tbuckley/cabot-search huggingface dataset:
Sustained and Bioresponsive Two‐Stage Delivery of Therapeutic miRNA via Polyplex Micelle‐Loaded Injectable Hydrogels for Inhibition of Intervertebral Disc Fibrosis
Authors: Ganjun Feng, Zengshi Zha, Yong Huang, Junjie Li, Yuheng Wang, Wendong Ke, Hongying Chen, Limin Liu, Yueming Song, Zhishen Ge
Journal: Advanced Healthcare Materials (2018)

Intervertebral disc degeneration (IDD) is frequently caused by gradual pathological changes inside intervertebral discs (IVDs) and progressive fibrosis. MicroRNA-29 (miR-29) family possesses potent fibrosis suppression capability, but their application for treatment of chronic IDD is limited due to lack of suitable local delivery systems. In this report, given various overexpressed matrix metalloproteinases (MMPs) during IDD, injectable MMP-degradable hydrogels encapsulating MMP-responsive polyplex micelles are developed for sustained and bioresponsive delivery of miR-29a into nucleus pulposus cells via a two-stage process. Cationic block copolymers are designed to complex miR-29a, and subsequently mixed with the poly(ethylene glycol) (PEG) gelation precursors and MMP-cleavable peptide cross-linkers for in situ formation of polyplex micelle-encapsulated hydrogels in the diseased IVDs. In the presence of MMPs, the polyplex micelles are first released by MMP cleavage of the hydrogels, and subsequently, MMPs-responsive detachment of PEG shells from polyplex micelles contributes to efficient cellular uptake and endosomal escape. MiR-29a is demonstrated to effectively silence the expression of MMP-2, inhibit the fibrosis process, and reverse IDD in animal models through blocking the β-catenin translocation pathway from the cytoplasm to the nucleus. This two-stage bioresponsive local miRNA delivery system represents a novel and promising strategy for the treatment of chronic IDD.
Deferred systemic therapy (DST) in the prospective metastatic renal cell cancer (MaRCC) registry.
Authors: Michael Roger Harrison, Nrupen Anjan Bhavsar, Steven Paul Wolf, Brian Addis Costello, Ulka N. Vaishampayan, Christos Kyriakopoulos, Walter Michael Stadler, Hans J. Hammers, Leonard Joseph Appleman, Che-Kai Tsao, Sumanta K. Pal, Arif Hussain, Heather S.L. Jim, Azah Borham, Daniel J. George
Journal: Journal of Clinical Oncology (2016)

e16084 Background: Metastatic renal cell carcinoma (mRCC) is a heterogeneous disease, often presenting with an indolent course. Our prior retrospective work indicates many patients (pts) may not receive systemic therapy (ST) in the first year after mRCC diagnosis (dx); however, prospective data is limited. This analysis reports baseline characteristics of pts receiving DST as the initial management decision in the first 145 pts enrolled in a multicenter, prospective, observational registry. Methods: MaRCC Registry will enroll 500 pts from up to 60 US academic (ACAD) and community sites with ~2 years of recruitment and ≥ 3 years of follow-up. Eligible pts are age ≥ 18 years with a dx of mRCC and no prior ST for mRCC at study entry. Pts currently not on ST but who are being observed are permitted. Key endpoints include treatment (tx) characteristics (e.g. agents, sequence, duration, reasons for therapy choice and discontinuation), tx effectiveness (e.g. ORR, PFS, OS), quality of life, medication adherence, and health resource utilization. DST was defined as anything other than ST (eg local therapy) as the initial management decision. Results: At data cutoff, 145 pts were accrued; 68 pts (47%) had DST: median age 66; 75% male; 78% ACAD; 88% clear cell histology; and 37% stage IV at dx. Reasons for DST included Active Surveillance (AS) or Local Therapy (LT) in N = 44 and Other Reasons in N = 24. Most common reasons for DST-Other group were Awaiting Trial (N = 6), Hospice (N = 5), and Pt Declined Tx (N = 4). At baseline pts in the DST-AS/LT group were more likely to have: Medicare, < Stage IV at dx, normal neutrophils or Hgb, and > 1 yr since initial dx. After median 3.2 mos follow up, 16 DST pts were subsequently treated with ST (DST to ST) with significant differences in baseline characteristics among pts remaining in DST, switched from DST to ST, and initially managed with ST. Conclusions: In early experience, 30% of pts in MaRCC initially received active surveillance or local therapy. DST-AS/LT pts may have different baseline characteristics than pts in DST-Other Reason group, as do pts remaining in DST versus those transitioning from DST to ST in a short time. MaRCC will prospectively describe the management and outcomes of the under-studied DST population.
Impact of age on outcomes with PD-(L)1 blockade in patients (Pts) with non-small cell lung cancer (NSCLC).
Authors: Morgan Lichtenstein, Ryan David Nipp, Kelly Goodwin, Danyon Anderson, Richard Newcomb, Justin F. Gainor
Journal: Journal of Clinical Oncology (2018)

10040 Background: As the population ages, it has become increasingly important to understand the risks and benefits of novel agents among older adults with cancer. Immunotherapy (IO) has revolutionized the treatment of advanced NSCLC, but less is known about the activity of PD-(L)1 blockade in older adults (≥70 years). In these pts, immunosenescence may theoretically blunt the effectiveness of anti-PD-(L)1 therapy and/or alter its toxicity profile. We sought to assess the impact of age on clinical outcomes and rates of IO-related toxicities in pts with advanced NSCLC treated with anti-PD-(L)1. Methods: We retrospectively evaluated all pts with NSCLC at our institution treated with IO between 1/2013 and 10/2017. To assess progression-free survival (PFS) and overall survival (OS) across age groups, we performed Kaplan-Meier and Cox regression models adjusted for sex, ECOG, comorbidity, stage at diagnosis (dx), time since dx with metastatic disease, and lines of treatment prior to IO. IO-related toxicities, steroid use, and hospitalizations were also compared. Results: Of 245 pts, 141 (58%) were < 70 years and 104 (42%) were ≥70 years old. Compared with younger pts, older pts had higher comorbidity scores (6.9 vs 6.6, p = 0.024), worse ECOG scores (1.4 vs 1.2, p = 0.011), and lower stage at dx (stage 4: 50% vs 75%, p < 0.001). Older and younger pts had similar median PFS (2.6 vs 2.0 months, p = 0.14) with PD-(L)1 blockade; multivariable models demonstrated equivalent PFS across age groups (HR: 0.81, p = 0.19). Older pts had a worse median OS (8.6 vs 14 months, p = 0.10). After adjusting for key confounders, however, multivariable models demonstrated no significant difference in OS by age (HR = 1.4 p = 0.070). Overall, 102 (42%) pts experienced IO-toxicities with no significant difference by age (41% vs 44%, p = 0.69). Thyroiditis (17%), pneumonitis (10%), and dermatitis (9%) were most common. Toxicity-associated steroid use (26% vs 25%, p = 1.0) and IO-related hospitalizations (12% vs 10%, p = 0.68) did not differ between age groups. Conclusions: Older pts with NSCLC experienced similar toxicity and survival compared to younger pts receiving PD-(L)1 blockade, suggesting that IO may be a viable treatment option for the geriatric population.
TCT-211 Technical Success of Acute Stroke Interventions Performed by Cardiologists – Single Center Experience
Authors: Marius Hornung, Stefan Bertog, Sameer Gafoor, Iris Grunwald, Stefan Weidauer, Kolja Sievert, Ilona Hofmann, Laura Vaskelyte, Horst Sievert
Journal: Journal of the American College of Cardiology (2018)
Phase I study of single agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).
Authors: Christian Grommes, Thomas Joseph Kaley, Craig Nolan, Antonio Marcilio Padula Omuro, Julia Wolfe, Ingo K. Mellinghoff, Lisa Marie DeAngelis
Journal: Journal of Clinical Oncology (2016)

2046 Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for patients with recurrent/refractory disease. Response rates range between 30-60% with a progression free survival (PFS) of 2-6 months. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates ibrutinib in patients with recurrent/refractory (r/r) PCNSL and secondary CNS lymphoma (SCNSL). Methods: Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, KPS ≥ 50, normal end-organ function, and unrestricted number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Ten patients were enrolled (3 at 560 mg; 7 at 840 mg). Median age was 70 (range 21-80); 7 were women. Median ECOG was 1 (0: 1, 1: 5, 2: 4). 70% had PCNSL and 30% SCNSL. Six had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 1 both. Patients were highly pretreated: 2 (both SCNSL) had prior stem cell transplant; 3 (2 PCNSL, 1 SCNSL) prior radiation. The median prior CNS directed therapy was 2; all methotrexate regimens. Two patients withdrew despite clinical and radiographic response. Treatment has been well tolerated with 2 grade 4 toxicities (neutropenia and lymphopenia) that resolved after the drug was held. The most common toxicities observed were hyperglycemia, hypercholesteremia, and thrombocytopenia. After a median follow-up of 150 days, 9/10 patients were evaluated for response: 4 CR (3 in CSF; 1 in the parenchyma), 3 PR, and 2 PD; 78% overall response rate. In 2 patients response has not been confirmed in a 2ndtreatment assessment. Median time to first response was 28 days. The median PFS is 6 months. A higher CSF drug concentration was observed at higher doses of Ibrutinib and at steady state. Continued enrollment is ongoing at 840 mg in an expansion cohort. Molecular testing is ongoing to associate genomic alterations and outcome. Conclusions: Patients with CNS lymphoma tolerate Ibrutinib at 560 and 840mg well. Targeted agents might be an alternative therapeutic approach to be investigated for refractory/recurrent CNS lymphoma patients. Clinical trial information: NCT02315326.
Phase I/II study of nivolumab and ipilimumab combined with nintedanib in advanced NSCLC.
Authors: Sonam Puri, Sandrine Niyongere, Monica Sheila Chatwal, Theresa A. Boyle, Dung-Tsa Chen, David Noyes, Scott Joseph Antonia, Jhanelle Elaine Gray
Journal: Journal of Clinical Oncology (2018)

TPS9112 Background: Combination immunotherapy with nivolumab and ipilimumab has proven clinical activity in NSCLC. There is growing evidence to suggest that the tumor microenvironment (TME) may interfere with effective immune recognition, even in the presence of checkpoint inhibitors. Unpublished preclinical data from our group demonstrates that human lung cancer derived cancer-associated fibroblasts (CAFs) inhibit tumor infiltrating lymphocyte activation and are potentially immunosuppressive. Targeting the TME may represent an important synergistic approach in immunotherapy. Nintedanib is an orally available triple kinase inhibitor that is active against NSCLC, inhibits CAFs, and targets VEGFR, FGFR and PDGFR. Based on these observations a phase IB/II trial of the combination of nintedanib, nivolumab and ipilimumab was initiated in NSCLC patients. Methods: This is a single institution, investigational, non-randomized, parallel assignment phase I/II clinical trial of patients with locally advanced or metastatic NSCLC. Eligible patients can be immunotherapy naïve or with disease progression following immunotherapy. Primary objective of phase I is to determine the tolerability of concurrent administration of the proposed regimen. Three dose levels of nintedanib (100mg, 150 mg and 200 mg twice daily) are given with fixed doses of nivolumab (3mg/kg every 2 weeks) and ipilimumab (1mg/kg every 6 weeks). Dose escalation will be done by the modified continuous re assessment method (O, Quigley et al, 1990). Phase II is divided into two single arm cohorts (Arm A: Treatment or immunotherapy naïve; Arm B: Immunotherapy pretreated). Enrollment to phase II will be done by the Bayesian two-stage design method. The primary objective of phase II is to determine the efficacy of the combination regimen in NSCLC. Key secondary objectives are overall survival and progression free survival. The sample size calculation of 18 patients in phase I and 80 patients in phase II assumes 18 months for accrual and 2-3 years for follow up. Enrollment to phase I was started on 29th January 2018 and to date 1 patient has been enrolled. Serial blood and tumor biopsies are obtained to evaluate potential predictive and resistance mechanisms. Clinical trial information: NCT03377023.
Ranking the efficacies of FOLFOX and FOLFIRI with or without anti-EGFR therapy or bevacizumab in wild-type-RAS metastatic colorectal cancer according to primary tumor location: A network meta-analysis.
Authors: Mingyi Zhou, Lingyu Fu, Lu Zhang, Jingdong Zhang
Journal: Journal of Clinical Oncology (2018)

e15529 Background: The rankings of different FOLFOX and FOLFIRI regimens with or without anti-epidermal growth factor (EGFR) therapy or bevacizumab in patients with wild-type-RAS metastatic colorectal cancer (mCRC) according to primary tumor location (PTL) are unclear. Methods: We searched PubMed, ClinicalTrials.gov, Cochrane Systematic Reviews, the Cochrane Collaboration Central Register of Controlled Clinical Trials, conference databases, and references for papers published up to October 30, 2017. We estimated hazard ratios (HRs) for progression-free survival (PFS), overall survival (OS), and objective response rate (ORR), and ranked the efficacies of all the regimens from best to worst. We also performed subgroup analyses according to PTL. Results: Seven RCTs were included, of which the CRYSTAL, PRIME, FIRE3, PEAK, and TAILOR studies included subgroup analyses according to PTL. Subgroup analyses according to PTL ranked the efficacies of seven of these regimens (FOLFOX alone or plus cetuximab, panitumumab, or bevacizumab, and FOLFIRI alone or plus cetuximab or bevacizumab). FOLFOX plus cetuximab was better than FOLFOX plus panitumumab or bevacizumab in patients with left-sided wild-type-RAS mCRC, while FOLFIRI plus cetuximab was better than FOLFIRI plus bevacizumab. For the patients with right-sided wild-type-RAS mCRC, there was no significant difference among seven regimens. However, in terms of OS, FOLFOX plus cetuximab was better than FOLFOX plus panitumumab or bevacizumab, and FOLFIRI plus bevacizumab was better than FOLFIRI plus cetuximab. Conclusions: FOLFOX or FOLFIRI plus cetuximab may be better than other regimens in patients with left-sided wild-type-RAS mCRC, while bevacizumab plus FOLFIRI or cetuximab plus FOLFOX might be optimal in patients with right-sided wild-type-RAS mCRC.
“Fat Shadows” From DXA for the Qualitative Assessment of Lipodystrophy: When a Picture Is Worth a Thousand Numbers
Authors: Rasimcan Meral, Benjamin J. Ryan, Noemi Malandrino, Abdelwahab Jalal, Adam H. Neidert, Ranganath Muniyappa, Barış Akıncı, Jeffrey F. Horowitz, Rebecca J. Brown, Elif A. Oral
Journal: Diabetes Care (2018)

OBJECTIVE Lipodystrophy syndromes are a heterogeneous group of disorders associated with selective absence of fat. Currently, the diagnosis is established only clinically. RESEARCH DESIGN AND METHODS We developed a new method from DXA scans called a “fat shadow,” which is a color-coded representation highlighting only the fat tissue. We conducted a blinded retrospective validation study to assess its usefulness for the diagnosis of lipodystrophy syndromes. RESULTS We evaluated the fat shadows from 16 patients (11 female and 5 male) with generalized lipodystrophy (GL), 57 (50 female and 7 male) with familial partial lipodystrophy (FPLD), 2 (1 female and 1 male) with acquired partial lipodystrophy, and 126 (90 female and 36 male) control subjects. FPLD was differentiated from control subjects with 85% sensitivity and 96% specificity (95% CIs 72–93 and 91–99, respectively). GL was differentiated from nonobese control subjects with 100% sensitivity and specificity (95% CIs 79–100 and 92–100, respectively). CONCLUSIONS Fat shadows provided sufficient qualitative information to infer clinical phenotype and differentiate these patients from appropriate control subjects. We propose that this method could be used to support the diagnosis.
Recovery of Over-Ground Walking after Chronic Motor Complete Spinal Cord Injury
Authors: Claudia A. Angeli, Maxwell Boakye, Rebekah A. Morton, Justin Vogt, Kristin Benton, Yangshen Chen, Christie K. Ferreira, Susan J. Harkema
Journal: New England Journal of Medicine (2018)

Persons with motor complete spinal cord injury, signifying no voluntary movement or sphincter function below the level of injury but including retention of some sensation, do not recover independent walking. We tested intense locomotor treadmill training with weight support and simultaneous spinal cord epidural stimulation in four patients 2.5 to 3.3 years after traumatic spinal injury and after failure to improve with locomotor training alone. Two patients, one with damage to the mid-cervical region and one with damage to the high-thoracic region, achieved over-ground walking (not on a treadmill) after 278 sessions of epidural stimulation and gait training over a period of 85 weeks and 81 sessions over a period of 15 weeks, respectively, and all four achieved independent standing and trunk stability. One patient had a hip fracture during training. (Funded by the Leona M. and Harry B. Helmsley Charitable Trust and others; ClinicalTrials.gov number, NCT02339233 .).
P04.45 Periarteriolar glioblastoma stem cell niches express bone marrow hematopoietic stem cell niche proteins
Authors: V V V Hira, J R Wormer, H Kakar, B Breznik, B van der Swaan, R Hulsbos, W Tigchelaar, Z Tonar, M Khurshed, R J Molenaar, C J F van Noorden
Journal: Neuro-Oncology (2018)

In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1 α (SDF-1α), C-X-C chemokine receptor type 4 (CXCR4), osteopontin (OPN), and cathepsin K (CatK) are expressed in hypoxic GSC niches around arterioles in five human glioblastoma samples. In HSC niches, HSCs are retained by binding of SDF-1α and OPN to their receptors CXCR4 and CD44, respectively. Protease CatK cleaves SDF-1α to release HSCs out of niches. The aim of the present study was to reproduce the immunohistochemical localization of these GSC markers in 16 human glioblastoma samples with the addition of three novel markers. Furthermore, we assessed the type of blood vessels associated with GSC niches. In total, we found seven GSC niches containing CD133-positive and nestin-positive GSCs as a single-cell layer exclusively around the tunica adventitia of 2% of the CD31-positive and SMA-positive arterioles and not around capillaries and venules. Niches expressed SDF-1α, CXCR4, CatK, OPN, CD44, hypoxia-inducible factor-1α and vascular endothelial growth factor. We show that GSC niches are present around arterioles and express bone marrow HSC niche proteins.
Selection of highly stable genes for the transcriptomic evaluation of lung cancer.
Authors: I. Tirado-Hurtado, Jhajaira M Araujo, Cesar H. Saravia, María Requena, Christian Diego Rolfo, Luis E. Raez, Joseph A. Pinto, Claudio J. Flores
Journal: Journal of Clinical Oncology (2018)

e24318 Background: Evaluation of healthy lung tissues sections from patients with lung cancer as comparator for genomic studies could produce an unwanted bias because the healthy tissue is also exposed to carcinogens producing alterations in gene expression. Our aim in this work was to identify highly stable genes in healthy lung tissues as reference genes with normalization purposes to evaluate lung-tumor transcriptomes. Methods: We evaluated all transcripts evaluated with RNA-Seq (RPKM) of non-tumoral lung tissues (n = 320) from the Genotype-Tissue Expression (GTEx) project. To select the candidate reference genes, we first choose genes with the most stable expression defined for this study as genes with coefficient of variation < 15%, with patterns of normal distribution, low frequencies of alterations ( < 10%) in the TCGA dataset for squamous cell lung cancer and whose expression is not associated with the clinical outcome (assessed in a meta-analysis in KM-plotter for lung cancer). Results: Eleven genes (GNB1, THRAP3, PEX19, TGOLN2, ARIH2, UBE2D2, TMED4, SART3, SNX1, VPS4A and RANBP3) had lowest coefficient of variation, of which PAX19 was excluded because it had a high frequency of alterations (11%). In the meta-analysis in KM-plotter, four 4 genes (GNB1, VPS4A, SART3 and RANBP3) were related with the outcome. Finally, SART3, RANBP3, GNB1 and VPS4A were selected as reference genes. The geometric mean (GM) of the four genes had a low coefficient of variation (9.2%) and was suitable for normalization when compared with the TCGA dataset of squamous cell lung cancer (Table 1). Conclusions: We suggest four genes with normalization purposes to improve the direct comparison between healthy lung tissues with lung tumors. Table 1. Candidate references genes in lung tissue Name Mean SD CV Standard error of the mean (SEM) Normality test SART3 9.85 1.30 13.17 0.073 0.914 RANBP3 14.26 2.08 14.56 0.116 0.741 GNB1 92.38 12.86 13.92 0.719 0.836 VPS4A 37.61 5.53 14.70 0.309 0.666 GM 26.3 2.4 9.16 0.134
PHASE II evaluation of dalantercept for persistent or recurrent epithelial ovarian and related cancers: An NRG oncology study.
Authors: Robert Allen Burger, Wei Deng, Vicky Makker, Heather A. Lankes, Carol Aghajanian, Heidi J. Gray, James Lloyd Wade, Steven E. Waggoner, Douglas A. Levine
Journal: Journal of Clinical Oncology (2016)

e17050 Background: Activin receptor-like kinase 1 (ALK1) drives the maturation phase of angiogenesis. We conducted a two-stage, phase II trial of dalantercept, a soluble ALK1 inhibitor receptor fusion protein, in patients with persistent or recurrent ovarian, fallopian tube or primary peritoneal carcinoma, with correlative endpoints. Methods: Eligibility criteria included measurable disease, 1-2 prior cytotoxic regimens and GOG performance status (PS) ≤ 2. Dalantercept was administered subcutaneously at 1.2 mg/kg every 3 weeks until disease progression or development of unacceptable toxicity. The primary null hypothesis was response rate ≤ 0.10 and rate of ≥ 6-month progression-free survival without receipt of non-protocol therapy (EFS-6) ≤ 0.15, using RECIST 1.1 criteria. Tumor and plasma biomarkers were assessed by immunohistochemistry (IHC), gene expression, and ELISA in an exploratory fashion in association with EFS-6, with an unadjusted p-value of < 0.05 considered interesting. Results: The first stage was closed after enrollment of 30 participants with median age of 56.5 years, high-grade serous histology in 76.7%, 2 prior regimens in 46.7%, and platinum-free interval ≤ 6 months in 73.3%. All participants discontinued dalantercept, 24 (80.0%), 5 (16.7%) and 1 (3.3%) due to progression, toxicity, and other reason, respectively. The median number of treatment cycles per patient was 2 (range 1 – 29). There were six treatment-related grade 3 AEs and no grade ≥ 4 AEs. There were no objective responses. EFS-6 was 20% (6 out of 30 participants, 90% CI 9.1% to 35.7%). Biomarkers deemed interesting were BMP10 IHC score (worse EFS-6, HR 2.85); plasma BMP9 (improved EFS-6, HR 0.36); plasma VEGF (worse EFS-6, HR 3.45). ALK1 tumor IHC or plasma level was not associated with outcome. Four of 125 genes were deemed interesting. Conclusions: Though well tolerated, dalantercept as administered had limited efficacy in this patient population overall. Several biomarkers consistent with dalantercept’s proposed mechanism of action were associated with the primary outcome, but these associations will require further validation through properly controlled follow-up studies. Clinical trial information: NCT01720173.