The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented. METHODS: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability. RESULTS: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer. CONCLUSIONS: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex.

The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

Clinical and radiological septic joint analysis of spontaneous sternoclavicular joint infections: achieving the best outcomes-a systems engineering approach.

OBJECTIVES: Spontaneous sternoclavicular joint infection (SSCJI) is a rare and poorly understood disease process. This study aims to identify factors guiding effective management strategies for SSCJI by using data mining. METHODS: An Institutional Review Board-approved retrospective review of patients from 2 large hospitals (2010-2022) was conducted. SSCJI is defined as a joint infection without direct trauma or radiation, direct instrumentation or contiguous spread. An interdisciplinary team consisting of thoracic surgeons, radiologists, infectious disease specialists, orthopaedic surgeons, hospital information experts and systems engineers selected relevant variables. Small set data mining algorithms, utilizing systems engineering, were employed to assess the impact of variables on patient outcomes. RESULTS: A total of 73 variables were chosen and 54 analysed against 11 different outcomes. Forty-seven patients [mean age 51 (22-82); 77% male] met criteria. Among them, 34 underwent early joint surgical resection (<14 days), 5 patients received delayed surgical intervention (>14 days) and 8 had antibiotic-only management. The antibiotic-only group had comparable outcomes. Indicators of poor outcomes were soft tissue fluid >4.5 cm, previous SSCJI, moderate/significant bony fragments, HgbA1c >13.9% and moderate/significant bony sclerosis. CONCLUSIONS: This study suggests that targeted antibiotic-only therapy should be considered initially for SSCJI cases while concurrently managing comorbidities. Patients displaying indicators of poor outcomes or no symptomatic improvement after antibiotic-only therapy should be considered for surgical joint resection.

Metabolic signatures of thymomas: potential biomarkers and treatment targets.

OBJECTIVES: A study of tumour metabolic reprogramming has revealed disease biomarkers and avenues for therapeutic intervention. Metabolic reprogramming in thymoma is currently understudied and largely unknown. This study utilized metabolomics and isotope tracing with 13C-glucose to metabolically investigate thymomas, adjacent thymic tissue and benign thymic lesions. METHODS: From 2017 to 2021, 20 patients with a suspected thymoma were recruited to this prospective Institutional Review Board approved clinical trial. At the time of surgery, 11 patients were infused with 13C-glucose, a stable, non-radioactive tracer which reports the flow of carbon through metabolic pathways. Samples were analysed by mass spectrometry to measure the abundance of >200 metabolites.13C enrichment was measured in patients who received 13C-glucose infusions. RESULTS: Histological analysis showed that 9 patients had thymomas of diverse subtypes and 11 patients had benign cysts. In our metabolomic analysis, thymomas could be distinguished from both adjacent thymus tissue and benign lesions by metabolite abundances. Metabolites in pyrimidine biosynthesis and glycerophospholipid metabolism were differentially expressed across these tissues.13C-glucose infusions revealed differential labelling patterns in thymoma compared to benign cysts and normal thymus tissue. The lactate/3PG labelling ratio, a metabolic marker in aggressive lung tumours correlated with lactate uptake, was increased in thymomas (1.579) compared to normal thymus (0.945) and benign masses (0.807) (thymic tissue versus tumour P = 0.021, tumour versus benign P = 0.013). CONCLUSIONS: We report metabolic biomarkers, including differential 13C labelling of metabolites from central metabolism, that distinguish thymomas from benign tissues. Altered glucose and lactate metabolism warrant further investigation and may provide novel therapeutic targets for thymoma.

The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system. METHODS: Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis. RESULTS: Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region. CONCLUSIONS: The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b).

Training Cardiothoracic Residents in Robotic Lobectomy Is Cost-Effective With No Change in Clinical Outcomes.

Objective: Our objective was to evaluate for any changes in quality or cost when robotic lung resection is used with significant trainee participation. Methods: All anatomic lung resections between January 2006 and June 2016 were identified from a prospectively maintained database. Clinical data were recorded by double entry. Cost and cancer-related data were gathered from the business analytics department and tumor registry. Robotic outcomes were compared to an ongoing thoracotomy and video-assisted thoracic surgery (VATS) experience. Propensity scores using age, sex, and comorbidities were assigned for statistical analysis. Survival was evaluated using the Kaplan-Meier method. Results: Of 523 consecutive cases, 483 were included (211 robotic, 210 thoracotomy, 62 VATS). There were 74 robotic cases (35%) performed by trainees as the console surgeon. Length of stay was shortest for robotics (3 days) compared to thoracotomy (7 days, P < 0.001) and VATS (5 days, P = 0.010). Complications occurred in 33% of robotic cases, 42% of VATS cases (P = 0.854), and 52% of thoracotomy cases (P < 0.001). Stage I non-small cell lung cancer 3-year overall survival for robotics, thoracotomy, and VATS was 79.5%, 74.3%, and 74.0%, respectively (P > 0.25). There was no significant difference in negative margin rates. Total cost related to the hospitalization for surgery was $5,721 less for robotics compared to thoracotomy (P = 0.003) but comparable to VATS. Trainees served as console surgeon in 0% of cases in the first 2 years of robotics but increased to 79% in the last year of the study. Conclusions: Robotic lung resection can be safely performed and taught in an academic medical center without sacrificing quality or cost.

Upfront Brain Treatments Followed by Lung Surgery Improves Survival for Stage IV Non-small Cell Lung Cancer Patients With Brain Metastases: A Large Cohort Analysis.

Background: Current treatment guidelines for stage IV non-small cell lung cancer (NSCLC) with brain metastases recommend brain treatments, including surgical resection and radiotherapy (RT), in addition to resection of the primary lung tumor. Here, we investigate the less-studied impact of treatment sequence on the overall survival. Methods: The National Cancer Database was queried for NSCLC patients with brain metastases who underwent surgical resection of the primary lung tumor (n = 776). Kaplan-Meier survival curves with log-rank test and propensity score stratified Cox regression with Wald test were used to evaluate the associations between various treatment plans and overall survival (OS). Results: Compared to patients who did not receive any brain treatment (median OS = 6.05 months), significantly better survival was observed for those who received brain surgery plus RT (median OS = 26.25 months, p < 0.0001) and for those who received brain RT alone (median OS = 14.49 months, p < 0.001). Patients who received one upfront brain treatment (surgery or RT) before lung surgery were associated with better survival than those who received lung surgery first (p < 0.05). The best survival outcome (median OS 27.1 months) was associated with the sequence of brain surgery plus postoperative brain RT followed by lung surgery. Conclusions: This study shows the value of performing upfront brain treatments followed by primary lung tumor resection for NSCLC patients with brain metastases, especially the procedure of brain surgery plus postoperative brain RT followed by lung surgery.

EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.

How I do it: robotic-assisted Ivor Lewis esophagectomy.

Advances in minimally invasive techniques, including robotic surgical technology, have led to improved outcomes in esophagectomy. In this article, we detail our approach to the robotic Ivor Lewis esophagectomy.

Inhalational delivery of induced pluripotent stem cell secretome improves postpneumonectomy lung structure and function.

Cell-free secretory products (secretome) of human induced pluripotent stem cells (iPSCs) have been shown to attenuate tissue injury and facilitate repair and recovery. To examine whether iPSC secretome facilitates mechanically induced compensatory responses following unilateral pneumonectomy (PNX), litter-matched young adult female hounds underwent right PNX (removing 55%-58% of lung units), followed by inhalational delivery of either the nebulized-conditioned media containing induced pluripotent stem cell secretome (iPSC CM) or control cell-free media (CFM); inhalation was repeated every 5 days for 10 treatments. Lung function was measured under anesthesia pre-PNX and 10 days after the last treatment (8 wk post-PNX); detailed quantitative analysis of lung ultrastructure was performed postmortem. Pre-PNX lung function was similar between groups. Compared with CFM control, treatment with iPSC CM attenuated the post-PNX decline in lung diffusing capacity for carbon monoxide and membrane diffusing capacity, accompanied by a 24% larger postmortem lobar volume and distal air spaces. Alveolar double-capillary profiles were 39% more prevalent consistent with enhanced intussusceptive angiogenesis. Frequency distribution of the harmonic mean thickness of alveolar blood-gas barrier shifted toward the lowest values, whereas alveolar septal tissue volume and arithmetic septal thickness were similar, indicating septal remodeling and reduced diffusive resistance of the blood-gas barrier. Thus, repetitive inhalational delivery of iPSC secretome enhanced post-PNX alveolar angiogenesis and septal remodeling that are associated with improved gas exchange compensation. Results highlight the plasticity of the remaining lung units following major loss of lung mass that are responsive to broad-based modulation provided by the iPSC secretome.NEW & NOTEWORTHY To examine whether the secreted products of human induced pluripotent stem cells (iPSCs) facilitate innate adaptive responses following loss of lung tissue, adult dogs underwent surgical removal of one lung, then received repeated administration of iPSC secretory products via inhalational delivery compared with control treatment. Inhalation of iPSC secretory products enhanced capillary formation and beneficial structural remodeling in the remaining lung, leading to improved lung function.

Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non-Small Cell Lung Cancer.

PURPOSE: Itraconazole has been repurposed as an anticancer therapeutic agent for multiple malignancies. In preclinical models, itraconazole has antiangiogenic properties and inhibits Hedgehog pathway activity. We performed a window-of-opportunity trial to determine the biologic effects of itraconazole in human patients. EXPERIMENTAL DESIGN: Patients with non-small cell lung cancer (NSCLC) who had planned for surgical resection were administered with itraconazole 300 mg orally twice daily for 10-14 days. Patients underwent dynamic contrast-enhanced MRI and plasma collection for pharmacokinetic and pharmacodynamic analyses. Tissues from pretreatment biopsy, surgical resection, and skin biopsies were analyzed for itraconazole and hydroxyitraconazole concentration, and vascular and Hedgehog pathway biomarkers. RESULTS: Thirteen patients were enrolled in this study. Itraconazole was well-tolerated. Steady-state plasma concentrations of itraconazole and hydroxyitraconazole demonstrated a 6-fold difference across patients. Tumor itraconazole concentrations trended with and exceeded those of plasma. Greater itraconazole levels were significantly and meaningfully associated with reduction in tumor volume (Spearman correlation, -0.71; P = 0.05) and tumor perfusion (Ktrans; Spearman correlation, -0.71; P = 0.01), decrease in the proangiogenic cytokines IL1b (Spearman correlation, -0.73; P = 0.01) and GM-CSF (Spearman correlation, -1.00; P < 0.001), and reduction in tumor microvessel density (Spearman correlation, -0.69; P = 0.03). Itraconazole-treated tumors also demonstrated distinct metabolic profiles. Itraconazole treatment did not alter transcription of GLI1 and PTCH1 mRNA. Patient size, renal function, and hepatic function did not predict itraconazole concentrations. CONCLUSIONS: Itraconazole demonstrates concentration-dependent early antivascular, metabolic, and antitumor effects in patients with NSCLC. As the number of fixed dose cancer therapies increases, attention to interpatient pharmacokinetics and pharmacodynamics differences may be warranted.

Increased reporting but decreased mortality associated with adverse events in patients undergoing lung cancer surgery: Competing forces in an era of heightened focus on care quality?

INTRODUCTION: Advances in surgical techniques have improved clinical outcomes and decreased complications. At the same time, heightened attention to care quality has resulted in increased identification of hospital-acquired adverse events. We evaluated these divergent effects on the reported safety of lung cancer resection. METHODS AND MATERIALS: We analyzed hospital-acquired adverse events in patients undergoing lung cancer resection using the National Hospital Discharge Survey (NHDS) database from 2001-2010. Demographics, diagnoses, and procedures data were abstracted using ICD-9 codes. We used the Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicators (PSI) to identify hospital-acquired adverse events. Weighted analyses were performed using t-tests and chi-square. RESULTS: A total of 302,444 hospitalizations for lung cancer resection and were included in the analysis. Incidence of PSI increased over time (28% in 2001-2002 vs 34% in 2009-2010; P<0.001). Those with one or more PSI had increased in-hospital mortality (aOR = 11.1; 95% CI, 4.7-26.1; P<0.001) and prolonged hospitalization (12.5 vs 7.8 days; P<0.001). However, among those with PSI, in-hospital mortality decreased over time, from 17% in 2001-2002 to 2% in 2009-2010. CONCLUSIONS: In a recent ten-year period, documented rates of adverse events associated with lung cancer resection increased. Despite this increase in safety events, we observed that mortality decreased. Because such metrics may be incorporated into hospital rankings and reimbursement considerations, adverse event coding consistency and content merit further evaluation.

Closing the gap: Contribution of surgical best practices to outcome differences between high- and low-volume centers for lung cancer resection.

BACKGROUND: Clinical outcomes for resected early-stage non-small cell lung cancer (NSCLC) are superior at high-volume facilities, but reasons for these differences remain unclear. Understanding these differences and optimizing outcomes across institutions are critical to the management of the increasing incidence of these cases. We evaluated the extent to which surgical best practices account for resected early-stage NSCLC outcome differences between facilities according to case volume. METHODS: We performed a retrospective cohort study for clinical stage 1 or 2 NSCLC undergoing surgical resection from 2004 to 2013 using the National Cancer Database (NCDB). Surgical best practices (negative surgical margins, lobar or greater resection, lymph node (LN) dissection, and examination of > 10 LNs) were compared between the highest and lowest quartile volumes. RESULTS: A total of 150,179 patients were included in the cohort (89% white, 53% female, median age 68 years). In a multivariate model, superior overall survival (OS) was observed at highest volume centers compared to lowest volume centers (hazard ratio (HR) = 0.89; 95% CI, 0.82-0.96; P = .002). After matching for surgical best practices, there was no significant OS difference (HR = 0.95; 95% CI, 0.87-1.05; P = .32). Propensity score-adjusted HR estimates indicated that surgical best practices accounted for 54% of the numerical OS difference between low-volume and high-volume centers. Each surgical best practice was independently associated with improved OS (all P ≤ .001). CONCLUSION: Quantifiable and potentially modifiable surgical best practices largely account for resected early-stage NSCLC outcome differences observed between low- and high-volume centers. Adherence to these guidelines may reduce and potentially eliminate these differences.

Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

BACKGROUND: In non-small cell lung cancer (NSCLC), 18fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. This study used stable glucose isotope tracing to determine whether the SUVm predicts glycolytic metabolism or other glucose fates in tumors. METHODS: In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with 13C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUVm, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index. RESULTS: For each patient, 13C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index. CONCLUSIONS: SUVm does not correlate with glycolytic metabolism in human NSCLC but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.

Minimally Invasive and Robotic Esophagectomy: A Review.

Great advances have been made in the surgical management of esophageal disease since the first description of esophageal resection in 1913. We are in the era of minimally invasive esophagectomy. The current three main approaches to an esophagectomy are the Ivor Lewis technique, McKeown technique, and the transhiatal approach to esophagectomy. These operations were associated with a high morbidity and mortality. The recent advances in minimally invasive surgical techniques have greatly improved the outcomes of these surgical procedures. This article reviews the literature and describes the various techniques available for performing minimally invasive esophagectomy and robot-assisted esophagectomies, the history behind the development of these techniques, the variations, and the contemporary outcomes after such procedures.

Outcomes of neoadjuvant and adjuvant chemotherapy in stage 2 and 3 non-small cell lung cancer: an analysis of the National Cancer Database.

INTRODUCTION: The current recommendation for the treatment of stage II and III NSCLC is surgery with chemotherapy. While the convention is to administer chemotherapy postoperatively (adjuvant chemotherapy), inconsistent results have been reported regarding the administration of chemotherapy preoperatively (neoadjuvant chemotherapy). Therefore, a comprehensive analysis of neoadjuvant chemotherapy use in NSCLC is needed. RESULTS: Of the 35,134 NSCLC patients identified, 18,684 received surgery alone, 1,154 received surgery with neoadjuvant chemotherapy, and 15,296 received surgery with adjuvant chemotherapy. Race, Charlson-Deyo score, facility type, insurance type and stage of disease are associated with the use of neoadjuvant chemotherapy. In the case of stage II disease, adjuvant chemotherapy showed improved survival (median OS = 80.8 months) over neoadjuvant chemotherapy (OS = 67.0 months) and surgery alone (OS = 51.0 months). For stage III disease, adjuvant chemotherapy (OS = 49.0 months) showed improved survival over surgery alone (OS = 24.3 months), followed by neoadjuvant chemotherapy (OS = 42.0 months). After propensity score matching, adjuvant chemotherapy was found to provide a survival advantage over neoadjuvant in both stage II (HR = 0.70; p = 5.8e-3) and stage III (HR = 0.77; p = 0.011) NSCLC. CONCLUSIONS: Our analysis finds a survival advantage for neoadjuvant chemotherapy when compared to surgery alone, but no advantage compared to adjuvant chemotherapy in the treatment of resectable stage II and III NSCLC. METHODS: The National Cancer Database (NCDB) was queried for all cases of stage II and III NSCLC from 2006 to 2012. These patients were stratified by stage, and the factors affecting use of neoadjuvant chemotherapy and the effects of neoadjuvant versus adjuvant chemotherapy on overall survival (OS) were investigated.

Pulmonary paraganglioma in a 10-year-old: a case report and review of the literature.

Paraganglioma is a rare extra-adrenal tumor of the paraganglia often found in association with sympathetic and parasympathetic nerves. The case presented is of a 10-year-old boy with hemoptysis who was found to have an obstructive bronchial mass. He underwent surgical resection and biopsy confirmed primary pulmonary paraganglioma. He was subsequently found to have an associated genetic syndrome. This is the first case report describing a primary pulmonary paraganglioma in a child.

TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer.

Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-κB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients.