tbuckley/cabot-search huggingface dataset:
Abstract 12163: Pre-existing Medical Comorbidity is not Associated With Neurological Outcomes in Comatose Survivors of Cardiac Arrest Undergoing Targeted Temperature Management
Authors: Arash Nayeri, Nirmanmoh Bhatia, Benjamin Holmes, Nyal Borges, William Armstrong, Michael Young, Quinn Wells, John McPherson
Journal: Circulation (2016)

Introduction: Evidence regarding the significance of pre-existing medical comorbidity in comatose survivors of cardiac arrest who undergo targeted temperature management (TTM) remains limited. Hypothesis: Increasing burden of medical comorbidity will predict poor neurological outcomes following TTM. Methods: We analyzed a prospectively collected cohort of 314 consecutive comatose survivors of cardiac arrest treated with TTM at a tertiary care hospital between 2007 and 2014. Overall burden of medical comorbidity was estimated with the use of the Charlson Comorbidity Index (CCI). Poor neurological outcome at hospital discharge, defined as a Cerebral Performance Category (CPC) score &gt;2, was the primary outcome. Secondary outcomes included death prior to hospital discharge and at 1 year following cardiac arrest. Results: Amongst all patients, the median CCI score was 1 (IQR 0-3, range 0-11). A poor neurological outcome at hospital discharge was observed in 193 (61%) patients. One hundred and seventy-nine (57%) patients died prior to hospital discharge and a total of 195 (62%) patients had died at 1 year post-arrest. In multivariable logistic regression, elevated CCI scores were not associated with increased odds of poor neurological outcomes (OR 1.04, 95% CI 0.90-1.19, p=0.608) or death (OR 0.99, 95% CI 0.86-1.13, p=0.816) at hospital discharge. No association was seen between CCI scores and death at 1 year post-arrest (OR 1.09, 95% CI 0.95-1.26, p=0.220), Table 1 . Conclusions: Increasing burden of medical comorbidity is not associated with neurological outcomes or survival in patients treated with TTM. Pre-existing comorbidity should not affect a patient’s candidacy for this treatment. Table 1. Adjusted odds ratios of poor neurological outcomes and death. CCI, Charlson Comorbidity Index; CI, confidence interval; CPR, cardiopulmonary resuscitation; OR, odds ratio; ROSC, return of spontaneous circulation; TTM, targeted temperature management.
CheckMate 602: An open-label, randomized, phase 3 trial of combinations of nivolumab, elotuzumab, pomalidomide and dexamethasone in relapsed/refractory multiple myeloma.
Authors: Sagar Lonial, Paul G. Richardson, Donna Ellen Reece, Hesham Mohamed, Suresh Shelat, Jesus San Miguel
Journal: Journal of Clinical Oncology (2017)

TPS8052 Background: Multiple myeloma (MM) cells may evade immune surveillance by suppressing immune responses through the PD-1 pathway, via upregulation of PD-L1. 1 Nivolumab (nivo), a PD-1 immune checkpoint inhibitor that blocks PD-L1 interaction and disrupts MM-mediated PD-1 signaling, demonstrated modest activity as monotherapy in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in a phase 1b study. 2 Pomalidomide, an immunomodulatory drug (IMiD), may sensitize MM cells to PD-1 blockade, and has shown efficacy with dexamethasone (Pd) for RRMM. Elotuzumab (elo), an anti-SLAMF7 monoclonal antibody, directly activates natural killer cells and facilitates antibody-dependent cell-mediated cytotoxicity. Preclinical work suggests PD-1 blockade may enhance elo efficacy 3 ; thus nivo + Pd + elo may increase clinical benefit. Methods: CheckMate 602 (NCT02726581) is a phase 3, open-label, randomized study of efficacy and safety of nivo + Pd (N-Pd) vs Pd in pts with RRMM. Nivo combined with elo + Pd (NE-Pd) will be evaluated in an exploratory arm. Eligible pts must have measurable MM after ≥2 prior lines of therapy (LoTs) that included an IMiD and proteasome inhibitor, each for ≥2 consecutive cycles, alone or combined, and be refractory to their last LoT. Pts with prior elo are eligible. A planned 406 pts will be randomized 3:3:1 to N-Pd, Pd and NE-Pd, stratified by LoT (2 vs 3+) and International Staging System disease stage (I–II vs III). Pts in the Pd arm may cross over to the NE-Pd arm at disease progression. Pts are enrolled at 119 sites in 13 countries. Coprimary endpoints (N-Pd and Pd arms): objective response rate (ORR) and progression-free survival (PFS), assessed by an independent review committee. Secondary endpoints (N-Pd and Pd arms): time to response, duration of response, investigator-assessed ORR and PFS. Exploratory endpoints include ORR and PFS (NE-Pd arm), and safety/tolerability and minimal residual disease status (all arms). 1. Liu et al. Blood 2007;110:296–304 2. Lesokhin et al. JCO 2016;34:2698–704 3. Bezman et al. Haematologica 2016;101:161–2 [S450] Study support: BMS. Writing support: A Gill, Caudex, funded by BMS. Clinical trial information: NCT02726581.
Factors associated with secondary malignancy in pediatric Hodgkin's lymphoma.
Authors: Nicholas A Madden, Bryan M Rabatic, David Zaenger, Joseph A Marascio, Sherif Shaaban, Catherine L Ferguson, Theodore S. Johnson, Edward M Marchan, William D Martin, Mahboubeh Pishgou, Jed W Howington, John G Stewart, Maryam Aletan, Ahmad Amoush, Ke Huang, Ahmad M Albasheer, Byron G Dasher, Feng-Ming (Spring) Kong, Waleed F Mourad
Journal: Journal of Clinical Oncology (2016)

10538 Background: Pediatric Hodgkin’s lymphoma (HL) is a curable pediatric cancer., with newer protocols focusing on limiting long term toxicity. Radiation therapy (RT) has been associated with development of secondary malignancies (SMs). Here we investigate the factors associated with SMs in pediatric HL. Methods: All patients in the SEER database diagnosed with HL at ages 0-19 years from 1973-2012 were assessed for metachronous SMs. Patient and treatment related factors were assessed to determine risk. Observed-to-expected ratios (O/E) were calculated for each tumor site comparing the HL cohorts development of cancer to what would be expected based on incidence rates for the general population. P < 0.05 was used to determine significance. Results: 6572 patients with pediatric HL were identified. Median survival had not been reached at 20 years. 332 SMs (O/E 5.87) were observed. Patients treated with RT developed 240 SMs (O/E 6.50) including 206 solid tumors compared with 81 SMs (O/E 4.81) and 69 solid tumors (O/E 4.92) in patients without RT (p < 0.05). Highest rates of SMs occurred in salivary gland (O/E 27.3), soft tissue (21.87), breast (10.19) and endocrine cancers (8.53). Increased rates of SMs were also observed for digestive, respiratory, female genital, urinary, brain, and hematologic malignancies. RT patients had higher rates of salivary gland, digestive, respiratory, soft tissue, breast, and hematologic cancers compared to patients not receiving RT. By race, blacks were associated with the highest O/E ratio for solid tumors regardless of treatment. Females were at higher risk for all SMs and solid tumors alone compared with males. There was no significant difference between stage and risk of SM.Utilization of RT decreased from a peak of 71% from 1973-1979 to 47% in patients treated after 2010, and fewer total patients developed SMs by decade with time. After death from HL, SM was the second leading cause of mortality in this cohort. Conclusions: Pediatric HL, regardless of treatment, is associated with predisposition to SM. Females, blacks, and RT patients are at highest risk. Identification of additional patient and tumor factors associated with this predisposition to malignancy are needed to optimize treatment and surveillance.
Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy
Authors: Shyam S. Bansal, Mohamed Ameen Ismahil, Mehak Goel, Guihua Zhou, Gregg Rokosh, Tariq Hamid, Sumanth D. Prabhu
Journal: Circulation (2019)

Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and they promote immune activation and left ventricular (LV) remodeling.Adult male wild-type C57BL/6 mice, Foxp3-diphtheria toxin receptor transgenic mice, and tumor necrosis factor (TNF) α receptor-1 (TNFR1)-/- mice underwent nonreperfused myocardial infarction to induce HF or sham operation. LV remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays.Compared with wild-type sham mice, CD4+Foxp3+ Tregs in wild-type HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after myocardial infarction, beyond the early phase of wound healing, and exhibited proinflammatory T helper 1-type features with interferon-γ, TNFα, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated antiangiogenic and profibrotic properties. Selective Treg ablation in Foxp3-diphtheria toxin receptor mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T cells and systemic inflammation and enhancing tissue neovascularization. Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a C-C chemokine ligand 5/C-C chemokine receptor 5-dependent manner. Anti-CD25-mediated Treg depletion in wild-type mice imparted similar benefits on LV remodeling, circulating angiogenic cells, and tissue neovascularization.Proinflammatory and antiangiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.
Prognostic evaluation of a new class of liquid biopsy biomarkers in patients with metastatic colorectal cancer: Using the tumor microenvironment as a source of protein biomarkers.
Authors: Stephanie Nina Kehlet, Anette Høye, Mogens Karsboel Boisen, Julia S. Johansen, Morten A Karsdal, Nicholas Willumsen, Janine Erler
Journal: Journal of Clinical Oncology (2018)

3588 Background: The local microenvironment of a tumor plays an important role in colorectal cancer (CRC) progression. A desmoplastic stroma surrounding the tumor, characterized by excessive collagen deposition, can result in reduced drug delivery into the tumor, leading to poor prognosis and lack of therapy response. Here we present a new class of liquid biopsy proteins, reflecting collagen formation (desmoplasia) and evaluate their prognostic use in CRC. Methods: Pro-peptides from collagen type III (PRO-C3) and collagen type VI (PRO-C6) were measured with ELISAs in pre-treatment (standard of care chemotherapy) serum from 40 patients with metastatic CRC (mCRC) and 40 healthy donors. Biomarker levels in patients and healthy donors were compared using unpaired, two-tailed Mann-Whitney test. The biomarkers were further evaluated by univariate Cox-regression analysis for their association with overall survival (OS) and progression-free-survival (PFS). Results: Serum levels of PRO-C3 and PRO-C6 were significantly elevated in patients with mCRC compared to healthy donors (PRO-C3: 11.5 ng/mL vs. 6.8 ng/mL, p < 0.0001, PRO-C6: 8.0 ng/mL vs. 5.9 ng/mL, p < 0.0001). The median OS was 266 or 213 days in biomarker high patients (75th percentile) vs. 1330 or 979 days in biomarker low patients (25th percentile) for PRO-C3 (HR 8.7, 95%CI 2.7-28.2) and PRO-C6 (HR 6.8, 95%CI 2.3-20.3), respectively. The median PFS was 251 or 267 days in biomarker high patients (75th percentile) vs. 329 or 496 days in biomarker low patients (25th percentile) for PRO-C3 (HR 2.3, 95%CI 0.7-7.1) and PRO-C6 (HR 2.6, 95%CI 0.8-9.0), respectively. Conclusions: This study evaluated the prognostic use of a new class of liquid biopsy biomarkers, namely small peptides originating from the tumor microenvironment that are released into the circulation as a consequence of tumorigenesis. High serum levels of PRO-C3 and PRO-C6 (collagen formation) were significantly associated with poor OS and shorter PFS in patients with mCRC. This may suggests that increased collagen deposition around the tumor, limits cancer therapy delivery into the tumor, resulting in a lack of response to therapy.
Tracking the interplay between circulating and tumor-infiltrating T cells using AmpliSeq-based Ion Torrent TCRβ immune repertoire sequencing.
Authors: Timothy Looney, Geoffrey Lowman, Elizabeth Linch, Denise Topacio, Lauren Miller, Lifeng Lin, Aleksandr Pankov, Janice Au-Young, Mark Andersen, Ann Mongan, Fiona Hyland
Journal: Journal of Clinical Oncology (2017)

e14518 Background: TCRβ immune repertoire analysis by next-generation sequencing is emerging as a valuable tool for research studies of the tumor microenvironment and potential immune responses to future cancer immunotherapy. Here we describe a multiplex PCR-based TCRβ sequencing assay that takes advantage of the exceptionally low base-call error rate and long read capability of the Ion S5 530 chip. The S530 chip provides &gt; 15M reads, allowing for sample sequencing in multiplex. The research assay utilizes AmpliSeq technology and Framework 1 and Constant gene targeting primers to provide comprehensive coverage of TCRβ CDR 1, 2 and 3 from RNA input with a hands-on time of less than 30 minutes. CDR region sequences reveal the antigen specificity of the receptor and may be genetically modified to increase TCR affinity for tumor antigen. Methods: We evaluated assay performance by sequencing TCRβ rearrangements from normal donor peripheral blood leukocyte (PBL) cDNA that had been spiked with 30 reference rearrangements taken from the literature. We then used our assay to evaluate the extent of clonal overlap between matched tumor infiltrating lymphocyte (TIL) and peripheral blood leukocyte repertoires in an individual with squamous cell carcinoma of lung. Results: Results from sequencing of spike-in reference rearrangements indicate that the assay is accurate and sensitive over 5 logs of input template amount while showing minimal amplification bias. Sequencing of matched PBL and TIL repertoires revealed that a subset of the PBL repertoire (8%) consisted of clones also found in TIL. Technical replicates showed high concordance (r &gt; .96) in the frequency of detected clones, indicating that the results were reproducible and samples were sequenced to an appropriate depth. Conclusions: In summary, these data suggest that AmpliSeq-based multiplex PCR and Ion Torrent sequencing provide unbiased, reproducible, scalable, complete, and accurate information for immune repertoire research sequencing applications.
Doxorubicin (D), gemcitabine (G), ifosfamide (I) and the EZH2 inhibitor EPZ-011989 in epithelioid sarcoma (ES): A comparison of different regimens in a patient-derived xenograft (PDX) model.
Authors: Nadia Zaffaroni, Anna Maria Frezza, Valentina Zuco, Alessandro Gronchi, Chiara Colombo, Sandro Pasquali, Paolo Giovanni Casali, Angelo Paolo Dei Tos, Paola Collini, Maria A. Pantaleo, Annalisa Astolfi, Valentina Indio, Monica Tortoreto, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2018)

11578 Background: ES is a rare soft tissue sarcoma with two variants, i.e., the proximal and the distal. Retrospective data on the activity of anthracycline- and G-based regimens are available. EZH2 inhibitors, which target the INI1 pathway that is inactivated in ES, are currently being tested in clinical trial. Comparisons of these agents are not available and unlikely to be prospectively evaluated. We comparatively assess these agents in a proximal-type INI1-deleted ES PDX. Methods: A PDX model (ES-1) was established by subcutaneously xenotransplanting into immunodeficient (SCID) mice tumor fragments obtained from a patient with primary, proximal-type, INI1 deleted ES of the forearm. After tumor propagation in SCID mice for three consecutive passages, the PDX was considered established. Mice were randomized to receive D and I, as single agents or in combination (D+I), G and the EZH2 inhibitor EPZ-011989 (E) (8 mice/experimental group). Drug activity was assessed in terms of tumor volume inhibition (TVI%). RNA-seq was performed on samples obtained from patient primary tumor and from ES-1 before and after treatment with E. Results: As single agents, both D and I showed a modest antitumor effect. Conversely, D+I induced an almost complete tumor growth inhibition (max TVI: 94%). A comparable antitumor activity was caused by G (max TVI: 98%). E initially induced a tumor growth stabilization, followed by a progressive reduction of tumor volume starting from end of treatment (max TVI: 89%). Consistently with its mechanism of action, E inhibited trimethylation and increased acetylation of H3K27, as detected by Western Blot in tumor samples at different intervals from the end of mouse treatment. Analysis of RNAseq data is ongoing. Conclusions: Our preclinical results in a proximal-type ES INI1-deleted PDX model showed a strong and comparable antitumor activity for D+I, G and E. These data support clinical use of G and D+I and confirm that EZH2 is a therapeutic target in proximal-type ES. Experiments with D and G combined to E are planned. To which extent these preclinical findings can be extended to distal ES subtype is left to be defined.
RNAi-Mediated β-Catenin Inhibition Promotes T Cell Infiltration and Antitumor Activity in Combination with Immune Checkpoint Blockade
Authors: Shanthi Ganesh, Xue Shui, Kevin P. Craig, Jihye Park, Weimin Wang, Bob D. Brown, Marc T. Abrams
Journal: Molecular Therapy (2018)

Wnt/β-catenin signaling mediates cancer immune evasion and resistance to immune checkpoint therapy, in part by blocking cytokines that trigger immune cell recruitment. Inhibition of β-catenin may be an effective strategy for increasing the low response rate to these effective medicines in numerous cancer populations. DCR-BCAT is a nanoparticle drug product containing a chemically optimized RNAi trigger targeting CTNNB1, the gene that encodes β-catenin. In syngeneic mouse tumor models, β-catenin inhibition with DCR-BCAT significantly increased T cell infiltration and potentiated the sensitivity of the tumors to checkpoint inhibition. The combination of DCR-BCAT and immunotherapy yielded significantly greater tumor growth inhibition (TGI) compared to monotherapy in B16F10 melanoma, 4T1 mammary carcinoma, Neuro2A neuroblastoma, and Renca renal adenocarcinoma. Response to the RNAi-containing combination therapy was not dependent on Wnt activation status of the tumor. Importantly, this drug combination was associated with elevated levels of biomarkers of T cell-mediated cytotoxicity. Finally, when CTLA-4 and PD-1 antibodies were combined with DCR-BCAT in MMTV-Wnt1 transgenic mice, a genetic model of spontaneous Wnt-driven tumors, complete regressions were achieved in the majority of treated subjects. These data support RNAi-mediated β-catenin inhibition as an effective strategy to increase response rates to cancer immunotherapy.
Efficacy of ginger for chemotherapy-induced nausea and vomiting (CINV) prophylaxis in breast cancer patients receiving adriamycin – cyclophosphamide (AC) regimen: Randomized double-blind placebo-control crossover study.
Authors: Lucksamon Thamlikitkul, Nopadol Soparattanapaisarn
Journal: Journal of Clinical Oncology (2016)

e21621 Background: Data on efficacy of ginger for CINV prophylaxis are conflicting. Several studies observed a reduction in incidence and severity of CINV when ginger was given along with highly emetogenic chemotherapy. The objective of the study was to determine an efficacy of ginger in reducing CINV in breast cancer patients who are receiving AC regimen which has moderate emetogenicity. Methods: Breast cancer patients receiving the first cycle of AC regimen who developed moderate nausea reported by the patients using visual analog scale from 0 (no nausea) to 100 (unbearable nausea) with score at least 40 were recruited. Eligible patients were randomized to receive either 500 mg ginger capsule or placebo twice a day for 5 days starting on the first day of the second cycle of AC regimen. The patients were switched to receive another drug in the third cycle. Nausea severity and vomiting incidence were recorded once a day during the first 5 days after receiving the study medication. Ondansetron and dexamethasone were given in all cycles. Primary outcome was a reduction in nausea score. To detect a reduction of nausea score at least 20 with 5% type I error (2-sided) and 20% type II error, 34 patients were required. Results: Thirty-four patients were enrolled during February and December 2015. Mean (range) of nausea score in the first cycle of AC regimen was 58 (40-90). Thirty-three patients (97%) received same AC dose in the second and third cycle. There was no interaction between the sequence of treatment and primary outcome (p = 0.5). Mean (SE) of maximum nausea score when the patients received ginger and placebo were 35.36 (4.43) and 32.17 (3.71), respectively. The difference in mean maximum nausea score was 3 (95% confidence interval, -3 to 9; p = 0.3). There was no difference in vomiting incidence, rate of rescue medication use, incidence of chemotherapy dose reduction or delay and adverse events. Conclusions: Ginger at the study dose is safe but it confers no additional benefit in reducing nausea severity when ondansetron and dexamethasone are given for CINV prophylaxis in breast cancer patients receiving AC regimen. Clinical trial information: NCT02390648.