tbuckley/cabot-search huggingface dataset:
Prospective evaluation of minimal residual disease in multiple myeloma following autologous stem cell transplantation(ASCT) and consolidation therapy.
Authors: Mukesh Patekar, Lalit Kumar, Atul Sharma, Ritu Gupta, Sreenivas Vishnubhatla, Ramavath Devendra Naik, Rohit Ramesh Pai, Akash Tiwari, Meetu Dahiya
Journal: Journal of Clinical Oncology (2018)

e20033 Background: Induction therapy followed by autologous stem cell transplantation (ASCT) and maintenance therapy remains the standard approach in multiple myeloma (MM). The definitive role of consolidation therapy after ASCT is not known. We prospectively studied the impact of 2 cycles of Bortezomib, lenalidomide, and dexamethasone (RVd) consolidation therapy on minimal residual disease (MRD) in patients with MM post ASCT. Methods: Between June 2016 and July 2017,forty six patients were screened; of these 41 patients were recruited on day +100 post ASCT. Median age was 52 years (range, 32 to 66 years), 63.4% were males. 56% had ISS stage III and 36.6% had the extramedullary disease. 28% had received 2 lines of therapy prior to ASCT. Pre-transplant 85.4% patients had chemosensitive disease (CR 36.6%; VGPR 24.4%; PR 24.4%). Patients had received high dose melphalan 200 mg/m2 for conditioning. Patients received two cycles (q28days) of bortezomib (1.3mg/m2 weekly subcutaneously), lenalidomide (15mg/day orally for 15days), and dexamethasone 40 mg once a week as consolidation. The primary objective was response rate after consolidation therapy. Secondary objectives were MRD negativity, progression-free survival (PFS) and toxicity of consolidation therapy. MRD assessment was done with multi-parametric flow cytometry with a sensitivity of 0.001%. Response assessment was done as per the IMWG response criteria. Results: Post ASCT, 78% patients attained CR, 17.1% VGPR and 4.9% PR. Post-consolidation; CR rate increased to 95%. MRD negativity rate on day 100 post-ASCT and post two cycles of consolidation was 52.5% and 77.5%, respectively.At a median follow up of 11 months, median PFS and OS have not reached. Estimated one-year PFS and OS is 87% and 94% respectively. Five patients relapsed post consolidation with a median time of 14.7 months (range: 6.9 to18.6 months). Three of 5 patients were MRD positive post-consolidation. Day 100 and post-consolidation MRD positivity was more in the relapsed cohort. (p = 0.01 and p = 0.006 respectively) Conclusions: Consolidation therapy with two cycles of RVd improves response rate and MRD negativity rate post-ASCT. Clinical trial information: CTRI/2017/06/008741.
Costs associated with treatment induced peripheral neuropathy in patients with multiple myeloma (MM).
Authors: Sumeet Panjabi, Xue Song, Kathleen Wilson, Jerry Kagan
Journal: Journal of Clinical Oncology (2016)

8048 Background: MM- and MM-treatment induced peripheral neuropathy (TIPN) impairs quality of life and imposes function limitations in patients. The economic burden attributable to PN in MM patients is not well understood in real-world practice settings. We examined medical costs attributable to TIPN in MM patients in the US. Methods: Adult patients diagnosed with MM (ICD-9-CM code 203.0x) and ≥1 MM treatment between 7/1/2006 - 3/31/2015 were extracted from MarketScan claims databases. Patients had ≥12-month continuous enrollment (baseline) before initiation of first MM treatment (index date), and were followed for ≥3 months until inpatient death or end of data. “TIPN” was identified by ICD-9-CM claim codes indicating PN post index (8-270 days) and no PN claims during baseline and ≤7 days post-index. Patients without a PN diagnosis anytime during the study period served as controls. Controls were propensity score matched to TIPN patients in a ratio of up to 3:1 based on demographic and clinical characteristics. Medical costs per patient per month (PPPM, in 2015 $) in the post-index period are reported. Results: A total of 10,716 patients met study criteria and 10.7% had TIPN; 1120 TIPN and 3265 controls were matched. Baseline characteristics in the two groups were similar (mean age: 64; male: 61-62%; renal disease: 24-25%; mean follow up: 22-24 months). PPPM total costs were significantly higher by $1059 (p=0.018) for TIPN patients than controls, which were driven by inpatient admissions and outpatient medical costs. Conclusions: TIPN is prevalent in patients with MM; it adds to the complexity and cost of MM treatment. There is an unmet need for effective novel treatments that do not add to the economic burden associated with TIPN. TIPN Patients Controls p-value Mean SD Mean SD During the whole post-period (PPPM) Inpatient admission $4504 $9273 $4029 $8262 0.108 Outpatient medical $7877 $7829 $7376 $7788 0.063 Outpatient prescription $3596 $3227 $3513 $3306 0.466 Total $15978 $13437 $14919 $12767 0.018 Quarterly costs post-index (PPPM) 0-90 days $21327 $18600 $18872 $15579 <0.001 91-180 days $21972 $22593 $18436 $20349 <0.001 181-270 days $14415 $17936 $14406 $20281 0.991 271 to 360 days $12130 $17917 $11276 $14636 0.190
A new algorithm predicting imminent disease progression in advanced NSCLC patients by machine-learning integration of five serum biomarkers.
Authors: Yuri Kogan, Marina Kleiman, Shmuel Shannon, Moran Elishmereni, Eldad Taub, Larisa Aptekar, Ronen Mordechay Brenner, Raanan Berger, Hovav Nechushtan, Zvia Agur
Journal: Journal of Clinical Oncology (2018)

e21190 Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in America. Predicting disease progression just prior to its clinical manifestation would allow an earlier switch to the next treatment line, thus preventing major decline in the patient's state and potentially improving response to therapy. Yet, present serum tumor biomarkers, e.g. carcinoembryonic antigen (CEA), lack the power to foresee progression. We developed PrediCare, a new diagnostic algorithm for continuous monitoring and alerting to approaching progression in late-stage NSCLC, based on input from several tumor markers. Methods: The PrediCare algorithm was designed to process patient data in treatment by machine-learning modeling. Data of late-stage NSCLC patients under first-line standard-of-care therapies, collected in a retrospective observational trial (NCT02577627), served for algorithm training/testing. The algorithm’s predictive ability was evaluated using diverse features of 1-5 longitudinally measured serum tumor markers (CEA, CA125, CA15.3, CA19.9, NSE), as pre-selected by receiver-operating-characteristic analysis. Performance was evaluated by cross-validation. Results: NSCLC patients (n = 167) were assessed; median follow-up time was 101 days. The 5-marker combination showed strong prediction ability, with 66% sensitivity (accurate prediction of 109/165 progression events) and 91% specificity (15/165 false positives). Positive and negative predictive values, accuracy and Cohen’s kappa were 88%, 70%, 84% and 0.58, respectively. The algorithm’s performance with all five markers was superior to that of our previously shown 3-marker algorithm, and significantly surpassed the limited capacity (sensitivity/specificity) of each of these markers when used separately. Conclusions: Our algorithm is new in integrating five standard tumor biomarkers in a unique way for predicting imminent disease progression in advanced NSCLC. Use of our algorithm offers superiority over current interpretation of these markers in the clinic, and may aid in improving treatment navigation as well as potentially increasing survival.
Abstract 12823: Estimated Cardiorespiratory Fitness and Incident Atrial Fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Abhishek Bose, Wesley T O’Neal, Aleena Bennett, Suzanne E Judd, Waqas T Qureshi, Xuemei Sui, Virginia J Howard, George Howard, Elsayed Z Soliman
Journal: Circulation (2016)

Background: Poor cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular disease (CVD). However, wide utilization of CRF in CVD risk assessment is limited due to its cost, and the need for exercise equipment and skilled personnel. Estimated CRF (e-CRF) based on readily available clinical and self-reported data is a promising alternative though its role as a predictor of incident atrial fibrillation (AF) remains unclear. Methods: This study included 10,126 participants (54.5% women, 35% African American, mean age 63.2 years) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who were free of AF at the time of enrollment (2003-2007). Baseline e-CRF was determined using non-exercise algorithms (Table footnote). Incident AF cases were identified at a follow-up examination by electrocardiogram or self-reported medical history. Multivariable logistic regression was used to calculate the odds ratio (ORs) and 95% confidence intervals (CIs) for the association between baseline e-CRF and incident AF. Results: After a median follow-up of 9.4 years, 906 (8.9%) participants developed AF. In a multivariable model adjusted for demographics, baseline CVD risk factors, and potential confounders, each 1-unit increase in e-CRF was associated with a 5% lower risk of AF development (p=0.007). This association remained significant after further adjustment for incident coronary heart disease, heart failure, and stroke, and was stronger in women than men (interaction p-value =0.05). No significant interaction by age, sex, race, history of CVD, or physical limitations was observed. Conclusion: e-CRF using non-exercise algorithms is a useful predictor of incident AF, and the protective effect is more pronounced among women. e-CRF using non-exercise algorithms may serve as a useful alternative to CRF measured by costly and time consuming exercise testing.
Abstract 19010: Strial Pattern Hearing Loss is Associated With Impaired Endothelial Function and Increased Carotid Intima-Media Thickness
Authors: Michael Widlansky, Lisa E Rein, Sergey Tarima, Christopher Mueller, Naomi M Hamburg, Ramachandran S Vasan, Gary F Mitchell, David R Friedland
Journal: Circulation (2016)

Introduction: The stria vascularis of the inner ear is exquisitely sensitive to impairment of blood flow and damage to this structure is associated with low frequency (LF) hearing loss. Strial patt...
Comprehensive molecular characterization of pediatric treatment-induced glioblastoma: Germline DNA repair defects as a potential etiology.
Authors: John Thomas Lucas, John DeSisto, Gang Wu, Andrew Donson, Suzanne Baker, Michael A. Arnold, Smita Bhatia, Patrick Flannery, Rakeb Lemma, Lakotah Hardie, Lindsey Marie Hoffman, Kathleen Doris, Arthur Liu, Nicholas K. Foreman, Rajeev Vibhakar, Sariah Allen, Thomas E. Merchant, Adam L. Green, Brent Orr
Journal: Journal of Clinical Oncology (2018)

10573 Background: Pediatric treatment-induced high grade glioma (TIGs) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy. We now evaluate copy-number, sequence and epigenetic alterations in an expanded TIG cohort. Methods: Whole Genome (WGS) or Whole Exome Sequencing (WES), and Illumina Infinium 450/850K methylation profiling was performed on TIG (N = 34) and non-TIG (N = 29) pediatric high grade gliomas (pHGG) from a multi-institutional cohort and the Childhood Cancer Survivors Study Group. WGS/WES was performed on matched germline DNA from 15 TIGs and 23 non-TIG pHGG. Results: Survival between TIG and non-TIG pHGG was comparable (p = 0.43). On methylation profiling, 19/27 TIGs clustered into a subclass of IDH-wild type midline GBM. Recurrent copy number alterations included 1p loss (13/34), 1q gain (13/34), Ch.13 loss (13/34), PDGFRA gain/amplification (17/34), and CDKN2A loss (14/34). WGS identified a mean germline mutation load of 1.50 mut/Mb. There was no difference in the number of coding and noncoding mutations in TIG and non-TIG groups. Noncoding and coding region mutational spectrums seemed to be biased toward A-- > G and C-- > T respectively. TIG cases had frequent pathogenic germline alterations in DNA repair genes including BARD1, BRCA1, BRCA2, ATR, and PMS1. Conclusions: TIGs are enriched for specific defined epigenetic subgroups, and are characterized by recurrent chromosomal aberrations and frequent germline defects in DNA repair pathways.
P01.143 Unravelling the immune response components landscape in diffuse gliomas using immunophenotyping approach
Authors: I Hermelo, J Haapasalo, K Nordfors, H Haapasalo, M Nykter, K Granberg
Journal: Neuro-Oncology (2018)

One of the biggest caveats in diffuse glioma therapy is anti-tumor immune response suppression. By using cell-cell interactions like secreting cytokines and grow factors that modulate recruited macrophages and resident microglia, neoplastic cells do manage to promote favorable immediate milieus within healthy brain tissue. The aim of this study is to estimate proportions of immune- related cells in diffuse gliomas. Starting with fresh tumor biopsies, tissue integrity is mechanically disrupted followed by an enzymatic digestion. After initial output filtering, cell suspension is cleared from debris by gradient centrifugation. Immune cell fraction is enriched by magnetic cell sorting using anti-CD45 beads (leucocyte common antigen). CD45+ (positive) or column retained fraction, contains majority of the immune cells present in the tumor biopsy whereas CD45- (negative) or column eluted fraction, is comprised by tumor cells and other non-immune system related cells. Flow cytometry based cell-phenotyping approach has been used aiming for T lymphocyte, B lymphocyte, macrophage and granulocyte cell types estimation. Accordingly, we can point out proportion differences between different diffuse gliomas entities like an anaplastic astrocytoma (AA) grade III World Health Organization and glioblastoma (GBM) grade IV. Our results show a strong macrophage-related component and reveal a substantial granulocyte component in a GBM patient compared to the AA patient Altogether, this novel approach allows portraying preliminary immune proportions differences from AA grade III and a GBM grade IV patients, helping into the grounding step towards further understanding on how immune response is conformed in diffuse gliomas.
Efficacy and safety of nab-paclitaxel plus s-1 in the first-line treatment of advanced pancreatic cancer.
Authors: Wen Zhang, Chun-Xia Du, Yongkun Sun, Lin Yang, Chengxu Cui, Zhichao Jiang, Jinwan Wang, Ai-Ping Zhou
Journal: Journal of Clinical Oncology (2018)

e16217 Background: Gemcitabine has been approved as the standard chemotherapy for advanced pancreatic cancer since 1996. FOLFIRINOX significantly improved ORR and OS than GEM single-agent, but the significant increase of grade 3/4 adverse reactions, limited its wide application. The FDA approved nab-Paclitaxel for advanced pancreatic cancer in 2013. S-1 has demonstrated potential value in the treatment of advanced pancreatic cancer in Japan. We conducted a single arm, prospective, phase II study on the first-line treatment of advanced pancreatic cancer with nab-Paclitaxel and S-1 to investigate the efficacy and safety. Methods: Patients with untreated metastatic pancreatic cancer were treated with nab-Paclitaxel and S-1. Nab-Paclitaxel was administered intravenously on days 1 and 8 at 120mg/m2, S-1 of 120mg (the surface area≥1.5m2), 100mg (the surface area≥1.25m2-1.5m2) and 80mg (the surface area <1.25m2) was given 2 times daily on days 1-14, for every 3 weeks. Patients who achieved overall objective response and stable disease after 6 cycles therapy were given S-1 maintenance treatment until disease progression or unacceptable toxicity. The primary objective was objective response rate (ORR) according to RECIST v1.1 criteria, and the secondary objectives were disease control rate (DCR), progress-free survival (PFS), overall survival (OS) and safety. Results: Between 12/2014 and 07/2017, 32 patients were entered in this monocentric phase II trial. The ORR in intention to-treat (ITT) population (N = 32) was 53.1%, the disease control rate (DCR) was 87.5%. In the 30 evaluable patient population, the ORR and DCR were 56.7%, 93.3%. In 29 patients(90.6%)with elevated carbohydrate antigen 19-9 (CA19-9) at baseline,15 patients (52.3%) had ≥ 50% decline from baseline CA19-9. The median follow-up time was 12 months (range 6-26), the median PFS was 6.2 months, the median OS was 13.6 months. The incidence of grade 3/4 neutropenia was 27.6%. The incidence of other grade 3 adverse was 13.9%. Conclusions: Nab-paclitaxel and S-1 showed encouraging ORR, OS and manageable toxicities, which is an effective alternative treatment regimen for advanced pancreatic cancer.
Comprehensively assessing the clinical trial landscape in oncology over the last 10 years.
Authors: Jonathan Crowther, David john Cocker
Journal: Journal of Clinical Oncology (2017)

e18023 Background: Since the establishment of clinical trial registries such as ClinicalTrials.gov the number of such registries and the volume of data within the registries has quadrupled. Many studies have assessed the clinical trial landscape within their research field and have been hindered by inadequate search queries. Several approaches within these studies have implemented descriptive statistical analysis by examining specific indications or by searching for trials often using vague search terms such as “neoplasms”. This type of analysis permits the integration of potentially non-relevant noisy data which, impairs the overall analysis quality, Methods: In this study, we developed a semantic ontology linking algorithm to comprehensively merge 16 trial registries, 198,000 clinical trials, 10,000 molecules from multiple drug databases and PubMed, thus rendering and identifying indications, treatment, sites and investigators into one resource. The method allowed for a semantically cleaned and collapsed database to be queried more effectively with higher reliability in results. Results: The second proponent of our study was to assess the international oncology trial landscape over the last 10 years. The last major analysis in 2009 identified a significant preference for United States clinical sites in large cancer trials. Since this study, oncology has evolved toward a precision therapy approach and adaptive design model. This 2017 analysis shows an increasing concentration of US based clinical activity. For lung cancer trials with a US component, the top 100 US clinical research sites in the US are involved in 86% of the phase 1 trials, representing 55% of the total enrolment. When analyzing site usage for phase 3, this share drops to 67% of trials, representing just 8,5% of the total patient enrolment targets. Conclusions: The semantic ontology and algorithms and exploiting real-world data to mapped out and re-evaluate the status of cancer trials globally and gave insights into how cancer trials are progressing in the future. Understanding this evolution is of high importance for clinical trial planning and global trial country and site optimization.
Origin of exon skipping-rich transcriptomes in animals driven by evolution of gene architecture
Authors: Xavier Grau-Bové, Iñaki Ruiz-Trillo, Manuel Irimia
Journal: Genome biology (2018)

Alternative splicing, particularly through intron retention and exon skipping, is a major layer of pre-translational regulation in eukaryotes. While intron retention is believed to be the most prevalent mode across non-animal eukaryotes, animals have unusually high rates of exon skipping. However, when and how this high prevalence of exon skipping evolved is unknown. Since exon skipping can greatly expand proteomes, answering these questions sheds light on the evolution of higher organismal complexity in metazoans. We used RNA-seq data to quantify exon skipping and intron retention frequencies across 65 eukaryotic species, with particular focus on early branching animals and unicellular holozoans. We found that only bilaterians have significantly increased their exon skipping frequencies compared to all other eukaryotic groups. Unlike in other eukaryotes, however, exon skipping in nearly all animals, including non-bilaterians, is strongly enriched for frame-preserving sequences, suggesting that exon skipping involvement in proteome expansion predated the increase in frequency. We also identified architectural features consistently associated with higher exon skipping rates within all studied eukaryotic genomes. Remarkably, these architectures became more prevalent during animal evolution, indicating co-evolution between genome architectures and exon skipping frequencies. We suggest that the increase of exon skipping rates in animals followed a two-step process. First, exon skipping in early animals became enriched for frame-preserving events. Second, bilaterian ancestors dramatically increased their exon skipping frequencies, likely driven by the interplay between a shift in their genome architectures towards more exon definition and recruitment of frame-preserving exon skipping events to functionally diversify their cell-specific proteomes.
The role of patient financial assistance programs (PAPs) in reducing costs for cancer patients.
Authors: Yousuf Zafar, Steven Paul Wolf, Jennifer Watson, Lisa Vlastelica, Veena Shankaran, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2016)

e18269 Background: Limited transparency exists regarding eligibility and benefits for PAPs. Little is known about the extent of financial assistance provided by PAPs to reduce costs for prescription, anticancer drugs. Methods: This is a retrospective study of prescription anticancer drug costs and PAP coverage at an academic, referral cancer center’s specialty pharmacy. Drug, cost, and coverage data were collected from the specialty pharmacy database for prescriptions filled from January, 2013 to November, 2015. Prescriptions with missing co-pay, insurance, or financial assistance amount were excluded. Descriptive statistics summarized characteristics of prescriptions. Results: Of 9388 anticancer drug prescriptions filled, 9092 (97%) had complete cost data and were included. The 5 most common drugs prescribed were capecitabine (23%), temozolomide (13%), enzalutamide (9%), letrozole (5%), and tamoxifen (4%). 61% of prescriptions resulted in out-of-pocket costs for patients. The median co-pay was $20 per prescription (interquartile range (IQR) $10-69). The median cash price charged by the specialty pharmacy was $2782 per prescription (IQR $255-7698), and the median amount covered by insurance was $2532 per prescription (IQR $139-7060). Prescriptions filled with commercial insurance most commonly received PAP assistance (43%). Only 16% of prescriptions received financial assistance from PAPs, and of those, the vast majority (87%) received assistance for less than 25% of prescription price. The median amount of financial assistance provided by PAPs per prescription was $0; the mean was $88 (SD $428), amounting to 3% of median prescription cash price. Conclusions: Monthly costs for anticancer drug prescriptions were high, but the majority of costs were covered by insurance. Only a small minority of prescriptions received financial assistance from PAPs, and the proportion of financial assistance was small relative to the price billed to insurance. PAPs play a modest role in reducing anticancer prescription-related costs.