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Follow a path of diminishing uncertainty when a patient has a solitary pulmonary nodule. Ideally, malignant nodules will be resected promptly and benign ones identified with minimal intervention. [ABSTRACT FROM AUTHOR]

Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth., (Copyright © 2024 by The American Association of Immunologists, Inc.)

The elimination of cancer cells critically depends on the immune system. However, cancers have evolved a variety of defense mechanisms to evade immune monitoring, leading to tumor progression. Complement factor H (CFH), predominately known for its function in inhibiting the alternative pathway of the complement system, has recently been identified as an important innate immunological checkpoint in cancer. CFH-mediated immunosuppression enhances tumor cells' ability to avoid immune recognition and produce an immunosuppressive tumor microenvironment. This review explores the molecular underpinnings, interactions with immune cells, clinical consequences, and therapeutic possibilities of CFH as an innate immune checkpoint in cancer control. The difficulties and opportunities of using CFH as a target in cancer immunotherapy are also explored., Competing Interests: EFP is a Founder, CEO and Board Member of Grid Therapeutics, LLC. MJC and EBG are Founders and Board Members of Grid Therapeutics, LLC. RS, RTB, JG and YWH have no potential conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Saxena, Gottlin, Campa, Bushey, Guo, Patz and He.)

Immuno-oncology has revolutionized cancer care, drug development, the design of clinical trials, standard treatment paradigms, and the evaluation of response to therapy. These are all areas, however, that have not fully incorporated principles of tumor immunology. Insufficient emphasis is put on the effect drugs have on the immune system, and specifically, the impact that multiple lines of therapy can have on the functioning of the immune system, hindering a robust anti-tumor immune response. A paradigm shift in how we approach the development of novel immunotherapeutic agents is necessary to facilitate the effective improvements in patient outcomes., Competing Interests: EP is a Founder, Board Member, and the CEO of Grid Therapeutics, LLC. EG is a Founder of Grid Therapeutics, LLC. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Patz, Gottlin and Simon.)

Objectives: To assess the prevalence of lung cancer in Lung-RADS category 4 patients, and to elucidate if clinical or imaging features help differentiate benign lesions from lung cancer., Materials/methods: A retrospective review of lung cancer screening (LCS) studies at a single university screening program between January 2018 and December 2021 identified all patients with Lung-RADS category 4 lesions. Patient demographics, symptoms within the prior 6 months, and imaging features were recorded., Results: During the defined period, 4819 baseline and annual LCS exams were performed; 7.6 % (n = 368) of exams had category 4 nodules and 59 (1.2 %) patients had biopsy-proven lung cancer. Distribution of Lung-RADS category 4 lesions and lung cancer diagnosis were as follows: 4A - 223 nodules, 6.3 % malignant; 4B - 114 nodules, 20.2 % malignant; and 4X - 31 nodules, 71.0 % malignant. Symptoms were reported in 9.0 % (n = 20) of category 4A (2 were malignant), 15.8 % (n = 18) category 4B (1 was malignant) and 22.6 % (n = 7) category 4X (5 were malignant). Imaging features associated with malignancy included endobronchial obstruction with distal atelectasis, pleural tethering, irregular shape, cavitation, and heterogeneous cystic appearance. Twenty-four nodules increased in size, however, only 7 were biopsy proven. Relative to the risk seen with 4A disease, multivariable logistic analyses showed that the odds of a malignancy increased significantly by 3.8 fold (95 % CI: 1.9, 7.9) and 39.2 fold (95 % CI: 14.9, 103.0) with 4B and 4X disease, respectively (p < 0.0001). A separate analysis involving only category 4A and 4B patients jointly showed that disease category (OR = 3.0; 95 % CI: 1.5, 6.4) and additional imaging features (OR = 3.2; 95 % CI: 1.4, 7.0) were significant predictors of malignancy. The presence of clinical symptoms was not statistically associated with lung cancer., Conclusions: Lung-RADS 4 nodules were found in 7.6% of LCS examinations and 16% of these nodules were lung cancer. The probability of lung cancer increases from category 4A to 4X, and imaging features may help differentiate benign from malignant nodules in this LCS category., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: In vivo , cancer cells respond to signals from the tumor microenvironment resulting in changes in expression of proteins that promote tumor progression and suppress anti-tumor immunity. This study employed an orthotopic immunocompetent model of lung cancer to define pathways that are altered in cancer cells recovered from tumors compared to cells grown in culture., Methods: Studies used four murine cell lines implanted into the lungs of syngeneic mice. Cancer cells were recovered using FACS, and transcriptional changes compared to cells grown in culture were determined by RNA-seq., Results: Changes in interferon response, antigen presentation and cytokine signaling were observed in all tumors. In addition, we observed induction of the complement pathway. We previously demonstrated that activation of complement is critical for tumor progression in this model. Complement can play both a pro-tumorigenic role through production of anaphylatoxins, and an anti-tumorigenic role by promoting complement-mediated cell killing of cancer cells. While complement proteins are produced by the liver, expression of complement proteins by cancer cells has been described. Silencing cancer cell-specific C3 inhibited tumor growth In vivo . We hypothesized that induction of complement regulatory proteins was critical for blocking the anti-tumor effects of complement activation. Silencing complement regulatory proteins also inhibited tumor growth, with different regulatory proteins acting in a cell-specific manner., Discussion: Based on these data we propose that localized induction of complement in cancer cells is a common feature of lung tumors that promotes tumor progression, with induction of complement regulatory proteins protecting cells from complement mediated-cell killing., Competing Interests: Author EP patent issued to Grid Therapeuticss for inhibitors of complement factor H; chief executive officer, founder, and board member of Grid Therapeutics; stock or stock options in Grid Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kleczko, Poczobutt, Navarro, Laskowski, Johnson, Korpela, Gurule, Heasley, Hopp, Weiser-Evans, Gottlin, Bushey, Campa, Patz, Thurman and Nemenoff.)

Peroxisomes play a role in lipid metabolism and regulation of reactive oxygen species, but its role in development and progression of non-small cell lung cancer (NSCLC) is not well understood. Here, we investigated the associations between 9708 single-nucleotide polymorphisms (SNPs) in 113 genes in the peroxisome-related pathways and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) and the Harvard Lung Cancer Susceptibility (HLCS) study. In 1185 NSCLC patients from the PLCO trial, we found that 213 SNPs were significantly associated with NSCLC overall survival (OS) (p ≤ 0.05, Bayesian false discovery probability [BFDP] ≤ 0.80), of which eight SNPs were validated in the HLCS data set. In a multivariate Cox proportional hazards regression model, two independent SNPs (rs9384742 DDO and rs9825224 PEX5L) were significantly associated with NSCLC survival (hazards ratios [HR] of 1.17 with 95% CI [confidence interval] of 1.06-1.28 and 0.86 with 95% CI of 0.77-0.96, respectively). Patients with one or two protective genotypes had a significantly higher OS (HR: 0.787 [95% CI: 0.620-0.998] and 0.691 [95% CI: 0.543-0.879], respectively). Further expression quantitative trait loci analysis using whole blood and lung tissue showed that the minor allele of rs9384742 DDO was significantly associated with decreased messenger RNA (mRNA) expression levels and that DDO expression was also decreased in NSCLC tumor tissue. Additionally, high PEX5L expression levels were significantly associated with lower survival of NSCLC. Our data suggest that variants in these peroxisome-related genes may influence gene regulation and are potential predictors of NSCLC OS, once validated by additional studies., (© 2022 Wiley Periodicals LLC.)

Background: Lymphocyte activation is part of a complex microenvironment that affects the development and progression of solid tumors. The present study analyzed the associations between genetic variants in lymphocyte activation-related genes and survival of patients with non-small cell lung cancer (NSCLC)., Methods: Our study evaluated the associations of 14,400 (1,599 genotyped and 12,801 imputed) single-nucleotide polymorphisms (SNPs) in 176 lymphocyte activation pathway-related genes with survival of 1,185 NSCLC patients in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 984 NSCLC patients from the Harvard Lung Cancer Susceptibility (HLCS) trial., Results: Multivariable Cox proportional hazards regression analyses identified two distinct and possibly functional variants in forkhead box P1 ( FOXP1 ; rs2568847 G>C) and RAR-related orphan receptor A ( RORA ; rs922782 T>G) that were significantly and independently associated with overall survival (OS) [adjusted hazards ratios (HRs) of 1.21 and 0.82, respectively; 95% confidence intervals (CI), 1.11 to 1.32 and 0.76 to 0.88, respectively; P=5.38×10 -6 and 2.68×10 -2 , respectively]. Combined analysis of the unfavorable genotypes showed a significant correlation with both OS and disease-specific survival (DSS) in patients with NSCLC patients from PLCO trial (both P trend <0.0001). Further expression quantitative trait loci (eQTL) analysis using RORA mRNA expression and genotype data in the 1000 Genomes Project demonstrated that the RORA rs922782 G allele predicted mRNA expression levels., Conclusions: Genetic variants in FOXP1 and RORA of the lymphocyte activation pathway may be promising predictors of NSCLC survival. The RORA rs922782 G allele may predict NSCLC survival, possibly by controlling RORA mRNA expression., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-104/coif). The authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Background There are currently no evidence-based guidelines for the management of enlarged mediastinal lymph nodes found on lung cancer screening (LCS) CT scans. Purpose To assess the frequency and clinical significance of enlarged mediastinal lymph nodes on the initial LCS CT scans in National Lung Screening Trial (NLST) participants. Materials and Methods A retrospective review of the NLST database identified all CT trial participants with at least one enlarged (≥1.0 cm) mediastinal lymph node identified by site readers on initial CT scans. Each study was reviewed independently by two thoracic radiologists to measure the two largest nodes and to record morphologic characteristics. Scans with extensively calcified mediastinal lymph nodes or nodes measuring less than 1 cm were excluded. Frequency and time to lung cancer diagnosis, lung cancer stage, and histologic findings were compared between NLST participants with and without lymphadenopathy. Results Of the 26 722 NLST participants, 422 (1.6%) had enlarged noncalcified mediastinal lymph nodes on the initial LCS CT scan. Mediastinal lymphadenopathy was associated with an increase in lung cancer cases (72 of 422 participants [17.1%; 95% CI: 13.6, 21.0] vs 1017 of 26 300 [3.9%; 95% CI: 3.6, 4.1]; P < .001), earlier diagnosis (restricted mean survival time ± standard error, 2285 days ± 44 vs 2611 days ± 2; P < .001), the presence of lung nodules ( P < .001), advanced stage at presentation (22 of 72 participants [31%] with cancer at stage IIIA vs 410 of 1017 [40.3%] at stage IA; P < .001), and increased mortality ( P < .001). The majority of participants with lung cancers in the LCS group with mediastinal lymphadenopathy were detected at initial LCS CT (50 of 422 participants [11.8%; 95% CI: 8.9, 15.3] vs T1-T7, 22 of 422 [5.3%; 95% CI: 3.3, 7.8]; P < .001). There was no association between mediastinal lymphadenopathy and lung cancer histologic findings, CT appearance, or location of lung nodules ( P > .05 based on unadjusted pairwise association analyses). Conclusion Noncalcified mediastinal lymphadenopathy in the low-dose lung cancer screening study sample was associated with an increase in lung cancer, an earlier diagnosis, more advanced-stage disease, and increased mortality. More aggressive treatment of these patients appears warranted. © RSNA, 2021 Online supplemental material is available for this article. See also the editorials by McLoud and by Mascalchi and Zompatori in this issue.

Background: Biomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis., Objectives: The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence., Methods: Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level., Results: In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray's test, P= 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P= 0.4670)., Conclusions: The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence.

Accumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P =0.001) and 0.82 (0.73-0.91 and P =0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets ( P trend =0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Liu, Luo, Patz, Glass, Su, Lin, Christiani and Wei.)

Background: Single nucleotide polymorphisms (SNPs) are often associated with distinct phenotypes in cancer. The present study investigated associations of cancer risk and outcomes with SNPs discovered by whole exome sequencing of normal lung tissue DNA of 15 non-small cell lung cancer (NSCLC) patients, 10 early stage and 5 advanced stage., Methods: DNA extracted from normal lung tissue of the 15 NSCLC patients was subjected to whole genome amplification and sequencing and analyzed for the occurrence of SNPs. The association of SNPs with the risk of lung cancer and survival was surveyed using the OncoArray study dataset of 85,716 patients (29,266 cases and 56,450 cancer-free controls) and the Prostate, Lung, Colorectal and Ovarian study subset of 1,175 lung cancer patients., Results: We identified 4 SNPs exclusive to the 5 patients with advanced stage NSCLC: rs10420388 and rs10418574 in the CLPP gene, and rs11126435 and rs2021725 in the M1AP gene. The variant alleles G of SNP rs10420388 and A of SNP rs10418574 in the CLPP gene were associated with increased risk of squamous cell carcinoma (OR = 1.07 and 1.07; P = 0.013 and 0.016, respectively). The variant allele T of SNP rs11126435 in the M1AP gene was associated with decreased risk of adenocarcinoma (OR = 0.95; P = 0.027). There was no significant association of these SNPs with the overall survival of lung cancer patients (P > 0.05)., Conclusions: SNPs identified in the CLPP and M1AP genes may be useful in risk prediction models for lung cancer. The previously established association of the CLPP gene with cancer progression lends relevance to our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zou, Li, Wong, Bushey, Campa, Gottlin, Liu, Wei, Rodrigo and Patz.)

The mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10 -4 ), 1.26 (1.12-1.42, 1.10 × 10 -4 ) and 0.73 (0.63-0.86, 1.63 × 10 -4 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (P trend  < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC., (© 2021 UICC.)

Introduction: To determine the clinical significance of category 3 (CAT3) abnormalities and the necessity of a 6-month follow-up computed tomography (CT). We also explored features associated with increased lung cancer risk., Methods: From the National Lung Screening Trial database, we identified participants with CAT3 lesions at prevalence screen. Rates of lung cancer and lung cancer-specific deaths (LSDs) were compared between those who underwent first follow-up CT before 6 months (early diagnostic group) and those who underwent annual screening (annual diagnostic group). We estimated the change in LSD if the 6-month CT was eliminated. Regression analysis was performed to identify features associated with participants with CAT3 who developed lung cancer., Results: A total of 1763 CAT3s were identified (6.6% of all participants who had low-dose CT), with 108 lung cancers (6.1%) and 41 LSDs (2.3%) in a 7-year period. Rates of lung cancer (7.5% versus 3.1%) and LSD (4.0% versus 1.0%) were higher in the early diagnostic group than in the annual diagnostic group. We estimated an increase in LSD of 0.6% of all participants with CAT3 (24.4% of all LSDs) if the 6-month CT was not performed. Multivariate regression analysis found that increased age, emphysema, and a part-solid nodule greater than 5 mm were associated with participants with CAT3 who developed lung cancer., Conclusions: CAT3 lesions are uncommon, and eliminating the 6-month CT would potentially increase LSD by 0.6% of all patients with CAT3. Age, emphysema, and part-solid nodule greater than 5 mm may be useful in risk prediction models to determine which participants with CAT3 are more likely to develop lung cancer and suggest which patients may need more intense follow-up., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Exosomes are a class of extracellular vesicles (EVs) that are mediators of normal intercellular communication, but exosomes are also used by tumor cells to promote oncogenesis and metastasis. Complement factor H (CFH) protects host cells from attack and destruction by the alternative pathway of complement-dependent cytotoxicity (CDC). Here we show that CFH can protect exosomes from complement-mediated lysis and phagocytosis. CFH was found to be associated with EVs from a variety of tumor cell lines as well as EVs isolated from the plasma of patients with metastatic non-small cell lung cancer. Higher levels of CFH-containing EVs correlated with higher metastatic potential of cell lines. GT103, a previously described antibody to CFH that preferentially causes CDC of tumor cells, was used to probe the susceptibility of tumor cell-derived exosomes to destruction. Exosomes were purified from EVs using CD63 beads. Incubation of GT103 with tumor cell-derived exosomes triggered exosome lysis primarily by the classical complement pathway as well as antibody-dependent exosome phagocytosis by macrophages. These results imply that GT103-mediated exosome destruction can be triggered by antibody Fc-C1q interaction (in the case of lysis), and antibody-Fc receptor interactions (in the case of phagocytosis). Thus, this work demonstrates CFH is expressed on tumor cell derived exosomes, can protect them from complement lysis and phagocytosis, and that an anti-CFH antibody can be used to target tumor-derived exosomes for exosome destruction via innate immune mechanisms. These findings suggest that a therapeutic CFH antibody has the potential to inhibit tumor progression and reduce metastasis promoted by exosomes., Competing Interests: Drs. Gottlin, Campa, and Patz are founders of Grid Therapeutics, LLC, which is supplying GT103 for a Phase 1b clinical trial. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Although natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., DOCK2 rs261083 G>C, VAV2 rs2519996 C>T and EPHB1 rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with adjusted hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, P = 3.34×10 -4 ), 1.28 (1.12-1.47, P = 4.57×10 -4 ) and 0.75 (0.67-0.83, P = 1.50×10 -7 ), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset ( P trend <0.0001 and <0.0001, respectively). Moreover, the survival-associated DOCK2 rs261083 C allele had a significant correlation with reduced DOCK2 transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced EPHB1 transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that DOCK2 and EPHB1 genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes., Competing Interests: None., (AJCR Copyright © 2021.)

The human IgG3 subclass is conspicuously absent among the formats for approved monoclonal antibody therapies and Fc fusion protein biologics. Concern about the potential for rapid degradation, reduced plasma half-life, and increased immunogenicity due to marked variation in allotypes has apparently outweighed the potential advantages of IgG3, which include high affinity for activating Fc γ receptors, effective complement fixation, and a long hinge that appears better suited for low abundance targets. This review aims to highlight distinguishing features of IgG3 and to explore its functional role in the immune response. We present studies of natural immunity and recombinant antibody therapies that elucidate key contributions of IgG3 and discuss historical roadblocks that no longer remain clearly relevant. Collectively, this body of evidence motivates thoughtful reconsideration of the clinical advancement of this distinctive antibody subclass for treatment of human diseases. Abbreviations: ADCC - Antibody-Dependent Cell-mediated CytotoxicityADE - Antibody-dependent enhancementAID - Activation-Induced Cytidine DeaminaseCH - Constant HeavyCHF - Complement factor HCSR - Class Switch RecombinationEM - Electron MicroscopyFab - Fragment, antigen bindingFc - Fragment, crystallizableFcRn - Neonatal Fc ReceptorFcγR - Fc gamma ReceptorHIV - Human Immunodeficiency VirusIg - ImmunoglobulinIgH - Immunoglobulin Heavy chain geneNHP - Non-Human Primate.

The complement system is involved in the immunosurveillance of pathogens and tumour cells. Proteomic profiling revealed that extracellular vesicles (EVs) released by metastatic hepatocellular carcinoma (HCC) cells contained a significant number of complement proteins. Complement Factor H (CFH), an abundant soluble serum protein that inhibits the alternative complement pathway, was found to be highly expressed in EVs of metastatic HCC cell lines. Here, we investigated the functional role of EV-CFH and explored the therapeutic efficacy of targeting EV-CFH with an anti-CFH antibody in HCC. The results showed that EVs that are enriched in CFH promoted HCC cell growth, migration, invasiveness and enhanced liver tumour formation in mice. EV-CFH also promoted metastasis, which was significantly abrogated when treated with an anti-CFH antibody. These findings demonstrate an unexplored function of EV-CFH in protecting HCC cells by evading complement attack, thereby facilitating tumorigenesis and metastasis. Lastly, we demonstrated the therapeutic efficacy of an anti-CFH antibody in suppressing tumour formation in a syngeneic mouse model. This study suggests a new therapeutic strategy for HCC, by inhibiting EV-CFH with a tumour specific anti-CFH antibody., Competing Interests: The authors report no conflict of interest. E.F.P. is a co‐founder and CEO of Grid Therapeutics., (© 2020 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Although lymphangiogenesis is a vital step in lung cancer metastasis, the association between lymphangiogenesis and non-small cell lung cancer (NSCLC) survival remains unclear. Since single-nucleotide polymorphisms (SNPs) have been reported to predict NSCLC survival, we investigated associations between SNPs in lymphangiogenesis-related pathway genes and NSCLC survival in a discovery genotyping dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility Study. We evaluated associations between 34,509 genetic variants (3252 genotyped and 31,257 imputed) in 247 genes involved in lymphangiogenesis-related pathway and NSCLC survival. After validation, we finally identified two independent SNPs ( SYK rs11787670 A>G and ITGA1 rs67715745 T>C) to be significantly associated with NSCLC overall survival (OS), with adjusted hazards ratios of 0.77 and 0.83 (95% confidence interval =0.66-0.90, P =7.20×10 -4 ) and 0.84 (95% confidence interval =0.75-0.92, P =3.50×10 -4 ), respectively. Moreover, an increasing number of combined protective alleles of these two SNPs was significantly associated with an improved NSCLC OS and disease-specific survival (DSS) in the PLCO dataset ( P trend =0.011 and 0.006, respectively). Furthermore, the addition of these protective alleles to the prediction model for the 5-year survival increased the time-dependent area under the curve both from 87% to 87.67% for OS ( P =0.029) and from 88.54% to 89.06% for DSS ( P =0.022). Subsequent expression quantitative trait loci (eQTL) functional analysis revealed that the rs11787670 G allele was significantly associated with an elevated SYK mRNA expression in normal tissues. Additional analyses suggested a suppressor role for both SYK and ITGA1 in NSCLC survival. Collectively, these findings indicated that SYK rs11787670 A>G and ITGA1 rs67715745 T>C may be independent prognostic factors for NSCLC survival once further validated., Competing Interests: None., (AJCR Copyright © 2020.)

The nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes, and its genetic variation and functional dysregulation are involved in pathogenesis of several cancers. To systematically evaluate the role of NLRP3 in predicting outcomes of patients with non-small cell lung cancer (NSCLC), we performed a two-phase analysis for associations between genetic variants in NLRP3 inflammasome pathway genes and NSCLC survival by using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We used multivariate Cox proportional hazards regression analysis with Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 20,730 single-nucleotide polymorphisms (SNPs) in 176 genes and overall survival of 1,185 NSCLC patients from the PLCO trial. We further validated the identified significant SNPs in another GWAS dataset with survival data from 984 NSCLC patients of the Harvard Lung Cancer Susceptibility (HLCS) study. The results showed that two independent SNPs in two different genes (i.e., BIRC3 rs11225211 and NRG1 rs4733124) were significantly associated with the NSCLC overall survival, with a combined hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.74-0.93 and P = 0.0009] and 1.18 (95% CI = 1.06-1.31) and P = 0.002], respectively. However, further expression quantitative trait loci (eQTL) analysis showed no evidence for correlations between the two SNPs and mRNA expression levels of corresponding genes. These results indicated that genetic variants in the NLRP3 imflammasome pathway gene-sets might be predictors of NSCLC survival, but the molecular mechanisms underlying the observed associations warrant further investigations., Competing Interests: None., (AJCR Copyright © 2020.)

Background: Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC)., Methods: We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients., Results: In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs ( PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10 -4 ] and 1.18 (95% CI: 1.08-1.29 and 1.32×10 -4 , respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10 -5 ). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues., Conclusions: Genetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-318). EFP reports personal fees from Grid Therapeutics, personal fees from OncoCyte, outside the submitted work. The other authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in nonsmall cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (p < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295 G > T, AMD1 rs1279590 G > A and MSRA rs73534533 C > A) were replicated in the validation dataset, and their meta-analysis showed an adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and p meta  = 2.86 × 10 -6 , 0.81 (0.73-0.91) and p meta  = 4.63 × 10 -4 , and 0.77 (0.68-0.89) and p meta  = 2.07 × 10 -4 , respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (p trend  < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (p < 0.0001 and < 0.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients., (© 2019 UICC.)

Introduction: Indeterminate pulmonary lesions (IPL) detected by CT pose a significant clinical challenge, frequently necessitating long-term surveillance or biopsy for diagnosis. In this pilot investigation, we performed whole exome sequencing (WES) of plasma cell free (cfDNA) and matched germline DNA in patients with CT-detected pulmonary lesions to determine the feasibility of somatic cfDNA mutations to differentiate benign from malignant pulmonary nodules. Methods: 33 patients with a CT-detected pulmonary lesions were retrospectively enrolled ( n = 16 with a benign nodule, n = 17 with a malignant nodule). Following isolation and amplification of plasma cfDNA and matched peripheral blood mononuclear cells (PBMC) from patient blood samples, WES of cfDNA and PBMC DNA was performed. After genomic alignment and filtering, we looked for lung-cancer associated driver mutations and next identified high-confidence somatic variants in both groups. Results: Somatic cfDNA mutations were observed in both groups, with the cancer group demonstrating more variants than the benign group (1083 ± 476 versus 553 ± 519, p < 0.0046). By selecting variants present in >2 cancer patients and not the benign group, we accurately identified 82% (14/17) of cancer patients. Conclusions: This study suggests a potential role for cfDNA for the early identification of lung cancer in patients with CT-detected pulmonary lesions. Importantly, a substantial number of somatic variants in healthy patients with benign pulmonary nodules were also found. Such "benign" variants, while largely unexplored to date, have widespread relevance to all liquid biopsies if cfDNA is to be used accurately for cancer detection.

The complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody-based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two-phase analysis of two independently published genome-wide association studies (GWASs) for associations between genetic variants in a complement-related immunity gene-set and overall survival of non-small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false-positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single-nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single-locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07-1.40, P = 0.002] and 1.16 (1.07-1.27, 6.45 × 10 -4 ), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival-associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement-related immunity genes might be predictors of NSCLC survival, particularly for the short-term survival, possibly by modulating the expression of genes involved in the host immunity., (© 2018 UICC.)

Computed tomography (CT) is the standard imaging test used for the screening and assessment of suspected lung cancer, but distinguishing malignant from benign nodules by CT is an ongoing challenge. Consequently, a large number of avoidable invasive procedures are performed on patients with benign nodules in order to exclude malignancy. Improving cancer discrimination by non-invasive imaging could reduce the need for invasive diagnostics. In this work we focus on developing a gold nanoparticle contrast agent that targets the epidermal growth factor receptor (EGFR), which is expressed on the cell surface of most lung adenocarcinomas. Three different contrast agents were compared for their tumor targeting effectiveness: non-targeted nanoparticles, nanoparticles conjugated with full-sized anti-EGFR antibodies (cetuximab), and nanoparticles conjugated with a single-domain llama-derived anti-EGFR antibody, which is smaller than the cetuximab, but has a lower binding affinity. Nanoparticle targeting effectiveness was evaluated in vitro by EGFR-binding assays and in cell culture with A431 cells, which highly express EGFR. In vivo CT imaging performance was evaluated in both C57BL/6 mice and in nude mice with A431 subcutaneous tumors. The cetuximab nanoparticles had a significantly shorter blood residence time than either the non-targeted or the single-domain antibody nanoparticles. All of the nanoparticle contrast agents demonstrated tumor accumulation; however, the cetuximab-targeted group had significantly higher tumor gold accumulation than the other two groups, which were statistically indistinguishable from one another. In this study we found that the relative binding affinity of the targeting ligands had more of an effect on tumor accumulation than the circulation half life of the nanoparticles. This study provides useful insight into targeted nanoparticle design and demonstrates that nanoparticle contrast agents can be used to detect tumor receptor overexpression. Combining receptor status data with traditional imaging characteristics has the potential for better differentiation of malignant lung tumors from benign lesions., Competing Interests: The authors have declared that no competing interests exist.

Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. We report the spectrum of sequential CT findings in patients with advanced stage lung cancer who received nivolumab in an effort to better inform appropriate imaging strategies., Materials and Methods: We identified all patients at our institution with advanced NSCLC who received nivolumab. Pre- and posttreatment CT scans were reviewed and categorized based on radiographic response to therapy. Demographic data as well as survival data were recorded., Results: There were 34 patients with advanced NSCLC who received nivolumab with sufficient follow-up data. Nineteen patients were classified as responders to treatment; 6 (32%) of 19 showed improvement on their initial follow-up CT and had an average survival of 11.2 months, whereas 13 (68%) of 19 responders initially had stable or progressive disease on CT with an average survival of 11.6 months. Fifteen patients were classified as nonresponders to treatment with an average survival of 3.4 months., Conclusion: Novel immunotherapies such as nivolumab mechanistically differ from conventional chemotherapy. Some patients have improved survival despite initial radiographic progression of disease. Our findings underscore the heterogeneous radiographic appearance at follow-up CT in patients with lung cancer who ultimately respond to nivolumab., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL) has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC) due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH). We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

Introduction: Most pulmonary nodules found on imaging studies are indeterminate, but because of the concern for lung cancer, all patients require further evaluation with resultant radiation risk, significant cost, and delays in diagnosis. We hypothesized that a diagnostic blood test based on detection of autoantibodies against cancer antigens would be able to distinguish a benign nodule from lung cancer., Methods: We identified a panel of 25 serum autoantibodies associated with NSCLC and constructed a protein microarray containing the autoantigens. We tested the microarray with human sera (from 125 patients with NSCLC and 125 matched controls with a benign nodule) and attempted to develop a classification algorithm that would separate the two groups., Results: In the training data set the logistic regression c-index statistic was 0.691; in the validation data set, the model predicting the score generated from the training set model had a c-index of 0.490. The relationship between the score and outcome (final diagnosis) was not statistically significant (p = 0.460)., Conclusions: When the current panel of antigens and assay format was used, classification algorithms based on levels of autoantibodies to cancer antigens did not prove to have statistically significant value for predicting the presence of cancer. We suggest that there are inherent biological limitations to this approach., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Unlabelled: In contrast to its inhibitory effects on many cells, IL10 activates CD8(+) tumor-infiltrating lymphocytes (TIL) and enhances their antitumor activity. However, CD8(+) TILs do not routinely express IL10, as autocrine complement C3 inhibits IL10 production through complement receptors C3aR and C5aR. CD8(+) TILs from C3-deficient mice, however, express IL10 and exhibit enhanced effector function. C3-deficient mice are resistant to tumor development in a T-cell- and IL10-dependent manner; human TILs expanded with IL2 plus IL10 increase the killing of primary tumors in vitro compared with IL2-treated TILs. Complement-mediated inhibition of antitumor immunity is independent of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) immune checkpoint pathway. Our findings suggest that complement receptors C3aR and C5aR expressed on CD8(+) TILs represent a novel class of immune checkpoints that could be targeted for tumor immunotherapy. Moreover, incorporation of IL10 in the expansion of TILs and in gene-engineered T cells for adoptive cell therapy enhances their antitumor efficacy., Significance: Our data suggest novel strategies to enhance immunotherapies: a combined blockade of complement signaling by antagonists to C3aR, C5aR, and anti-PD-1 to enhance anti-PD-1 efficacy; a targeted IL10 delivery to CD8(+) TILs using anti-PD-1-IL10 or anti-CTLA4-IL10 fusion proteins; and the addition of IL10 in TIL expansion for adoptive cellular therapy. Cancer Discov; 6(9); 1022-35. ©2016 AACR.See related commentary by Peng et al., p. 953This article is highlighted in the In This Issue feature, p. 932., (©2016 American Association for Cancer Research.)

Some patients with cancer never develop metastasis, and their host response might provide cues for innovative treatment strategies. We previously reported an association between autoantibodies against complement factor H (CFH) and early-stage lung cancer. CFH prevents complement-mediated cytotoxicity (CDC) by inhibiting formation of cell-lytic membrane attack complexes on self-surfaces. In an effort to translate these findings into a biologic therapy for cancer, we isolated and expressed DNA sequences encoding high-affinity human CFH antibodies directly from single, sorted B cells obtained from patients with the antibody. The co-crystal structure of a CFH antibody-target complex shows a conformational change in the target relative to the native structure. This recombinant CFH antibody causes complement activation and release of anaphylatoxins, promotes CDC of tumor cell lines, and inhibits tumor growth in vivo. The isolation of anti-tumor antibodies derived from single human B cells represents an alternative paradigm in antibody drug discovery., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Annual low-dose CT screening for lung cancer has been recommended for high-risk individuals, but the necessity of yearly low-dose CT in all eligible individuals is uncertain. This study examined rates of lung cancer in National Lung Screening Trial (NLST) participants who had a negative prevalence (initial) low-dose CT screen to explore whether less frequent screening could be justified in some lower-risk subpopulations., Methods: We did a retrospective cohort analysis of data from the NLST, a randomised, multicentre screening trial comparing three annual low-dose CT assessments with three annual chest radiographs for the early detection of lung cancer in high-risk, eligible individuals (aged 55-74 years with at least a 30 pack-year history of cigarette smoking, and, if a former smoker, had quit within the past 15 years), recruited from US medical centres between Aug 5, 2002, and April 26, 2004. Participants were followed up for up to 5 years after their last annual screen. For the purposes of this analysis, our cohort consisted of all NLST participants who had received a low-dose CT prevalence (T0) screen. We determined the frequency, stage, histology, study year of diagnosis, and incidence of lung cancer, as well as overall and lung cancer-specific mortality, and whether lung cancers were detected as a result of screening or within 1 year of a negative screen. We also estimated the effect on mortality if the first annual (T1) screen in participants with a negative T0 screen had not been done. The NLST is registered with ClinicalTrials.gov, number NCT00047385., Findings: Our cohort consisted of 26 231 participants assigned to the low-dose CT screening group who had undergone their T0 screen. The 19 066 participants with a negative T0 screen had a lower incidence of lung cancer than did all 26 231 T0-screened participants (371·88 [95% CI 337·97-408·26] per 100 000 person-years vs 661·23 [622·07-702·21]) and had lower lung cancer-related mortality (185·82 [95% CI 162·17-211·93] per 100 000 person-years vs 277·20 [252·28-303·90]). The yield of lung cancer at the T1 screen among participants with a negative T0 screen was 0·34% (62 screen-detected cancers out of 18 121 screened participants), compared with a yield at the T0 screen among all T0-screened participants of 1·0% (267 of 26 231). We estimated that if the T1 screen had not been done in the T0 negative group, at most, an additional 28 participants in the T0 negative group would have died from lung cancer (a rise in mortality from 185·82 [95% CI 162·17-211·93] per 100 000 person-years to 212·14 [186·80-239·96]) over the course of the trial., Interpretation: Participants with a negative low-dose CT prevalence screen had a lower incidence of lung cancer and lung cancer-specific mortality than did all participants who underwent a prevalence screen. Because overly frequent screening has associated harms, increasing the interval between screens in participants with a negative low-dose CT prevalence screen might be warranted., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Intratumoral B lymphocytes are an integral part of the lung tumor microenvironment. Interrogation of the antibodies they express may improve our understanding of the host response to cancer and could be useful in elucidating novel molecular targets. We used two strategies to explore the repertoire of intratumoral B cell antibodies. First, we cloned VH and VL genes from single intratumoral B lymphocytes isolated from one lung tumor, expressed the genes as recombinant mAbs, and used the mAbs to identify the cognate tumor antigens. The Igs derived from intratumoral B cells demonstrated class switching, with a mean VH mutation frequency of 4%. Although there was no evidence for clonal expansion, these data are consistent with antigen-driven somatic hypermutation. Individual recombinant antibodies were polyreactive, although one clone demonstrated preferential immunoreactivity with tropomyosin 4 (TPM4). We found that higher levels of TPM4 antibodies were more common in cancer patients, but measurement of TPM4 antibody levels was not a sensitive test for detecting cancer. Second, in an effort to focus our recombinant antibody expression efforts on those B cells that displayed evidence of clonal expansion driven by antigen stimulation, we performed deep sequencing of the Ig genes of B cells collected from seven different tumors. Deep sequencing demonstrated somatic hypermutation but no dominant clones. These strategies may be useful for the study of B cell antibody expression, although identification of a dominant clone and unique therapeutic targets may require extensive investigation.

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma., (Copyright ©ERS 2015.)

Characterization of the humoral immune response in selected patients with cancer who uniformly do well may lead to the development of novel therapeutic strategies. We have previously shown an association between patients with early-stage nonmetastatic lung cancer and autoantibodies to complement factor H (CFH). CFH protects normal and tumor cells from destruction by the alternative complement pathway by inactivating C3b, a protein that is essential for formation of a lytic complex on the cell surface. Here, we show that CFH autoantibodies in lung cancer patients recognize a conformationally distinct form of CFH in vitro, are IgG3 subclass, and epitope map to a crucial functional domain of CFH known to interact with C3b. Purified CFH autoantibodies inhibited binding of CFH to A549 lung tumor cells, increased C3b deposition, and caused complement-dependent tumor cell lysis. This work demonstrates that CFH autoantibodies isolated from patients with lung cancer can kill tumor cells in vitro, suggesting that they may perform this function in vivo as well. Development of specific antibodies to the conformationally distinct epitope of CFH may lead to a useful biologic therapy for lung cancer., (©2015 American Association for Cancer Research.)

Introduction: Patients with stage I non-small-cell lung cancer (NSCLC) have a wide variation in outcomes, most likely because there are undetected metastases at presentation. We retrospectively reviewed patients with early stage lung cancer to determine if FDG uptake of the primary tumor as measured on positron emission tomography (PET) at the time of diagnosis was associated with overall survival (OS) or time to recurrence (TTR)., Methods: We reviewed the Tumor Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5-year period who underwent an FDG-PET/computed tomography within 90 days before surgery. Kaplan-Meier curves were used to describe the survival and TTR experience within subgroups defined by PET maximum standardized uptake value (SUVmax). Cox proportional hazards model was used to assess the impact of PET SUVmax as a continuous variable on OS and TTR. Logistic regression was used to analyze the effect of SUVmax on dichotomized outcomes., Results: Three hundred thirty-six consecutive patients (176 women and 160 men) with stage I NSCLC were retrospectively reviewed. Mean SUVmax was 9.2 ± 6.9 (range 0.6-30.3). The hazard or risk of dying and recurrence increased significantly as SUVmax increased (p = 0.0008 and 0.024, respectively)., Conclusions: Preoperative FDG uptake in the primary tumor in patients with stage I disease is associated with OS and TTR. This may be useful in identifying early stage patients who may benefit from more aggressive therapy after surgical resection.

Background: The NLST (National Lung Screening Trial) showed reduced lung cancer mortality in high-risk participants (smoking history of ≥30 pack-years) aged 55 to 74 years who were randomly assigned to screening with low-dose computed tomography (LDCT) versus those assigned to chest radiography. An advisory panel recently expressed reservations about Medicare coverage of LDCT screening because of concerns about performance in the Medicare-aged population, which accounted for only 25% of the NLST participants., Objective: To examine the results of the NLST LDCT group by age (Medicare-eligible vs. <65 years)., Design: Secondary analysis of a group from a randomized trial (NCT00047385)., Setting: 33 U.S. screening centers., Patients: 19 612 participants aged 55 to 64 years (under-65 cohort) and 7110 participants aged 65 to 74 years (65+ cohort) at randomization., Intervention: 3 annual rounds of LDCT screening., Measurements: Demographics, smoking and medical history, screening examination adherence and results, diagnostic follow-up procedures and complications, lung cancer diagnoses, treatment, survival, and mortality., Results: The aggregate false-positive rate was higher in the 65+ cohort than in the under-65 cohort (27.7% vs. 22.0%; P < 0.001). Invasive diagnostic procedures after false-positive screening results were modestly more frequent in the older cohort (3.3% vs. 2.7%; P = 0.039). Complications from invasive procedures were low in both groups (9.8% in the under-65 cohort vs. 8.5% in the 65+ cohort). Prevalence and positive predictive value (PPV) were higher in the 65+ cohort (PPV, 4.9% vs. 3.0%). Resection rates for screen-detected cancer were similar (75.6% in the under-65 cohort vs. 73.2% in the 65+ cohort). Five-year all-cause survival was lower in the 65+ cohort (55.1% vs. 64.1%; P = 0.018)., Limitation: The oldest screened patient was aged 76 years., Conclusion: NLST participants aged 65 years or older had a higher rate of false-positive screening results than those younger than 65 years but a higher cancer prevalence and PPV. Screen-detected cancer was treated similarly in the groups., Primary Funding Source: National Institutes of Health.

Introduction: Treatment patterns and cost implications of increased positron emission tomography imaging use since Medicare approval in 1998 are not well understood. We examined rates of surgery, radiotherapy, and chemotherapy and inpatient and total health care costs between 1998 and 2005 among Medicare beneficiaries with non-small-cell lung cancer., Methods: Patients in this retrospective cohort study were 51,374 Medicare beneficiaries diagnosed with non-small-cell lung cancer between 1996 and 2005. The main outcome measures were receipt of surgical resection, radiotherapy, and chemotherapy and inpatient and total health care costs within 1 year of diagnosis., Results: Between 1996-1997 and 2004-2005, the proportion of patients undergoing surgical resection decreased from 29% to 25%, the proportion receiving radiation therapy decreased from 49% to 43%, and inpatient costs decreased from $28,900 to $26,900. The proportion of patients receiving chemotherapy increased from 25% to 40% and total costs increased from $47,300 to $52,200 (p < 0.001 for all comparisons). Changes in use and costs remained after adjustment for shifting demographic characteristics during the study period., Conclusions: Adoption of positron emission tomography between 1998 and 2005 was accompanied by decreases in rates of surgery and radiotherapy and in short-term inpatient costs among Medicare beneficiaries with non-small-cell lung cancer, although there was an increase in chemotherapy and overall costs.

Importance: Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment., Objective: To estimate overdiagnosis in the National Lung Screening Trial (NLST)., Design, Setting, and Participants: We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm., Main Outcomes and Measures: We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis (PS), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer., Results: During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non-small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38., Conclusions and Relevance: More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.

Positron emission tomography computed tomography(PET-CT) imaging has emerged as an essential clinical diagnostic tool in the evaluation of thoracic abnormalities. Currently, its primary role is for tumor imaging; it helps to differentiate benign from malignant nodules, stage tumors, determine response, and follow patients after therapy is complete. It has also been used for nononcologic diseases, but the indications are less well defined. PET is a fundamental component of the molecular imaging initiative, and as new more specific imaging probes and better instrumentation are developed, PET-CT is certain to improve diagnostic accuracy and become even more integrated into the imaging armamentarium., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)