tbuckley/cabot-search huggingface dataset:
Survival meta-analysis from fifteen years of a standard systemic therapy in malignant pleural mesothelioma.
Authors: Joseph S. Friedberg, Melissa Culligan
Journal: Journal of Clinical Oncology (2019)

e20066 Background: Malignant pleural mesothelioma is a rare malignancy with an annual incidence of 3,000 cases in the US and is still considered incurable. The standard of care for this cancer, a combination of pemetrexed and a platinum drug, was established in 2003 as the result of a landmark study that reported a median overall survival of 12.1 months for this combination in patients not eligible for surgery. The aim of the current analysis was to determine if there has been a change in the outcome for this population in the past 15 years. Methods: A PubMed search was performed and 9 prospective, randomized or single arm (minimum n = 50), trials were selected. All studies included patients treated using pemetrexed in combination with platimun as front line therapy in unresectable mesothelioma patients. Average and weighted average OS were calculated and also corrected per the reported odds ratio for survival between the epithelioid and non-epithelioid histologies. Results: The average OS was 12.9 months and the weighted average OS was 13.3 months (range: 8.5 – 16.1 months). The two studies showing the highest median OS (MAPS and LUME-meso) had a higher percentage of tumors with epithelioid histology, which could explain their favorable outcome. Adjusting the average OS using the reported odds ratios for survival between epithelioid and non-epithelioid histologies eliminated the superior outcome in these studies. Furthermore, correcting average survival per the original ratio between tumor histologies for all studies included in the meta-analysis showed an average and weighted average OS lower than 13 months. Conclusions: This analysis strongly supports the contention that survival results for nonoperative patients with mesothelioma should be stratified by histology, epithelioid versus nonepithelioid, similar to the trend in the surgical mesothelioma literature. When factoring in histology, it appears that overall advances in patient care and additional treatments have not significantly changed the overall survival for nonoperative mesothelioma patients in the last 15 years. This meta-analysis underscores the desperate need for new and innovative treatments for this cancer.
A phase I, open label, multicenter dose escalation study of AZD2811 nanoparticle in patients with advanced solid tumors.
Authors: Melissa Lynne Johnson, Jan G. C. E. Cosaert, Gerald Steven Falchook, Suzanne Fields Jones, Donald Strickland, Carol Greenlees, Julie Charlton, Alexander MacDonald, Philip Overend, Carrie Adelman, Howard A. Burris, Elizabeth J. Pease, Gargi Surendra Patel, Judy Sing-Zan Wang
Journal: Journal of Clinical Oncology (2019)

3098 Background: Aurora kinase B (AURKB) represents a potential target for therapy in solid and hematological malignancies. AURKB inhibitor AZD1152 (barasertib) was previously investigated in solid tumor pts in a phase I setting. AZD2811-nanoparticle (np) is a novel, encapsulated slow release AURKB inhibitor offering several advantages over AZD1152 (Ashton S et al., Sci Transl Med 2016). We report the completed dose-escalation safety, pharmacokinetics (PK), preliminary activity and defined maximum tolerated dose (MTD) of AZD2811-np in pts with advanced solid tumors (NCT02579226). Methods: Adult pts with advanced solid tumors received AZD2811-np IV on Day 1 (D1) and 4 (D4) Q4 week (wk) in six cohorts 15-200 mg/infusion without the use of g-csf in cycle 1. D1 Q4wk and Q3wk schedules were investigated up to 600 mg/infusion (including cohorts with mandatory g-csf prophylaxis on day 8). A standard 3+3 design was used. PK was assessed in cycle 1. Results: 50 pts were recruited into 12 cohorts. D1, D4 Q4wk schedule: 24 pts (15, 25,38, 50, 100 mg/infusion (n=3/cohort), 200 mg/infusion (n=9)). All cohorts were tolerated. Transient grade 4 neutropenia was observed in 7/9 pts at 200 mg/infusion, including 1 DLT (gr4 &gt; 7 days) D1 Q4wk: 200 mg(n=3) was tolerated. D1 Q3wk: 23 pts were evaluated (200/400 mg (n=3,7), and 400/600/500 mg with mandatory g-csf (n=3/5/6)). 400 mg without g-csf was not tolerated (1 gr3 mucosal inflammation &amp; 1 gr4 neutropenia &gt; 7 days). 600 mg with g-csf was not tolerated (gr3 febrile neutropenia &amp; gr3 fatigue). 25/50 pts experienced AE ≥gr 3 (21 considered AZD2811-np-related, 19 neutropenia-related, no deaths within-DLT period). AZD2811-np caused transient gr1/2 fatigue, nausea, diarrhoea and mucosal inflammation. AZD2811 total blood PK appears dose proportional with a t 1/2 of 30-50 hours irrespective of schedule. Released AZD2811 concentrations ~1% of total. 14 pts (28%) had disease stabilisation. 1 prostate ca. pt had a confirmed partial response (PR) (continued tx to 451 days). Conclusions: The MTD for AZD2811-np is 500 mg D1 Q3wk. AZD2811-np is now being investigated in a small cell lung cancer expansion. Clinical trial information: NCT02579226.
Outcomes among patients with a history of substance abuse in non-small cell lung cancer: A county hospital experience.
Authors: Kyle Concannon, John Henry Thayer, Roxana Hicks, Vicky Wu, Isaac Jenkins, Christina S Baik, Hannah M. Linden
Journal: Journal of Clinical Oncology (2019)

e20031 Background: Insufficient outpatient care among vulnerable patients, such as those with a history of alcohol or illicit substance use disorder (SUD), may contribute to poor outcomes in non-small cell lung cancer (NSCLC). We hypothesize that patients with newly diagnosed localized NSCLC and a history of SUD have a shorter time from diagnosis to last known contact, greater rates of depression, less family support, poorer follow-up, and increased emergency room and inpatient usage compared to those without a history of SUD. Methods: To investigate this, we conducted a retrospective review of all lung cancer patients with localized non-small cell carcinoma (N = 52) with visits between 9/2012 and 9/2018 at an academic county hospital with a dedication to the underserved in a major US city. Data were collected from electronic medical records manually and analyzed using ANOVA for continuous variables or Pearson's Chi-squared for categorical data. Results: Among patients with localized NSCLC (n = 52), 44% had a history of SUD. The mean time from diagnosis to last known contact and rate of loss-to-follow-up among those with a history of SUD vs no history of SUD was: 2.9 vs 4.4 years (p = 0.14) and 26.1% vs 20.7% (p = 0.64) respectively. Patients with history of SUD were more likely to live without family members and have a history of depression, anxiety or PTSD than those without a SUD history; 78.3% vs 44.8% (p = 0.023) and 60.9% vs 20.7% (p = 0.004). In the year following diagnosis the mean percentage of missed appointments, number of ER visits, number of inpatient stays, and total length of inpatient stay for patients with history of SUD vs no history of SUD were: 19% vs 8% (p = 0.01), 3.7 vs 1.4 (p = 0.08), 2.6 vs 0.9 (p = 0.10), and 17.7 vs 5.9 days (p = 0.06) respectively. Conclusions: In this retrospective analysis of patients with localized NSCLC, those with a history of SUD had shorter time from diagnosis to last known contact without increased rates of loss-to-follow-up. They also had greater rates of depression, less family support, increased rates of missed appointments, more emergency room visits, increased hospitalizations, and increased total duration of inpatient stay in the year following their diagnosis.
First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors.
Authors: George D. Demetri, Jason J. Luke, Antoine Hollebecque, John D. Powderly, Alexander I. Spira, Vivek Subbiah, Dominic W. Lai, Huibin Yue, Sreeneeranj Kasichayanula, Scott Gulbranson, James Purcell, Melinda Myzak, Randy Robinson, Victor Manuel Villalobos, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2019)

3004 Background: ABBV-085 is an ADC (conjugated to monomethyl auristatin E, drug:antibody ratio of 2:1) directed against leucine-rich repeat containing 15 (LRRC15), a type 1 transmembrane protein highly expressed on the surface of sarcomas and cancer-associated fibroblasts in stroma of many other cancers. ABBV-085 induced antitumor activity in both in vitro and xenograft models of sarcoma. This phase 1, first-in-human, 2-part study assessed the safety/tolerability of ABBV-085 in patients (pts) with advanced solid tumors (NCT02565758). Methods: Eligible pts (≥18 yr; advanced solid tumors) received ABBV-085 intravenously in a 3+3 dose-escalation (DE) design; 0.3- to 4.8-mg/kg doses every 2 wk (8 cohorts). Pharmacokinetics (PK) were assessed in cycle 1 and cycle 3. Results: As of Dec 2018, 78 pts were enrolled in monotherapy DE and dose-expansion (EXP) cohorts (≤2.7 mg/kg, n = 21; 3.6 mg/kg, n = 45; 4.2 mg/kg, n = 6; 4.8 mg/kg, n = 6); median age: 58 yr (range 21–84); median treatment (Tx) duration: 6.2 wk (range 0.3–54.4). Overall, 77 (98.7%) pts reported ≥1 Tx-emergent adverse events (TEAEs). Fatigue (48.7%) was most common; 19 (24.4%) pts reported grade 1/2 blurred vision (reversible on study discontinuation). Grade ≥3 TEAEs were reported in 56 (71.8%) pts; anemia (14.1%) was the most common. Dose-limiting toxicities occurred at 3.6 mg/kg (n = 1; anemia), 4.2 mg/kg (n = 1; hypertriglyceridemia), and 4.8 mg/kg (n = 2; ileus and nausea); 3.6 mg/kg was chosen as the recommended phase 1b dose (RP1bD). PK exhibited dose-proportional increase in the area under the curve after single-dose administration; half-life was 2.84 days at the RP1bD. Of the 27 sarcoma pts (DE [n = 8]/EXP [n = 19] cohorts; undifferentiated pleomorphic sarcoma [n = 10], osteosarcoma [n = 10], and other sarcomas [n = 7]) treated at the RP1bD, 4 (14.8%) had confirmed partial response (PR; 2 [7.4%] unconfirmed), 8 (29.6%) had stable disease, 11 (40.7%) had progressive disease; 2 (7.4%) were not evaluable. The median duration of response (confirmed responders) was 7.6 mo (95% CI: 5.6–9.2). Updated safety and efficacy data will be reported. Conclusions: ABBV-085 was well tolerated with durable PR observed in pts with advanced sarcomas. Clinical trial information: NCT02565758.
Non-small cell lung cancer (NSCLC) next generation sequencing (NGS) using the Oncomine Comprehensive Assay (OCA) v3: Integrating expanded genomic sequencing into the Canadian publicly funded health care model.
Authors: Kirstin Perdrizet, Tracy Stockley, Jennifer H. Law, Muqdas Shabir, Tong Zhang, Lisa W Le, Anthea Lau, Ming Sound Tsao, Prodipto Pal, Michael Cabanero, Hyangmi Ko, Joerg Schwock, Suzanne Kamel-Reid, Geoffrey Liu, Adrian G. Sacher, Penelope Ann Bradbury, Frances A. Shepherd, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2019)

2620 Background: Standard of care (SOC) molecular diagnostics for stage IV NSCLC patients in Ontario, Canada includes publicly reimbursed EGFR/ALK, and selected BRAF and ROS-1 testing. Other genomic alterations are not tested routinely; however, enhanced molecular testing may broaden treatment options for patients. This study evaluated costs, identified actionable targets, and determined clinical trial eligibility as a result of using the OCAv3 NGS in stage IV NSCLC patients. Methods: In a prospective study of stage IV NSCLC out-patients at Princess Margaret Cancer Centre (Toronto) without EGFR/ALK/KRAS/BRAF alteration (unless failure of prior targeted therapy), diagnostic samples were tested by OCAv3 (ThermoFisher; 161 genes: hotspots, fusions, and copy number variations). Primary endpoints were incremental actionable targets and clinical trial opportunities as a result of broader OCAv3 testing. Secondary endpoints include feasibility and cost from the Canadian public healthcare perspective, and treatment outcomes. Results: Of 65 enrolled patients (Feb 2018-Jan 2019; 40 (62%) completed/14 (21%) screen fail/ 11 (17%) pending), median age of completed cohort was 65, 60% (N = 24) female, never/light smokers 68% (N = 27), Asian 38% (N = 15), previously treated 33% (N = 13). Actionable targets beyond SOC were identified in 33% (N = 13): ERBB2 (N = 8), BRAFV600 (N = 3), NRG fusion (N = 1), MET exon 14 (N = 1). New clinical trial options were identified in 70%. Failure of NGS was secondary to insufficient tissue [91% (N = 10) of screen failures; usually due to tissue exhaustion from prior SOC molecular testing]. Incremental costs per case beyond EGFR/ALK are estimated at $540 CAD. If ROS-1 and BRAF testing were publicly reimbursed at current rates, the incremental profiling cost with OCAv3 would be $90 CAD per case. Conclusions: Although a key barrier to implementation is lack of funding for NGS in the Canadian publicly funded system, the OCAv3 consolidates genomic testing, identifies additional actionable targets, and substantially increases clinical trial eligibility for patients at a small incremental cost. Clinical trial information: NCT03558165.
The prognosis of diffuse midline glioma H3 K27M mutant.
Authors: Donghwan KIM, Chun Kee Chung
Journal: Journal of Clinical Oncology (2019)

e13548 Background: Diffuse Midline Glioma is rare spinal cord primary tumor. Unfortunately it is known that the prognosis is poor, and it was added to the WHO guidelines in 2016 as a grade IV. It is so rare that the prognosis of the diffuse midline glioma in spinal cord is not well known yet. So we want to analyze the prognosis of the spinal cord diffuse midline glioma and find out about the molecular profile. Methods: We retrospectively reviewed of 10 diffuse midline glioma H3-K27M mutant patients who underwent surgery in a single institute, 2015.09~2018.04. We analyzed the demographic data, overall survival, progression free survival and molecular profile which includes PTEN, BRAF, EGFR, MGMT methylation status, c-MET, IDH1, 1p/19q deletion. Results: Mean age was 44.8 yr; male to female ratio was 5:5. Tumor was located conus medullaris (8), CT Junction(1), Cervical(1). One was given gross total resection and the other was a partial resection or biopsy. All patient were treated with CCRT. Medial overall survival was 47.8 months, and median progression free survival was 21 months. One case each was found for BRAF, C-MET, IDH1, PTEN and EGFR. Conclusions: This study was conducted on patients collected for a relatively short period. This study reported survival analysis and molecular profile. These mutations are known to be mainly associated with MAPK pathway. So there may be a correlation between H3-K27M and MAPK pathway. Results indicating the association of MAPK and H3K27M can be found in some literature. Further research is needed.
Stratification of oncotype (ODX) Recurrence Score (RS) by Breast Cancer Index (BCI) and its relation to discordance.
Authors: Krystal Pauline Cascetta, Brittney Shulman Zimmerman, Jenna Enson, Meng Ru, Nicole J. Zubizarreta, Shabnam Jaffer, Amy Tiersten
Journal: Journal of Clinical Oncology (2019)

e12025 Background: ODX is a gene-expression panel predictive of 10-year risk of distant recurrence and has shown prognostic value in both node-negative (LN-) and node-positive (LN+) breast cancer (BC) patients. BCI predicts 10-year risk of recurrence and also identifies those that may benefit from extended adjuvant endocrine therapy (EET). We stratified ODX RS by BCI to compare its precision in predicting recurrence category and its relation to discordance. Methods: 49 women with HR+, LN- and LN+ BC with available ODX and BCI RS with median follow up of 6 years were included. BCI risk groups were evaluated using predetermined cutoffs. RS were stratified by traditional ODX and TAILORx cutoffs and were considered discordant if there was a 1-step or 2-step difference between ODX risk group (low, intermediate, high) and tumor grade (well, moderately and poorly differentiated). N (%) or median (range) were used to describe patients’ characteristics between BCI groups and compared by chi-square test or Fisher’s exact at the confidence level of 5%. Results: Using traditional RS cutoffs, BCI reclassified 42.3% of patients with low RS as intermediate (IR) or high risk (HR). 69% with intermediate RS were reclassified to low risk (LR) and 12% were upgraded to HR by BCI. 27% of low and intermediate RS had a high benefit from EET. 2-step discordance was 14.3%. Using TAILORx RS cutoffs, BCI reclassified 20% of patients with low RS as IR. None were upgraded to HR. In the intermediate RS group, 58% were reclassified as LR and 14% as HR. 24% of intermediate RS had a high benefit from EET. 2-step discordance was 2%. Conclusions: Patients classified as LR by TAILORx RS cutoffs are less likely to be reclassified as high or intermediate risk by BCI. No significant association was found between discordance among ODX RS and tumor grade and BCI prediction of recurrence or benefit of EET.
Investigation to metastasis of regional lymph node station and prediction to long-term survival following esophagectomy in thoracic esophageal cancer with stage T1 to T3.
Authors: Yin Li, Jianjun Qin, Xiaofei Li, Xiangning Fu, Lunxu Liu, Yang Liu, Lin Xu, Deruo Liu, Jian Hu, Heng Zhao, Wei Sun, Haiying Yang
Journal: Journal of Clinical Oncology (2019)

e15519 Background: The Lymph node metastasis (LNM) trends toward inferior outcomes for the esophageal cancer (EC) patients after radical operation. However, it is not well known for status to metastasis of regional lymph node (RLN) and impacts of RLN metastasis on long-term survival following esophagectomy, especially in squamous cell carcinoma. Methods: Data was extracted from the Collaborative Prospective Esophageal Cancer Database (designed by LinkDoc Technology Co, Ltd.) for patients with stage T1-3 thoracic tumors who underwent radical esophagectomy between 1 January 2010 and 30 June 2017 across ten hospitals with high volume of surgeries in China. The rate of LNM in every lymph node station was defined as the number of patients with LNM in the station divided by the number of patients with examination of lymph node (ELN) in the station. The hazard ratios (RLN metastasis versus no RLN metastasis) for postoperative survival were analyzed by method of multivariate cox’s proportional hazard models, and confounders such as age, sex, histological grade, stage T, tumor size and neoadjuvant therapy were adjusted. Results: Total 6485 patients (mean age: 61.80±8.13) were included, composing of 75.2% male and 24.8% female. For tumor types, there were 95.5% squamous cell carcinoma, 2% adenocarcinoma and 2.5% others. The rates of RLN metastasis and hazard ratios are in the table. Conclusions: Besides lymph node station 8, LNM was commonly found at station 1,2,4,16,17 and 20 in thoracic stage T1-3 EC. The RLN metastasis predicted inferior postoperative long-term survival. [Table: see text]
DDR1 may be a good biomarker for brain tumors.
Authors: Dilek Erdem, Mahmut Büyüksimsek, Meral Gunaldi, Nilgun Sahin
Journal: Journal of Clinical Oncology (2019)

e13557 Background: There are two important hardness in the treatment of central nerve system tumors; first of it is tumor heterogenity while the second is biomarker deficiency which can be target in the tumor tissue. For the reason we aimed to examine discoidin domain receptor (DDR1), a tyrosine kinase receptor , which may be thought to be effective in cell adhesion. Methods: 38 brain tumor were evaluated for tissue DDR1 messenger ribonucleic acid and blood DDR1 levels. We compared these with 10 control group tissue and blood levels of DDR1. Results: All brain tumor and control group tissues and blood samples were found DDR1 value positive. DDR1 levels of brain tumor tissues and blood samples were statistically higher when compared with DDR1 levels of control group tissue and blood samples. Conclusions: DDR1, found statistically higher among brain tumor tissues and blood samples may be a useful biomarker for the therapy and management of these patients.
TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers
Authors: Jorge L. Del-Aguila, Bruno A. Benitez, Zeran Li, Umber Dube, Kathie A. Mihindukulasuriya, John P. Budde, Fabiana H. G. Farias, Maria Victoria Fernández, Laura Ibanez, Shan Jiang, Richard J. Perrin, Nigel J. Cairns, John C. Morris, Oscar Harari, Carlos Cruchaga
Journal: Molecular Neurodegeneration (2019)

Low frequency coding variants in TREM2 are associated with Alzheimer disease (AD) risk and cerebrospinal fluid (CSF) TREM2 protein levels are different between AD cases and controls. Similarly, TREM2 risk variant carriers also exhibit differential CSF TREM2 levels. TREM2 has three different alternative transcripts, but most of the functional studies only model the longest transcript. No studies have analyzed TREM2 expression levels or alternative splicing in brains from AD and cognitively normal individuals. We wanted to determine whether there was differential expression of TREM2 in sporadic-AD cases versus AD-TREM2 carriers vs sex- and aged-matched normal controls; and if this differential expression was due to a particular TREM2 transcript.We analyzed RNA-Seq data from parietal lobe brain tissue from AD cases with TREM2 variants (n = 33), AD cases (n = 195) and healthy controls (n = 118), from three independent datasets using Kallisto and the R package tximport to determine the read count for each transcript and quantified transcript abundance as transcripts per million.The three TREM2 transcripts were expressed in brain cortex in the three datasets. We demonstrate for the first time that the transcript that lacks the transmembrane domain and encodes a soluble form of TREM2 (sTREM2) has an expression level around 60% of the canonical transcript, suggesting that around 25% of the sTREM2 protein levels could be explained by this transcript. We did not observe a difference in the overall TREM2 expression level between cases and controls. However, the isoform which lacks the 5' exon, but includes the transmembrane domain, was significantly lower in TREM2- p.R62H carriers than in AD cases (p = 0.007).Using bulk RNA-Seq data from three different cohorts, we were able to quantify the expression level of the three TREM2 transcripts, demonstrating: (1) all three transcripts of them are highly expressed in the human cortex, (2) that up to 25% of the sTREM2 may be due to the expression of a specific isoform and not TREM2 cleavage; and (3) that TREM2 risk variants do not affect expression levels, suggesting that the effect of the TREM2 variants on CSF levels occurs at post-transcriptional level.