training is adequately preparing physicians to address this topic, we conducted a national survey of oncology trainees to determine attitudes, practices, and knowledge about medical cannabis in cancer care. Methods: An interdisciplinary team developed an electronic questionnaire assessing trainees’ current practices regarding cannabis recommendations in cancer care and their knowledge of its effectiveness and risks compared with conventional care for cancer-related symptoms. We contacted 155 oncology training programs throughout the U.S. and asked that they distribute the survey to their trainees. Primary outcomes were: whether trainees reported discussing or recommending cannabis with/to patients and whether they felt sufficiently informed to make such recommendations. We presented data as proportions and used chi-square tests to compare proportions between groups. Results: Forty training programs from 25 states participated; of the 462 trainees in these programs, 187 completed surveys, yielding a response rate of 40%. Of the participants, 52% were female, 53% White, 33% Asian, and 5% Hispanic. One third (34%) graduated medical school before 2015, and 22% attended medical school outside the US. While 24% of trainees reported having received training regarding medical cannabis, only 12% felt sufficiently informed to make cannabis recommendations. Despite this, 91% reported having discussed cannabis with patients, and 58% reported recommending cannabis clinically to more than five patients in the prior year. Many viewed it as useful adjunctive therapy that was at least as effective as conventional treatments for: anorexia/cachexia (72%), nausea/vomiting (45%), and pain (41%). Over half (55%) believed that cannabis was beneficial to patients at the end of life; 31%, patients in active treatment; 11%, cancer survivors; 20%, the elderly with cancer and 16%, young adults with cancer. Peer-reviewed material (30%), lectures or webinars by another physician (29%), and patients and their families (22%) were the most commonly cited sources of information regarding medical cannabis. Oncologists who reported at least one area of focus as supportive/palliative care were more likely to feel sufficiently informed to make recommendations than oncologists without this focus (17% vs. 4%, P = 0.01); no other demographic or practice characteristics were associated with feeling sufficiently informed (all P &gt; 0.10). Conclusions: Although most oncology trainees discuss cannabis use with their patients, the majority do not feel sufficiently informed about its use in cancer care. This represents an unmet need in contemporary oncology training, trainee satisfaction, and patient care.
Single-cell transcriptomic analyses of cardiac immune cells reveal that Rel-driven CD72-positive macrophages induce cardiomyocyte injury
Authors: Shi-Hao Ni, Jin-Dong Xu, Shu-Ning Sun, Yue Li, Zheng Zhou, Huan Li, Xin Liu, Jian-Ping Deng, Yu-Sheng Huang, Zi-Xin Chen, Wen-Jun Feng, Jia-Jia Wang, Shao-Xiang Xian, Zhong-Qi Yang, Sheng Wang, Ling-Jun Wang, Lu Lu
Journal: Cardiovascular Research (2021)

The goal of our study was to investigate the heterogeneity of cardiac macrophages (CMφs) in mice with transverse aortic constriction (TAC) via single-cell sequencing and identify a subset of macrophages associated with heart injury.We selected all CMφs from CD45+ cells using single-cell mRNA sequencing data. Through dimension reduction, clustering, and enrichment analyses, CD72hi CMφs were identified as a subset of pro-inflammatory macrophages. The pseudo-time trajectory and ChIP-Seq analyses identified Rel as the key transcription factor that induces CD72hi CMφ differentiation. Rel KD and Rel-/- bone marrow chimaera mice subjected to TAC showed features of mitigated cardiac injury, including decreased levels of cytokines and ROS, which prohibited cardiomyocyte death. The transfer of adoptive Rel-overexpressing monocytes and CD72hi CMφ injection directly aggravated heart injury in the TAC model. The CD72hi macrophages also exerted pro-inflammatory and cardiac injury effects associated with myocardial infarction. In humans, patients with heart failure exhibit increased CD72hi CMφ levels following dilated cardiomyopathy and ischaemic cardiomyopathy.Bone marrow-derived, Rel-mediated CD72hi macrophages play a pro-inflammatory role, induce cardiac injury and, thus, may serve as a therapeutic target for multiple cardiovascular diseases.
Determining the cancer diagnostic interval using administrative data in a cohort of patients with pancreatic ductal adenocarcinoma (PDAC).
Authors: Bailey Paterson, Shiying Kong, Alyson Mahar, Colleen Webber, Richard M. Lee-Ying, Winson Y. Cheung, Patti Groome, Safiya Karim
Journal: Journal of Clinical Oncology (2021)

e13551 Background: PDAC is a leading cause of cancer death that is often diagnosed at an advanced stage. Population-based administrative data can be a valuable resource for studying the diagnostic interval, defined as the time from the first related healthcare encounter to cancer diagnosis. The objective of this study was to determine the diagnostic interval in a cohort of patients with PDAC using an empirical approach. Methods: This is a retrospective, cohort study of patients diagnosed with PDAC from 2007 – 2015 in Alberta, Canada. We used the Alberta Cancer Registry, physician billing claims, hospital discharge and emergency room visits to identify and categorize cancer-related healthcare encounters before diagnosis. We used statistical control charts to define the lookback period for each encounter category and used these lookback periods to identify the earliest encounter that represented the start of the diagnostic interval (index contact date). The end of the interval was the diagnosis date. Quantile regression was used to determine factors associated with the diagnostic interval. Results: We identified 3,142 patients with PDAC. Median age of diagnosis was 71 (IQR 61-80). We identified an index contact date and thus a diagnostic interval in 96.5% of patients. The median diagnostic interval length was 76 days (IQR 21-191; 90th percentile 276 days). A higher Elixhauser comorbidity score (+18.57 days/ 1 point increase, 95% CI 16.07-21.07, p&lt;0.001) and stage 3 disease compared to stage 2 disease (+22.55 days, 95% CI 5.02-40.08, p=0.01) were associated with a longer diagnostic interval. Conclusions: In this cohort of patients with PDAC, there was a wide range in the diagnostic interval with 10% of patients having a diagnostic interval of approximately 9 months. Diagnostic interval research using administrative databases can understand variations in diagnosis times and can inform early detection efforts by identifying where and in whom delays may occur.
Impact of lenvatinib (LEN) dose-intensity and starting dose on survival among patients with advanced hepatocellular carcinoma (HCC): Results from a Canadian multicenter database (HCC CHORD).
Authors: Carla Pires Amaro, Michael J Allen, Jennifer J. Knox, Erica S. Tsang, Howard John Lim, Richard M. Lee-Ying, Kelvin K. Chan, Jessica Qian, Brandon M. Meyers, Alia Thawer, Sulaiman Mohammed Saif Al-Saadi, Tina Hsu, Ravi Ramjeesingh, Hatim Karachiwala, Tasnima Abedin, Vincent C. Tam
Journal: Journal of Clinical Oncology (2021)

e16142 Background: The REFLECT trial established LEN as a first-line treatment option for HCC. However, decreased LEN exposure is common due to adverse events leading to dose reductions and treatment discontinuations. The aim of this study was to evaluate whether starting dose or dose-intensity of LEN affects survival. To our knowledge, this is the first study to examine dosing of LEN and survival in HCC patients treated outside of Asia. Methods: From July 2018 to December 2019, HCC patients treated with first-line LEN from 10 different Canadian cancer centers were included. Overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR) were retrospectively analyzed and compared across different mean dose-intensities (&gt; 66.7% vs &lt;=66.7%) and starting dose groups (Full vs reduced). Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models. DCR and ORR were determined radiographically according to the treating physician´s assessment in clinical notes and not RECIST 1.1 or mRECIST. Results: A total of 173 patients were included. Median age was 67 years, 77% were men and 23% East Asian. The most frequent causes of liver disease were hepatitis C (38%) and B (20%). 56% of patients received localized treatment prior to LEN. Of those, 24% had TACE, 6% TARE and 8% had liver transplant. Before starting LEN 31% of patients were ECOG 0 and 57% were ECOG 1. Most patients were Child-Pugh A (81%) and BCLC stage C (73%). Main portal vein invasion was present in 15% of the patients. Median follow-up was 4.5 months. LEN was started at full dose in 54% of patients and 60% had a mean dose intensity greater than 66.7%. ORR, PFS and OS results and their comparison between the different starting dose and dose-intensities are shown in the table. In a multivariate model that adjusted for age, gender, stage, ECOG, Child-Pugh, BCLC, cirrhosis, liver etiology disease (hepatitis B, C and non-viral), presence of tumor thrombus, prior transplant and localized treatment, dose intensity (&gt;66.7 vs &lt;=66.7% [HR 0.70, 95% CI 0.42-1.18; p=0.18]) was not a predictor of survival. Conclusions: In HCC patients starting LEN at a reduced dose does not appear to compromise survival. LEN dose-intensity of &gt; 66.7% was associated with improved survival, but not after controlling for potential confounders.[Table: see text]
Bone Marrow Stromal Cell Mediated Drug Resistance in AML Cells: Role of Extracellular Vesicles and AKT Signaling
Authors: Hamenth kumar Palani, Saravanan Ganesan, Nithya Balasundaram, Ansu Abu Alex, Sachin David, Uday Prakash Kulkarni, Alok Srivastava, Biju George, Poonkuzhali Balasubramanian, Vikram Mathews
Journal: Blood (2017)
HGG-42. PEDIATRIC H3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) SHOWS ROBUST RESPONSE TO IMIPRIDONE BASED COMBINATION THERAPY
Authors: Robyn Borsuk, Lanlan Zhou, Wen-i Chang, Yiqun Zhang, Varun Prabhu, Joshua Allen, Nikos Tapinos, Rishi Lulla, Wafik El-Deiry
Journal: Neuro-Oncology (2021)

Abstract ONC201 is a first-in-class small molecule imipridone therapy, which is known to selectively induce apoptosis of cancer cells independent of p53. This novel chemotherapeutic, as well as its analogs ONC206 and ONC212, has been shown to have potent preclinical efficacy against H3K27M mutant diffuse intrinsic pontine glioma (DIPG). We sought to identify synergy between imipridones and other FDA-approved chemotherapeutics. Seven patient-derived DIPG cell lines, six H3.3K27M mutant (SU-DIPG-IV, SU-DIPG-13, SU-DIPG-25, SUDIPG-27, SU-DIPG-29, SF8628), and one H3.1K27M mutant (SU-DIPG-36) were grown in culture and exposed to first and second generation imipridones, both as monotherapies and in combination with histone de-acetylase inhibitors [HDACi], Marizomib, Etoposide, and Temozolomide. A dose dependent response was demonstrated across all cell lines, with increased potency of ONC206 and ONC212 as compared to ONC201, with half maximal inhibitory concentration (IC50) of 0.11 µM, 0.03 µM, and 1.46 µM respectively. Strong synergy is demonstrated between ONC201 and Panobinostat with best combination index (CI) of 0.01. ONC201 similarly shows strong synergy with Romidepsin with best CI of 0.02, and Marizomib with best CI of 0.18. Combination of ONC201 and Etoposide or Entinostat shows some synergy, with best CI of 0.53 and 0.71 respectively. When combined with Temozolomide, some synergy is evident, however, there is overall poor efficacy, with lack of cell death even at the highest doses of Temozolomide. Second generation imipridones show a similar pattern of strong synergy with Panobinostat, Romidepsin, and Marizomib. Immunoblotting showed evidence of apoptosis, as measured by the induction of PARP cleavage, with a combination of imipridones and Panobinostat, as well as induction of integrated stress response with a combination of imipridones and Romidepsin. These results are indicative of promising synergy between imipridones and Panobinostat, Romidepsin, or Marizomib against H3K27M mutant DIPG, combinations which should be considered for future clinical trials.
Dynamics of the SARS-CoV-2 antibody response up to 10 months after infection
Authors: Hao Wang, Yu Yuan, Mingzhong Xiao, Li Chen, Youyun Zhao, None Haiwei Zhang, Pinpin Long, Yana Zhou, Xi Xu, Yanshou Lei, None Bihao Wu, Tingyue Diao, Hao Cai, Li Liu, Zuoyu Shao, Jingzhi Wang, Yansen Bai, Kai Wang, Miao Peng, Linlin Liu, Shi Han, Fanghua Mei, Kun Cai, Yake Lei, An Pan, Chaolong Wang, Rui Gong, Xiaodong Li, Tangchun Wu
Journal: Cellular and Molecular Immunology (2021)
Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve <i>ALK</i>-positive non-small cell lung cancer (<i>ALK</i>+ NSCLC).
Authors: Hiroshige Yoshioka, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Young Hak Kim, Koichi Azuma, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takuya Yoshimoto, Tomohide Tamura
Journal: Journal of Clinical Oncology (2021)

9022 Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) in Japanese patients randomized to the ALC, compared with those assigned in the CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p&lt;0·0001) by the Independent Review Facility (IRF) (Hida et al., Lancet 2017). The final PFS and 2nd overall survival (OS) interim analysis (IA) data were subsequently reported (Nakagawa et al., Lung cancer 2020). Here, we report the final OS data. Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (Japanese approved dose 300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. The primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 68.6 months in the ALC arm and 68.0 months in the CRZ arm, death events occurred in 40.8% and 39.4% in the ALC and the CRZ arms, respectively. Five-year survival rates for patients in the ALC and CRZ arm were 60.85% and 64.11%, respectively. The final OS HR was 1.03 (95%CI 0.67-1.58), however, median OS was not reached in either arm. Of note, patients in the CRZ arm tended to have their treatment switched earlier than those in the ALC arm (median time to treatment-switch: 12.3 months vs. NE). Most of the patients (78.8%) in the CRZ arm received ALC as a 1st subsequent therapy, whereas only 10.7% of patients in the ALC arm received CRZ. Conclusions: In this final J-ALEX OS analysis, prolongation of OS in the ALC arm was not observed compared to the CRZ arm. However, OS result may be substantially confounded since 78.8% of the patients in the CRZ arm received ALC as initial, subsequent therapy. Clinical trial information: 132316.
The impact of socioeconomic status on stage at presentation, receipt of diagnostic imaging, receipt of treatment, and overall survival in colorectal cancer patients.
Authors: Rajan Shah, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2021)

10565 Background: Socioeconomic factors have been identified to influence patterns of care in colorectal cancer yet current literature findings are sparse, conflicting, and often incomplete. As such, this study investigates the impact of socioeconomic status (SES) on stage at presentation, receipt of diagnostic imaging, receipt of treatment, and overall survival (OS) in a universal healthcare system. Methods: The Ontario Cancer Registry was accessed to identify a cohort of patients diagnosed with colorectal adenocarcinoma from 2007-2016 in Ontario, Canada. Linkage to administrative datasets allowed study of the impact of SES, measured by mean neighbourhood household income divided into quintiles (Q1-Q5; Q1 = lowest income), on stage, imaging, treatments, and OS. Multivariable regression analyses of all endpoints were adjusted for age, sex, comorbidity, and rurality with OS models also adjusting for imaging and treatment. Results: 39,802 colon and 13,164 rectal patients were identified. Lower SES patients were more likely to present at a higher stage in both cohorts. Lower SES colon patients were less likely to receive magnetic resonance imaging (MRI) of the abdomen, liver resection, adjuvant oxaliplatin, and all palliative systemic therapies studied. In rectal patients, lower SES was associated with decreased receipt of MRI pelvis, rectal cancer resection in early stages, adjuvant oxaliplatin, and most palliative chemotherapies studied. All OS models found that lower SES was associated with poorer OS. Conclusions: These findings suggest disparities across the continuum of cancer care persist even within a universal healthcare system. Further efforts should be directed towards temporal research, identifying barriers, and subsequently applying this information to actionable policies.