tbuckley/cabot-search huggingface dataset:
Identification of osimertinib resistance mechanisms using plasma cell-free DNA and tissue biopsy in EGFR-mutated T790M-positive Japanese patients with lung cancer.
Authors: Ryo Ariyasu, Ken Uchibori, Kazuma Kiyotani, Takahiro Yoshizawa, Yosuke Dotsu, Junji Koyama, Masafumi Saiki, Tomoaki Sonoda, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Atsushi Horiike, Makoto Nishio, Ryohei Katayama
Journal: Journal of Clinical Oncology (2018)

e21051 Background: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has proven efficacy in EGFR-T790M-positive patients. We previously demonstrated that the high ratio of T790M- to EGFR-activating mutations assessed with droplet digital PCR (ddPCR) correlated with higher osimertinib response. However, despite significant tumor shrinkage, the disease eventually progresses owing to osimertinib resistance acquisition. EGFR-C797S/T790M compound mutation has been reported as a resistant mechanism, and we and other groups have already been suggested some overcoming strategies to the mutation. Thus, the detection of C797S with ddPCR and identification of other resistant mechanisms is imperative. Methods: We collected tumor and/or plasma samples from 23 patients in our hospital with progressed disease during osimertinib administration. We used ddPCR to assess the rate of C797S, T790M loss. After establishing patient-derived cancer cells (PDCs), we analyzed the resistant mechanisms using FISH, IHC, next -generation sequencing (NGS), and cellular signaling analysis. Results: We detected C797S (2390G > C or 2389T > A) in 20.0% of patients (4/20), 17.6% of cancer cells (3/17), and 25.0% (3/12) of plasma; the T790M loss was detected in 70.0% of patients (14/20), 64.7% of cancer cells (11/17), and 66.7% of plasma (8/12). Furthermore, the concordance rate between the tumor cell and plasma cell-free DNAs for detecting C797S and T790M was 85.7% (6/7) and 100% (7/7), respectively. FISH did not detect the MET amplification in all samples (0/5), and the transformation to SCLC with Rb loss was identified in 11.8% of cancer cells (2/17). In other mechanisms, NGS detected EGFR-C797G and a new MEK2 mutation. Lastly, the MEK inhibitor trametinib combination re-sensitized one of the PDCs to osimertinib. Conclusions: Favorable concordance by ddPCR can detect C797S in tissue and plasma cell-free DNA, suggesting that the C797S mutation is evaluated with minimal invasiveness. NGS and further analysis by establishing PDCs would facilitate the identification of unidentified resistance mechanisms.
Phase I study of trametinib and neoadjuvant chemoradiation (CRT) in patients with locally advanced rectal cancers (LARC) that harbor KRAS, BRAF, or NRAS mutations.
Authors: Christina Sing-Ying Wu, Terence Marques Williams, Lai Wei, Hamida Umar, Arsen Savysan, Sameh Mikhail, Kristen Keon Ciombor, Anne M. Noonan, Sameek Roychowdhury, Samer S El-Dika, Somashekar Krishna, Bennie Upchurch, Mark Arnold, Alan Harzman, Sherif Abdel-Misih, William Cirocco, Tanios S. Bekaii-Saab, Evan John Wuthrick
Journal: Journal of Clinical Oncology (2016)

e14126 Background: KRAS, NRAS, and BRAF mutations constitutively activate and dysregulate the MAPK pathway in colorectal cancer. Pre-clinical data suggest that MEK 1/2 inhibition radiosensitizes RAS mutant cancers. Thus, we conducted a phase I study with trametinib, a MEK1/2 inhibitor, in combination with 5-FU CRT in patients with LARC. Methods: A phase I study for patients with stage II or III rectal cancer that harbor KRAS, NRAS, or BRAF mutations. It is a standard 3+3 design with 3 dose levels of trametinib: 0.5mg, 1mg, and 2mg daily, given in combination with 5-FU 225mg/m2/day (5 days week) and a total of 50.4 Gy radiation (1.8 Gy daily fractions). Trametinib is administered with a 5-day lead-in, and for the duration of CRT. Patients then undergo surgery 6-10 weeks later. There is an expansion cohort planned for a total of 12 patients at the maximum tolerated dose (MTD). The primary endpoint is to determine the MTD of trametinib with CRT. Results: Thirty-five patients have been screened and 10 patients (8 male, 2 female) enrolled. Median age is 54 years (range 38-64). Nine patients are evaluable for toxicities thus far. Patients have been enrolled to all 3 dose levels without dose-limiting toxicities, and the 10th patient is receiving trametinib 2mg. There are no grade 4 toxicities, and the most common toxicities observed are shown (Table). Skin rash due to trametinib (2mg) led to dose-reduction in 1 patient and holding trametinib in another, both for the last 3 days of CRT. There were no interruptions in radiation therapy; 5FU was held for 3 days in 1 patient due to mucositis. Conclusions: Trametinib in combination with CRT has been well-tolerated. Additional patient enrollment and longer follow-up time are needed to detect activity of MTD on rates of pathologic response, local control, distant relapse, and survival. Clinical trial information: NCT01740648. Grade 1 N (%) Grade 2 N (%) Grade 3 N (%) Hematological Leukopenia 1 (11) 1(11) 0 Lymphopenia 4 (44) 0 2 (22) Anemia 2 (22) 2 (22) 0 Thrombocytopenia 3(33) 0 0 Non-Hematological Diarrhea 7 (78) 1 (11) 0 Generalized skin rash 3 (33) 0 0 Nausea 3 (33) 0 0 Dyspepsia 2 (22) 0 0 Oral mucositis 1 (11) 1 (11) 0 Fatigue 2 (22) 0 0 Hyperglycemia 2 (22) 0 0 Rectal pain 1 (11) 2 (22) 0
Apatinib for patients with advanced sarcoma: Initial clinical experience.
Authors: Na Zhou, Congmin Liu, Helei Hou, Chuantao Zhang, Dong Liu, Xiaofeng Cheng, Xiaomei Xu, Yakun Zhang, Ling Yang, Xiaofei Wang, Xiaochun Zhang
Journal: Journal of Clinical Oncology (2016)

e22533 Background: Advanced sarcoma progressed quickly with abundant blood supply, which is known for its poor clinical response to chemotherapy. Apatinib, a novel small molecule tyrosine kinase inhibitor targeted VEGFR2, which has been recommended as third-line treatment for metastatic gastric cancer patients, showed improved PFS and OS in patients with metastatic gastric cancer who had experienced treatment failure with two or more chemotherapy regimens. This study is an initial clinical experience about curative effect and adverse reaction of Apatinib for patients with advanced sarcoma. Methods: Six patients pathological diagnosed as sarcoma (3 men and 3 women; median age 58 years, range 29-79) were enrolled between December, 2014 and May, 2015. Of them, two patients were soft tissue sarcoma, one was abdominal sarcoma, and the other 3 were osteosarcoma,breast sarcoma and chondrosarcoma respectively. All patients underwent previous surgery and chemotherapy, and they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1. 850 mg/day of Apatinib was continuously administered for one month. During the therapy period, we observed the curative effect and adverse events closely. Informed consent was obtained from each patient before enrollment. Results: After continuous administration of Apatinib, computed tomography (CT) scan evaluation revealed that partial response (PR) occurred in 3 of 6 patients and other 3 showed stable disease (SD). As for adverse events, 1 patient showed leukopenia, one showed thrombocytopenia and no severe bone marrow depression appeared. Hypertension is one of the most frequent adverse reactions, which appeared in 3of 6 patients who were getting to be normal under oral antihypertensive agent. Others like hand-foot syndrome, hoarseness and temple elevated transaminase appeared in 1 patient respectively and could be better controlled. Conclusions: Apatinib is a safe and effective oral targeted drug on patients with advanced sarcoma, who had undergone failure of chemotherapy. It could provide a new therapy strategy for patients with advanced sarcoma. To further investigate the role of Apatinib in advanced sarcoma, large sample and additional clinical trials are needed.
Prognostic and predictive role of circulating eNOS and EPHB4 in metastatic colorectal cancer patients receiving bevacizumab.
Authors: Giorgia Marisi, Emanuela Scarpi, Alessandro Passardi, Oriana Nanni, Angela Ragazzini, Martina Valgiusti, Giovanni Luca Frassineti, Dino Amadori, Paola Ulivi
Journal: Journal of Clinical Oncology (2016)

e23083 Background: There aresome controversies regarding the choice of agent and optimal sequence to use for the treatment of metastatic colorectal cancer (mCRC) and it is now widely accepted that novel predictive biomarkers are needed to improve patient selection and optimize the use of bevacizumab (B). We analyzed the potential usefulness of 4 circulating biomarkers to predict B efficacy and to monitor disease. Methods: Peripheral blood samples collected at different times (baseline, first clinical evaluation and disease progression) were available for 129 of the 376 patients enrolled in the prospective multicentric ITACa trial (NCT01878422) and randomized to receive FOLFOX4/FOLFIRI (CT) with or without B. Sixty-four patients received CT plus B and65 received CT only (control group). mRNA was isolated and used for gene expression analysis of COX2, VEGF-A, EPHB4 and eNOS by a quantitative RT-PCR method. Baseline expression levels of the markers and their modulation during therapy were correlated with objective response (OR), progression-free (PFS) and overall survival (OS). Results: Baseline expression levels of the 4 markers were not associated with response, PFS or OS. B-treated patients with a reduction > 30% in EPHB4 levels from baseline to first clinical evaluation showed a higher rate of complete or partial response. In particular, among responders (complete and partial response), 75% had a reduction > 30% in EPHB4 levels compared to 47.4% in non-responders (stable and progressive disease) (p = 0.048). We also observed a trend towards significance in the control group (p = 0.064). Moreover, B-treated patients with a reduction > 30% in eNOS levels from baseline to first clinical evaluation showed a better median OS compared to those with a reduction < 30% (31.6 months, [95% CI 21.3-42.9] vs 14.4 months [95% CI 11.2-27.5]; HR 0.44 [95% CI 0.21-0.91], p = 0.027). No significant differences were observed with regard to PFS. Conclusions: Our datasuggest that reduced expression of EPHB4 and eNOS from baseline to first clinical evaluation could be used as indicators of prognosis and response to treatment with bevacizumab. Partially funded by Roche S.p.A. and the Italian Medicines Agency (AIFA).
High serum free light chain concentration (&gt;1000mg/dl) at the time of relapse to predict poor prognosis in multiple myeloma.
Authors: Abhishek Chilkulwar, Anna Miller, Prerna Mewawalla, Gina Berteotti, Anna Kaminsky, Santhosh Sadhashiv, Entezam A. Sahovic, John Lister
Journal: Journal of Clinical Oncology (2016)

8064 Background: There have been significant improvements in the outcomes for multiple myeloma patients over the past 10 years. However, the prognosis of the disease remains highly variable. While some patients experience 15+ year survivals, others succumb to it in a few months. Many studies have focused on the description of prognostic factors to predict outcomes amidst this heterogeneity. Baseline serum free light chain concentration is a known prognostic indicator for plasma cell neoplasms and normalization of free light chain ratio with treatment has been associated with a favorable prognosis. Furthermore high serum free light chain ratio correlates with elevated serum creatinine, elevated LDH and extensive marrow infiltration. It has not, however, been described if high free light chains at relapse have any impact on prognosis. Objectives: To determine if serum free light chain concentration > 1000mg/dl at the time of relapse has an impact on overall survival. Methods: The results of free light chain assay of all patients evaluated at Western Pennsylvania Hospital between 2002-2012 were screened and those patients with serum free light chain concentration > 1000mg/dl at relapse were identified. A retrospective chart review of these patients was conducted and multiple variables were analyzed. Results: A total of 20 patients with free light chains greater than 1000 mg/dl at relapse were identified. Median age at diagnosis was 57.2 years (41.1-81.3 years). The median survival at relapse of patients with free light chain greater than 1000 mg/dl was found to be 5.2 months (1.6-9.8 months). Age, sex, stage, immunoglobulin subtype or the free light chain subtype had no impact on the overall survival. Conclusions: Patients with multiple myeloma who relapse with free light chain concentration greater than 1000 mg/dl have a very poor prognosis and high early mortality. A larger study to evaluate elevated free light chains as a prognostic indicator at relapse should be done so we can use it as a tool for management and prognostication of our myeloma patients. Identifying these patients and promptly instituting therapy for aggressive disease may improve outcomes in these subset of patients.
Early response metrics for predicting trial outcomes: A report from volumetric CT for precision analysis of clinical trials (Vol-PACT).
Authors: Patrick Hilden, Mithat Gonen, Dana E. Connors, Ying Tang, Binsheng Zhao, Hao Yang, Sanja Karovic, Jessica Flynn, Stacey Adam, Antonio Tito Fojo, Gary Kelloff, Michael L. Maitland, Geoffrey R. Oxnard, Lawrence Howard Schwartz, Chaya S. Moskowitz
Journal: Journal of Clinical Oncology (2018)

3581 Background: The high frequency of negative phase III oncology trials following positive phase II results indicates a need for improved metrics which assess treatment effect. Vol-PACT is an ongoing private-public partnership launched to collect source imaging data from phase III trials with a goal of developing improved methods of assessing therapies in randomized clinical trials. With 8 phase III industry sponsored datasets received and more expected, Vol-PACT is among the largest collective cancer imaging databases with fully annotated measurements of target, non-target, and new lesions. Methods: Images from 4 phase III trials in metastatic colorectal cancer (mCRC) were evaluated and benchmarked against 4 phase III trials in other solid tumors. Lesions were measured directly on CT images using semi-automated algorithms. Four metrics quantifying change from baseline through 2 cycles (week 8-16) were evaluated: RECIST response rate, percent change over time, absolute change over time, and log change over time. One thousand phase II trials were simulated by resampling without replacement (50 pts/arm). The average standardized difference between arms was determined across simulations. The weighted linear correlation was estimated between average standardized difference and hazard ratios estimating progression-free survival benefit (PFS HR). Results: With sample sizes of 289 to 921 patients per trial (n = 4,074 across the 8 trials), PFS HR values ranged from 0.4 to 1.2 (6 significant, p < 0.05). For mCRC trials, correlations with PFS HR were 0.87 for RECIST response rate, 0.86 for percent change over time, 0.96 for absolute change over time, and 0.73 for log change over time. For other trials they were 0.80, 0.94, 0.94, and 0.95, respectively. Across the full set of 8 trials, observed correlations were 0.64, 0.90, 0.93, and 0.87. Conclusions: Continuous response metrics derived from original CT images correlated strongly with PFS HR across mCRC and other trials, and may be more informative than RECIST response categories. Development of metrics based on volumetric measurements are ongoing, as is the analysis of data from emerging immunotherapy trials.
TCT-152 Clinical predictors of discordance between instantaneous wave-free ratio and fractional flow reserve
Authors: Hidekuni Kirigaya, Kensuke Matsushita, Kozo Okada, Noriaki Iwahashi, Nobuhiko Maejima, Toshiaki Ebina, Kouichi Tamura, Kiyoshi Hibi, Kazuo Kimura
Journal: Journal of the American College of Cardiology (2018)
Relationship of Familial Hypercholesterolemia and High Low-Density Lipoprotein Cholesterol to Ischemic Stroke
Authors: Sabina Beheshti, Christian M. Madsen, Anette Varbo, Marianne Benn, Børge G. Nordestgaard
Journal: Circulation (2018)

Background: Familial hypercholesterolemia (FH) is a condition with very high concentrations of low-density lipoprotein (LDL) cholesterol and high risk of ischemic heart disease including myocardial infarction. However, there is limited and contradictory information on whether FH and high LDL cholesterol per se confer high risk of ischemic stroke. We tested the hypotheses that individuals in the general population with FH and/or high LDL cholesterol have higher risk of ischemic stroke. Methods: The associations of FH and high LDL cholesterol with ischemic stroke risk were tested in both causal, genetic, and observational analyses using 106 412 individuals from the CGPS (Copenhagen General Population Study; 2823 ischemic strokes and 3792 myocardial infarctions) and/or 10 372 individuals from the CCHS (Copenhagen City Heart Study; 945 ischemic strokes and 1142 myocardial infarctions). FH causative mutations were LDLR W23X(rs267607213), W66G(rs121908025) and W556S, and APOB R3500Q(rs5742904). A Mendelian randomization design tested whether high LDL cholesterol per se has a causal effect on ischemic stroke risk, using a combination of the FH causative mutations and common genetic variants associated with high LDL cholesterol. Results: The cumulative incidences in individuals in the CGPS with and without FH causative mutations were similar for ischemic stroke ( P =0.50) but not for myocardial infarction ( P &lt;0.001): at age 80 years, 4% and 7% of these individuals developed ischemic stroke and 20% and 8% myocardial infarction, with similar results in the CCHS. There was no association between clinical FH and ischemic stroke, except if personal premature ischemic heart disease was included in the clinical FH criteria. Ischemic heart disease at baseline was associated with higher ischemic stroke risk, explaining the higher ischemic stroke risk in those with high LDL cholesterol. For a 1 mmol/L higher LDL cholesterol, the genetic causal risk ratio was 1.11 (0.62–2.02) for ischemic stroke and 1.45 (1.08–1.93) for myocardial infarction. Conclusions: FH and high LDL cholesterol did not confer an increased risk of ischemic stroke. A positive association with ischemic stroke observed for some clinical FH criteria and high LDL cholesterol appears to be due to previous ischemic heart disease, rather than to high LDL cholesterol per se.
Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study
Authors: Anton Pottegård, Kasper Bruun Kristensen, Martin Thomsen Ernst, Nanna Borup Johansen, Pierre Quartarolo, Jesper Hallas
Journal: BMJ (2018)

Abstract Objective To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products. Design Nationwide cohort study. Setting Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses. Participants 5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant’s exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag. Main outcome measures Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined. Results The final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null. Conclusions The results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.
Budgetary impact of lipegfilgrastim to the Brazilian public healthcare system.
Authors: Agota Szende, Jason Allaire, Jennifer Urwongse, Marco Petti, Omar Tomey Mendez, Udo W. Mueller, Andre Vicente, Stephen D. Stefani, Boxiong Tang
Journal: Journal of Clinical Oncology (2016)

e14072 Background: Recombinant granulocyte-colony stimulating factors (G-CSFs) reduce the risk of chemotherapy-induced neutropenia. Lipegfilgrastim (LIP) is a novel, long-acting, once-per-cycle G-CSF not currently reimbursed by public authorities in Brazil, while the short-acting G-CSF filgrastim (FIL) is the standard of care. A budget impact model was developed from the perspective of the Brazilian public healthcare system to estimate the 5-year net cost associated with the introduction of LIP versus 11-administration FIL and pegfilgrastim (PEG), another long-acting, once-per cycle G-CSF. Methods: A decision analytic model used inputs based on national data, clinical trial evidence including meta-analysis, and expert opinion to estimate the changes in drug and medical costs due to the introduction of LIP. Health outcomes and costs for the pre- and post-LIP scenarios were combined with population and market share information to calculate the expenditure and budget impact associated with the introduction of LIP and changing treatment patterns over 5 years, assuming that 5% of eligible patients would be treated with LIP in the first year, followed by 15%, 25%, 50%, and 85% in each subsequent year. A series of one-way sensitivity analyses were conducted. Results: G-CSF drug and administration cost per patient over a course of 4 chemotherapy cycles was estimated to be R$12,621 for LIP/PEG and R$14,351 for FIL. The base-case market uptake of LIP led to savings of R$61,538,591 in overall medical costs over 5 years, with fewer G-CSF administrations resulting in the greatest budget savings. Total annual expenditure decreased yearly. Health outcomes were estimated to improve following the introduction of LIP: the number of neutropenic events decreased by 17,141 and deaths linked to febrile neutropenia decreased by 239 over 5 years. Sensitivity analyses suggested that the number of FIL administrations required, the cost of G-CSF treatments, and the relative risk ratio of severe and febrile neutropenia incidence for FIL had the largest impact on model results. Conclusions: The base-case budget impact model estimated a reduction in overall medical costs along with improved health outcomes over 5 years following the introduction of LIP in Brazil.