tbuckley/cabot-search huggingface dataset:
Preclinical assessment of PM21-particle expanded natural killer cells for ovarian cancer treatment.
Authors: Jeremiah Oyer, Sarah B. Gitto, Deborah Altomare, Dean A. Lee, Alicja Copik
Journal: Journal of Clinical Oncology (2017)

127 Background: Ovarian cancer has high recurrence rate and could benefit from immunotherapy with NK cells. A necessity for NK cell therapy is an efficient way to generate high doses of NK cells. The best method currently used in clinical trials is ex vivo NK cell expansion by co-culture with K562 CML cells, modified to express 41-BBL and membrane bound IL21 (K562.mb21). However feeder cell based methods are limited to ex vivo co-culture, difficult to disseminate, and not allowed in many jurisdictions. To overcome these limitations and to further improve NK cell therapy, we developed a feeder cell free particle based method for NK cell stimulation. These particles (PM21) are nano-scale, made from cell membranes of K562.mb21 cells, and efficiently stimulate NK cell expansion (mean 825 fold in 14 days, range 163–2216, n = 13). Methods: PM21 particles were prepared from K562.mb21 cells with a procedure developed by our group. NK cells were expanded by culturing CD3 depleted PBMCs with PM21 particles or by co-culture with K562.mb21 cells for 14 days as previously described. NSG mice ( ≥ 8 per group) were implanted ip with 1 x 10 6 SKOV3 ovarian tumor cells, seeded 8 days, and then treated with vehicle or NK cells expanded with PM21 or K562.mb21 cells (two doses of 10 x 10 6 , injected 6 days apart), with or without in vivo administration of PM21 particles (600 µg, 3x weekly), and IL2 (25 KU, 3x weekly), all delivered ip. Survival analysis was performed with log rank (Mantel-Cox) test. Results: Treatment of SKOV3 engrafted NSG mice with NK cells, expanded with K562.mb21 cells or with PM21 particles, allowed significant ( &lt; 0.0001) 10 day increase in survival compared to untreated animals that succumbed on average 21 days after start of treatment. Administration of ip PM21 particles enhanced survival by 5 days (p = 0.056) over no in vivo PM21 groups. Conclusions: NK cells prepared with PM21 particles or with K562.mb21 cells are equivalent in anti-SKOV3 efficacy and in vivo application of PM21 particles provides further benefit. Clinical translation is underway and clinical trials are being planned. PM21 particles can be the next step in development of NK cell therapy for enhancing both efficacy and dissemination of NK cell therapeutics for ovarian cancer.
163P The influence of 2nd and 3rd generation TKI in EGFR mt+ and ALK+ patients on OS and PFS: Results of the NOWEL network
Authors: J. Roeper, M. Netchaeva, A. Lueers, M. Falk, M. Tiemann, C. Wesseler, G. Wiest, S. Sackmann, D. Ukena, F. Griesinger
Journal: Journal of Thoracic Oncology (2018)
Factors Associated With Response to Placebo in Patients With Irritable Bowel Syndrome and Constipation
Authors: Sarah Ballou, Alissa Beath, Ted J. Kaptchuk, William Hirsch, Thomas Sommers, Judy Nee, Johanna Iturrino, Vikram Rangan, Prashant Singh, Mike Jones, Anthony Lembo
Journal: Clinical Gastroenterology and Hepatology (2018)
95P Intubated versus non-intubated general anesthesia for minimally invasive video-assisted thoracic surgery (VATS) in octogenarians
Authors: N. Ilic, D. Ilic, J. Juricic, D. Krnic, N. Frleta Ilic, I. Simundza, D. Orsulic
Journal: Journal of Thoracic Oncology (2018)
Molecular profiling of circulating tumor cells in non-metastatic breast cancer.
Authors: Victoria Forte, Weizhu Zhu, Dany Barrak, Alexander Ring, Vasu Punj, Debu Tripathy, Min Yu, Akshara Raghavendra, Gloria Yang, Julie E. Lang
Journal: Journal of Clinical Oncology (2015)

11028 Background: Circulating tumor cells are prognostic in all stages of breast cancer (BC), yet few studies have examined their molecular biology in non-metastatic BC. We have previously reported a method for isolation and gene expression profiling of pure CTCs that permits gene expression profiling without background subtraction of leukocytes. We hypothesized that transcriptional profiling of CTCs prior to therapy may predict for pathologic complete response (pCR) to neoadjuvant chemotherapy (NC) in Stage II-III breast cancer. Methods: We are currently enrolling patients to a prospective, observational clinical study in which CTCs are enumerated and captured from 20 mL peripheral blood (PB) via immunomagnetic enrichment based on EpCAM followed by fluorescence-activated cell sorting (IE-FACS). CTCs and tumors are profiled with RNA Seq via the Illumina HiSeq (primary predictor); NanoString PAM50 and real-time polymerase chain reaction will be used as validation studies. Results: To date, we have isolated CTCs from 29/33 patients (88%). No CTCs were found in 23 healthy controls. The median number of CTCs isolated was 7 (range 0-65). We will analyze our primary endpoint when n = 20 and n = 40 NC treated patients. Currently 12/33 patients had NC and 21 had no NC; 10/12 patients had CTCs isolated and 5/10 patients had a pCR. RNA Seq of the first 17 patients CTCs shows clear differentiation between CTCs and PB with 253 differentially expressed genes with a fold-change of at least 2 (false-discovery rate adjusted p < 0.001). A gene set enrichment analysis of the 17 CTC samples demonstrated up-regulation of cancer related pathways (p < 0.001). RNA Seq and validation studies of additional CTC and tumor samples is currently in progress. Conclusions: RNA Seq of rare CTCs is feasible in Stage II-III breast cancer and shows evidence of oncogenes and tumor suppressor genes.
T cell–induced CSF1 promotes melanoma resistance to PD1 blockade
Authors: Natalie J. Neubert, Martina Schmittnaegel, Natacha Bordry, Sina Nassiri, Noémie Wald, Christophe Martignier, Laure Tillé, Krisztian Homicsko, William Damsky, Hélène Maby-El Hajjami, Irina Klaman, Esther Danenberg, Kalliopi Ioannidou, Lana Kandalaft, George Coukos, Sabine Hoves, Carola H. Ries, Silvia A. Fuertes Marraco, Periklis G. Foukas, Michele De Palma, Daniel E. Speiser
Journal: Science Translational Medicine (2018)

T cells promote immunosuppression in melanoma through CSF1 induction and macrophage recruitment.
Synergistic effect of reirradiation and PD-1 inhibitors in recurrent high-grade gliomas.
Authors: Fabio Massaiti Iwamoto, Laura Donovan, Lauren R. Schaff, Tony J. C. Wang, Andrew B. Lassman
Journal: Journal of Clinical Oncology (2017)

105 Background: To date, studies of single agent PD-1 or PDL-1 inhibitors in recurrent high-grade gliomas (HGG) have shown infrequent responses ( &lt; 10%) and limited efficacy. Reirradiation is considered one of the standard salvage regimens for selected patients with recurrent gliomas but tumor responses are also infrequent ( &lt; 5%). Radiotherapy counteracts the immunosuppressive tumor microenvironment by increasing MHC class I expression and enhancing tumor neoantigen presentation and has a significant synergistic effect with PD-1 inhibition in preclinical models of glioma. Methods: From December 2014 to June 2016, 20 patients (14 men, 6 women) with recurrent HGG were treated with the combination of reirradiation and PD-1 inhibitors. 18 patients had a glioblastoma, 1 anaplastic astrocytoma and 1 anaplastic oligodendroglioma. The median KPS at the start of this regimen was 70 (50 to 80). The median number of prior treatments for recurrent tumor was 2 (1-4), 100% had prior radaition, 95% prior temozolomide and 55% prior bevacizumab. 8 patients received pembrolizumab (2 mg/Kg every 3 weeks) and 12 patients received nivolumab (3 mg/Kg or 240 mg flat dose every 2 weeks). Median reirradiation dose was 35 Gy (12 Gy to 35 Gy). Results: There were 7 confirmed partial responses (35% objective response rate, ORR), 5 stable disease and 8 progressive disease. The median duration of response was 5 months (2.2 to 10+ months). Median PFS was 4 months and median OS was 10 months. Most common side effects were increased ALT (3 patients) and fatigue (2 patients). There was no obvious case of cerebral edema related to treatment. 5 patients required a mild increase of dexamethasone (2-4 mg) and all other 15 patients had decreased or stable dexamethasone dosage after the reirradiation. Conclusions: PD-1 inhibitors in combination with re-irradiation can be administered safely to patients with recurrent HGG. The ORR of 35% is an early signal of the potential synergist effect of the combination of PD-1 inhibitors with re-irradiation in HGG. This retrospective analysis of a heavily pre-treated population of recurrent HGG showed significantly higher ORR than either PD-1 inhibitors or re-irradiation alone. A clinical trial under development to test this hypothesis.
Preliminary results from a phase II study of nivolumab for patients with metastatic adrenocortical carcinoma (ACC).
Authors: Ludimila Cavalcante, Benedito A. Carneiro, Ricardo Lima Barros Costa, Young Kwang Chae, Alfred Rademaker, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

96 Background: ACC is an exceedingly rare malignancy with an estimated incidence of 0.7 cases per million per year. Patients presenting with metastatic disease have an estimated 5-year survival rate of &lt; 15%, without effective standard treatment options. Immunotherapy approaches such as checkpoint inhibitors have emerged as effective therapies for multiple malignancies. Nivolumab, a monoclonal IgG4 antibody against the programmed death-1 (PD-1) receptor on T-cells, acts by inhibiting the interaction with PD-L1 and PD-L2 and thus eliciting an increased anti-tumor immune response. This phase II study will assess the efficacy of nivolumab monotherapy according to objective response rate (ORR) in patients with advanced ACC – the study is currently in the patient enrollment phase. Methods: Patients with metastatic or locally advanced ACC with disease progression after treatment with ≥ 1 line of therapy (including mitotane and/or chemotherapy), or not eligible for first-line chemotherapy are currently being enrolled on this phase II study. Nivolumab is given at a fixed dose of 240mg IV q2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. Planned accrual of up to 33 patients will follow a Simon two stage design with interim analysis for efficacy after 10 evaluable patients are enrolled. Results: This is an initial report of the first 7 evaluable patients enrolled on study. Median age 57 years; female (4/7); endocrine hyperfunction (2/7); prior chemotherapy with EDP +/- mitotane (5/7). Patients were treated with a median of 4 doses of nivolumab. Median time to progression of 8 weeks. Best overall response rate thus far has been progression of disease in 5 pts, with 2 pts pending evaluation. Grade 3 or 4 adverse events (AEs) at least possibly related to nivolumab: tremor, hypokalemia (1 pt each). Reported grade 1 and 2 AEs: LFT elevation (3 pts), lower extremity edema (2 pts), lymphopenia, urinary frequency and fatigue (1 pt each). Conclusions: Nivolumab has been well tolerated in this population of patients with metastatic ACC. Clinical trial information: NCT02720484.
Distinct Patterns of Selection in Selenium-Dependent Genes between Land and Aquatic Vertebrates
Authors: Gaurab K Sarangi, Frédéric Romagné, Sergi Castellano
Journal: Molecular Biology and Evolution (2018)

Selenium (Se), a sparse element on earth, is an essential micronutrient in the vertebrate diet and its intake depends on its content in soils and waters worldwide. Selenium is required due to its function in selenoproteins, which contain selenocysteine (Sec), the 21st amino acid in the genetic code, as one of their constituent residues. Selenocysteine is analogous to the amino acid cysteine (Cys), which uses the abounding element sulfur instead. Despite the irregular distribution of Se worldwide, its distinct biochemical properties have made the substitution of Sec for Cys rare in vertebrate proteins. Still, vertebrates inhabited environments with different amounts of Se and may have distinctly adapted to it. To address this question, we compared the evolutionary forces acting on the coding sequences of selenoprotein genes and genes that regulate Se between vertebrate clades and between the Se-dependent genes and their paralogs with Cys. We find that the strength of natural selection in genes that use or regulate Se is distinct between land vertebrates and teleost fishes and more variable than in the Cys paralogs, particularly in genes involved in the preferential supply of Se to some organs and the tissue-specific expression of selenoproteins. This is compatible with vertebrates adapting to Se scarcity in land and its abundance in waters. In agreement, teleost fishes duplicated and subfunctionalized or neofunctionalized selenoprotein genes and maintained their capacity for Se transport in the body, which declined (under neutrality) for millions of years in terrestrial vertebrates. Dietary Se has thus distinctly shaped vertebrate evolution.
Changes in the quality of life of advanced melanoma patients after 12 weeks of treatment with ipilimumab compared to gp100 in a phase III clinical trial.
Authors: Becca Harvey, Dawn Lee, Anne-Francoise Gaudin, Beatrice Gueron, Bruno Bregman, Céleste Lebbé, Isabelle Borget
Journal: Journal of Clinical Oncology (2013)

9084 Background: This study analyses health-related quality of life (HRQL) outcomes for ipilimumab (ipi) with and without gp100 and gp100 alone during the 12 week treatment (T) induction period compared to baseline. The aim of this study was to express the HRQL as proportions of patients experiencing changes during the induction period, when most of the immune-related adverse events (ir-AE) on ipi occur. Methods: Data from the MDX010-20 trial, including 676 previously treated patients (pts) with unresectable stage III or IV melanoma, was analysed. Differences between ipi with/without gp100 and gp100 alone in terms of HRQL 12 weeks after randomisation according to the EORTC QLQ-C30 were searched for. The sample consisted of 388 pts (ipi: 83; ipi + gp100: 227; gp100: 78) completing both baseline and week (W)12 questionnaires. Ordinal regression was performed for these pts to determine a T effect on W12 scores (in ordered categories) whilst adjusting for key covariates. Fisher’s Exact Test was used to detect differences between Ts for each EORTC domain when considering mean change in scores, categorised as “clinically worse” (≤-10 on functional domains, ≥10 on symptoms), “stable” (&gt;-10 to &lt;10) and “clinically improved” (≥10 on functional domains, ≤-10 on symptoms). Results: There were no significant differences for any domain score between the 3 T arms at W12. The odds of attaining high HRQL scores at W12 were heavily dependent on the baseline scores; baseline scores explained most of the variability as per regression analysis. There was no significant difference between the 3 T arms in terms of pts showing a clinically significant reduction or improvement in HRQL. HRQL remained globally stable from baseline to W12, in &gt; 50% of pts for most domains. Conclusions: Ipi with/without gp100 does not have a significant negative HRQL impact in stage III-IV melanoma during the T induction phase relative to gp100 alone after adjustment for differences in baseline scores. The lower rate of pts showing HQRL reduction and the absence of difference with gp100 suggest that ir-AE have little impact on HRQL. Further HRQL studies are needed, as efficacy benefits of ipi continue after W12.
Gene expression signatures of response to anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in patients with CLL and ALL.
Authors: Elena Orlando, Rebecca Leary, Simon F. Lacey, Joseph Fraietta, Felipe Bedoya, David Ambrose, Nicholas Wilcox, Shannon L. Maude, Noelle V. Frey, Bruce L Levine, Stephan A. Grupp, David L. Porter, Regina Young, Wendy Winckler, Michael Morrissey, Carl H. June, Jan Joseph Melenhorst, Jennifer Brogdon, Hans Bitter
Journal: Journal of Clinical Oncology (2017)

137 Background: The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3ζ-signaling CAR (CTL019) has shown remarkable activity and induces long-term remissions in a subset of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). In ALL, CTL019 induces a complete response (CR) in over 90% of patients while in CLL 25% of patients obtain a CR. It is not fully understood why only certain patients respond to therapy. Methods: We employed next generation sequencing of RNA (RNAseq) to identify predictive indicators of response to CTL019. We performed RNAseq on leukapheresis and manufactured product T cells prior to re-infusion from 35 CLL and 7 pediatric ALL patients with heavily pre-treated and high-risk disease. To characterize potency, we performed RNAseq on the infusion product after stimulation with the CAR. Results: We find that durable remission in CLL is associated with gene expression signatures of early memory and T-effector cells, while T cells from non-responding patients are enriched in signatures of T-regulatory cells, terminal differentiation, and exhaustion. In following the results from CLL, we find that pediatric ALL manufactured T cells are significantly enriched for an early memory, naïve T cell state and all achieved a CR. In parallel in vitro experiments, stimulation of the infusion product further demonstrated that CTL019 cells from CRs have an increased capacity for activation upon stimulation. We tested if we could extend these observations to identify a phenotype of T cells that is predictive of response prior to CTL019 manufacturing and find that the signatures predictive of response at the pre-infusion stage are also observed at the earlier leukapheresis time point. Conclusions: These findings suggest that intrinsic T cell fitness dictates response to CAR T cells. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to adoptive transfer strategies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products. Clinical trial information: NCT01029366, NCT01747486, NCT01626495.
Multiplatform Genomic Roadmap of Hepatocellular Carcinoma: A Matter of Molecular Heterogeneity
Authors: Hyun Goo Woo, Yoon Jun Kim
Journal: Hepatology (2018)

Woo, Hyun Goo M.D., Ph.D.; Kim, Yoon Jun M.D., Ph.D.Editor(s): Corey, Kathleen E.4; Malhi, Harmeet5 Author Information
41P Gender based variations in presentation and management of lung cancer at a south Asian tertiary referral centre
Authors: V. Vashistha, C. Choudhari, A. Garg, A. Gupta, G. Parthasarathy, C. Mohan, K. Madan, V. Hadda, G.C. Khilnani, A. Mohan
Journal: Journal of Thoracic Oncology (2018)
Fracking and Climate Change—Reply
Authors: Russell A. Wilke, Jerome W. Freeman
Journal: JAMA (2018)

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Abstract 12679: Circulating High-Density Lipoprotein Particle Profiles Are Independently Associated With Heart Failure With Preserved Ejection Fraction and Predict Adverse Clinical Outcomes
Authors: Wynn G Hunter, Robert W McGarrah, Jacob P Kelly, Carol Haynes, Damian M Craig, Eric J Velazquez, William E Kraus, Svati H Shah
Journal: Circulation (2016)

Introduction: High-density lipoprotein particle concentration (HDL-P) and size (HDL-Sz) impact atherogenesis and inflammation, both of which are implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). However, the role of HDL in HFpEF has not been well evaluated. We characterized HDL particle characteristics in a large cardiovascular cohort to determine association with HFpEF and prognostic capability in this growing patient population. Methods: HFpEF cases (N=1004), HFrEF controls (N=782), and No-HF controls (N=4742) were identified in the CATHGEN biorepository of sequential patients undergoing cardiac catheterization. HFpEF was defined by left ventricular EF (LVEF) ≥45% and history of HF; HFrEF was defined similarly, except for LVEF &lt;45%; No-HF had LVEF ≥45%, and no history of HF. NMR-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. Multivariable analysis of variance was used to compare HDL profiles among groups; proportional hazards modeling evaluated associations among HDL profiles and time-to all-cause mortality and major adverse cardiac events. Results: HDL-Sz, large HDL-P, and small HDL-P differed significantly across groups (all P ≤0.006). Mean HDL-Sz was higher in HFrEF than HFpEF, both of which were higher than No-HF (all two-way P &lt;0.0001 ) . Large HDL-P was greater in HFrEF than HFpEF ( P =0.007); by contrast, small HDL-P was lower in HFrEF than HFpEF, which were both lower than No-HF (all P ≤0.0002). Greater HDL-Sz and large HDL-P were associated with increased risk of adverse events; whereas, greater small HDL-P was associated with decreased risk (Table). Conclusions: In the largest analysis of HDL profiles in HFpEF, we identified derangements in HDL-P and HDL-Sz independently associated with adverse events. These findings suggest that HDL profiling may be helpful in identifying high-risk HFpEF subtypes, and could provide new insights into HFpEF pathophysiology.