Programmed Death Ligand-1 and Tumor Mutation Burden Testing of Patients With Lung Cancer for Selection of Immune Checkpoint Inhibitor Therapies: Guideline From the College of American Pathologists, Association for Molecular Pathology, International Association for the Study of Lung Cancer, Pulmonary Pathology Society, and LUNGevity Foundation.

CONTEXT.­: Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. OBJECTIVE.­: To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. DESIGN.­: The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. RESULTS.­: Six recommendation statements were developed. CONCLUSIONS.­: This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and TMB testing in the clinical setting.

Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson's Disease Pathology.

Parkinson's disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

BACKGROUND: The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aß42) and tau levels in AD. METHODS: This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. RESULTS: Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aß42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aß42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aß42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (ß = - 0.154, p = 0.0112; ß = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (ß = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aß42 level for non-Hispanic AA and Hispanic participants compared with White participants. CONCLUSION: Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.

Initial Steps in Creating a Patient-Centric Addendum to Clinical Trial Informed Consent Forms.

Introduction: The purpose of the informed consent form (ICF) is to outline the risks and benefits of an interventional clinical trial to potential participants. The aim of this study was to explore the feasibility of a short addendum to the ICF, summarizing key points most relevant to potential participants. Methods: A sample of 20 ICFs was reviewed against the requirements of the U.S. federal regulation documents and assessed for readability. Alongside the ICF review, we conducted focus groups and one-on-one interviews with people with lung cancer (n = 9) to learn what information was most important when considering participation in a clinical trial using a hypothetical phase 3 ICF. Results: The 20 ICFs reviewed were from phases 1 to 3, expanded-access, and single-patient trials covering predominantly NSCLC; 60% were global. The mean length of the ICFs was 21 (range: 15-34) pages. The average reading level was tenth grade whereas the average U.S. reading level was eighth grade. Readability varied by section, the "purpose of the study" section had the highest reading level. In the qualitative research component, participants were "overwhelmed" by the hypothetical ICF. Participants were also asked to list information for the addendum; their suggestions broadly map to federal regulations. An addendum with reference to sections in the ICF for additional details was well received. Conclusions: The variations in ICF architecture and readability make it difficult for patients to make an informed decision to participate in a clinical trial. Implications extend beyond lung cancer, highlighting key areas for ICF improvements and providing a roadmap for developing a patient-centric addendum.

Patient Report on the Impact of Coronavirus Disease 2019 and Living With Lung Cancer.

Introduction: Several studies have highlighted coronavirus disease 2019 (COVID-19)-related disruptions in treatment and care in people living with lung cancer. However, few studies have assessed patient-reported perspectives on treatment disruption. This study aims to report the patient perspectives on the impact of COVID-19, vaccination access, and coverage on people living with lung cancer. Methods: Data are from a larger online longitudinal study being run by a lung cancer nonprofit organization, LUNGevity Foundation. The survey is open to all patients living with lung cancer and their caregivers. These analyses focus on data captured in the COVID-19 module and the vaccine questionnaire. Descriptive statistics were computed for categorical and ordinal variables. Results: Overall, 164 people living with lung cancer completed the COVID-19 module. Of these, 54% reported disruption in access to treatment, appointments, participating in research and clinical trials. Participants living with stage IV disease were likely to be more concerned about COVID-19 (35%) compared with those with stage I, II, and III. More than half (66%) had tested for COVID-19 of this group 88% tested negative. There was a correlation among participants testing positive for COVID-19 and the number of household members who also tested positive for COVID-19. In the sample who completed the vaccine survey, almost all (98%) were vaccinated against COVID-19. When a recommendation came from a health care professional, an oncologist was the most likely referral source (33%). Conclusions: An integrative patient-reported view on the impact of COVID-19 is important for adequate preparation to ensure undisrupted treatment and allocation of resources.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Plain language summary and patient perspective of the 2020 lung cancer screening recommendations by the US Preventive Services Task Force.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the research carried out by the United States Preventive Services Task Force (USPSTF for short) during a review and update of their lung cancer screening recommendations made in 2013. The USPSTF reviewed the results of clinical studies that used a type of scan called low dose computed tomography (LDCT for short). They wanted to see how successful LDCT was at finding lung cancers in people ho hadn't shown any physical signs of lung cancer, but had a history of smoking and were over 50 years of age. WHAT WERE THE RESULTS?: The review found that performing yearly LDCT scans in people who are at high risk of developing lung cancer is beneficial, as it means that some patients will be diagnosed earlier than they would be without this type of screening. People considered to be at high risk of developing lung cancer include: Adults aged 50 to 80 years who have smoked a pack of 20 cigarettes per day for 20 years or two packs per day for 10 years; OR Adults aged 50 to 80 years who currently smoke or have stopped smoking within the last 15 years. WHAT DO THE RESULTS OF THE STUDY MEAN?: The information gained from reviewing the research enabled the USPSTF to update their lung cancer screening recommendations.

Plain language summary and patient perspective of the European Society for Medical Oncology expert consensus statements on treating EGFR-positive non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This article provides a plain language summary and patient perspective of a new set of recommendations made by the European Society for Medical Oncology (ESMO for short). These recommendations are also called expert consensus statements. They cover the management of people with a type of lung cancer called epidermal growth factor receptor-positive non-small-cell lung cancer (EGFR-positive NSCLC for short). WHY WERE THE RECOMMENDATIONS DEVELOPED?: The ESMO Clinical Practice Guidelines are used by healthcare professionals when treating people with cancer, but they don't necessarily have all the information healthcare professionals need to make decisions for with people with EGFR-positive NSCLC. So, in 2021, 32 healthcare professionals who are experts in treating people with EGFR-positive NSCLC worked together to produce recommendations to fill these gaps about EGFR-positive NSCLC. This was called a consensus-building process and it also included patient advocates. WHAT RECOMMENDATIONS DID THEY MAKE?: The experts discussed four main topics including how people with different stages of EGFR-positive NSCLC are diagnosed and treated, and how clinical studies are done. They reviewed the scientific information that exists on these subjects. They reached an agreement and developed the recommendations that are summarized here.

Plain language summary and patient perspective of the American Society for Clinical Oncology guideline: management of stage 3 non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a guideline on the management of stage 3 non-small-cell lung cancer, also known as NSCLC. This guideline was written by the American Society for Clinical Oncology (ASCO for short) and published in the Journal of Clinical Oncology. WHY WERE THE GUIDELINES DEVELOPED?: The purpose of the ASCO guideline is to provide recommendations to healthcare professionals in the US including oncologists, surgeons, pathologists, radiologists, and nurses on how best to diagnose and treat people with stage 3 NSCLC. HOW WERE THE GUILDEINES DEVELOPED?: The ASCO guideline is based on the latest research and scientific evidence to make certain the recommendations are up to date and based on reliable data and best practice. In 2021, a group of experts were asked by ASCO to form an Expert Panel. The Expert Panel reviewed the results of 127 clinical research studies on NSCLC that were done between 1990 and 2021. They looked at how NSCLC had been diagnosed and treated in these studies, as well as at patients' survival and quality of life. The Expert Panel used these findings and their own expertise to form their recommendations and produce the 2021 ASCO Guideline called 'Management of Stage 3 Non-Small-Cell Lung Cancer: ASCO Guideline'. WHAT INFORMATION DOES THE GUIDELINE CONTAIN?: The guideline aims to answer the following questions: What are the most precise ways to confirm and stage NSCLC in people suspected of having a stage 3 disease? Which patients with stage 3 NSCLC can be treated most successfully with surgery? Which patients who can be treated with surgery could also have an additional therapy before their surgery? Which patients who can be treated with surgery could also have an additional treatment after their surgery? Which treatment and/or management is most suitable for patients who cannot have surgery?

2022 cancer statistics: Focus on lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a medical journal article called 'Cancer statistics, 2022'. The data in this summary provides detailed information about lung cancer and less detailed information about other cancers. The researchers from the original study used data gathered from previous years to produce a cancer forecast, predicting the number of new cancer diagnoses and deaths in the United States in 2022. WHAT WERE THE RESULTS?: The review of the data up to 2019 found that compared to previous years: Advanced lung cancer diagnoses had decreased Local stage lung cancer diagnoses had increased Deaths had slowed for lung cancer Deaths continued to reduce for breast cancer, but the rate of this reduction had slowed down Female breast cancer diagnoses were slowly increasing each year Prostate cancer diagnoses stayed similar Local stage prostate cancer diagnoses stayed similar Advanced prostate cancer diagnoses had increased each year The researchers estimated that over 1.9 million new cancer cases would be diagnosed and over half a million cancer deaths would occur in the United States in 2022. This figure includes approximately 350 deaths per day from lung cancer, which was found to be the leading cause of cancer death in the United States. WHAT DO THE RESULTS OF THE STUDY MEAN?: The study found that progress in reducing the number of people being diagnosed with breast and prostate cancer has stalled. Although there were fewer lung cancers diagnosed, this reduction was likely caused by changes in screening and advancements in lung cancer treatments. The American Cancer Society recommended that investing more funds in detecting cancers early as well as developing targeted treatments would help to reduce cancer death rates. This would also help to address the differences in access to cancer care that exist based on racial, social and economic inequalities.

Plain language summary and patient perspective of the revised STARS study: long-term results of a study that compared the effectiveness of radiotherapy to surgery in people with non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study called revised STARS. The STARS study involved people with non-small-cell lung cancer, also known as NSCLC. The cancer was less than 5 cm in size and had not spread to other parts of the body (known as stage 1 cancer). The study compared the effectiveness of surgery versus a type of radiotherapy treatment, called stereotactic ablative radiotherapy (also known as SABR) as a treatment for people with NSCLC. Researchers wanted to find out how likely people were to be alive after treatment or if their cancer had grown or spread to other parts of their body (also known as progressed). WHAT WERE THE RESULTS?: The study found that the long term outcomes were similar between SABR and surgery. People with NSCLC were as likely to be alive 3 years after treatment with SABR compared to surgery. WHAT DO THE RESULTS OF THE STUDY MEAN?: SABR may be an alternative to surgery for people with stage 1 NSCLC which is less than 5 cm in size and has not spread to other parts of the body Clinical Trial Registration: NCT02357992 (ClinicalTrials.gov).

Differential expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in Alzheimer's disease and HIV-1 associated neurocognitive disorders.

The United Nations projects that one in every six people will be over the age of 65 by the year 2050. With a rapidly aging population, the risk of Alzheimer's disease (AD) becomes a major concern. AD is a multifactorial disease that involves neurodegeneration in the brain with mild dementia and deficits in memory and other cognitive domains. Additionally, it has been established that individuals with Human Immunodeficiency Virus-1 (HIV-1) experience a 5 to 10-year accelerated aging and an increased risk of developing HIV-associated neurocognitive disorders (HAND). Despite a significant amount of clinical evidence pointing towards a potential overlap between neuropathogenic processes in HAND and AD, the underlying epigenetic link between these two diseases is mostly unknown. This study is focused on identifying differentially expressed genes observed in both AD and HAND using linear regression models and a more robust significance analysis of microarray. The results established that the dysregulated type 1 and 2 interferon pathways observed in both AD and HAND contribute to the similar pathologies of these diseases within the brain. The current study identifies the important roles of interferon pathways in AD and HAND, a relationship that may be useful for earlier detection in the future.

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.

A New Approach to Simplifying and Harmonizing Cancer Clinical Trials-Standardizing Eligibility Criteria.

Importance: Clinical trial sponsors rely on eligibility criteria to control the characteristics of patients in their studies, promote the safety of participants, and optimize the interpretation of results. However, in recent years, complex and often overly restrictive inclusion and exclusion criteria have created substantial barriers to patient access to novel therapies, hindered trial recruitment and completion, and limited generalizability of trial results. A LUNGevity Foundation working group developed a framework for lung cancer clinical trial eligibility criteria. The goals of this framework are to (1) simplify eligibility criteria, (2) facilitate stakeholders' (patients, clinicians, and sponsors) search for appropriate trials, and (3) harmonize trial populations to support intertrial comparisons of treatment effects. Observations: Clinicians and representatives from the pharmaceutical industry, the National Cancer Institute, the US Food and Drug Administration (FDA), the European Medicines Agency, and the LUNGevity Foundation undertook a process to identify and prioritize key items for inclusion in trial eligibility criteria. The group generated a prioritized library of terms to guide investigators and sponsors in the design of first-line, advanced non-small cell lung cancer clinical trials intended to support marketing application. These recommendations address disease stage and histologic features, enrollment biomarkers, performance status, organ function, brain metastases, and comorbidities. This effort forms the basis for a forthcoming FDA draft guidance for industry. Conclusions and Relevance: As an initial step, the recommended cross-trial standardization of eligibility criteria may harmonize trial populations. Going forward, by connecting diverse stakeholders and providing formal opportunity for public input, the emerging FDA draft guidance may also provide an opportunity to revise and simplify long-standing approaches to trial eligibility. This work serves as a prototype for similar efforts now underway for other cancers.

A qualitative study of interactions with oncologists among patients with advanced lung cancer.

INTRODUCTION: To support the care of lung cancer patients, oncologists have needed to stay current on treatment advancements and build relationships with a new group of survivors in an era where lung cancer survivorship has been re-defined. The objectives of the study were to (1) understand the perspectives of advanced lung cancer patients whose tumors have oncogenic alterations about their care experiences with their oncologist(s) and (2) describe the perceptions of advanced lung cancer patients about seeking second opinions and navigating care decisions. METHODS: In this qualitative study, patients with advanced lung cancer (n = 25) on targeted therapies were interviewed to discuss their ongoing experience with their oncologists. We used deductive and inductive qualitative approaches in the coding of the data. We organized the data using the self-determination framework. RESULTS: Patients described both positive and negative aspects of their care as related to autonomy, provider competency, and connectedness. Patients sought second opinions for three primary reasons: expertise, authoritative advice, and access to clinical trial opportunities. When there is disagreement in the treatment plan between the primary oncologist and the specialist, there can be confusion and tension, and patients have to make difficult choices about their path forward. CONCLUSIONS: Patients value interactions that support their autonomy, demonstrate the competency of their providers, and foster connectedness. To ensure that patients receive quality and goal-concordant care, developing decision aids and education materials that help patients negotiate recommendations from two providers is an area that deserves further attention.

Effect of drug-to-lipid ratio on nanodisc-based tenofovir drug delivery to the brain for HIV-1 infection.

Background: Combination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood-brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge. Methods: This study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo. Result: The nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models. Conclusion: The study provides potential applications of nanodiscs for HIV-1 therapy development.

The 2021 Global Lung Cancer Therapy Landscape.

INTRODUCTION: The lung cancer treatment landscape has substantially evolved over the past decade. However, a systematic analysis of the current global drug development landscape has not been conducted. METHODS: We curated and analyzed a comprehensive list of therapeutic entities (TEs) in preclinical development and clinical trials for lung cancer. RESULTS: On the basis of our analysis of 707 TEs, we found a consistent forward trajectory in the development pipeline for both NSCLC and SCLC. Most of the TEs were in the advanced stages of clinical trials. Targeted therapies continue to dominate in the non-immuno-oncology space. Immuno-oncology targets are expanding beyond inhibitors of the programmed death-ligand 1 axis. CONCLUSIONS: Our analysis highlights a robust portfolio of both preclinical and clinical TEs and suggests that lung cancer treatment is going to become even more biomarker-driven.