Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Serum Vitamin D Is Inversely Associated with Blood Eosinophil Count Among Adults with Allergic Asthma.

OBJECTIVE: To evaluate the role that serum vitamin D concentration plays in the number of eosinophils in peripheral blood in adults with allergic asthma. MATERIAL AND METHODS: A total of 142 patients were categorized based on different cutoff points for eosinophils: ≥200, ≥300, ≥400, and ≥500 cells/mL. The vitamin D concentration was stratified into <20 and ≥20 ng/mL. The association between vitamin D (independent variable) and eosinophils (dependent variable) was explored using multivariate analysis. RESULTS: The average number of eosinophils in the included patients was 418 cells/mL, and 33.8% of the included patients had vita- min D concentrations ≥20 ng/mL. Asthmatic patients with vitamin D< 20 ng/mL had a higher mean concentration of eosinophils than did asthmatic patients with vitamin D ≥20 ng/mL (464 ± 377.7 eosinophils/mL vs. 327.8 ± 247.2 eosinophils/mL, P = .025). We also observed that vitamin D was inversely correlated with eosinophil count (rho = 0.244, P = .003). In the multivariate analysis, vitamin D <20 ng/mL showed a significant inverse association with each cutoff value for eosinophilia (odds ratio >1). CONCLUSION: Vitamin D concentrations <20 ng/mL are associated with a significant increase in the number of eosinophils in blood. Studies that analyze the use of vitamin D supplements as complementary therapy for the treatment of asthma are needed.

Longitudinal change in cerebro-placental ratio (CPR) between 37 and 40 weeks of pregnancy is associated with non-reassuring fetal status and increased risk of cesarean section.

OBJECTIVE: To evaluate in low-risk pregnancies if longitudinal change in cerebro-placental ratio (CPR) between 37 and 40 weeks of pregnancy is associated with cesarean section (CS) for non-reassuring fetal status (NRFS) during labor. METHODS: This is a prospective observational study of women with singleton low-risk pregnancies who underwent an ultrasound scan at 36 + 0 to 37 + 6 and 39 + 0 to 41 + 6 weeks of pregnancy, when the CPR was calculated from the middle cerebral artery (MCA) and umbilical artery (UA) pulsatility indices. Managing professionals were kept blinded to the Doppler results. The association of the longitudinal change between both CPR (z-velocity) to CS for NRFS was evaluated by logistic regression. RESULTS: A total of 401 pregnancies were included. The mean time interval between both CPR evaluations was 21 days (SD 7). A CS for fetal distress was performed in 7% of pregnancies. Independent of the CPR at 37 weeks, the likelihood of CS for fetal distress was significantly decreased by the longitudinal changes from 37 to 40 weeks (OR 0.61, 95%CI 0.4-0.92; p=.018). This association remained significant after further adjustment for potential confounders (nulliparity, maternal weight at booking and estimated fetal weight at 37): (OR 0.64, 95%CI 0.41-0.98; p=.044). CONCLUSIONS: The longitudinal change of CPR between 37 and 40 weeks is associated with the need for CS for NRFS during labor.

Evaluation of the electrochemical response of Saccharomyces cerevisiae using screen-printed carbon electrodes (SPCE) modified with oxidized multi-walled carbon nanotubes dispersed in water - Nafion®.

The evaluation of the electrochemical determination of Saccharomyces cerevisiae was carried out using a screen-printed carbon electrode (SPCE) modified with Nafion-dispersed oxidized multi-walled carbon nanotubes (OMWCNT). The morphology was studied using scanning electron microscopy (SEM), showing a complete modification of the surface with the nanotubes and yeast interaction with them instead of the graphite surface. The redox couple Fe(CN)6 4-/Fe(CN)6 3- was used to determine the electroactive area, the heterogeneous transfer constant, and the Nafion® effect. Results showed increases in electroactive area and heterogeneous transfer constant of 146% and 20.4%, respectively, due to the presence of nanotubes. Studies of the Nafion® effect showed that the polymeric membrane affects the electroactive area but not the heterogeneous transfer constant. Studies of the scan rate effect show that yeast oxidation is an irreversible mixed control process. As the concentration and scan rate increased, the anodic potential shifted toward more anodic values. The relationship between yeast concentration and the anodic current density (current/electroactive area) of yeast showed a linear range between 0.61 and 7.69 g L-1, the limit of detection (LOD) and the limit of quantification (LOQ) were 0.17 g L-1, and 0.61 g L-1, respectively, and the sensibility obtained was 0.03 µA L g-1 mm-2. These results show that with the screen-printed carbon electrodes it is possible to improve the electrochemical determination of this microorganism, enhancing the analytical parameters and quantification, allowing greater portability and decreasing measurement times and associated waste.

Pediatric health and life domain priorities: A national survey of people with spinal cord injury and their parents and caregivers.

CONTEXT/OBJECTIVE: No information is available regarding priorities for pediatric-onset spinal cord injury (SCI). This study described the Health and Life (H&L) domain priorities of youth with pediatric-onset SCI and their parents/caregivers living in Spain. DESIGN: A cross-sectional survey. SETTING: Two SCI rehabilitation centers. PARTICIPANTS: Sixty participants, youth with pediatric-onset SCI (n = 26) and parents/caregivers (n = 34). INTERVENTIONS: Not applicable. OUTCOME MEASURES: Median overall priorities calculated on the basis of importance, unhappiness, and research measured with a new survey of pediatric H&L domains and rated using a 5-point Likert Scale. RESULTS: A total of 60 surveys were received providing information on 35 individuals with SCI: 2-7-year-olds (25.7%), 8-12-year-olds (22.9%), 13-17-year-olds (31.4%), and 18-25-year-olds (20.0%). The top three overall H&L priorities reported by parents/caregivers of 2-12-year-olds were "parenthood expectations" (84%), "leg/foot movement" (83%), and "bladder" function (83%), compared to "dressing/undressing" (78%), "walking/ability to move" (77%) and "bladder" function (77%) rated for 13-25-year-olds. "Sit-to-stand" (79%), "leg/foot movement" (78%) and "arm/hand movement" (77%) were reported as priorities by 13-25-year-olds. The 13-25-year-olds highlighted "sit-to-stand" (100%), "eating/drinking" (54%), and "physical function" (94%) as their top unhappiness, importance, and research priorities, respectively. Significant differences between tetraplegia and paraplegia were found in "mobility in the community" (unhappiness item) for 13-25-years-old. CONCLUSION: Health domains were considered the top overall H&L priorities by parents/caregivers of 13-25-year-olds, compared to life domains reported for their 2-12-year-olds. This survey will aid rehabilitation professionals to engage stakeholders to implement a comprehensive SCI management program for the pediatric population.

Quantitative analysis of dysautonomia in patients with autonomic dysreflexia.

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20 mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.

Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response.

Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.This article is highlighted in the In This Issue feature, p. 211.

Cell-free Circulating Tumor DNA Variant Allele Frequency Associates with Survival in Metastatic Cancer.

PURPOSE: Physicians are expected to assess prognosis both for patient counseling and for determining suitability for clinical trials. Increasingly, cell-free circulating tumor DNA (cfDNA) sequencing is being performed for clinical decision making. We sought to determine whether variant allele frequency (VAF) in cfDNA is associated with prognosis. EXPERIMENTAL DESIGN: We performed a retrospective analysis of 298 patients with metastatic disease who underwent clinical comprehensive cfDNA analysis and assessed association between VAF and overall survival. RESULTS: cfDNA mutations were detected in 240 patients (80.5%). Median overall survival (OS) was 11.5 months. cfDNA mutation detection and number of nonsynonymous mutations (NSM) significantly differed between tumor types, being lowest in appendiceal cancer and highest in colon cancer. Having more than one NSM detected was associated with significantly worse OS (HR = 2.3; P < 0.0001). VAF was classified by quartiles, Q1 lowest, Q4 highest VAF. Higher VAF levels were associated with a significantly worse overall survival (VAF Q3 HR 2.3, P = 0.0069; VAF Q4 HR = 3.8, P < 0.0001) on univariate analysis. On multivariate analysis, VAF Q4, male sex, albumin level <3.5 g/dL, number of nonvisceral metastatic sites >0 and number of prior therapies >4 were independent predictors of worse OS. CONCLUSIONS: Higher levels of cfDNA VAF and a higher number of NSMs were associated with worse OS in patients with metastatic disease. Further study is needed to determine optimal VAF thresholds for clinical decision making and the utility of cfDNA VAF as a prognostic marker in different tumor types.

Correction: A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

[This corrects the article DOI: 10.18632/oncotarget.16018.].

Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA.

PURPOSE: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies. EXPERIMENTAL DESIGN: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA). RESULTS: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04). CONCLUSIONS: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

OCTANE: Oncology Clinical Trial Annotation Engine.

PURPOSE: Many targeted therapies are currently available only via clinical trials. Therefore, routine precision oncology using biomarker-based assignment to drug depends on matching patients to clinical trials. A comprehensive and up-to-date trial database is necessary for optimal patient-trial matching. METHODS: We describe processes for establishing and maintaining a clinical trial database, focusing on genomically informed trials. Furthermore, we present OCTANE (Oncology Clinical Trial Annotation Engine), an informatics framework supporting these processes in a scalable fashion. To illustrate how the framework can be applied at an institution, we describe how we implemented an instance of OCTANE at a large cancer center. OCTANE consists of three modules. The data aggregation module automates retrieval, aggregation, and update of trial information. The annotation module establishes the database schema, implements data integration necessary for automation, and provides an annotation interface. The update module monitors trial change logs, identifies critical change events, and alerts the annotators when manual intervention may be needed. RESULTS: Using OCTANE, we annotated 5,439 oncology clinical trials (4,438 genomically informed trials) that collectively were associated with 1,453 drugs, 779 genes, and 252 cancer types. To date, we have used the database to screen 4,220 patients for trial eligibility. We compared the update module with expert review, and the module achieved 98.5% accuracy, 0% false-negative rate, and 2.3% false-positive rate. CONCLUSION: OCTANE is a general informatics framework that can be helpful for establishing and maintaining a comprehensive database necessary for automating patient-trial matching, which facilitates the successful delivery of personalized cancer care on a routine basis. Several OCTANE components are publically available and may be useful to other precision oncology programs.

Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA.

PURPOSE: Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer. PATIENTS AND METHODS: Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications. RESULTS: We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96). CONCLUSION: cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.

Precision Oncology Decision Support: Current Approaches and Strategies for the Future.

With the increasing availability of genomics, routine analysis of advanced cancers is now feasible. Treatment selection is frequently guided by the molecular characteristics of a patient's tumor, and an increasing number of trials are genomically selected. Furthermore, multiple studies have demonstrated the benefit of therapies that are chosen based upon the molecular profile of a tumor. However, the rapid evolution of genomic testing platforms and emergence of new technologies make interpreting molecular testing reports more challenging. More sophisticated precision oncology decision support services are essential. This review outlines existing tools available for health care providers and precision oncology teams and highlights strategies for optimizing decision support. Specific attention is given to the assays currently available for molecular testing, as well as considerations for interpreting alteration information. This article also discusses strategies for identifying and matching patients to clinical trials, current challenges, and proposals for future development of precision oncology decision support. Clin Cancer Res; 24(12); 2719-31. ©2018 AACR.

Physician interpretation of genomic test results and treatment selection.

BACKGROUND: Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results. METHODS: On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable. RESULTS: Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS). CONCLUSIONS: Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2018;124:966-72. © 2017 American Cancer Society.

"Personalized Cancer Therapy": A Publicly Available Precision Oncology Resource.

High-throughput genomic and molecular profiling of tumors is emerging as an important clinical approach. Molecular profiling is increasingly being used to guide cancer patient care, especially in advanced and incurable cancers. However, navigating the scientific literature to make evidence-based clinical decisions based on molecular profiling results is overwhelming for many oncology clinicians and researchers. The Personalized Cancer Therapy website (www.personalizedcancertherapy.org) was created to provide an online resource for clinicians and researchers to facilitate navigation of available data. Specifically, this resource can be used to help identify potential therapy options for patients harboring oncogenic genomic alterations. Herein, we describe how content on www.personalizedcancertherapy.org is generated and maintained. We end with case scenarios to illustrate the clinical utility of the website. The goal of this publicly available resource is to provide easily accessible information to a broad oncology audience, as this may help ease the information retrieval burden facing participants in the precision oncology field. Cancer Res; 77(21); e123-6. ©2017 AACR.

Precision oncology: neither a silver bullet nor a dream.

Precision oncology is not an illusion, nor is it the magic bullet that will eradicate all cancers. Precision oncology is simply another weapon in our growing armament against cancer. Rather than honing in on the failures of a relatively young field, one should advocate for integrating its successes into widespread clinical practice, especially for indications, such as: ABL, ALK, BRAF, BRCA1, BRCA2, EGFR, KIT, KRAS, PDGFRA, PDGFRB, ROS1, BCR-ABL, FLT3 and ROS1, where aberrations have been shown to alter responses to US FDA approved drugs - that is, level 1 data. Moreover, to truly assess the promise of precision oncology, we must first begin by defining our expectations for this field. Importantly, we must recognize that the conception of precision oncology arose as an antithesis of the 'one-size fits all' cancer therapeutics approach. Consequently, tools used for evaluating these conventional, large-scale trials, are not directly transferable for assessing nonconventional, smaller-scale trials needed for evaluating precision oncology. Hence, a thorough vetting of precision oncology as another tool of the trade, must first begin by reassessing our expectations for this field, as well as current clinical trial designs and end point measurements. Importantly, we must recognize that most targeted therapy approaches are in their infancy, with only monotherapy approaches being assessed and combination therapies likely being necessary to fulfill the promise of precision oncology.

A feasibility study of returning clinically actionable somatic genomic alterations identified in a research laboratory.

PURPOSE: Molecular profiling performed in the research setting usually does not benefit the patients that donate their tissues. Through a prospective protocol, we sought to determine the feasibility and utility of performing broad genomic testing in the research laboratory for discovery, and the utility of giving treating physicians access to research data, with the option of validating actionable alterations in the CLIA environment. EXPERIMENTAL DESIGN: 1200 patients with advanced cancer underwent characterization of their tumors with high depth hybrid capture sequencing of 201 genes in the research setting. Tumors were also tested in the CLIA laboratory, with a standardized hotspot mutation analysis on an 11, 46 or 50 gene platform. RESULTS: 527 patients (44%) had at least one likely somatic mutation detected in an actionable gene using hotspot testing. With the 201 gene panel, 945 patients (79%) had at least one alteration in a potentially actionable gene that was undetected with the more limited CLIA panel testing. Sixty-four genomic alterations identified on the research panel were subsequently tested using an orthogonal CLIA assay. Of 16 mutations tested in the CLIA environment, 12 (75%) were confirmed. Twenty-five (52%) of 48 copy number alterations were confirmed. Nine (26.5%) of 34 patients with confirmed results received genotype-matched therapy. Seven of these patients were enrolled onto genotype-matched targeted therapy trials. CONCLUSION: Expanded cancer gene sequencing identifies more actionable genomic alterations. The option of CLIA validating research results can provide alternative targets for personalized cancer therapy.

ALK: a tyrosine kinase target for cancer therapy.

The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and alectinib-are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.