tbuckley/cabot-search huggingface dataset:
Gene expression signature after one dose of neoadjuvant pembrolizumab associated with tumor response in head and neck squamous cell carcinoma (HNSCC).
Authors: Eejung Kim, Sarah Palackdharry, Benyamin Yaniv, Jonathan Mark, Alice Tang, Keith Wilson, Yash Patil, Edith Janssen, Laura Conforti, Vinita Takiar, Benjamin Hinrichs, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2018)

6059 Background: Immune checkpoint inhibitors have been shown to induce durable tumor response in a subset of recurrent and/or metastatic HNSCC. Higher expression of PD-L1, INF-γ, and composite signatures such as "T cell-inflamed" profiles have been reported as biomarkers of response. However, prospective study of gene expression profiles after a single dose of Pembrolizumab compared to pre-treatment biopsy have not been reported. As a part of study "Phase II Investigation of Adjuvant Combined Cisplatin and Radiation with Pembrolizumab in Resected HNSCC" (NCT02641093), we have investigated gene expression changes associated with Pembrolizumab pathological response in HNSCC. Methods: Total RNA was extracted from 11 paired samples of pre- and post- one dose of Pembrolizumab. Total RNA was subjected to a hybridization-based digital counting assay (Nanostring®), which measures mRNAs of 770 immune-related genes and controls. RNA counts were normalized and log-transformed. Gene expression comparison analysis was performed between pre- and post- Pembrolizumab treatment and between five responders and six non-responders. Response was defined as more than 10% of pathologic treatment effect. Results: Higher expression of PD-L1, PD-L2, and INF-γ in pre-treatment samples were associated with tumor response after one dose of Pembrolizumab (Welch's t-test, p = 0.015, 0.021, 0.006). Existence of T cells, B cells, NK cells, macrophages, neutrophils in pre-treatment samples were not predictive with response. However, macrophages, T and B lymphocytes were increased in post-treatment samples of responders, implying that these were recruited effectors. There was no such difference in NK cells and neutrophils. INF-γ induced genes including CXCL9, OASL, IFI35, and IDO1 showed higher expression in responders (Welch's t-test p = 0.004, 0.005, 0.007, 0.01). Conclusions: Inflamed tumor microenvironment, evidenced by increased INF-γ irrespective of lymphocyte infiltration is associated with pathological response after a single dose of Pembrolizumab in HNSCC.
Association of anti-PD-1 (PD1) induced pneumonitis with persistent imaging and lung function abnormalities in some patients.
Authors: Douglas Buckner Johnson, Kevin B Taylor, Justine Vanessa Cohen, Noura Ayoubi, Daniel Ying Wang, Amber L Voorhees, Ryan J. Sullivan, Zeynep Eroglu, Richard Glenn Abramson
Journal: Journal of Clinical Oncology (2018)

e15147 Background: Pneumonitis may complicate PD1 therapy although overt clinical symptoms usually resolve with steroids. The long-term effects on respiratory function, however, are not well defined. Methods: We screened all melanoma patients (pts) treated with PD1 +/- ipilimumab (ipi) from 3 large centers to identify 31 pts with pneumonitis, defined by characteristic radiographic findings. We collected longitudinal symptomatic data, treatment, imaging results, and pulmonary function testing (PFT). Results: Among 3 centers, 31 pts had pneumonitis; median age (range) was 60 (35 – 82), 18 received PD1 monotherapy and 13 ipi + PD1. Median time to symptom onset was 5.7 mo from PD1 start (range 0.2 – 21.8 mo), whereas median time to imaging abnormalities occurred sooner at median 4.8 mo. 23 pts presented with respiratory symptoms whereas 8 were asymptomatic; 11 pts were hospitalized and all symptomatic pts received steroids. At a median of 22.1 mo follow-up, 28 pts (90%) had clinical resolution of symptoms; 3 pts had persistent dyspnea on exertion, cough, and wheezing, respectively. Among 27 pts with > 6 mo follow up, 12 (44%) had complete radiographic resolution, 11 (41%) had resolution of pneumonitis but had persistent scarring, and 4 (15%) had persistent or minimally improved groundglass opacities and/or nodular densities. Persistence (vs. resolution) of radiographic findings was not associated with initial need for hospitalization, symptomatic presentation, steroid dose, or PD1 regimen (ipi + PD1 vs. PD1). Among 4 pts with serial PFTs, lung function largely improved with time but two pts had persistent mild obstructive or restrictive abnormalities, including in one with persistent parenchymal scarring. Conclusions: Symptoms of PD1 induced pneumonitis resolved quickly and in almost all pts. Imaging abnormalities, however, typically improved but persistent scarring or inflammation was frequent. Further study of subclinical pulmonary effects of PD1 is needed.
Abstract 19696: Blood Pressure Homeostasis and Renal Function Depends on Normal c-myb Activity in Bone Marrow-Derived Cells
Authors: Eric A Shikatani, Andrew Levy, Rickvinder Besla, Abdul Momen, Hangjun Zhang, Michelle Chen, Craig Simmons, Phyllis Billia, Clinton Robbins, Scott Heximer, James Scholey, Steffen-Sebastian Bolz, Mansoor Husain
Journal: Circulation (2016)

Objective: We showed that the proto-oncogene c-myb regulates proliferation and differentiation of vascular smooth muscle cells (VSMCs) from specific adult vessel-resident progenitors and embryonic stem cells, however it was not known if c-Myb also regulates contractile function of VSMCs and integrated cardiovascular physiology. Approach and Results: Mice homozygous for a hypomorphic c-myb allele with compromised c-Myb activity (hh) were compared to wild-type (WT). Hemodynamic assessments revealed decreased systolic (104±2 vs. 120±1 mmHg; P < 0.0001) and diastolic (71±2 vs. 83±1 mmHg; P < 0.001) blood pressure (BP) in hh compared to WT mice, which was confirmed by radiotelemetry in awake mice. Echocardiography found no differences in cardiac structure or function, and perfusion myography showed no defects in contractile function of hh arteries. Differences in plasma cytokines and biochemistry were observed. While plasma keratinocyte chemokine (KC) was elevated in hh mice, osmotic pump infusion of KC did no...
Patient-reported distress in myelodysplastic syndromes and its relationship with clinical outcomes.
Authors: Jesse D Troy, Carlos deCastro, Mary Ruth Pupa, Greg P. Samsa, Amy Pickar Abernethy, Thomas William LeBlanc
Journal: Journal of Clinical Oncology (2017)

e21564 Background: The National Comprehensive Cancer Network (NCCN) defines distress as an unpleasant emotional experience associated with the psychosocial complications of cancer. Patients with myelodysplastic syndromes (MDS) are at risk for distress given the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress from ambulatory adult MDS patients visiting a single tertiary care medical center from July 2013-Sept 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with the NCCN Distress Thermometer (DT) and Problem List (PL). Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression, controlling for age and risk stratification at diagnosis (Low or Intermediate/High Risk by IPSS, IPSS-R, or WPSS), ever use of therapy (hypomethylating agents/lenalidomide/growth factors/transfusions/chelation), Charlson comorbidity score, ever-report of fatigue, and frequency of fatigue. Results: We abstracted 376 DT (median = 1, range = 0-10) from 606 visits and 110 patients (median = 2 DT/patient, range = 1-16). NCCN guidelines suggest DT &gt; = 4 should be evaluated for referral to specialty services to address unmet needs. Fifty-four patients (49%) had at least 1 DT &gt; = 4 and 20 (18%) had 2 or more DT &gt; = 4. Ninety-eight patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median = 4 problems/patient/visit, range = 1-23). The 5 most frequent were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification, a single-point increase on the DT was associated with an increased risk of death (HR = 1.18, 95% confidence interval: 1.01, 1.36). Conclusions: The distress burden is high inMDS, and patient-reported distress scores are associated with clinical outcomes after controlling for typical prognostic variables. Distress should be further studied as a marker of prognosis and of unmet needs in this population.
Opioid Use After Open Resection or Video-Assisted Thoracoscopic Surgery for Early-Stage Lung Cancer
Authors: Stephanie Tuminello, Rebecca M Schwartz, Bian Liu, Grace Mhango, Juan Wisnivesky, Raja Flores, Emanuela Taioli
Journal: JAMA Oncology (2018)

small cell lung cancer, both scoring 4 on the ESMO-MCBS scale.Of the remaining single-arm trials, 8 (29.6%) scored 3, 8 (29.6%) scored 2, 5 (18.5%) scored 1 and 4 trials (14.8%) scored 0.Discussion | The observation of common and durable response to targeted therapy and immunotherapy has raised questions about whether traditional randomized trials are necessary to support drug approval. 6 The ability to study a drug's ORR, especially in clearly defined target populations, makes the singlearm study design appealing as a pathway to approval.The ability to identify target populations has been aided by increasing understanding of the molecular basis of cancer, which has allowed anatomically defined cancers to be subdivided into smaller, molecularly defined subtypes more likely to respond to targeted therapies.Our data confirm that ORR is a common end point in single-arm studies supporting accelerated approval of anticancer therapies.However, a small proportion of single-arm studies met the threshold for substantial clinical benefit defined by ESMO-MCBS, version 1.1.These results are unsurprising because, to meet substantial benefit thresholds using the ESMO-MCBS, a single-arm trial must show substantial efficacy as well as improvement in quality of life or have data from confirmatory postmarketing study.The low proportion of single-arm trials that meet the threshold for substantial benefit may reflect a lack of supporting data or unrealistic thresholds in the ESMO framework.In conclusion, approximately one-third of trials supporting FDA drug approval meet the threshold for substantial clinical benefit as measured by ESMO-MCBS.Compared with RCTs, approvals supported by single-arm studies are less likely to show substantial benefit using ESMO-MCBS.It is likely that this reflects the high thresholds for substantial benefit used to calibrate the ESMO-MCBS for single-arm trials.
First comprehensive report of impact of genomic alterations, chemotherapy, targeted therapy and immunotherapy on outcomes in the genomics driven squamous master protocol LungMAP.
Authors: Vassiliki Papadimitrakopoulou, Mary Weber Redman, David R. Gandara, Fred R. Hirsch, Philip C. Mack, Corey J. Langer, Martin J. Edelman, Charu Aggarwal, Mark A. Socinski, Scott N. Gettinger, Saiama Naheed Waqar, Katie Griffin, Natasha B. Leighl, Taofeek Kunle Owonikoko, Jeffrey D. Bradley, Suresh S. Ramalingam, Tom Stinchcombe, Charles David Blanke, Karen Kelly, Roy S. Herbst
Journal: Journal of Clinical Oncology (2018)

9019 Background: Lung-MAP (S1400) is an umbrella protocol for genomic screening of previously treated squamous cell lung cancer patients and evaluation of targeted therapies in biomarker-matched groups and immunotherapy in patients without putative drivers. The protocol opened on June 16, 2014. Nine sub-studies have activated; the original 5 are closed, 4 are currently accruing. Methods: Tumor samples are analyzed by FoundationOne NGS assay. Completed studies evaluated taselisib (T) for PI3K mutations, palbociclib(P) for cell cycle gene alterations (CCGA), AZD4547(A) for FGFR alterations, rilotumumab and erlotinib(RE) for c-MET positive tumors, and durvalumab(Dur) . Originally including randomization to docetaxel(Doc), the studies were amended to single-arm phase 2 . Outcomes by treatment and biomarkers were assessed using a Cox model adjusting for performance status, lines of therapy, age, and gender. Prognosis of biomarkers was evaluated from time of study assignment. Results: As of January 5, 2018, 1407 patients registered to screening, 1244 with biomarker results and 529 patients have registered to a sub-study. Fifty-six eligible patients registered to Doc, 66 to Dur, and 90 to a targeted therapy arm (25 to A, 31 to P, 26 to T, 5 to E, 3 to RE). Relative to the Doc (median = 7.6 months(m)), overall survival was better for Dur (HR [95%CI]: 0.63 [0.42-0.96], median = 11.6 m). There was no significant difference with targeted therapy versus Doc (HR [95%CI]:1.05 [0.68-1.65], median = 7.0 m). FGFR alterations may be associated with worse prognosis (p = 0.06). Clinical trial information: NCT02154490. Conclusions: The outcomes with targeted therapies in these genomically complex tumors suggest limited efficacy and support the efficacy of immunotherapy. FGFR alterations are associated with poor survival. Continued evaluation of novel targets and therapeutics including immunotherapy within LungMAP are planned. Biomarker Prevalence Biomarker + (Median in months) Biomarker - (Median in months) HR [95% CI], p-value PI3K 8% 6.7 6.8 1.0 [0.78-1.29], 0.88 CCGA 19% 6.6 6.9 1.03 [0.85-1.24], 0.81 FGFR 16% 5.4 7.0 1.20 [0.99-1.46], 0.06
Intra-tumour heterogeneity in the regulation of immune-tolerogenic pathways in primary and metastatic hepatocellular carcinoma (HCC).
Authors: David James Pinato, Stephane Victor, Paolo Spina, Pritesh Trivedi, Mario Pirisi, Michela Burlone, James M Black, Rosalba Minisini, Monica Leutner, Renzo Boldorini, Francesco A Mauri, Rohini Sharma
Journal: Journal of Clinical Oncology (2017)

e14614 Background: Anti-PD-1/PD-L1 checkpoint inhibitors have shown preliminary evidence of activity in HCC. PD-L1 status is a putative predictor of response, however PD ligands expression can be heterogeneous across sampled sites, with implications in the development of immunotherapy. Methods: We constructed a tissue microarray from 77 patients: 56 with surgically resected and 21 with intermediate/advanced HCC in whom 20 matching metastases were also available. Tumour and surrounding cirrhosis were analysed for PD-L1 and PD-L2 expression by immunohistochemistry. FFPE-extracted RNA was analyzed on the NanoString nCounter system using 12 paired primary/metastatic HCC cores from 6 patients, with validation in a subset of further 24 specimens. Results: Surgically resected cases were Child A (51/56, 91%), BCLC A (45/56, 80%). In resected tumour cores 11/56 (20%) were PD-L1 and 18/56 (32%) were PD-L2 positive. Surrounding cirrhotic liver revealed PD-L1 in the lymphocytic infiltrate in 8/56 samples (14%), whilst PD-L2 expression was found in the cirrhotic background in 29/56 cases (52%). PD-L2 expression in cirrhotic (p = 0.03) but not in tumour cores (p = 0.13) correlated with more advanced BCLC stage. In patients with intermediate-advanced HCC (n = 21), the prevalence of tumour PD-Ls expression was 40% (8/21) for both markers. Concordance between PD-L1 positive primary and metastases was 33% and 85% in PD-L1 negative tumours. In contrast, there was universal concordance between in PD-L2 expression between primary and metastatic HCC (p &lt; 0.001). Targeted transcriptomic profiling revealed a subset of 40 genes involved in innate and adaptive immunity to be differentially regulated across primary and metastatic disease. Conclusions: Intra-tumour heterogeneity in the expression of PD-L1 is common in HCC, whilst PD-L2 is homogeneously distributed in primary and metastatic deposits. Unsupervised transcriptomic profiling confirms differential activation of innate and adaptive immune-related pathways in the metastatic dissemination of liver cancer. This has profound implications in the clinical development of immune response biomarkers in HCC.
TCT-505 Temporal changes of stent apposition immediately after stent deployment using optical coherence tomography
Authors: Hyuck Jun Yoon, Seung-Ho Hur, Yun-Kyeong Cho, Chang-Wook Nam, Sang-Woong Choi, Jun-Hyok Oh, Cheol Hyun Lee, In-Cheol Kim, Hyungseop Kim, Hyoung-Seob Park
Journal: Journal of the American College of Cardiology (2018)
The effect of acupuncture versus cognitive behavior therapy on insomnia in cancer survivors: A randomized clinical trial.
Authors: Jun J. Mao, Sharon Xie, Katherine Duhamel, Ting Bao, Philip W. Kantoff, Qing Susan Li, Frances Barg, Sarah Song, Philip Gehrman, Sheila N. Garland
Journal: Journal of Clinical Oncology (2018)

10001 Background: Insomnia is a common and debilitating disorder experienced by up to 60% of cancer survivors. We evaluated the effectiveness of acupuncture versus cognitive behavior therapy for insomnia (CBT-I). Methods: We conducted a randomized clinical trial of acupuncture vs. CBT-I among 160 post-treatment cancer survivors with clinically diagnosed insomnia disorder. Acupuncture involved stimulating body points with needles. CBT-I included sleep restriction, stimulus control, cognitive restructuring, relaxation training, and education. The intervention duration was eight weeks (primary end point) with a follow up assessment at 20 weeks. Insomnia severity, measured by the Insomnia Severity Index, was the primary outcome. Results: The mean age of participants was 61.5 years, 57% (n = 91) were women, and 29.4% (n = 47) were non-white. At the end of treatment, acupuncture reduced insomnia severity by 8.3 points (95% CI 7.3-9.4), compared to 10.9 points (95% CI 9.8-12.0) for CBT-I, with CBT-I being the more effective treatment overall (2.6, 95% CI 1.1 – 4.1, P = 0.0007). Patients with mild insomnia were significantly more likely to respond to CBT-I than acupuncture (85% vs. 18%, p < 0.0001); however, patients with moderate to severe insomnia had similar response rates to CBT-I and acupuncture (75% vs. 66%, p = 0.26). Both groups had few mild adverse events and maintained improvements up to 20 weeks. Both groups also had similar improvement in quality of life in physical health (p = 0.46) and mental health (p = 0.44) during the study. Conclusions: While both acupuncture and CBT-I resulted in clinically meaningful and durable effects among cancer survivors with insomnia, CBT-I was more effective, especially among patients with mild insomnia symptoms. Patients and oncology clinicians can use these findings to inform their choice of insomnia treatment. Clinical trial information: NCT02356575.
Identifying patient-specific neoepitopes for cell-based and vaccine immunotherapy targets in breast cancer patients by HLA typing and predicting MHC presentation from whole genome and RNA sequencing data.
Authors: Andrew Nguyen, John Z Sanborn, Charles Joseph Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong, Stephen Charles Benz
Journal: Journal of Clinical Oncology (2016)

11606 Background: Anti-HER2 therapies have demonstrated success in improving the outcomes of patients (pts) with HER2-positive breast cancer; however, a high proportion of pts either do not respond to treatment or develop resistance to these agents. We developed an informatics platform that establishes HLA typing and predicts MHC presentation from whole genome sequencing (WGS) and RNA sequencing (RNAseq) data to identify neoepitopes among pts with HER2-positive breast cancer. Our platform provides a foundation for the development of next-generation, pt-specific cancer cell-based and vaccine immunotherapies. Methods: WGS and RNAseq data from The Cancer Genome Atlas (TCGA) were available for 19 HER2-positive breast cancer pts. Neoepitopes were identified by creating all permutations of 9-mer amino acid strings derived from identified single nucleotide variants and were filtered against all possible 9-mer peptide sequences created from every known human gene. In silico HLA typing was determined from WGS and RNAseq data using the HLA forest algorithm. NetMHC 3.4 was used to obtain the predicted binding affinities of neoepitopes to HLA alleles. Results: The numbers of predicted neoepitopes identified by WGS, neoepitopes expressed per RNAseq, and neoepitopes having binding affinity to any of the pts’ MHC class 1 HLA alleles were 10434, 5332, and 560, respectively, equivalent to an average of 9.8 high-quality neoepitopes per sample. The majority of neoepitopes were unique to each pt, with only 1 that was shared between 2 pts. Across all HER2-positive breast cancers, ~6% of neoepitopes occurred in cancer driver genes.Conclusions: We discovered that the majority of neoepitopes among pts with HER2-positive breast cancer were unique to each pt. For pts who do not respond to HER2-targeted agents, high-throughput identification of neoepitopes could serve as the basis for the development of pt-specific, cell-based and vaccine immunotherapies. Regardless of biomarker status or tissue of origin, all cancer pts may benefit from neoepitope-based immunotherapies.
TCT-763 Comparative Analysis Evaluating Imaging Modalities for Aortic Annulus Sizing and a Proposed New Technique Utilizing Three-Dimensional Trans-Esophageal Echocardiography: A Prospective, Blinded Study
Authors: Mohamad Lazkani, Michael Morris, Divya Ratan Verma, H. Kenith Fang, Philipp Blanke, Kapilan Selvakumar, Richard Gerkin, Ashish Pershad, Jonathon Leipsic, George Gellert
Journal: Journal of the American College of Cardiology (2018)
TCT-534 Clinical impacts of periprocedural myocardial injury after transcatheter aortic valve replacement
Authors: Hanbit Park, Sang Yong Om, Yong-Hoon Yoon, Minsoo Kim, Sang-Cheol Cho, Sangwoo Park, Tae oh Kim, Sun Hack Lee, Osung Kwon, Kyusup Lee, Do-yoon Kang, Pil Hyung Lee, Jung-Min Ahn, Soo-Jin Kang, Duk-Woo Park, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)