tbuckley/cabot-search huggingface dataset:
Apostream to isolate circulating tumor cells (CTC) from castration-resistant prostate cancer patients (CRPC) that express androgen receptor variant 7 (AR-V7) associated with resistance to AR-targeting drugs.
Authors: Darren W. Davis, Asifa Haider, Valerie Pierron, Fabien Schmidlin
Journal: Journal of Clinical Oncology (2016)

e23025 Background: Emerging evidences indicate that prostate tumors adapts to androgen-directed therapies via AR-V7 signaling. These tumors progress to incurable CRPC leading to a need to monitor therapy resistance. This study evaluated ApoStream technology to capture AR-V7 expressing CTCs from blood originating from primary tumor cells (epithelial) and those that undergo epithelial-mesenchymal transition (EMT) of CRPC patients. Methods: Blood (8ml) collected from consented CRPC patients (n = 10) was enriched for CTCs by ApoStream. The CTCs were evaluated for AR-V7 multiplexed immunofluorescent assay to identify [Epithelial] (CK, EpCAM, E-Cadherin) and [EMT](Vimentin, N-Cadherin, Twist)- CD45+/- subtypes . The cell counts (normalized to per ml) for each phenotype and the expression of AR-V7 was measured using laser scanning cytometry. Prior to testing patient samples, each marker was qualified in positive (HeLa, MCF7, VCaP, LNCaP) and negative cells (MCF7 and PBMCs). Next AR-V7 multiplexing assay was tested in cancer cell lines (VCaP and LNCaP) spiked into healthy donor PBMCs (n = 3) and enriched via ApoStream. The specificity of AR-V7 was tested in LNCaP (express AR-V7), PC3-Parental (PC3-P negative for AR expression) and PC3-AR (PC3 transfected with AR-wt). Results: AR-V7 expression was specific for LNCaP, while PBMCs, PC3-AR or PC3-P cells lacked expression. ApoStream enriched cancer cells from cell lines expressed AR-V7 in both epithelial and EMT CTCs. Epithelial CTCs were detected in 6/10 patients in CD45-(range: 0-56, median: 9.5) and in 7/10 in CD45+ (range: 0-7, median: 1) cells. Mesenchymal CTCs were detected in 5/10 patients for both CD45- (range: 0-13, median: 0.5) and CD45+ (range: 0-211, median: 0.5) cells. AR-v7 expression was detected in both epithelial and EMT CTCs. Conclusions: ApoStream enriched epithelial and EMT CTCs from CRPC blood demonstrating utility in recovering cancer cells with multiple phenotypes. Furthermore, detection of AR-V7 + CTCs was possible indicating clinical relevance and utility of CTCs as an alternative tissue biopsy for assessing resistance in CRPC.
Local treatment with bisphosphonates to restore activity of α2-macroglobulin and α1-proteinase inhibitor in osteolytic metastases from breast cancer.
Authors: Artem A. Barashev, Oleg I. Kit, Elena M. Frantsiyants, Larisa S. Kozlova, Larisa Nikolaevna Vashchenko, Marina I. Vereskunova, Ludmila Ya. Rozenko
Journal: Journal of Clinical Oncology (2018)

e13105 Background: The purpose of the study was to determine the activity of universal blood plasma inhibitors in cancer patients with solitary osteolytic metastases from breast cancer in local treatment with bisphosphonates. Methods: The blood plasma of 78 patients aged 39-73 years with solitary osteolytic metastases (pT3-4NхM1) was studies, as well as the blood plasma of 39 donors (N). 34 patients of the control group (CG) received standard complex treatment; 44 patients of the main group (MG) received an additional local treatment with zoledronic acid. All patients underwent intramedullary osteosynthesis or percutaneous vertebro- and osteoplasty. Kinetics of α2-Macroglobulin (α2M) and α1-Proteinase Inhibitor (α1PI) was determined spectrophotometrically on days 1 and 7 after surgery and in 1 and 6 months. Statistica 10.0 was used for the statistical processing of the data. Results: Before treatment, the blood plasma of all patients demonstrated decreased activity of α2M and α1PI (р < 0.001). Activity of α2M in CG on days 1 and 7 after surgery was 2.4 and 1.6 times lower than N, and α1PI was 2.0 and 1.3 lower, respectively. In MG, α2M on days 1 and 7 was similar to N, while α1PI exceeded N by 1.5 and 1.6 times (p < 0.001). This coincided in time with a reduction (27 patients, 61.4%) or disappearance (16 patients, 36.4%) of the pain syndrome; by day 7, the pain was managed in 43 of 44 patients of MG. Watkins’ coefficient in MG by the time of discharge was 0.80-0.85. Pain reduction in CG was observed on day 7 in 35.3% (12 of 34 patients). Activity of α2M in CG in 1 and 6 months was 1.2 and 1.3 lower than N, in CG – exceeded N by 2.1 and 1.7 times, respectively. Activity of α1PI in CG in 1 and 6 months was still 1.3 times lower than N, while in MG it was 1.6 and 1.4 times higher than N. Conclusions: Prolonged activation of proteolysis in the development of osteolytic metastases resulted in depletion of α2M and α1PI in the blood plasma of all patients. Local intraoperative treatment with zoledronic acid restored the activity of α2M and α1PI in circulation from day 1 after surgery, contributing to its maintenance in the post-hospital period.
18F 2Fluoro-2deoxy-D-glucose positron emission tomography (FDG-PET) response to predict event-free survival (EFS) in intermediate risk (IR) or high risk (HR) rhabdomyosarcoma (RMS): A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG).
Authors: Douglas James Harrison, Marguerite T Parisi, Barry L. Shulkin, Yueh-Yun Chi, James Robert Anderson, Xinlei Mi, Suman Malempati, Leo Mascarenhas, Geoffrey Brian McCowage, Brenda Weigel, Suzanne L. Wolden, Torunn I. Yock, David A. Rodeberg, Andrea Anita Hayes-Jordan, Lisa A. Teot, Sheri L. Spunt, William H. Meyer, Douglas S. Hawkins
Journal: Journal of Clinical Oncology (2016)

10549 Background: Change in tumor size by anatomic imaging is not a reliable predictor of outcome in RMS. We reviewed metabolic response by FDG-PET for patients with IR and HR RMS enrolled on two COG therapeutic trials, ARST0531 and ARST08P1, to determine if FDG-PET was associated with EFS in RMS. Methods: In addition to anatomic imaging to assess radiographic response, FDG-PET was an optional observation for ARST0531 and ARST08P1. The timing of FDG-PET was at study entry, week 4 prior to radiation therapy (RT), and week 15 after RT on ARST0531 and at study entry, week 6, and week 19 (both prior to RT) on ARST08P1. Patients with measurable primary tumors at study entry were included in the analysis. Two nuclear medicine physicians who were blinded to patient outcomes reviewed the FDG-PET images and classified FDG-PET response as complete (CR), partial (PR), stable disease (SD), or progressive disease (PD). EFS by FDG-PET response category was compared by the log-rank test. Results: For ARST0531, 26 and 51 of 450 eligible patients had week 4 and 15 FDG-PET available for response evaluation, respectively. There was no difference in EFS between patients with CR compared to those with PR/SD/PD. For ARST08P1, 70 of 168 eligible patients had FDG-PET available for response evaluation. There was no difference in EFS for patients with CR primary site at week 6 or week 19 compared to those with PR/SD/PD (see table). Conclusions: Metabolic response as assessed by FDG-PET at the timepoints evaluated did not predict EFS in IR or HR RMS. For HR and IR RMS, FDG PET is no better than anatomic imaging in predicting EFS, although may improve the accuracy of initial staging or local control planning. STUDY n (3-year) EFS by FDG-PET Response p value CR PR/SD/PD ARST0531 Week 4 26 67% (n = 3) 52% (n = 23) 0.65 Week 15 51 59% (n = 33) 67% (n = 18) 0.70 ARST08P1 Week 6 70 16% (n = 24) 18% (n = 46) 0.73 Week 19 70 13% (n = 51) 28% (n = 19) 0.27
Lung cancer liquid biopsy assays by qPCR using iDDS probe and Wild Terminator methods.
Authors: Zhonglin Hao, James L. Murray, Peixu Hu, Germame Hailegiorgis Ajebo, Muhammad Furqan, Jun Zhang, Shou-Ching Tang, David A. Shafer
Journal: Journal of Clinical Oncology (2018)

e21178 Background: Liquid biopsy offers enormous potential healthcare benefits. Early detection of rare driver or resistance mutations increases the lead time before disease manifestation, enabling earlier medical intervention, potentially with targeted therapeutics. This may translate into better treatment outcomes, longer overall survival and better quality of life. Current liquid biopsy methods are limited by mis-annealing, causing low sensitivity and specificity. Exon 19 deletions and L858R point mutations are the most common EGFR mutations in lung cancer. Drug-resistance commonly occurs via the EGFR T790M mutation. Methods: GeneTAG Technology develops molecular diagnostic assays for cancer and infectious diseases, and their Internal DNA-Detection Switch (iDDS) probe system comprises two interacting components: a fluor-labeled probe, and a quencher-labeled antiprobe that is nearly complementary to the probe. In the absence of the intended target, the paired probe and anti-probe hybridize, quenching fluorescence and preventing off-target detection. This unique probe system shows superior single-base discrimination over a wider annealing-temperature range (10–30ºC) than common qPCR methods. Recently, we merged our iDDS probe technology with our Wild Terminator (WTx) methods that enable detection of rare mutants (0.1–0.01% frequency) by blocking amplification of the wild-type sequence. Results: In vitro, we detected APC (R1450Stop), BRAF (V600E), CTNNB1 (T41I, T41A), IDH1 (R132H), and IDH2 (R172K) variants at a trace frequency (1–0.01%) in an overwhelming background of genomic DNA. In a pilot study, the combined method showed greater sensitivity in detecting circulating EGFR variants from lung cancer patients than the FDA-approved cobas® EGFR Mutation Test. Sanger sequencing results showed 100% agreement with the WTx-iDDS probe assays, while revealing 7 false-negatives and 1 false-positive with the cobas test. Conclusions: This enhanced qPCR sensitivity exceeds the sensitivity of specialized platforms that have high instrumentation costs. Our higher sensitivity and specificity will enable development of inexpensive and platform-independent liquid biopsy assays.
TCT-701 Consecutive Intravascular Imaging Assessment up to 3 Years Following Implantation of Resorbable Magnesium Scaffolds
Authors: Himanshu Rai, Hector Garcia-Garcia, Michael Haude, Ralph Toelg, Evald Christiansen, Hüseyin Ince, Clemens von Birgelen, Alexandre Abizaid, Pedro A. Lemos, Emanuele Barbato, Javier Escaned, Michael Joner
Journal: Journal of the American College of Cardiology (2018)
CT perfusion in patients with advanced lung adenocarcinoma treated with conventional chemotherapy and antiangiogenesis therapy.
Authors: Ling-yu Ding, Zhe-long Jiang, Hai-ying Wu, Tie-bao Meng, Qiu-xia Yang, Ang Wu, Shi-xiu Wu
Journal: Journal of Clinical Oncology (2018)

e21099 Background: The aims of our study were to determine whether perfusion computed tomography (CT) imaging can allow evaluation of the effects of chemotherapy combined with anti-angiogenesis treatment in patients with advanced lung adenocarcinoma and to determine if changes in CT numbers correlate with the response to therapy as assessed by conventional response evaluation criteria in solid tumors (RECIST). Methods: Twenty-four patients with advanced lung adenocarcinoma underwent perfusion CT before and 42 days after pemetrexed, cisplatin and bevacizumab treatment. RECIST measurements and calculations of blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability (PS) were performed. Pearson correlation coefficient was used to assess the correlation between baseline CT numbers. Baseline and follow-up perfusion parameters of the tumor mass were tested for statistically significant differences and then were also compared on the basis of the therapy response assessed by RECIST criteria, using the repeated-measures analysis of variance (ANOVA). Results: Differences of BF value between baseline and post-therapy was significant (P = .024). Pearson correlation coefficient showed a significant correlation between baseline values of BF and BV (r = 0.428; P = .037), and BF and MTT (r = -0.609; P = .002). No significant correlations were found between BF and PS (P = .652), BV and MTT (P = .101), BV and PS (P = .066), and between MTT and PS (P = .227). Baseline PS value was significantly higher in responding patients than in the other patients (P = .017). No significant changes were found for baseline values of BF (P = .178), BV (P = .227), and MTT (P = .580) between patients with partial response, stable disease, or progressive disease. Conclusions: Perfusion CT imaging may allow evaluation of anti-angiogenesis therapy in lung cancer, demonstrating the potential as a tool for guiding lung cancer prognostication.
Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA
Authors: Mohammad Ariful Islam, Yingjie Xu, Wei Tao, Jessalyn M. Ubellacker, Michael Lim, Daniel Aum, Gha Young Lee, Kun Zhou, Harshal Zope, Mikyung Yu, Wuji Cao, James Trevor Oswald, Meshkat Dinarvand, Morteza Mahmoudi, Robert Langer, Philip W. Kantoff, Omid C. Farokhzad, Bruce R. Zetter, Jinjun Shi
Journal: Nature Biomedical Engineering (2018)
Tetrahydrouridine/decitabine/5-azacytidine for non-cytotoxic epigenetic-immunotherapy of NSCLC in vivo.
Authors: Kai Kang, Arjun Khunger, David S. Schrump, Mark P. Rubinstein, John M. Wrangle, Yogen Saunthararajah, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2018)

e24134 Background: Most advanced non-small cell lung cancer (NSCLC) cases do not respond to anti-PD1 therapy, because most NSCLC avoids immune-recognition in the 1st place, e.g, by epigenetic suppression of neo-antigen expression by DNA methyltransferase (DNMT1). DNMT1 is depleted by the clinical drugs decitabine (Dec) and 5-Azacytidine (5Aza), however, Dec/5Aza have trivial distribution into solid tissues because of rapid deamination by cytidine deaminase (CDA) in vivo, undermining application to treat NSCLC. We therefore combined a CDA inhibitor tetrahydrouridine (THU) with Dec/5Aza. Methods: Mice were inoculated with LL3-luc cells via tail vein (syngeneic) or patient tumor and PBMC via SC and tail vein (humanized PDX). Treatment with PBS (veh), THU-Dec/5Aza (10/0.1/1 mg/kg 3X/week), anti-PD1/Nivolumab (5 mg/kg ip q5d) or the combination was initiated after documentation of tumor engraftment (n = 5/group) Tumor burden, median survival (MS) were recorded. T-cell numbers/phenotype and drug PD were measured in blood and tumors. Results: Consistent with the pharmacologic rationale, THU-Dec/5Aza produced > 2-fold more DNMT1-depletion in tumor, and > 2-fold extension of MS, vs Dec or 5Aza alone. THU-Dec/5Aza or anti-PD1 alone increased MS vs PBS (THU-Dec/5Aza 60 d, anti-PD1 64 d, PBS 40 d), but strikingly, the combination produced cures. Immune-augmentation was demonstrated by > 5-fold increase in tumor infiltrating lymphocytes (TILs) with the combination vs PBS. An immune-basis for cures was confirmed by LL3-luc rechallenge, which did not engraft in surviving mice, but engrafted treatment naïve mice. Extending these results, in the humanized PDX, the combination again produced the greatest tumor regression (PBS 2.06 g, THU-Dec/5Aza 0.39 g, Nivolumab 0.54 g, combination 0.21 g). Again, TILs were increased ~5-fold with the combination vs PBS (p < 0.01). Also noted were significantly higher IFNγ, granzyme B, perforin expression in tumor 3.8, 4.2, 3.6-fold respectively vs PBS (p < 0.01). Conclusions: Combining THU with alternating Dec/5Aza realizes the value of DNMT1 as a molecular target that increases immune-recognition and destruction of NSCLC in vivo, scientific validation of our trial NCT02664181.
Abstract 15317: Deletion of Low Molecular Weight Protein Tyrosine Phosphatase (Acp1) Protects Against Stress-induced Cardiomyopathy
Authors: Salma Mahmoud, Fallou A Wade, Pearl Quijada, Kamar A Mohamed Adib Al-Haffar, Muhammad A Kunhi, Haruhiro Toko, Qussay Marashly, Karim Belhaj, Esra Ibrahim, Stephanie M Stanford, Roberto Alvarez, Yingge Liu, Dilek Colak, Maria C Jordan, Kenneth P Roos, Waleed A Al-Habeeb, Mark Sussman, Nunzio Bottini, Coralie Poizat
Journal: Circulation (2015)

Background: The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, is a ubiquitously expressed phosphatase whose in vivo function remains poorly understood. Genetic studies revealed an association between ACP1 and a variety of human cardiovascular disorders. However, evidence of a direct involvement of LMPTP in cardiac diseases is still lacking. Methodology: We generated the first mouse model of Lmptp deficiency and studied the response of the mice under basal condition or to long-term pressure overload using comprehensive experimental approaches such as q-PCR, siRNA technology, fluorescent microscopy and immuneprecipitation technique. Results: Acp1 -/- mice develop normally, and aging mice do not show any obvious signs of pathology in major tissues under basal condition. However, Acp1 -/- mice are strikingly resistant to pressure overload hypertrophy and heart failure. Lmptp expression is high in the embryonic mouse heart, decreased in the post-natal stage, and increased in the adult mouse and human failing heart. Consistent with their protected phenotype, Acp1 -/- mice subjected to pressure overload hypertrophy have attenuated fibrosis and decreased expression of hypertrophic markers. Transcriptional profiling and analysis of molecular signaling shows that the resistance of Acp1 -/- mice to pathological cardiac stress correlates with marginal expression of fetal cardiac genes, increased insulin receptor beta phosphorylation and inactivation of CaMKIIδ pathway. Conclusion: Our data show that ablation of Lmptp inhibits pathological cardiac remodeling and suggest that inhibition of LMPTP may be of therapeutic relevance for the treatment of heart failure in human.
Evolving changes in M-protein (M), quantitative involved immunoglobulin (Ig), and hemoglobin (Hb) to identify patients (pts) with ultra high-risk smoldering multiple myeloma (UHR-SMM).
Authors: Praful Kumar Ravi, Shaji Kumar, Jeremy Todd Larsen, Wilson I. Gonsalves, Francis Buadi, Martha Lacy, Ronald S. Go, Angela Dispenzieri, Prashant Kapoor, John Anthony Lust, Morie A. Gertz, Robert A. Kyle, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2016)

8004 Background: There are limited data on the impact of evolving changes in SMM biomarkers on risk of progression to multiple myeloma (MM). We aimed to utilize such changes to identify an UHR-SMM subgroup ( ≥ 80% risk of progression within 2yrs), a threshold recommended by the International Myeloma Working Group (IMWG) to meet diagnostic criteria for MM. Methods: From an IRB-approved database, we identified SMM pts treated between 1973 and 2014 at our institution. Only pts meeting the revised 2014 IMWG SMM diagnostic criteria were included, and those who received myeloma-specific therapy before progression or without adequate follow-up to permit study of evolving changes in biomarkers were excluded. Evolving change in monoclonal protein (eMP) was defined as ≥ 10% increase in M and/or Ig (M/Ig) within 6mths of diagnosis (only if M ≥ 3) and/or ≥ 25% increase in M/Ig within 12mths, with a required minimum increase of 0.5g/dL in M and/or 500mg/dL in Ig. Evolving change in Hb (eHb) was defined as ≥ 0.5g/dL decrease within 12mths of diagnosis. Results: The total cohort comprised 191 pts; 135 (70.7%) progressed to MM, with 61 (31.9%) progressing within 2yrs of diagnosis. Median time to progression (mTTP) was 3.9yrs and median follow-up was 10.4yrs. On multivariable analysis adjusting for factors known to predict for progression to MM, ≥ 20% bone marrow plasma cells at SMM diagnosis (BMPC ≥ 20%) [OR = 3.26 (1.27-8.40), p = 0.014], eMP [OR = 7.26 (2.89-18.26), p < 0.001] and eHb [OR = 6.01 (2.24-16.13), p < 0.001] were independent predictors of progression within 2yrs; all 3 risk factors (RFs) retained significance if eHb required confirmation with a second value. A risk model comprising these variables was constructed, with mTTP of 12.3yrs, 4.2yrs, 2.8yrs and 1.0yrs in pts with none, 1, 2, and 3 RFs respectively (p < 0.001). The 2-yr risk of progression was 82.8% in pts with both eMP and eHb, and increased to 90.9% in those with all 3 RFs. Conclusions: Pts with eMP and eHb, with or without BMPC ≥ 20%, had ≥ 80% risk of progression to MM within 2yrs and comprise an UHR-SMM subgroup. Further validation is required before these parameters can be added to diagnostic criteria for MM.
Updated safety and clinical activity of durvalumab monotherapy in previously treated patients with stage IIIB/IV NSCLC.
Authors: Ani Sarkis Balmanoukian, Scott Joseph Antonia, Wen-Jen Hwu, Omid Hamid, Martin Gutierrez, Rahima Jamal, Guy Heinrich Maria Jerusalem, Myung-Ju Ahn, Dong-Wan Kim, David Cunningham, Sang-We Kim, Julie R. Brahmer, Jose Lutzky, Jared Weiss, Xiaoping Jin, Joyce Antal, Ashok Kumar Gupta, Neil Howard Segal
Journal: Journal of Clinical Oncology (2017)

9085 Background: Preliminary analyses of an ongoing Phase 1/2 study of single-agent durvalumab showed antitumor activity and a tolerable safety profile in advanced NSCLC, with higher ORR and longer OS in pts with high vs. low/negative PD-L1 tumor expression. Here we present updated safety analyses (primary endpoint) for all NSCLC pts and clinical activity based on investigator-assessed RECIST v1.1 in pts who had received prior treatment for advanced NSCLC. Methods: Durvalumab (10 mg/kg q2w) was given until unacceptable toxicity or disease progression, or for up to 12 mos; retreatment was permitted upon disease progression after completion of 12 mos of treatment. PD-L1 expression was assessed using the Ventana PD-L1 (SP263) Assay (PD-L1 high = ≥25% and PD-L1 low/negative = &lt;25% of tumor cells with membrane staining). Results: As of 24 Oct 2016, 245 pts with previously treated NSCLC (53% squamous) received durvalumab and were followed for a median of 29.2 (range 0.3–40.5) mos; 142 pts (58%) had treatment-related adverse events (AEs), most frequent: fatigue (18%), decreased appetite (9%), and nausea, rash, and diarrhea (each 8%). 25 pts (10%) had treatment-related Grade 3/4 AEs, most frequent: fatigue and hyponatremia (each 2%); there were no treatment-related deaths. 4% had treatment-related serious AEs including colitis and pneumonitis (each 2%). In the overall population, 12 mo OS rate was 47% (95% CI 40–53) and 18 mo OS rate was 38% (95% CI 31–45). Antitumor activity and survival by PD-L1 status are shown in the table. Conclusions: Consistent with earlier reports, durvalumab had a manageable safety profile in Stage IIIB/IV NSCLC, with encouraging clinical activity as 2L+ therapy. Higher tumor PD-L1 expression enriched clinical benefit of response rate and survival endpoints. Clinical trial information: NCT01693562. [Table: see text]