tbuckley/cabot-search huggingface dataset:
A systematic review of surrogate endpoints (SEPs) for overall survival (OS) in metastatic colorectal cancer (mCRC).
Authors: Seerat Anand, Daniel Tannenbaum, Robert Asa Horn, Van K. Morris, Benny Johnson, Cathy Eng, Scott Kopetz, Michael J. Overman, Kanwal Pratap Singh Raghav, Arvind Dasari
Journal: Journal of Clinical Oncology (2019)

e18206 Background: Although progression free survival (PFS) and overall response rate (ORR) are common endpoints in mCRC trials, validation of these as SEPs for OS across the evolving landscape of systemic treatment in mCRC, with novel therapeutics and expanding lines of treatment, is limited. We aimed to evaluate the potential surrogacy of PFS and RR for OS and explore variations across trial factors. Methods: We identified phase 3 randomized trials of systemic therapy in mCRC between 1986 - 2016 from 4 electronic databases. Data regarding endpoints and trial variables were extracted from published reports. Spearman’s coefficient (r) and linear regression were used to evaluate rank correlations between A) PFS and ORR with OS of both treatment and control arms (arm level analysis); B) net improvement in outcomes using hazard ratio (HR) for PFS and relative risk (RR) for ORR with HR for OS (trial level analysis). Results: A total of 128 trials containing 233 and 230 arms reporting on PFS and ORR, respectively, were identified. Arm level analysis revealed that correlation of PFS and ORR with OS was 0.69 (95%CI: 0.6 – 0.7) and 0.79 (95%CI: 0.7 – 0.8), respectively ( P &lt; 0.001). Of 86 trials with reported HR for OS, PFS and ORR ratios were obtained for 84 and 74 trials, respectively. Trial level analysis revealed that correlation of PFS and ORR treatment effect with OS was 0.71 (95%CI: 0.6 – 0.8) and 0.58 (95%CI: 0.4 – 0.7), respectively ( P &lt; 0.001). Level of correlation for PFS and ORR varied with line of therapy, type of therapy and trial size (Spearman r shown in table). Conclusions: Both ORR and PFS are appropriate SEPs for OS for systemic therapy in mCRC but their relative value varies notably with line/type of therapy and study size. Judicious use of these SEPs in clinical trials accordingly to supplant OS may help improve trial designs and performance.[Table: see text]
Abstract 323: Re-expression of T-type Calcium Current in the Heart Protects from Stress-induced Hypertrophy and Heart Failure
Authors: Hiroyuki Nakayama, Ilona Bodi, Xiongwen Chen, Naser Jaleel, Steven R Houser, Arnold Schwartz, Jeffery D Molkentin
Journal: Circulation (2007)

Alterations in intracellular calcium handling are hypothesized to underlie cardiac disease through activating various calcium-dependent signaling pathways. For example, increased calcium influx or ...
Enrollment disparities in cancer clinical trials: A single institution experience.
Authors: Ariel Perez Perez, Nawid Mohammad Sarwari, Terra Warner, Liqiang Ni, Danny Landau
Journal: Journal of Clinical Oncology (2019)

e18128 Background: The importance of population heterogeneity in clinical cancer research is universally recognized. This study aims to identify possible disparities in trial participation at UF Health Cancer Center at Orlando Health. Methods: Data on patients’ enrollment, during the period from 01/01/2016 to 12/31/2016, was obtained from our research C-base. We utilized descriptive statistics to characterize the main demographic variables. Pearson's Chi-squared and Z-tests were utilized to compare percentages of enrolled versus not enrolled patients by ethnicity, race and gender. Results: A total of 3704 cases were established as new patients during the study period, of which 369 (10%) were enrolled in cancer research studies (Table). Our analysis showed statistically significant differences in enrollment by racial category (χ 2 = 95.09, df = 3, p &lt; 0.0000). American Indian (n = 6) and Native Hawaiian (n = 4), were excluded from the analysis due to small sample sizes and no enrollments. In addition we tested with the Z-stat whether the enrollment in each group was different from the population average (p = 0.10). The Caucasian group did not differ from the average (z = 0.3944; p &lt; 0.6933), whereas both the African American (z = -4.2286; p &lt; 0.0001) and the Asian group (z = -2.3102; p &lt; 0.0209) were under enrolled. The Others group was above the average (z = 8.4632; p &lt; 0.0001). There were also differences in enrollment by gender and ethnicity. Females were under enrolled as compared to Males (z = -7.0716; p &lt; 0.0001). The Hispanic group enrollment was significantly below the population average (z = -4.17; p &lt; 0.0001). Conclusions: We found significant differences in the enrollment of minorities in cancer trials in our institution. African Americans, Asians, Hispanics and Females were all under represented. The group labeled as Others requires further attention. [Table: see text]
Deriving real-world oral antineoplastic treatment endpoints: A comparison of automated data extraction versus manual chart abstraction.
Authors: James Lin Chen, Chhaya Shadra, Cheryl D. Cho-Phan, Aradhana Ghosh, Jonathan Hirsch
Journal: Journal of Clinical Oncology (2019)

e18070 Background: Real world data (RWD) is increasingly being used to generate evidence that informs clinical care. Calculating outcomes measures using RWD, such as time-on-treatment (ToT), requires accurate medication start/end dates. Whereas intravenously administered medication dates are typically available, dates for oral antineoplastics (OANs) are challenging as they are filled by specialty pharmacies and documented separately. To determine the feasibility of automated ToT extraction, we used the Syapse Learning Health Network to compare the utility of automated chart extraction (ACE) and of manual chart abstraction (MCA) from the electronic health record (EHR) in providing high-quality OAN data. Methods: We selected cancer patients (pts) from two histologies for whom OANs were prescribed. For these pts, ACE was compared to MCA. ACE data were derived from EHR structured medication lists through existing interoperability pipelines. MCA was performed by 4 trained data abstractors who reviewed the corresponding progress notes per pt. Expected date of OAN start/end, and actual medication start/end, were recorded as available. Chi-square and descriptive statistics were used for analysis. Results: 61 cancer pts (31 lung, 30 breast; mean age 62y [27-90]; 20% male) who received OAN from 3 multi-hospital medical systems were evaluated. ACE detected a greater number of expected start/end dates as compared to MCA (Table, P &lt; 0.001). In contrast, for actual start/end dates, the converse was true; ACE was inferior to MCA (P &lt; 0.001). Noteworthy, only 26% of pts had actual start/end dates using manual chart abstraction only. There was no concordance between the actual ACE and MCA dates. We evaluated if ACE expected ToT dates could be used as a surrogate for actual MCA ToT dates. Of the 12 pts satisfying this criteria, mean discordance in ToT was 19 days (1-71 days). Conclusions: MCA only captured actual ToT in a small minority of pts. ACE expected dates were a poor surrogate for ToT and highly discordant to over 2 months. Neither MCA nor ACE from EHR data were adequate for the majority of pts. Alternative mechanisms such as integration with additional data sources like specialty pharmacy dispensing records are essential. [Table: see text]
HIF1A genetic variability and late adverse events of radiotherapy in breast cancer.
Authors: Tanja Marinko, Katja Goricar, Vita Dolzan
Journal: Journal of Clinical Oncology (2019)

e12069 Background: Hypoxia-inducible factors (HIFs) are transcription factors that play an important part in the regulation of various cell processes involved in carcinogenesis such as cell proliferation, apoptosis, angiogenesis, and metastasis. Additionally, hypoxia could influence response to radiotherapy and radiation was shown to stabilize HIF-1α and affect release of cytokines. Previous studies have already shown that HIF1A genetic variability may modify cancer susceptibility, but data on its influence on treatment response are scarce. As nicotine induces HIF-1α expression, smoking could also modify treatment response. Our aim was to evaluate the association of common functional HIF1A rs11549465 polymorphism and smoking with late adverse events of radiotherapy in breast cancer patients. Methods: Our pilot retrospective study included 92 HER2-positive early breast cancer patients treated with adjuvant radiotherapy between 2005 and 2011. We isolated DNA from buccal swabs and genotyped all patients for HIF1A rs11549465 using competitive allele-specific PCR. Association of polymorphisms with adverse events and interaction with smoking was evaluated using logistic regression. Results: Median follow-up after radiotherapy was 4.2 (2.6-5.5) years. Overall, 30 (32.6%) patients reported late adverse events according to LENT-SOMA criteria, and 11 (12.0%) experienced skin toxicity according to CTCAE v.4.0 (Common Terminology Criteria for Adverse Events). Only 15 (16.3%) of patients were smokers. Minor allele frequency of HIF1A rs11549465 was 0.07. The studied polymorphism was not associated with late adverse events (OR = 0.75, 95% CI = 0.18-3.06, P = 0.688) or late skin toxicity (OR = 0.71, 95% CI = 0.08-6.15, P = 0.756) in our cohort of patients. We also observed no interaction between smoking, HIF1A genetic variability and late adverse events of radiotherapy. Conclusions: HIF1A rs11549465 was not associated with late adverse events of radiotherapy even if smoking was taken into account in our cohort of breast cancer patients.
Inner Ear Genes Underwent Positive Selection and Adaptation in the Mammalian Lineage
Authors: Francisco Pisciottano, Alejandro R Cinalli, Juan Matías Stopiello, Valeria C Castagna, Ana Belén Elgoyhen, Marcelo Rubinstein, María Eugenia Gómez-Casati, Lucía F Franchini
Journal: Molecular Biology and Evolution (2019)

The mammalian inner ear possesses functional and morphological innovations that contribute to its unique hearing capacities. The genetic bases underlying the evolution of this mammalian landmark are poorly understood. We propose that the emergence of morphological and functional innovations in the mammalian inner ear could have been driven by adaptive molecular evolution. In this work, we performed a meta-analysis of available inner ear gene expression data sets in order to identify genes that show signatures of adaptive evolution in the mammalian lineage. We analyzed ∼1,300 inner ear expressed genes and found that 13% show signatures of positive selection in the mammalian lineage. Several of these genes are known to play an important function in the inner ear. In addition, we identified that a significant proportion of genes showing signatures of adaptive evolution in mammals have not been previously reported to participate in inner ear development and/or physiology. We focused our analysis in two of these genes: STRIP2 and ABLIM2 by generating null mutant mice and analyzed their auditory function. We found that mice lacking Strip2 displayed a decrease in neural response amplitudes. In addition, we observed a reduction in the number of afferent synapses, suggesting a potential cochlear neuropathy. Thus, this study shows the usefulness of pursuing a high-throughput evolutionary approach followed by functional studies to track down genes that are important for inner ear function. Moreover, this approach sheds light on the genetic bases underlying the evolution of the mammalian inner ear.
Elderly patients have limited access to systemic therapy for metastatic renal cell carcinoma (mRCC) and shorter overall survival in Russia, Belarus and Kazakhstan.
Authors: Ilya Tsimafeyeu, Sergei Krasny, Nurzhan Nurgaliyev, Ilya Varlamov, Vladislav Petkau, Sufia Safina, Ruslan Zukov, Mikhail Mazhbich, Galina Statsenko, Olga Novikova, Igor Zaitsev, Dilara Kaidarova, Oxana Shatkovskaya, Pavel Moiseyev, Alexander Rolevich, Alesya Evmenenko, Irina L. Popova, Liubov Yu Vladimirova
Journal: Journal of Clinical Oncology (2019)

e23033 Background: Russia, Belarus and Kazakhstan are countries of the Eurasian Economic Union with upper-middle-income economies. Limited sources of the healthcare system could affect the treatment of individual cancer patients. The data on the treatment outcomes of elderly patients with mRCC are limited in these countries. RENSUR3 registry study assessed real-world data on the use of therapies in mRCC and overall survival (OS) in this population. Methods: Patients from Russia, Belarus and Kazakhstan were included in the retrospective multicenter registry study. To be eligible, patients were required to have mRCC diagnosed from January 2015 to January 2016. Anonymized data were collected through an online registry. The outcomes of interest were OS, patient characteristics and treatment patterns. Results: 1,094 adult mRCC patients were identified. Mean age at diagnosis of mRCC was 62.3 (SD, 11.2) years. 447 (41%) patients were 65 years and older. In total, 595 (54.4%) patients received systemic therapy for metastatic disease. 58% of elderly patients were not treated compared to 37% of younger patients. Cytokines were the most commonly used treatment in elderly patients (115 of 189 patients, 61%) while targeted therapy was more widely used in younger patients (223 of 406, 55%). Median OS was 12.7 months (95% CI 11.3-14.1) and 9.3 months (7.7-9.9) for patients aged &lt; 65 and ≥65 years, respectively (P &lt; 0.0001). Conclusions: More than half of elderly patients received no systemic therapy or had only cytokines for mRCC in Russia, Belarus and Kazakhstan which doubtless negatively affected OS in this population. Novel therapies should be considered as life-saving and a priority in elderly patients.
Express study: A trial in progress exploring the association between low level of genomic alteration and exceptional and unexpected response to targeted therapies in patients with solid tumors.
Authors: Olivia Le Saux, Antoine Italiano, Fabrice Andre, Thomas Filleron, Dominique Spaeth, Pierre-Etienne Heudel, Laurence Albiges, Thomas Denis Bachelot, Anthony Goncalves, Jean-Yves Pierga, Fabrice Barlesi, Valerie Boige, Celeste Lebbe, Laurent Mortier, Jean-Sebastien Frenel, Olivier Tredan, Marta Jimenez, François Legrand, Charles Ferte
Journal: Journal of Clinical Oncology (2019)

TPS3159 Background: Molecular targeted agents (MTA) resulted in breakthroughs in selected niches. It is often assumed that tumor regression is consecutive to an oncogenic de-addiction effect. An emerging hypothesis suggests that genomic instability may be associated with poor response to MTA. Indeed, the accumulation of defects in multiple oncogenes or tumor suppressor genes may result in the activation of multiple oncogenic pathways. These multiple signaling would mechanically result in a limitation of the oncogenic de-addiction process. Another hypothesis, suggests that tumor heterogeneity could also be associated with poor outcome under MTA. Such heterogeneity could also result from the genomic instability, and be appraised by bioinformatic and functional approaches. In this study, we thought to investigate whether molecular profiles reflecting a low level of genomic alterations in genes causally implicated in oncogenesis could be associated with an exceptional response (ER) to MTA. Methods: This is an exploratory, multicenter, multicohort, prospective trial conducted in 264 adult patients, with advanced breast, lung, colorectal, ovarian, kidney cancers and melanoma, having presented an ER to an approved MTA. ER is defined using the definition chosen by the NCI which combines the three criteria: - complete or partial response, - lasting &gt; 6 months, - and not expected in &gt; 10% of the patients in this drug – organ situation. The primary objective is to assess whether ER can be associated with a low level of genomic instability in the tumor. Low genomic instability is defined by the presence of less than the 5th quantile of genomic alterations (mutations, amplifications, deletions) to be expected in the given tumor type as per TCGA database. For each tumor type, the null hypothesis H0: π = 0.05 will be tested, against the one-sided alternative hypothesis π &gt; 0.05. For each of the 6 cohorts, a sample size of 44 patients is necessary to achieve 80% power at π = 15 with a one-sided level 5% test. Patients presenting an ER will be identified retrospectively, in a nationwide manner, then monthly reviewed and validated for inclusion by a panel of pathology experts. As of February 2019, 75 patients have been included. The identification of molecular traits associated with ER might serve the development of predictive classifiers for precision medicine. This study also represents a unique opportunity to better understand cancer biology. Clinical trial information: NCT02701907.
Hypericin enhances β-lactam antibiotics activity by inhibiting sarA expression in methicillin-resistant Staphylococcus aureus
Authors: Genzhu Wang, Liang Li, Xiukun Wang, Xue Li, Youwen Zhang, Jie Yu, Jiandong Jiang, Xuefu You, Yan Q. Xiong
Journal: Acta Pharmaceutica Sinica B (2019)

Bacteremia is a life-threating syndrome often caused by methicillin-resistant Staphylococcus aureus (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and β-lactam antibiotic resistance in Staphylococcus aureus. Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on β-lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of β-lactam antibiotics (e.g., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced sarA expression, and subsequently decreased mecA, and virulence-related regulators (e.g., agr RNAⅢ) and genes (e.g., fnbA and hla) expression in the studied MRSA strain. Importantly, the in vitro synergistic effect of hypericin with β-lactam antibiotic (e.g., oxacillin) translated into in vivo therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of β-lactam resistance against MRSA through sarA inhibition, and may allow us to repurpose the use of β-lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (e.g., oxacillin).
Proteomics analysis discovers biomarkers in serum months to years before small cell lung cancer: The HUNT study.
Authors: Olav Toai Duc Nguyen, Maria Markaki, Christina Chatzipantsiou, Animesh Sharma, Vincenzo Lagani, Ioannis Tsamardinos, Oluf D. Røe
Journal: Journal of Clinical Oncology (2019)

e20095 Background: The high incidence and high mortality rate of small-cell lung cancer (SCLC) calls for identification of methods for early diagnosis. Searching of cancer-related proteins and proteins signature in biofluids is an emerging approach in early diagnostic of malignancies. In the present study we have used proteomics-based profiling of serum collected 2 months to 5 years before SCLC diagnosis to search for early diagnostic biomarkers. Methods: All serum samples in this study were obtained from the Nord-Trøndelag Health Study (HUNT) Research Centre’s Biobank. Discovery sample set (Cohort I): Serum samples from 12 individuals that subsequently developed SCLC and 12 matched controls were obtained. Validation sample set (Cohort II): Serum samples from 5 future SCLC patients and 5 matched controls were obtained. The serum samples in both cohorts were collected in a time frame of 2 months to 5 years before diagnosis. All controls included in the study were matched to the cases for smoking status (pack years and quit time), gender and age, and were cancer-free at least 5 years before blood sampling. All subjects were smokers or ex-smokers. Twenty (20) µl of serum was depleted of its high-abundant proteins and the cleaned-up peptides were analysed by LC- MS with an Orbitrap Elite mass spectrometer. Data were processed/analysed using MaxQuant software. Using Cohort I as training set, proteins most related to diagnosis were identified at first with limma univariate analysis. Reference and equivalent signatures were identified using JADbio with SES as feature selection algorithm. The JADbio matched pipeline with 50 repetitions for performance assessment (AUC with 95% CI) was used. Results: In each serum sample the analysis detected 435 proteins in Cohort I and 609 proteins in Cohort II. Reference signature for 12 SCLC future cases vs 12 matched controls had a conservative AUC of 0.686 (95% CI: 0.557, 0.765) in the discovery cohort. Three proteins in the reference and equivalent signatures were also found to be differentially expressed in validation Cohort II; all three proteins discriminated small-cell lung cancer patients from their respective controls (AUC 0.757-0.826 in the discovery Cohort I and AUC 0.68-0.84 in the validation Cohort II). Conclusions: The results indicate that differential levels of a few proteins in serum may help detecting SCLC 2 months to 5 years prior to clinical diagnosis. This is one of the first large-scale proteomics screening studies of pre-diagnostic serum of future SCLC patients. Further validation studies are in progress.
Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.
Authors: Puyuan Xing, Li Junling, Xuezhi Hao, Yuxin Mu, Shouzheng Wang, Di Ma, Jing Lin, Hao Liu, Han Han-Zhang, Analyn Lizaso, Jianxing Xiang, Xinru Mao
Journal: Journal of Clinical Oncology (2019)

e20530 Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1 st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.