Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit.

PURPOSE: Immune checkpoint inhibition (ICI) therapy represents one of the great advances in the field of oncology, highlighted by the Nobel Prize in 2018. Multiple predictive biomarkers for ICI benefit have been proposed. These include assessment of programmed death ligand-1 expression by immunohistochemistry, and determination of mutational genotype (microsatellite instability or mismatch repair deficiency or tumor mutational burden) as a reflection of neoantigen expression. However, deployment of these assays has been challenging for oncologists and pathologists alike. METHODS: To address these issues, ASCO and the College of American Pathologists convened a virtual Predictive Factor Summit from September 14 to 15, 2021. Representatives from the academic community, US Food and Drug Administration, Centers for Medicare and Medicaid Services, National Institutes of Health, health insurance organizations, pharmaceutical companies, in vitro diagnostics manufacturers, and patient advocate organizations presented state-of-the-art predictive factors for ICI, associated problems, and possible solutions. RESULTS: The Summit provided an overview of the challenges and opportunities for improvement in assay execution, interpretation, and clinical applications of programmed death ligand-1, microsatellite instability-high or mismatch repair deficient, and tumor mutational burden-high for ICI therapies, as well as issues related to regulation, reimbursement, and next-generation ICI biomarker development. CONCLUSION: The Summit concluded with a plan to generate a joint ASCO/College of American Pathologists strategy for consideration of future research in each of these areas to improve tumor biomarker tests for ICI therapy.

Assessment of respiratory effort with EMG extracted from ECG recordings during prolonged breath holds: Insights into obstructive apnea and extreme physiology.

Breath holding divers display extraordinary voluntary control over involuntary reactions during apneic episodes. After an initial easy phase to the breath hold, this voluntary control is applied against the increasing involuntary effort to inspire. We quantified an electromyographic (EMG) signal associated with respiratory movements derived from broad bandpass ECG recordings taken from experienced breath holding divers during prolonged dry breath holds. We sought to define their relationship to involuntary respiratory movements and compare these signals with what is known to occur in obstructive sleep apnea (OSA) and epileptic seizures. ECG and inductance plethysmography records from 14 competitive apneists (1 female) were analyzed. ECG records were analyzed for intervals and the EMG signal was extracted from a re-filtered version of the original broad bandpass signal and ultimately enveloped with a Hilbert transform. EMG burst magnitude, quantified as an area measure, increased over the course of the struggle phase, correlated with inductance plethysmography measures, and corresponded to significant variance in heart rate variability. We conclude that an EMG signal extracted from the ECG can complement plethysmography during breath holds and may help quantify involuntary effort, as reported previously for obstructive sleep apnea. Further, given the resemblance between cardiac and respiratory features of the breath hold struggle phase to obstructive apnea that can occur during sleep or in association with epileptic seizure activity, the struggle phase may be a useful simulation of obstructive apnea for controlled experimentation that can help clarify aspects of acute and chronic apnea-associated physiology.

A National Assessment of Diagnostic Test Use for Patients with Advanced NSCLC and Factors Influencing Physician Decision-Making.

BACKGROUND: Diagnostic tests, including US Food and Drug Administration (FDA)-approved tests and laboratory-developed tests, are frequently used to guide care for patients with cancer, and, recently, have been the subject of several policy discussions and insurance coverage determinations. As the use of diagnostic testing has evolved, stakeholders have raised questions about the lack of standardized test performance metrics and the risk this poses to patients. OBJECTIVES: To describe the use of diagnostic testing for patients with advanced non-small-cell lung cancer (NSCLC), to analyze the utilization of FDA-approved versus laboratory-developed diagnostic tests, and to evaluate the impact of existing regulatory and coverage frameworks on diagnostic test ordering and physician treatment decision-making for patients with advanced NSCLC. METHODS: We conducted a 2-part study consisting of an online survey and patient chart review from March 1, 2019, to March 25, 2019, of physicians managing patients with advanced NSCLC. Respondents qualified for this study if they managed at least 5 patients with advanced NSCLC per month and had diagnosed at least 1 patient with advanced NSCLC in the 12 months before the survey. A total of 150 physicians completed the survey; before completing the survey, they were instructed to review between 4 and 8 charts of patients with stage IV NSCLC from their list of active patients. RESULTS: A total of 150 practicing oncologists who manage patients with advanced NSCLC responded to the survey and reviewed a total of 815 patient charts. Of these 815 patients, 812 (99.6%) were tested for at least 1 biomarker, including 73% of patients who were tested for EGFR, 70% tested for ALK, 58% tested for BRAF V600E, and 38% of patients tested for ROS1, by FDA-approved diagnostic tests. In all, 185 (83%) patients who tested positive for EGFR and 60 (83%) patients who tested positive for ALK received an FDA-approved targeted therapy for their biomarker. A total of 98 (65%) physicians responded that the patient's insurance coverage factored into their decision to order diagnostic tests and 69 (45%) physicians responded that cost or the patient's insurance coverage could influence them not to prescribe an indicated targeted therapy. CONCLUSION: The survey results indicate that diagnostic testing has become routine in the treatment of patients with advanced NSCLC, the use of FDA-approved diagnostic tests has increased, and insurance coverage and cost influence patient access to diagnostic testing as well as to targeted treatment options.

Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project.

BACKGROUND: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms. METHODS: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits. RESULTS: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers. CONCLUSIONS: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.

Tumor mutational burden standardization initiatives: Recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions.

Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.

The Value of Addressing Patient Preferences.

Recent scientific progress is, in some cases, leading to transformative new medicines for diseases that previously had marginal or even no treatment options. This offers great promise for people affected by these diseases, but it has also placed stress on the health care system in terms of the growing cost associated with some new interventions. Effort has been taken to create tools to help patients and health care providers assess the value of new medical innovations. These tools may also provide the basis for assessing the price associated with new medical products. Given the growing expenditures in health care, value frameworks present an opportunity to evaluate new therapeutic options in the context of other treatments and potentially lead to a more economically sustainable health care system. In summary, the contribution to meaningful improvements in health outcomes is the primary focus of any assessment of the value of a new intervention. A component of such evaluations, however, should factor in timely access to new products that address an unmet medical need, as well as the magnitude of that beneficial impact. To achieve these goals, value assessment tools should allow for flexibility in clinical end points and trial designs, incorporate patient preferences, and continually evolve as new evidence, practice patterns, and medical progress advance.

Assessment of arterial stiffness from pedal artery Korotkoff sound recordings: feasibility and potential utility.

Brachial artery (BA) Korotkoff sound (KS) timing reflects arterial stiffness. We recorded pedal artery (PA) KS in 68 healthy subjects using an electronic stethoscope and electrocardiography. Intervals between QRS complex of the electrocardiogram and KS waveform peaks (termed the QKD interval) were measured for 60 seconds, averaged, and QKD velocity (v) calculated. Carotid-BA and carotid-PA pulse wave velocities (PWVs) were measured by applanation tonometry. Analyzable KS recordings were obtained from BA and PA in 100% and 92% subjects. PA QKDv decreased less than BA QKDv with progressive cuff inflation. At diastolic blood pressure + 20 mm Hg (maximal yield), BA QKDv was independently associated with weight and pulse pressure, whereas PA QKDv was related to weight and age. PA QKDv correlated with its corresponding PWV stronger than BA QKDv. In conclusion, PA KS is optimally recorded at diastolic blood pressure + 20 mm Hg; PA QKDv is correlated with age and better correlates with PWV than does BA QKDv. This technique may provide a simple arterial stiffness measure.

Terrorism risks and cost-benefit analysis of aviation security.

We evaluate, for the U.S. case, the costs and benefits of three security measures designed to reduce the likelihood of a direct replication of the 9/11 terrorist attacks. To do so, we assess risk reduction, losses, and security costs in the context of the full set of security layers. The three measures evaluated are installed physical secondary barriers (IPSB) to restrict access to the hardened cockpit door during door transitions, the Federal Air Marshal Service (FAMS), and the Federal Flight Deck Officer (FFDO) Program. In the process, we examine an alternate policy measure: doubling the budget of the FFDO program to $44 million per year, installing IPSBs in all U.S. aircraft at a cost of $13.5 million per year, and reducing funding for FAMS by 75% to $300 million per year. A break-even cost-benefit analysis then finds the minimum probability of an otherwise successful attack required for the benefit of each security measures to equal its cost. We find that the IPSB is costeffective if the annual attack probability of an otherwise successful attack exceeds 0.5% or one attack every 200 years. The FFDO program is costeffective if the annual attack probability exceeds 2%. On the other hand, more than two otherwise successful attacks per year are required for FAMS to be costeffective. A policy that includes IPSBs, an increased budget for FFDOs, and a reduced budget for FAMS may be a viable policy alternative, potentially saving hundreds of millions of dollars per year with consequences for security that are, at most, negligible.

Use and quality of mental health services for Haitian youth.

OBJECTIVE: To describe the mental health service use of Haitian, African-American, and non-Latino White youth in a community mental health setting. Groups are compared on adherence to treatment guidelines for attention-deficit/hyperactivity disorder (ADHD) and depressive disorders. DESIGN: Retrospective review of outpatient mental health charts (n = 252) from five community sites in an urban area of the Northeastern United States. We recorded the total number and treatment type of sessions during the first six months of treatment. Guideline-adherent treatments were compared and predicted after controlling for clinical need. RESULTS: Most Haitian and African-American youth stopped treatment by six months, with the majority attending less than eight sessions. One third of Haitian and African-American patients attended just one session. Haitian patients who presented with less severe symptoms and dysfunction were more likely to have single-session treatments. Guideline-adherent treatment for ADHD and depression was less likely for Haitians. Older patients were more likely to receive adequate depression treatment. Haitian youth were relatively underinsured, had more family separations documented, and received Adjustment Disorder diagnoses more often. CONCLUSIONS: Haitian youth use outpatient mental health services in similar proportion to African-American youth and at lower rates than White youth. Guideline-adherent treatment for ADHD and depression is limited by low retention in care for Black youth. Low insurance coverage is likely an important contributor to reduced use of services, especially for Haitians. These findings are discussed in the context of providing culturally sensitive mental health care to diverse communities.

Exit vs. entrance block testing for cardiac lesion assessment.

Cardiac lesions are created to act as barriers which prohibit the transmission of cardiac myocyte contractile activity from one side of the lesion to the other. Testing for conduction block is the main way to acutely confirm the effectiveness of this therapy. There are two general methods used to test for conduction block. These methods are called: 1) "exit block testing" and 2) "entrance block testing." In this study, two different devices were used on n = 5 swine to determine if the method of lesion assessment (exit vs. entrance block testing) affected the ability to correctly identify if acute conduction block was achieved. No significant difference was found between conclusions drawn from either method of lesion assessment. However, the most robust lesion assessment will occur when both methods are employed so that the physician has the most information available for analysis.

Becoming a GP--a qualitative study of the career interests of medical students.

AIM: Only a minority of Australian graduates are interested in careers in general practice. The factors influencing medical students toward general practice as a career choice are poorly understood, even though this is important to the makeup of the medical workforce. METHODS: We ran 10 focus groups involving 82 first and final year medical students from three Australian medical schools in 2002, and analysed factors influencing participants' interest in working in general practice. RESULTS: About half the students were interested in general practice. Attractive factors were: the nature of the work (including its diversity), continuity of care, community context, and working conditions (including flexibility of training and work, availability of part time work and portability of qualifications). Negative factors included: the breadth of knowledge needed, boring work (in urban general practice), having to run a business, and working conditions (including relatively poor remuneration, overwork in rural general practice, and poor status of general practitioners). Some students were strongly influenced by negative attitudes of the GPs they were taught by, deciding against general practice as a career. DISCUSSION: Medical educators and GPs should be aware of this important influence.