tbuckley/cabot-search huggingface dataset:
Abstract 17473: Differences in Hospital Risk-standardized Mortality Rates for Acute Myocardial Infarction by Patient Age Group: Implications for Hospital Outcome Profiling
Authors: Kumar Dharmarajan, Yongfei Wang, Robert McNamara, Frederick Masoudi, Joseph Ross, Nihar Desai, Erica Spatz, James de Lemos, Gregg Fonarow, Paul Heidenreich, Deepak Bhatt, Susannah Bernheim, Lara Slattery, Yosef Khan, Jeptha Curtis
Journal: Circulation (2016)

Introduction: Hospital 30-day risk-standardized mortality rates (RSMRs) for acute myocardial infarction (AMI) are only calculated for Medicare beneficiaries ≥65 years-old. While these data are often used to guide quality improvement within hospitals, it is not known if outcomes for older patients reflect hospital quality more broadly. Hypothesis: Hospital 30-day RSMRs for older patients with AMI strongly correlate with 30-day RSMRs for all adult patients and 30-day RSMRs for younger patients with AMI. Methods: Retrospective study of AMI hospitalizations from 12/1/2011 to 11/30/2012 in the ACTION registry/GWTG linked to the National Death Index with direct identifiers. Hospital 30-day RSMRs for older patients, all adult patients, and younger patients with AMI were calculated using an EHR-based measure of 30-day mortality endorsed by the National Quality Forum for public reporting. We calculated the correlation coefficient of hospital 30-day RSMRs for older AMI patients with 30-day RSMRs for all adult AMI p...
Cervical microbiome role in outcomes of therapeutic HPV vaccination for cervical intraepithelial neoplasia.
Authors: Rahul Ravilla, Hannah Coleman, Luisa Chan, Cheryl-Emiliane Chow, Barbara Fuhrman, William Greenfield, Michael Scott Robeson, Kathryn Iverson, Horace J Spencer, Mayumi Nakagawa
Journal: Journal of Clinical Oncology (2018)

3099 Background: Clinical trials have suggested that the gut microbiome can modulate immunotherapy outcomes with checkpoint inhibitors (Kroemer et al, Nat rev immunology. Jan 2018). However, the role of cervical microbiome has not been investigated. We studied the effect of cervical microbiome on outcomes of a novel therapeutic HPV vaccine in women with high grade cervical neoplasia. Methods: We collected 65 cervical samples (34 pre-screen and 31 post-vaccination) from 34 women enrolled in a phase 1 therapeutic vaccine trial (Coleman et al. Cancer Immunol Immunotherapy. May 2016). Whole DNA was isolated from cervical Thinprep samples using the Qiagen DNA Mini Kit and amplified by PCR using a bacterial 16sRNA gene primer. eOTUs were identified using V1-V9 16S rRNA gene hybridization with G4 Phylochip™ (Second Genome, South San Francisco, CA). Alpha and beta diversity metrics were calculated. We used PERMANOVA analysis to test for associations of phylogenetic composition with patient demographics; HPV status; HLA type; circulating Th1, Th2, and Treg cells; local TFoxp3 cells and clinical response to the vaccine. Responders and non-responders were defined based on histological regression of cervical lesions. Results: Richness ranged from 72 to 365 eOTUs per sample, and Prevotellaceae and Lactobacillaceae were the most abundant families observed. We found that pre-screen samples from vaccine non-responders, as compared to responders, were enriched with the phyla Caldithrix, Nitrospirae and family Mycoplasmataceae and an unclassified family from order Entomoplasmatales. HPV16 status and HLA B40 status were significantly associated with beta diversity. Measures of pre- and post-vaccination alpha and beta diversity were not statistically significantly associated with response to vaccine. Also, we observed no correlations of microbiome metrics with immune parameters. Conclusions: Study findings suggest that cervical microbial composition may predict non-responsiveness to a therapeutic vaccine given to treat high-grade cervical neoplasia. Observed associations of cervical microbial composition with HLA B40 and HPV 16 status are of interest but require further investigation. Clinical trial information: NCT01653249.
Relationship between quality of life (QoL) and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients after chemotherapy: Results from the AFFIRM study.
Authors: Kurt Miller, David Cella, De Phung, Shevani Naidoo, Stefan Holmstrom, Cristina Ivanescu, Konstantina Skaltsa
Journal: Journal of Clinical Oncology (2016)

5060 Background: We investigated the association between QoL and clinical outcomes such as overall survival (OS) and radiographic progression-free survival (rPFS) from AFFIRM (NCT00974311; Scher et al, 2012). Methods: AFFIRM was a phase 3 trial in mCRPC patients progressing after chemotherapy, randomized to enzalutamide (160mg/day; n = 800) or placebo (n = 399). QoL was assessed at baseline and during treatment using the FACT-P instrument. Univariate Cox regression evaluated which individual QoL scores had prognostic value for rPFS or OS. Multivariate Cox regression evaluated the prognostic value of baseline and time-dependent QoL scores after adjusting for treatment and relevant clinical and demographic variables. FACT-P total score and subdomains (physical well-being [PWB]/functional well-being [FWB]/prostate cancer subscale [PCS]) were assessed in separate models. Results: In the univariate analysis, higher baseline scores (e.g. better QoL) for FACT-P total and subdomains were associated with reduced risk of death (hazard ratio [HR] range 0.78–0.84; p< 0.01) and progression (HR range 0.90–0.94; p< 0.01). Upon multivariate analysis, baseline QoL scores predictive of OS were FWB (HR 0.90; 95% CI 0.84, 0.96) and FACT-P total score (HR 0.88; 95% CI 0.84, 0.93). The FACT-P total score was predictive of rPFS (HR 0.95; 95% CI 0.91, 0.99). Associations between time-dependent QoL and OS were observed for all QoL outcomes. Every 10-point increase in FACT-P total score (i.e. improvement) was associated with a 19% decreased risk of death (HR 0.81; 95% CI 0.78, 0.84). Every 3-point increase in PWB, FWB, or PCS was associated with an 8%, 14%, and 9% decreased risk of death, respectively (PWB HR 0.92; 95% CI 0.86, 0.98; FWB HR 0.86; 95% CI 0.81, 0.92; PCS HR 0.91; 95% CI 0.86, 0.95). Conclusions: This research shows that baseline QoL is a prognostic factor of rPFS and OS and that changes in QoL during treatment are informative for the patient’s expected survival. This may help decision-making in the management of mCRPC. Clinical trial information: NCT00974311.
YH25448, a 3rd generation EGFR-TKI, in patients with EGFR-TKI-resistant NSCLC: Phase I/II study results.
Authors: Byoung Chul Cho, Ji-Youn Han, Sang-We Kim, Ki Hyeong Lee, Dong-Wan Kim, Yun-Gyoo Lee, Gyeong-won Lee, Jong-Seok Lee, Eun Kyung Cho, Joo-Hang Kim, Sung Sook Lee, Young Joo Min, Jin-Soo Kim, Sang Won Shin, HyeRyun Kim, Min Hee Hong, Jin Seok Ahn, Soongyu Choi, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2018)

9033 Background: The epidermal growth factor receptor (EGFR) T790M mutation is one of the most common acquired resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). YH25448 is an oral, potent, irreversible EGFR TKI that is highly selective for activating (EGFRm) and T790M resistance mutations. Methods: Patients with EGFRm advanced NSCLC with acquired resistance to EGFR-TKIs with or without asymptomatic brain metastases were enrolled in an open-label, multicenter, phase I/II study with dose escalation and expansion cohorts. YH25448 was administered once daily at doses of 20 to 240 mg in a 21 day cycle. Patients were assessed for safety, tolerability, pharmacokinetics and efficacy. T790M status was confirmed in the expansion cohorts. Results: A total of 105 patients (median age 62 years, female 61%) were enrolled. The dose escalation cohort included 33 patients administered with 20 to 240 mg once daily across 6 dose levels, and 72 patients in the dose expansion cohort were administered with 40 to 240 mg. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events (AEs) were pruritus (12%), decreased appetite (11%), rash (11%), and constipation (10%). AEs of grade 3 or higher were observed in 5% of the patients. Systemic exposure increased dose-dependently. Of the evaluable patients (n = 91) at data cut-off, the objective response rate (ORR) was 64% (95% confidence interval [CI], 53.0 to 73.6). The ORR for 76 of the T790M-positive patients was 67% (95% CI, 55.4 to 77.5), and for 15 of the T790M-negative patients was 47% (95% CI, 21.3 to 73.4). In patients with brain metastases (n = 9), the overall intracranial ORR was 56% (95% CI, 21.2 to 86.3). Conclusions: YH25448 was well tolerated and exhibits promising systemic and intracranial antitumor activity at multiple dose levels in EGFR T790M+ NSCLC patients. Clinical trial identifier: NCT03046992. ORR in T790M+ patients. Dose, QD 20 mg 40 mg 80 mg 120 mg 160 mg 240 mg Evaluable patients*, n 2 25 18 21 8 2 ORR, n (%) 2 (100) 17 (68) 11 (61) 15 (71) 4 (50) 2 (100) *Patients are evaluable for response if they have post-baseline radiological assessment (RECIST 1.1) or patients who discontinued prior to the post-baseline assessment.
Effect of an anti-MARCKS peptide (BIO-11006) on metastasis of lung cancer in vivo.
Authors: Kenneth B Adler, Indu Parikh, Anne Crews, Shijing Fang, Qi Yin, Brian Dickson
Journal: Journal of Clinical Oncology (2017)

e23017 Background: We have previously reported that administration of peptides that inhibit the function of MARCKS (myristoylated alanine-rich C Kinase Substrate) inhibit metastasis of human lung cancer cells orthotopically-injected into the left lung of SCID mice (Chen et al: Oncogene 33:3696–3706, 2014; Chen et al: Am J Resp Crit Care Med 190:1127-1138, 2015). Methods: Here, we administered an anti-MARCKS peptide, BIO-11006, as an inhaled aerosol in 2 models of lung cancer in SCID mice: PC-9 cells orthotopically injected into the left lung, and A549 cells injected into the tail vein. In the orthotopic model, initiation of treatment with BIO-11006 at day 4 post injection of cells and treatment every day thereafter for 4 weeks resulted in dramatic attenuation of tumor metastasis into the lung, heart and diaphragm, with similar attenuation whether the peptides were administered IP or via inhaled aerosol. In additional studies with this model, we waited until day 26 post orthotopic cell injection, a time when there was already extensive metastasis to the lung and distal organs, to begin daily treatment with BIO-11006 via inhalation. Results: There was complete inhibition of further metastasis and primary tumor growth when the animals were examined at day 38 post orthotopic injection of cells. Similar results with the tail vein model were observed: when the peptide was administered by aerosol starting at day 3 post tail vein inoculation, metastasis observed 8 weeks later in distal organs was inhibited by ~ 95% by treatment with inhaled BIO-11006. When PC-9 cells were examined via confocal microscopy, BIO-11006 was seen to cause a cytoskeletal rearrangement so that the cells took on a morphology favoring adherence to the substrate rather than movement. Conclusions: The results suggest that inhaled BIO-11006, already completed in phase 2 clinical trials in patients with COPD, appears to have potent antimetastatic effects in two different mouse models of lung cancer. Clinical trials of inhaled BIO-11006 in patients with advanced lung cancer were initiated in January of 2017.
Spatially controlled assembly of affinity ligand and enzyme cargo enables targeting ferritin nanocarriers to caveolae
Authors: Vladimir V. Shuvaev, Makan Khoshnejad, Katherine W. Pulsipher, Raisa Yu. Kiseleva, Evguenia Arguiri, Jasmina C. Cheung-Lau, Kathleen M. LeFort, Melpo Christofidou-Solomidou, Radu V. Stan, Ivan J. Dmochowski, Vladimir R. Muzykantov
Journal: Biomaterials (2018)
Tumor molecular profiling to differentiate extreme responses to first-line platinum-based chemotherapy in suboptimally debulked serous ovarian cancer patients.
Authors: Johanne I Weberpals, Trevor Pugh, Glenwood D. Goss, Bryan Lo, Natalie Andrews Wright, Laurence Bernard, Dax Torti, Jonathon Torchia, Prisni Rath, Alberto Leon, Kayla Marsh, Darren R. Hodgson, Gemma N Jones, Marc Duciaume, William J Howat, Paola Marco-Casanova, Martine P Roudier, Doreen Whelan, Harmanjatinder S. Sekhon
Journal: Journal of Clinical Oncology (2018)

5561 Background: Patients with advanced high grade serous ovarian cancer (SOC) who undergo a suboptimal debulking primary surgery typically have adverse clinical outcomes. However, a spectrum of sensitivity to first line platinum-based chemotherapy is observed but poorly understood. In this study, we perform molecular characterization of two groups of responders (extreme versus poor) to first line carboplatin/taxol chemotherapy in suboptimally debulked SOC patients. Methods: Suboptimally debulked SOC patients with advanced disease (stage III-IV) were grouped by response to first-line chemotherapy and clinicopathologic data collected. Extreme platinum-sensitive (PS) responders had a PFI (progression-free interval) > 12 months (mo) and platinum-resistant (PR) responders had a PFI < 6mo. Tissue specimens were used to interrogate the molecular features of both PS and PR cohorts using whole exome and transcriptome sequencing. Sequence alignment and variant calling were performed using GATK and annotation was performed using Variant Effect Predictor for assessment of non-synonymous tumor mutation burden (TMB) and discovery of novel mutational signatures to predict platinum response. Results: There were 39 patient samples analyzed from primary surgery (PS group = 20; PR group = 19). Median PFI for PS and PR patient cohorts was 30 mo and 3 mo (p < 0.001), respectively. In all tumors, in addition to BRCA and TP53 mutations, additional oncogenic mutations were noted in genes associated with PI3K/AKT/mTOR signaling and in epigenetic regulation. The PS samples were characterized by mutations in BRCA1/2 and the PR samples by mutations in MGA. Compared to tumors in the PR cohort, PS tumors had a significantly higher non-synonymous mutation rate using TMP analysis (p < 0.05) with a trend towards increased immune response. Additional bioinformatics analysis is ongoing and will include copy number variation analysis, immune inference using ESTIMATE and Gene Set Enrichment Analysis. Conclusions: Contracting a mutational signature is feasible from patient tumors at primary surgery and helps to elucidate extreme responses to platinum-based chemotherapy.
Acquired resistance to T cell adoptive transfer by inflammation-induced melanoma dedifferentiation.
Authors: Arnav Mehta, Yeon Joo Kim, Lidia Robert, Begonya Comin-Anduix, Beata Berent-Maoz, Alistair Cochran, James S. Economou, Paul Tumeh, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

3047 Background: Many patients that initially respond to cancer immunotherapy with adoptive cell therapy (ACT) using T cell receptor (TCR) engineered autologous T cells eventually develop resistance and experience relapse (termed acquired resistance) through mechanisms that remain poorly understood. Methods: We analyzed baseline and on-therapy tumor samples from 15 patients with metastatic melanoma that were treated with transgenic lymphocytes expressing a MART-1 TCR administered with a MART-1 peptide-pulsed dendritic cell vaccine. We studied in vitro the effect of inflammatory mediators and MART-1-specific T cells on human patient-derived melanoma cell lines, and performed bulk RNA-sequencing and methylation analysis of melanosome genes to gain further insight into mechanisms of acquired immunotherapy resistance in these cells. Results: Progression biopsies of metastatic melanoma lesions in one of the patients demonstrated phenotypic dedifferentiation as a resistance mechanism to ACT, a phenomenon previously only reported in murine models (Landsberg et al., Nature, 2012). After a three month period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) but expressing the inflammation-induced neural crest marker NGFR (or CD271). We validated inflammation-induced tumor dedifferentiation of 8 melanoma cell lines in vitro after stimulation with TNFa for 3 days, and identified gene pathways altered in dedifferentiated cells by RNA-sequencing. Gene set enrichment analysis revealed that TNFa treatment enriched for genes involved in epithelial to mesenchymal transition (NES = 1.92, FDR < 0.001) and neural crest stem cell identity (NES = 1.49, FDR = 0.016), and pathways in the innate anti-PD-1 resistance signature (IPRES). TNFa treatment also downregulated genes in the MITF pathway (NES = -2.38, FDR < 0.001). Conclusions: Inflammation-induced dedifferentiation is a new mechanism that can lead to acquired resistance to cancer immunotherapy.
Systemic therapy regimen outcomes in metastatic phyllodes tumors of the breast.
Authors: Amanda Marie Parkes, Shreyaskumar Patel, Cheuk Hong Leung, Heather Y. Lin, Anthony Paul Conley, Neeta Somaiah, Dejka M. Araujo, Maria Alejandra Zarzour, J Andrew Livingston, Joseph A. Ludwig, Vinod Ravi, Robert S. Benjamin, Ravin Ratan
Journal: Journal of Clinical Oncology (2018)

11554 Background: Phyllodes tumors of the breast (PT) account for < 1% of all primary breast neoplasms. Metastatic PT (MPT) are less common, limiting development of standardized treatment approaches. We sought to characterize the largest group of MPT thus far reported, evaluating outcomes with systemic therapy regimens. Methods: Adult MPT patients followed at MD Anderson Cancer Center from 1954-2015 were selected for retrospective chart review. Systemic therapy was sorted into five categories: Adriamycin/Ifosfamide (AI), other anthracycline regimens (A), other ifosfamide regimens (I), gemcitabine regimens (G), and other (O). Given one patient may have received > 1 regimen, we assumed that the effects of each regimen were independent. Descriptive statistics, response to treatment, and survival analyses were performed. Results: We identified 50 MPT patients. Most patients had metachronous metastases (47/50, 94%) and lung was the most common site of metastasis at time of MPT diagnosis (35/50 patients, 70%). Thirty-one of 50 MPT patients received 61 systemic regimens (range: 1-4 regimens per patient, median: 1). Overall response rate (ORR) was highest in AI (10/19 patients, 53%), followed by A (5/13, 38%), I (2/8, 25%), G (3/13, 23%), and O (1/8, 13%). Median overall survival (OS) was 10.7 months (95% CI: 8.67, 16.5). Sixty regimens had complete information available for progression free survival (PFS) analyses. Table 1 details median PFS by regimen. After adjusting for tumor size, comparing other therapies to AI, risk of progression/mortality was significantly higher with G, A, and O (Table 1). There was no statistically significant difference between AI and I. Conclusions: MPT patients are a unique population with limited characterization. Our study demonstrates superiority of AI, with I showing similar risk of progression/mortality, but lower ORR. Median PFS and risk of progression/mortality using multivariate cox regression. Systemic regimen Cases Total Median PFS (95% CI) (months) HR (95% CI) P-value AI 16 19 9.10 (5.03, 14.2) Ref I 8 8 5.10 (0.67, 12.1) 2.29 (0.88, 5.96) 0.090 A 12 12 3.65 (1.17, 7.90) 3.19 (1.38, 7.40) 0.007 G 12 13 2.80 (1.83, 4.60) 3.09 (1.31, 7.25) 0.010 O 6 8 1.67 (1.13, 7.77) 7.74 (2.42, 24.8) < .001
Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis
Authors: Dhadhang Wahyu Kurniawan, Arun Kumar Jajoriya, Garima Dhawan, Divya Mishra, Josepmaria Argemi, Ramon Bataller, Gert Storm, Durga Prasad Mishra, Jai Prakash, Ruchi Bansal
Journal: Journal of Controlled Release (2018)

Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.
Applications of wearable activity monitors (WAM) in cancer clinical trials (CT): A review of the literature.
Authors: Gillian K. Gresham, Steven Piantadosi, Lea Drye, Robert A. Figlin, Arvind Manohar Shinde
Journal: Journal of Clinical Oncology (2016)

e21598 Background: Wearable technology is increasingly being used in CTs to monitor physical activity (PA). WAMs contain multi-sensor systems which track steps, metabolic equivalents (METs), calories, and sleep. Although commonly used in healthy populations, their utility in cancer (CA) populations is being explored. The objective of this review is to evaluate applications of WAMs in CA trials. Methods: Pubmed, CENTRAL, and Embase were searched for CTs published between 2000 and 2015 to track the use of WAMs. CTs that used pedometers, accelerometers, or multi-sensor systems in CA adults were included. Details of the trial design, study population, types of WAMs, purpose for use, and activity outcomes were extracted. Results: A total of 467 CTs were identified. After removing duplicates, screening titles/abstracts and reviewing full-texts for eligible studies, 46 CTs were included and a total of 4926 patients (pts). Median trial size was 75 pts (IQR 36,150). Mean age ranged from 44.5 to 68.5 years. Overall, 70% of CTs included breast CA pts. Other CA types included colorectal (CRC), gastric, prostate, lung, ovarian, or any cancer type. Pts undergoing active treatment were included in 16% of CTs. The majority of CTs were of CA survivors (48.8%) of which 65% were breast. The primary applications of WAMs were for PA (63%), nutritional (4%), behavioral (15%) and sleep (19%) interventions. Study outcomes included steps, METs, active minutes, and sleep duration/efficiency. CA-related fatigue was evaluated in 8 CTs, quality-of-life in 18 CTs, and cachexia in 2 CTs. Accelerometers, pedometers, actigraphs or > 1 device, were used in 17, 14, 10 and 5 studies, respectively. WAM models varied across CTs with 14 manufacturers reported. Placement of device included wrist (40%), hip/waist (14%), ankle (5%) or not specified. Adherence was assessed in 14 CTs (IQR 70.5%-87%). Mean steps per day ranged from 2885 to 8476. Conclusions: WAMs have been widely used for objective measurement of PA, behavior and sleep in survivors and CA pts with relatively good prognosis, demonstrating feasibility. Their use to measure functional status, prognosis, and treatment tolerance in a broader range of CA pts should be further explored.