tbuckley/cabot-search huggingface dataset:
Comparative efficacy and safety of sorafenib in elderly versus non-elderly patients with advanced hepatocellular carcinoma (HCC) with varying liver dysfunction.
Authors: Sukeshi Patel Arora, Norma S. Ketchum, Jonathan Gelfond, Joel Michalek, Devalingam Mahalingam
Journal: Journal of Clinical Oncology (2018)

430 Background: Sorafenib is the only FDA-approved systemic therapy for advanced HCC. The incidence of HCC increases with age, peaking above 70 years; however, we have limited efficacy and safety data in the elderly. Given the prevalence of HCC in South Texas, we assessed the efficacy and safety of sorafenib in the elderly. Methods: Retrospective analysis of HCC patients (pts) receiving sorafenib from 2008-2013. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events version 4.0. Differences between age groups (65+, &lt; 65) for dose reduction (yes, no), and AEs were analyzed using Fisher’s Exact Test. Results: A total of 118 pts were included. Median age 57 (range 41-93; 65+ 26%). males 81%. Hispanic 73%, Non-Hispanic White 24%. ECOG PS 0–1 93 %. Causes of cirrhosis: Hepatitis C 66%, Hepatitis B 4%, EtOH 58%. Portal vein thrombosis 36%, Extrahepatic disease 38%. Child-Pugh score: A 56%, B 44%. BCLC class: B 13%, C 87%. Among 113 pts 34% were started at 400 mg daily versus 66% started at 800 mg daily. mOS was 11.2 months (mo) (95% CI: 7.8-14.0), mPFS 5.2 mo (95% Cl: 3.9-7.1). In subgroup analysis, mOS for &lt; 65 was 10.2 mo vs 13.5 mo for 65+ (HR 0.67, 95% CI: 0.39-1.16, p = 0.15). mPFS for &lt; 65 was 4.6 mo vs 6.2 mo for 65+ (HR 0.92, 95% CI: 0.58-1.45, p = 0.71). Among 109 pts, dose reductions in &lt; 65 vs 65+ were 64.6 vs 70% (P = 0.66); survival differences were not statistically significant. Among 75 pts there was a trend to improved survival in 65+ patients with AST/Platelet Ratio (APRI) &lt; / = 1.68, but not statistically significant. Sorafenib was tolerated in the elderly. In regards to nausea, fatigue, diarrhea and hand foot syndrome, difference in toxicity was not statistically significant in &lt; 65 versus 65+. Conclusions: In advanced HCC, elderly pts should be offered sorafenib, as it has efficacy and is tolerated in the elderly. Further prospective studies in the elderly are warranted, with evaluation of APRI as a prognostic marker.
Healthy lifestyle leads to better survival in colorectal cancer, study finds
Authors: Janice Hopkins Tanne
Journal: BMJ (2018)

Patients who followed a healthy lifestyle were more likely to survive stage III colorectal cancer in a large prospective cohort study from nearly two dozen university medical centers in the US and Canada.1

“To our knowledge, no prior study has evaluated the ACS [American Cancer Society] guidelines in relation to survival,” the researchers wrote. “Patients with colon cancer who had a healthy body weight, were physically active, and ate a diet rich in vegetables and fruits and chose whole over refined grains had a 42% lower risk of death during the [five year] study period than patients who did not engage in these behaviors.”

Furthermore, patients who changed to a healthier lifestyle after diagnosis had a …
Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT)
Authors: Mark Lebwohl, Andrew Blauvelt, Carle Paul, Howard Sofen, Jolanta Węgłowska, Vincent Piguet, Daniel Burge, Robert Rolleri, Janice Drew, Luke Peterson, Matthias Augustin
Journal: Journal of the American Academy of Dermatology (2018)

Phase 2 psoriasis studies with the Fc-free, PEGylated, anti-tumor necrosis factor biologic certolizumab pegol demonstrated meaningful clinical activity.Assess safety and efficacy of certolizumab in adults with moderate-to-severe chronic plaque psoriasis.Patients were randomized 3:3:1:3 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks for 16 weeks or etanercept 50 mg twice weekly for 12 weeks. Certolizumab-treated patients achieving a ≥75% reduction in Psoriasis Area and Severity Index (PASI) at week 16 from baseline PASI were rerandomized to certolizumab or placebo for 32 weeks. The primary endpoint was responder rate (≥75% reduction in PASI from baseline PASI) versus placebo (primary analysis) and etanercept (secondary analysis) at week 12; secondary endpoints included responder rates on various measures versus placebo at weeks 12, 16, and 48. Safety was assessed by treatment-emergent adverse events.All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. Certolizumab 400 mg was superior to and 200 mg was noninferior to etanercept. Adverse events were consistent with the anti-tumor necrosis factor class of drugs.Etanercept was administered by unblinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor.Both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. No new safety signals were observed.
Immune monitoring outcomes of patients with stage III/IV melanoma treated with a combination of pembrolizumab and intratumoral plasmid interleukin 12 (pIL-12).
Authors: Alain Patrick Algazi, Katy K. Tsai, Michael Rosenblum, Bernard A. Fox, Robert Hans Ingemar Andtbacka, Amy Li, Kathryn Toshimi Takamura, Mary Dwyer, Erica Browning, Reneta Talia, Chris Twitty, Mai H. Le, Sharron Gargosky, Jean S. Campbell, Carmen Ballesteros-Merino, Carlo Bruno Bifulco, Robert Pierce, Adil Daud
Journal: Journal of Clinical Oncology (2017)

78 Background: Recent publications support the emergence of predictive biomarkers for pembrolizomab in melanoma based on the expression of PD-L1 in the tumor microenvironment (Daud 2016a) or the frequency of PD-1 hi CTLA-4 hi on CD8 + TIL (Daud 2016b) whereby immunologically inactive tumors show poor response to immune checkpoint inhibition alone. Since intratumoral pIL-12 with electroporation (IT-pIL12-EP) increases TIL in both treated and untreated lesions, we hypothesize that non-response can be rescued with the combination of IT-pIL12-EP and anti-PD-1. Phase II clinical and immunological data are shown. Methods: Melanoma stage III/IV patients were enrolled with CD8 + TIL &lt; 25% PD-1 hi CTLA-4 + measured by flow cytometry (NCT02493361). PD-L1 IHC (22C3 Ab) was also evaluated. Patients were treated with pembrolizumab (200mg every 3 weeks) and IT-pIL12-EP. Patients were evaluated for ORR every 12 weeks (RECISTv1.1). Pre- and post-treatment blood and tumor specimens were collected, and analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by IHC. Results: TIL assessment for evaluable enrolled patients were &lt; 22% PD-1 hi CTLA-4 + , a value associated with anti-PD-1 non-response (Daud 2016b). Remarkably, although predicted to be an unresponsive population, the ORR was 40% (4CR/ 2PR) by RECISTv1.1. In patients with CR/PR, analysis of the tumor microenvironment revealed many significant immunological changes not seen in non-responders, including number and ratios of CD8 + :PD-L1 + by IHC, increased expression of NK, CD8 and ‘adaptive resistance’ markers by NanoString, as well as increased clonality and T cells by TCR sequencing. Conclusions: The excellent safety profile and striking 40% clinical response rate is encouraging as treated patients were predicted to be non-responsive to pembrolizumab. The correlative data shows an immune-directed mechanism that is differentiated between responders and non-responders suggesting the combination can effectively alter the tumor microenviroment to benefit patients otherwise unlikely to respond to anti-PD-1 monotherapy. Clinical trial information: NCT02493361.
Development of human NKG2D-CD3ε chimeric antigen receptor (CAR) for T-cell-mediated cancer immunotherapy.
Authors: Sergei Kusmartsev, Johaness Vieweg, Victor Prima
Journal: Journal of Clinical Oncology (2017)

150 Background: NKG2D is a lectin-like type 2 transmembrane receptor that expressed by natural killer cells and some T cell subsets. Stimulation of NKG2D receptor with specific agonistic ligands produces activating signals through signaling adaptor protein DAP10 leading to the enhanced cytokine production, proliferation, and cytotoxicity against tumor cells. There is strong evidence that NKG2D ligands are expressed in many human tumors, including melanoma, leukemia, myeloma, glioma, and carcinomas of the prostate, breast, lung, and colon. Recent studies also demonstrated that T cells bearing chimeric antigen receptor (CAR) NKG2D linked to CD3ζ (zeta) chain produce marked in vitro and in vivo anti-tumor effects. The aim of current study was to determine whether human T cells bearing chimeric antigen receptor (CAR) NKGD2 linked to CD3ε (epsilon) chain could be activated by the NKG2D-specific stimulation and able to kill human cancer cells. Given the important role of CD3ε in activation and survival of T cells, we hypothesized that NKG2D-CDε-bearing T cells could exert strong in vitro and in vivo anti-tumor effects. Methods: NKG2D CAR was produced by linking human NKG2D to DAP10 and the cytoplasmic portion of the CD3ε chain. Original full-length human cDNA clones were obtained from NIH Mammalian Gene Collection (MGC). Functional domain analysis and oligonucleotide design in the in-Fusion system of DNA cloning (Clontech) was used to generate the retroviral expression constructs. Results: Human PBMC-derived T cells were retrovirally transduced with newly generated NKG2D-CD3ε CAR DNA construct. These NKG2D CAR-expressing human T cells responded to NKG2D-specific activation by producing IFN-γ and exhibited significant cellular cytotoxicity against human tumor cells in vitro. In vivo studies demonstrated that NKG2D-CD3ε-bearing cells are capable of inhibiting growth of DU-145 human prostate cancer in the immunodeficient mice. Conclusions: Collectively, our data indicate the feasibility of developing chimeric antigen receptor NKG2D-CD3ε for T cells and suggest that adoptive transfer of T cells bearing NKG2D-CD3ε CAR could be potentially effective for immunotherapy of cancer patients.
Effect of RELT on regulation of the threshold of T-cell activation during sterile inflammation.
Authors: Seon-Hee Kim, Beom K. Choi, Chungyong Han, Byoung S. Kwon
Journal: Journal of Clinical Oncology (2017)

25 Background: Receptor expressed in lymphoid tissue (RELT) is a type I transmembrane protein, designated TNFRSF19-like, and primarily expressed in lymphoid tissues and immune cells. However, its immunological function has yet to be characterized. Methods: We developed RELT-deficient mice to examine the immunological role of RELT. The RELT –/– mice were exposed to viral and bacterial infection, chemical-induced liver injury, and tumor induction. Results: RELT –/– mice were viable and fertile, and developed normal lymphoid and myeloid cells. RELT transcripts were decreased in T cells and dendritic cells following their activation, and T-cell proliferation was enhanced in the absence of RELT in vitro. Nevertheless, we could not find significant changes in RELT –/– mice infected with virus or bacteria. However, liver injury and inflammation were significantly increased in RELT –/– mice in comparison to RELT +/+ mice after the injection of acetaminophen. Tumor growth rate was also slower in RELT –/– than RELT +/+ mice. Transfer of naïve or activated pmel-1 CD8 + T cells suppressed the growth of B16–F10 tumors and increased host CD8 + tumor-infiltrating cells more efficiently in RELT –/– than in RELT +/+ mice. In particular, naïve pmel-1 CD8 + T cells were present in increased numbers and activated forms in draining lymph nodes of RELT –/– than in RELT +/+ mice, whereas activated pmel-1 CD8 + T cells were not. Conclusions: As RELT –/– mice only showed significant differences in comparison to RELT +/+ mice in pathogen-associated-molecular-pattern-free conditions, these results provide evidence that RELT functions as a negative modulator of T cell responses in a sterile inflammation.
Risk of infectious toxicity associated with polymorphism in GSTP1 in children with acute lymphoblastic leukemia in a population of Amazonia.
Authors: Alayde vieira Wanderley, Ney PC Santos, Andre salim Khayat, Darlen cardoso de Almeida, Fernando Mello, Laudreisa costa Pantoja
Journal: Journal of Clinical Oncology (2014)

e21006 Background: Acute Lymphoblastic Leukemia (ALL) is the main cancer affecting children and adolescents. In the North of Brazil, more specifically in the metropolitan region of Belém, the LLA represents 39% of cases of childhood cancers.This study sought to identify pharmacogenetic molecular markers in metabolism metabolism genes of the main drugs used in chemotherapy for ALL, associated with analysis of ancestry in pediatric patients seen at a referral pediatric oncology service in the state of Pará and correlate with toxicity in these patients. The targets of this study were the GSTP1 (rs1695) and CYP3A5*3 (rs776746) genes involved in the therapeutic glucocorticoids, and MTHFR (rs1801133) and TYMS (rs16430) involved in therapeutic of Methotrexate drug, also to correlating the presence of the main toxicities. Methods: The genetic material was extracted from slides of bone marrow by using High Pure PCR Template Preparation kit. Subsequently, the SNPs were analyzed by snapshot technique, and the ancestry was evaluated by multiplex PCR followed by capillary electrophoresis. Results: Among the genotypes, the highest frequencies showed were: 61.6 % of Del/Ins in TYMS gene, 39.2 % of A/G in GSTP1 gene, 47.3% of C/C in CYP3A5*3 gene and 41.9% of C/C in MTHFR gene. We found a significant association (p ≤ 0.05) between the polymorphism of GSTP1 gene and severe infectious toxicity in ALL infant patients carriers of genotype AA, showing an increase of 57% in the risk to develop severe infectious toxicity when treated with glucocorticoid. No similar effect was observed in hematologic toxicity. The presence of death suggested a statistical trend for patients with higher contribution of Amerindian ancestry. Conclusions: This study suggests that the polymorphism in GSTP1 (rs 1695), genotype AA, is associated with increased incidence of infectious toxicity in patients who underwent treatment with glucocorticoid. The control of genomic ancestry was important to the present research, enabling the control of the ancestry effect in the associations.
Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one
Authors: Claudiu T. Supuran, Vincenzo Alterio, Anna Di Fiore, Katia D’ Ambrosio, Fabrizio Carta, Simona Maria Monti, Giuseppina De Simone
Journal: Medicinal Research Reviews (2018)

Human carbonic anhydrase (CA) IX is a tumor-associated protein, since it is scarcely present in normal tissues, but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. Due to these features, the characterization of its biochemical, structural, and functional features for drug design purposes has been extensively carried out, with consequent development of several highly selective small molecule inhibitors and monoclonal antibodies to be used for different purposes. Aim of this review is to provide a comprehensive state-of-the-art of studies performed on this enzyme, regarding structural, functional, and biomedical aspects, as well as the development of molecules with diagnostic and therapeutic applications for cancer treatment. A brief description of additional pharmacologic applications for CA IX inhibition in other diseases, such as arthritis and ischemia, is also provided.
Abstract 16547: Thrombin-Thrombomodulin Fusion Proteins as New Anticoagulants
Authors: Nicola Pozzi, Sergio Barranco-Medina, Enrico Di Cera
Journal: Circulation (2016)

Introduction:  Thrombin is a trypsin-like protease that plays opposing functional roles in blood coagulation due to the interaction with numerous macromolecular substrates, receptors and inhibitors. The specific binding of fibrinogen and PAR-1 to the exosite-1 leads to the conversion of fibrinogen to fibrin, platelet activation and clot formation. Binding of the cofactor thrombomodulin to the same exosite-1 hinders docking of the procoagulant substrates and accelerates the activation of protein C by 1500-fold thereby enabling the most powerful enzymatic anticoagulant system that exists  in vivo . Down-regulation and washout of thrombomodulin from the endothelium have been documented in pathological conditions such as atherosclerotic lesions, sepsis and disseminated intravascular coagulation leading to impaired activation of protein C and thrombosis.   Hypothesis:  A solution to this problem would be the administration of a thrombomodulin-independent protein C activator.   Results:  In this study we report the design, expression and functional characterization of a new family of fusion proteins that specifically activate protein C without the need of endogenous thrombomodulin. In our molecules, the enzyme thrombin is genetically fused via artificial linkers to the soluble extracellular portion of the cofactor thrombomodulin. A total of 6 fusion proteins were expressed in mammalian cells at high yield and high purify. As expected, their anticoagulant profile varies with the length of the artificial linker. An optimal anticoagulant activity is achieved with a linker composed of 31 and 41 amino acids. Specifically, the activity of the L31 and L41 fusion proteins towards procoagulant substrates such as fibrinogen and PAR-1 was reduced >100-fold while protein C activation was minimally affected (2-fold) compared to the endogenous complex.   Conclusions:  Similar values of specificity for protein C activation constitute evidence of productive docking between the subunits of thrombin and thrombomodulin  in vitro . However, the partial blockade of the procoagulant substrate suggests that further optimization of length, composition and localization of the linker and/or of the protein partners is necessary to achieve an exquisite anticoagulant profile.
Medical Care Costs Associated With Cancer in Integrated Delivery Systems
Authors: Matthew P. Banegas, K. Robin Yabroff, Maureen C. O'Keeffe-Rosetti, Debra P. Ritzwoller, Paul A. Fishman, Ramzi G. Salloum, Jennifer Elston Lafata, Mark C. Hornbrook
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: The high economic burden of cancer is projected to continue growing. Cost-of-care estimates are key inputs for comparative effectiveness and economic analyses that aim to inform policies associated with cancer care. Existing estimates are based largely on SEER-Medicare data in the elderly, leaving a knowledge gap regarding costs for patients aged <65 years. Methods: We estimated total and net medical care costs using data on individuals diagnosed with breast, colorectal, lung, or prostate cancer (n=45,522) and noncancer controls (n=314,887) enrolled in 1 of 4 participating health plans. Net costs were defined as the difference in mean total costs between patients with cancer and controls. The phase-of-care approach and Kaplan-Meier Sample Average method were used to estimate mean total and net 1- and 5-year costs (in 2015 US dollars) by cancer site, stage at diagnosis, and age group (<65 and ≥65 years). Results: Total and net costs were consistently highest for lung cancer and lowest for prostate cancer. Net costs were higher across all cancer sites for patients aged <65 years than those aged ≥65 years. Medical care costs for all cancers increased with advanced stage at diagnosis. Conclusions: This study improves understanding of medical care costs for the 4 most common invasive cancers in the United States. Higher costs among patients aged <65 years highlight limitations of relying on SEER-Medicare data alone to understand the national burden of cancer, whereas higher costs for patients with advanced-stage cancer underscore the importance of early detection to curtail high long-term costs. These cost estimates can be used in the development and evaluation of interventions and policies across the cancer care continuum.
Comprehensive genomic analysis with immunological parameters to obtain the biomarkers for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
Authors: Yuki Owada, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Takumi Yamaura, Mitsuro Fukuhara, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Daisuke Tanaka, Emi Ito, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
Journal: Journal of Clinical Oncology (2017)

107 Background: Several kinds of predictors of ICIs efficacy in NSCLC have been analyzed. PD-L1 expression of tumor, frequency of tumor infiltrating lymphocytes (TIL) and microsatellite instability are cited as potential predictors of treatment efficacy of ICIs, but these still seem to be immature. Lately, mutation load in tumor, presumably involving to neo-antigens in tumor tissue, is also thought to be one of more probable predictors for ICIs. However, the hypothesis is still limited and it is very hard to analyze the mutation load routinely in clinic. We here describe more definitive and easily detecting factors by using Next generation sequencing (NGS) and by analyzing conventional immunological and molecular parameters. Methods: 94 patients with NSCLC who undergone resection in our institution were subjected for this study. Mutation load in tumor samples was analyzed by whole exome sequencing using NGS. The major gene alteration was also analyzed by NGS. TILs and PD-L1 expression in tumor were immunohistochemically assessed by using CD8 and SP142 (anti-PD-L1 antibody). Results: The median value of mutation load was 54 genes (10-363). The factors; squamous cell carcinoma, EGFR-mutation negative, and TP53 alteration positive indicated close connection with higher mutation load. PD-L1 expression, TILs, gender, age, and etc. were not associated with mutation load. Multiple regression analysis shows that EGFR-mutation negative and TP53 alteration positive contribute to higher mutation load (p = 0.018, p = 0.015). Conclusions: Mutation load in tumor could be associated with EGFR-mutation and TP53 alteration status. These profiles could potentially be more simple biomarkers in treating ICIs.
Abstract 19216: IL-9 Promotes Mast Cell Activation and Endothelial Toxicity in Chronic Kidney Disease-Dependent Vein Graft Disease
Authors: Lisheng Zhang, Jiao-Hui Wu, Leigh Brian, Neil J Freedman
Journal: Circulation (2016)

Chronic kidney disease (CKD, with GFR < 60 ml/min/1.73 m2) independently predicts vascular events, including CABG vein graft failure. To elucidate mechanisms underlying this problem, we modeled CKD...