Treatment Decisions for Resectable Non-Small-Cell Lung Cancer: Balancing Less With More?

For patients with non-small-cell lung cancer (NSCLC), the outcomes for patients with resectable disease are historically poor compared with other solid organ malignancies. In recent years, there have been significant advances in multidisciplinary care, which have resulted in improved outcomes. Innovations in surgical oncology include the use of limited resection and minimally invasive techniques. Recent data in radiation oncology have suggested refinements in pre- and postoperative radiation therapy, resulting in optimization of techniques in the curative setting. Finally, the success of immune checkpoint inhibitors and targeted therapies in the advanced setting has paved the way for inclusion in the adjuvant and neoadjuvant settings, resulting in recent regulatory approvals for four regimens (CheckMate-816, IMpower010, PEARLS, ADAURA). In this review, we will provide an overview of the seminal studies informing advancements in optimal surgical resection, radiation treatment, and systemic therapy for resectable NSCLC. We will summarize the key data on survival outcomes, biomarker analyses, and future directions for perioperative studies.

Current Management of Stage IIIA (N2) Non-Small-Cell Lung Cancer: Role of Perioperative Immunotherapy, and Tyrosine Kinase Inhibitors.

There have been numerous recent advances in the treatmetn of stage IIIA non-small cell lung cancer. The most significant involve the addition of targeted therapies adn immune checkpoint inhibitors into perioperative care. These exciting advances are improving survival in this challenging patient population, but some-decade old controveries around the definition of resectability, prognositic importance of tumor response to induction therapy, and the role of pneumonectomy persist.

STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Molecular factors predicting relapse in early-stage non-small-cell lung cancer (ES-NSCLC) are poorly understood, especially in inoperable patients receiving radiotherapy (RT). In this study, we compared the genomic profiles of inoperable and operable ES-NSCLC. MATERIALS AND METHODS: This retrospective study included 53 patients with nonsquamous ES-NSCLC (stage I-II) treated at a single institution (University of Chicago) with surgery (ie, operable; n = 30) or RT (ie, inoperable; n = 23) who underwent tumor genomic profiling. A second cohort of ES-NSCLC treated with RT (Stanford, n = 39) was included to power clinical analyses. Prognostic gene alterations were identified and correlated with clinical variables. The primary clinical end point was the correlation of prognostic genes with the cumulative incidence of relapse, disease-free survival, and overall survival (OS) in a pooled RT cohort from the two institutions (N = 62). RESULTS: Although the surgery cohort exhibited lower rates of relapse, the RT cohort was highly enriched for somatic STK11 mutations (43% v 6.7%). Receiving supplemental oxygen (odds ratio [OR] = 5.5), 20+ pack-years of tobacco smoking (OR = 6.1), and Black race (OR = 4.3) were associated with increased frequency of STK11 mutations. In the pooled RT cohort (N = 62), STK11 mutation was strongly associated with inferior oncologic outcomes: 2-year incidence of relapse was 62% versus 20% and 2-year OS was 52% versus 85%, remaining independently prognostic on multivariable analyses (relapse: subdistribution hazard ratio = 4.0, P = .0041; disease-free survival: hazard ratio, 6.8, P = .0002; OS: hazard ratio, 6.0, P = .022). STK11 mutations were predominantly associated with distant failure, rather than local. CONCLUSION: In this cohort of ES-NSCLC, STK11 inactivation was associated with poor oncologic outcomes after RT and demonstrated a novel association with clinical hypoxia, which may underlie its correlation with medical inoperability. Further validation in larger cohorts and investigation of effective adjuvant systemic therapies may be warranted.

Integration of New Systemic Adjuvant Therapies for Non-small Cell Lung Cancer: Role of the Surgeon.

BACKGROUND: This review describes a new therapeutic landscape in the adjuvant treatment of resectable non-small cell lung cancer (NSCLC) and discusses the role of the surgeon in ensuring the best outcomes within this treatment paradigm. METHODS: We conducted a narrative literature review using the search terms "non-small cell lung cancer" and "adjuvant" to identify randomized Phase III trials of systemic adjuvant therapy for NSCLC through March 17, 2022. We also searched ClinicalTrials.gov to identify ongoing trials of adjuvant immunotherapies and targeted therapies for NSCLC. RESULTS: Three recent randomized Phase III trials reported significant improvements in disease-free survival with adjuvant immune checkpoint inhibitors or targeted therapy in patients with resectable NSCLC: IMpower010 (atezolizumab vs best supportive care; NCT02486718), KEYNOTE-091 (PEARLS) (pembrolizumab vs placebo; NCT02504372), and ADAURA (osimertinib vs placebo; NCT02511106). Numerous other Phase III trials evaluating adjuvant immune checkpoint inhibitors and targeted therapies are currently underway, many of which demonstrate an evolution of trial design and end points for adjuvant therapy trials. This rapidly changing treatment landscape requires a shift in the role of the surgeon to facilitate appropriate biomarker screening for planning of the perioperative period and molecular testing of the surgical specimen to guide adjuvant therapy. CONCLUSIONS: After decades of stagnation in the management of NSCLC, recent results with immune checkpoint inhibitors and targeted therapies are ushering in a new era of precision medicine in the adjuvant treatment of early-stage NSCLC. Surgeons have an important role in facilitating multidisciplinary care in this rapidly evolving landscape.

Racial differences in phenotypic frailty assessment among general thoracic surgery patients.

Objectives: The American Association for Thoracic Surgery recommends using frailty assessments to identify patients at higher risk of perioperative morbidity and mortality. We evaluated what patient factors are associated with frailty in a thoracic surgery patient population. Methods: New patients aged more than 50 years who were evaluated in a thoracic surgery clinic underwent routine frailty screening with a modified Fried's Frailty Phenotype. Differences in demographics and comorbid conditions among frailty status groups were assessed with chi-square and Student t tests. Logistic regressions performed with binomial distribution assessed the association of demographic and clinical characteristics with nonfrail, frail, prefrail, and any frailty (prefrail/frail) status. Results: The study population included 317 patients screened over 19 months. Of patients screened, 198 (62.5%) were frail or prefrail. Frail patients undergoing thoracic surgery were older, were more likely single or never married, had lower median income, and had lower percent predicted diffusion capacity of the lungs for carbon monoxide and forced expiratory volume during 1 second (all P < .05). More non-Hispanic Black patients were frail and prefrail compared with non-Hispanic White patients (P = .003) and were more likely to score at least 1 point on Fried's Frailty Phenotype (adjusted odds ratio, 3.77; P = .02) when controlling for age, sex, number of comorbidities, median income, diffusion capacity of the lungs for carbon monoxide, and forced expiratory volume during 1 second. Non-Hispanic Black patients were more likely than non-Hispanic White patients to score points for slow gait and low activity (both P < .05). Conclusions: Non-Hispanic Black patients undergoing thoracic surgery are more likely to score as frail or prefrail than non-Hispanic White patients. This disparity stems from differences in activity and gait speed. Frailty tools should be examined for factors contributing to this disparity, including bias.

Large non-functioning substernal parathyroid cyst: A case report and review of the literature.

OBJECTIVES: Parathyroid cysts are rare benign lesions of the head and neck that account for less than 1% of cystic neck masses. We present a rare case of a large 6 cm substernal parathyroid cyst. PRESENTATION OF CASE: An otherwise healthy 65 year-old female presented to the otolaryngology clinic for evaluation of an anterior, midline neck mass. On physical exam, she was noted to have a fullness in the anterior neck extending to the sternal notch. CT demonstrated an enlarged thyroid with a cyst extending to the aortic arch. Initial evaluation suggested a bilateral goiter with substernal extension. The cyst was managed with drainage and observation. After two years of continued growth, the patient underwent a left thyroid lobectomy and mediastinal mass resection via the cervical approach. Final pathology was consistent with a parathyroid cyst. CONCLUSIONS: Parathyroid cysts are a rare cause of neck mass in an adult, and a 6 cm substernal parathyroid cyst represents an unusual site and size for these cysts. Parathyroid cysts are not often considered on the differential of neck and mediastinal cystic lesions. However, appropriate steps should be taken to ensure a proper diagnosis for any cystic lesion in the neck.

Women in Thoracic Surgery 2020 Update-Subspecialty and Work-Life Balance Analysis.

BACKGROUND: While women comprise nearly half of medical school graduates, they remain underrepresented in cardiothoracic (CT) surgery. To better understand ongoing barriers, we aimed to delineate issues relevant to the CT subspecialities, emphasizing personal life. METHODS: An anonymous Research Electronic Data Capture (REDCap; hosted at Indiana University School of Medicine) survey link was emailed to female diplomats of the American Board of Thoracic Surgeons (ABTS). The survey included questions on demographics, professional accolades, practice details, and personal life. Survey responses were compared across subspecialities using χ2 testing. RESULTS: Of 354 female ABTS diplomats, we contacted 309, and 176 (57%) completed the survey. By subspecialty, 42% practice thoracic, 26% adult cardiac, and 10% congenital cardiac; 19% report a mixed practice. The subspecialties differed in length of training (congenital-the longest), practice location (mixed practice-less urban), and academic rank (thoracic-most full professors at 17%), but were largely similar in their personal lives. Among all respondents, 65% are in a committed relationship, but 40% felt that being a CT surgeon negatively impacted their ability to find a partner. Sixty percent have children, but 31% of those with children reported using assisted reproductive technology, surrogacy, or adoption. The number with leadership roles (eg, division chief, committee chair of national organization) did not differ among subspecialities, but was low, ranging from 0 to <30%. CONCLUSIONS: Women remain underrepresented in CT surgery, particularly in the academic rank of full professor and in leadership positions. We advocate for scholarship and mentorship opportunities to encourage women to enter the field, increased female leadership, and policies to enable families.

Pulmonary Parenchymal Changes in COVID-19 Survivors.

BACKGROUND: As the COVID-19 pandemic moves into the survivorship phase, questions regarding long-term lung damage remain unanswered. Previous histopathologic studies are limited to autopsy reports. We studied lung specimens from COVID-19 survivors who underwent elective lung resections to determine whether postacute histopathologic changes are present. METHODS: This multicenter observational study included 11 adult COVID-19 survivors who had recovered but subsequently underwent unrelated elective lung resection for indeterminate lung nodules or lung cancer. We compared these against an age- and procedure-matched control group who never contracted COVID-19 (n = 5) and an end-stage COVID-19 group (n = 3). A blinded pulmonary pathologist examined the lung parenchyma focusing on 4 compartments: airways, alveoli, interstitium, and vasculature. RESULTS: Elective lung resection was performed in 11 COVID-19 survivors with asymptomatic (n = 4), moderate (n = 4), and severe (n = 3) COVID-19 infections at a median 68.5 days (range 24-142 days) after the COVID-19 diagnosis. The most common operation was lobectomy (75%). Histopathologic examination identified no differences between the lung parenchyma of COVID-19 survivors and controls across all compartments examined. Conversely, patients in the end-stage COVID-19 group showed fibrotic diffuse alveolar damage with intra-alveolar macrophages, organizing pneumonia, and focal interstitial emphysema. CONCLUSIONS: In this study to examine the lung parenchyma of COVID-19 survivors, we did not find distinct postacute histopathologic changes to suggest permanent pulmonary damage. These results are reassuring for COVID-19 survivors who recover and become asymptomatic.

2020 Women in Thoracic Surgery Update on the Status of Women in Cardiothoracic Surgery.

BACKGROUND: Women in Thoracic Surgery (WTS) has previously reported on the status of women in cardiothoracic (CT) surgery. We sought to provide a 10-year update on women in CT surgery. METHODS: An anonymous research electronic data capture survey link was emailed to female diplomats of the American Board of Thoracic Surgery. Survey questions queried respondents regarding demographics, training, accolades, practice details, and career satisfaction. The survey link was open for 30 days. Results were compared with The Society of Thoracic Surgeons 2019 workforce survey. Descriptive analyses were performed using frequency and proportions. Comparisons were performed using Student's t tests, Fisher's exact tests, and χ2 tests. RESULTS: Of 354 female diplomats, 309 were contacted and 176 (57%) responded. The majority of respondents were aged 36 to 50 years (59%), white (67.4%), and had graduated from traditional-track programs (91.4%). Most respondents reported practicing in an urban (64%) and academic setting (73.1%). 36.4% and 23.9% reported a general thoracic and adult cardiac practice (22.7% mixed practice, 9.6% congenital). Fifty percent of respondents reported salaries between $400,000 and $700,000 annually; 37.7% reported salaries less than 90% of their male colleagues; 21.6% of respondents in academia are full professor; 53.4% reported having a leadership role. Whereas 74.1% would pursue a career in CT surgery again, only 27.3% agreed that CT surgery is a healthy and positive environment for women. CONCLUSIONS: The number of women in CT surgery has steadily increased. Although women are rising in academic rank and into leadership positions, salary disparities and the CT surgery work environment remain important issues in achieving a diverse work force.

CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer.

Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02-2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21-3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.

Determinants of electrocardiographic abnormalities in patients with pectus excavatum.

BACKGROUND: Electrocardiographic abnormalities such as cardiac axis deviation, conduction abnormalities and ST-segment, and T &P wave abnormalities have been reported in patients with pectus excavatum. The precise determinants of these electrocardiographic abnormalities have however not been systematically evaluated. We therefore carried out this exploratory study to assess the electrocardiographic abnormalities and their determinants in children and young adults with pectus excavatum. METHODS: Patients aged between 6 and 22 years with unrepaired pectus excavatum were eligible for enrollment in this preliminary hypothesis generating study, if they were seen at University of Chicago Medical Center between Jan 1, 2017 to Nov 30, 2020, and underwent an electrocardiogram during comprehensive evaluation for pectus excavatum. Pertinent data was collected from the medical charts. Unadjusted and adjusted logistic regression models were used to determine the effect of variables including age, BMI, inspiratory Haller's index, gender, right ventricular geometric distortion and FEV1/FVC (% predicted) on odds of electrocardiographic abnormalities (primary outcome variable). P-values of <0.05 were considered significant. RESULTS: The study group (16.6 ± 2.9 years, 80% symptomatic) consisted of 28 patients [Caucasian, male (n = 24, 86% each)]. A high proportion (86%) of these patients had geometric distortion of the right ventricle on noninvasive imaging and these patients had a higher Haller's index (4.4 ± 0.95 vs 3.3 ± 0.2, p = 0.03). Approximately 60% of the patients had an abnormal electrocardiogram. Unadjusted and adjusted logistic regression models were utilized to study the determinants of these electrocardiographic abnormalities. Haller's index, BMI, age, gender, geometric distortion of the right ventricle and lung function parameters [FEV1/FEV (% predicted)] were not associated with increased odds of electrocardiographic abnormalities. CONCLUSIONS: Electrocardiographic abnormalities, particularly deviation of cardiac axis, are common in patients with pectus excavatum. In this exploratory hypothesis generating study, Haller's index and geometric distortion of the right ventricle were not associated with these abnormalities. However, systematic multicentric efforts are needed to better define electrocardiographic abnormalities in patients with pectus excavatum and elucidate their precise determinants.

SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.IMPORTANCE With the ongoing pandemic, it is critical to understand how natural immunity against SARS-CoV-2 and COVID-19 develops. We have identified that subjects with more severe COVID-19 disease mount a more robust and neutralizing antibody response against SARS-CoV-2 spike protein. Subjects who mounted a larger response against the spike also mounted antibody responses against other viral antigens, including the nucleocapsid protein and ORF8. Additionally, this study reveals that subjects with more severe disease mount a larger memory B cell response against the spike. These data suggest that subjects with more severe COVID-19 disease are likely better protected from reinfection with SARS-CoV-2.

Fair and equitable subject selection in concurrent COVID-19 clinical trials.

Clinical trials emerged in rapid succession as the COVID-19 pandemic created an unprecedented need for life-saving therapies. Fair and equitable subject selection in clinical trials offering investigational therapies ought to be an urgent moral concern. Subject selection determines the distribution of risks and benefits, and impacts the applicability of the study results for the larger population. While Research Ethics Committees monitor fair subject selection within each trial, no standard oversight exists for subject selection across multiple trials for the same disease. Drawing on the experience of multiple clinical trials at a single academic medical centre in the USA, we posit that concurrent COVID-19 trials are liable to unfair and inequitable subject selection on account of scientific uncertainty, lack of transparency, scarcity and, lastly, structural barriers to equity compounded by implicit bias. To address the critical gap in the current literature and international regulation, we propose new ethical guidelines for research design and conduct that bolsters fair and equitable subject selection. Although the proposed guidelines are tailored to the research design and protocol of concurrent trials in the COVID-19 pandemic, they may have broader relevance to single COVID-19 trials.