Promotion of an Antitumor Immune Program by a Tumor-specific, Complement-activating Antibody.

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.

Mediastinal Lymphadenopathy in the National Lung Screening Trial (NLST) Is Associated with Interval Lung Cancer.

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.

Genetic variants in DDO and PEX5L in peroxisome-related pathways predict non-small cell lung cancer survival.

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.

Genetic variants of CHEK1, PRIM2 and CDK6 in the mitotic phase-related pathway are associated with nonsmall cell lung cancer survival.

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 (Ptrend < .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.

Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.

The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.

Potentially functional genetic variants in the complement-related immunity gene-set are associated with non-small cell lung cancer survival.

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.

Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients.

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 pmeta = 2.86 × 10-6 , 0.81 (0.73-0.91) and pmeta = 4.63 × 10-4 , and 0.77 (0.68-0.89) and pmeta = 2.07 × 10-4 , respectively). A genetic score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (ptrend < 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.

Lung cancer incidence and mortality in National Lung Screening Trial participants who underwent low-dose CT prevalence screening: a retrospective cohort analysis of a randomised, multicentre, diagnostic screening trial.

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.

Interrogation of individual intratumoral B lymphocytes from lung cancer patients for molecular target discovery.

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.

Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data.

(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.

National Lung Screening Trial findings by age: Medicare-eligible versus under-65 population.

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.

PET-CT: current applications and new developments in the thorax.

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.

Biomarkers to help guide management of patients with pulmonary nodules.

RATIONALE: Indeterminate pulmonary nodules are a common radiographic finding and require further evaluation because of the concern for lung cancer. OBJECTIVES: We developed an algorithm to assign patients to a low- or high-risk category for lung cancer, based on a combination of serum biomarker levels and nodule size. METHODS: For the serum biomarker assay, we determined levels of carcinoembryonic antigen, α1-antitrypsin, and squamous cell carcinoma antigen. Serum data and nodule size from a training set of 509 patients with (n = 298) and without (n = 211) lung cancer were subjected to classification and regression tree and logistic regression analyses. Multiple models were developed and tested in an independent, masked validation set for their ability to categorize patients with (n = 203) or without (n = 196) lung cancer as being low- or high-risk for lung cancer. MEASUREMENTS AND MAIN RESULTS: In all models, a large percentage of individuals in the validation study with small nodules (<1 cm) were assigned to the low-risk group, and a large percentage of individuals with large nodules (≥3 cm) were assigned to the high-risk group. In the validation study, the classification and regression tree algorithm had overall sensitivity, specificity, and positive and negative predictive values for determining lung cancer of 88%, 82%, 84%, and 87%, respectively. The logistic regression model had overall sensitivity, specificity, and positive and negative predictive values of 80%, 89%, 89%, and 81%, respectively. CONCLUSION: Integration of biomarkers with lung nodule size has the potential to help guide the management of patients with indeterminate pulmonary nodules.

Complement factor H: a novel innate immune checkpoint in cancer immunotherapy.

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.

Variations in use of PET among Medicare beneficiaries with non-small cell lung cancer, 1998-2007.

PURPOSE: To explore demographic and regional factors associated with the use of positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) and to determine whether their associations with PET use has changed over time. MATERIALS AND METHODS: The Office of Human Research Ethics at the University of North Carolina and the institutional review board of the Duke University Health System approved (with waiver of informed consent) this retrospective analysis of Surveillance Epidemiology and End Results Medicare data for Medicare beneficiaries given a diagnosis of NSCLC between 1998 and 2007. The primary outcome was change in the number of PET examinations 2 months before to 4 months after diagnosis, examined according to year and sociodemographic subgroup. PET use was compared between demographic and geographic subgroups and between early (1998-2000) and late (2005-2007) cohorts by using χ(2) tests. Factors associated with use of PET during the study period were further examined by using logit and linear probability multivariable regression analyses. RESULTS: The final cohort included 46 544 patients with 46 935 cases of NSCLC. By 2005, more than half of patients underwent one or more PET examinations, regardless of demographic subgroup. In multivariable logistic regression analysis, patients who underwent PET were more likely to be married, nonblack, and younger than 80 years and to live in census tracts with higher education levels or in the Northeast (P < .001 for all). Living within 40 miles of a PET facility was initially associated with undergoing PET (P < .001), but this association disappeared by 2007. Imaging rates increased more rapidly in patients who were nonblack (P ≤ .01), patients who were younger than 81 years (P < .001), and patients who lived in the Northeast and South (P < .001). CONCLUSION: PET imaging among Medicare beneficiaries with NSCLC was initially concentrated among nonblack patients younger than 81 years. Despite widespread adoption among all subgroups, differences within demographic subgroups remained.

Preliminary evaluation of biplane correlation (BCI) stereographic imaging for lung nodule detection.

A biplane correlation (BCI) imaging system obtains images that can be viewed in stereo, thereby minimizing overlapping structures. This study investigated whether using stereoscopic visualization provides superior lung nodule detection compared to standard postero-anterior (PA) image display. Images were acquired at two oblique views of ±3° as well as at a standard PA position from 60 patients. Images were processed using optimal parameters and displayed on a stereoscopic display. The PA image was viewed in the standard format, while the oblique views were paired to provide a stereoscopic view of the subject. A preliminary observer study was performed with four radiologists who viewed and scored the PA image then viewed and scored the BCI stereoscopic image. The BCI stereoscopic viewing of lung nodules resulted in 71 % sensitivity and 0.31 positive predictive value (PPV) index compared to PA results of 86 % sensitivity and 0.26 PPV index. The sensitivity for lung nodule detection with the BCI stereoscopic system was reduced by 15 %; however, the total number of false positives reported was reduced by 35 % resulting in an improved PPV index of 20 %. The preliminary results indicate observer dependency in terms of relative advantage of either system in the detection of lung nodules, but overall equivalency of the two methods with promising potential for BCI as an adjunct diagnostic technique.

Perspective: rethinking therapeutic strategies in oncology.

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.

Characterizing Lung-RADS category 4 lesions in a university lung cancer screening program.

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.

Antitumor Immune Mechanisms of the Anti-Complement Factor H Antibody GT103.

Development of novel therapeutic antibodies that not only kill tumor cells but modulate the adaptive immune response has the potential to produce long term anticancer immunity and a durable clinical response. We previously reported the discovery of anti-complement factor H (CFH) autoantibodies in patients with lung cancer that were associated with early-stage disease and exceptional outcomes. The human mAb GT103, produced from a single CFH autoantibody-expressing B cell of a patient with lung cancer, recognizes a conformationally distinct epitope on tumor cells, kills tumor cells, and inhibits tumor growth in animal studies. Recent experiments have shown that GT103 restructures the tumor microenvironment and initiates a robust antitumoral adaptive immune response. The current study further elucidates several mechanisms by which GT103 kills tumor cells and drives the immune program. Here we show GT103 has specificity for tumor cells without binding to native soluble CFH or normal tissues. GT103 causes complement C3 split product deposition on tumor cells in vitro and in vivo, triggers antibody-dependent cellular phagocytosis, and increases translocation of the danger-associated molecular pattern molecule calreticulin to the plasma membrane. We also demonstrate that GT103 causes B-cell activation in vitro and in vivo, and that GT103 antitumor activity in vivo is B-cell dependent. The complex mechanism of GT103, a tumor-specific antibody that kills tumor cells and stimulates an immune response, supports further development of this human-derived antibody as a novel therapeutic option for patients with lung cancer.

Identification of potential prognostic biomarkers in patients with untreated, advanced pancreatic cancer from a phase 3 trial (Cancer and Leukemia Group B 80303).

BACKGROUND: Patients with advanced stage adenocarcinoma of the pancreas have a poor prognosis. The identification of prognostic and/or predictive biomarkers may help stratify patients so that therapy can be individualized. METHODS: Serum samples from patients enrolled in the Cancer and Leukemia Group B 80303 phase 3 trial, "Randomized Study of Gemcitabine With Versus Without Bevacizumab in Patients With Locally Advanced or Metastatic Adenocarcinoma of the Pancreas" were used to discover novel biomarkers. For the discovery phase, 40 sera were selected based on length of survival and type of therapy, and subjected to liquid chromatography coupled to tandem mass spectrometry analysis (LC-MS-MS). The top features (proteins) were then further selected for validation by enzyme-linked immunosorbent assay (ELISA). RESULTS: Quantification by nano-LC-MS-MS resulted in 1452 peptides mapping to 156 proteins across all 40 samples, 92 of which had 2 or more peptides. After curation of the data, the authors selected 1 putative prognostic protein, alpha 1-antichymotrypsin (AACT), and 2 putative predictive proteins, histidine-rich glycoprotein (HRG) and complement factor H (CFH), for validation by ELISA. AACT was found to be negatively correlated with overall survival (τ = -0.30 [-0.38, -0.22]; P < .00001). There was no evidence for interaction with bevacizumab and HRG, but there was some evidence for a weak positive correlation of HRG with overall survival (τ = 0.11 [0.03, 0.19]; P < .01). CFH was found to be neither a predictive nor a prognostic factor for overall survival. CONCLUSIONS: AACT may be a useful prognostic marker in patients with advanced stage pancreatic carcinoma, although additional validation studies are needed.