Primary Lung Lesions Research Articles

Enhancing Survival Outcome Predictions in Metastatic Non-Small Cell Lung Cancer Through PET Radiomics Analysis

(1) Background: Advanced-stage lung cancer poses significant management challenges. The goal of this study was to identify crucial clinical and PET radiomics features that enable prognostic stratification for predicting outcomes. (2) Methods: PET radiomics features of the primary lung lesions were extracted from 99 patients with stage IVB NSCLC, and the robustness of these PET radiomics features was evaluated against uncertainties stemming from extraction parameters and contour variation. We trained three survival risk models (clinical, radiomics, and a composite) through a penalized Cox model framework. We also created a Balanced Random Forest classification predictive model, using the selected features, to predict 1-year survival. (3) Results: We identified 367 common PET radiomics features that exhibited robustness to perturbations introduced by contour variation and extraction parameters. Our findings indicated that both the radiomics and the composite model outperformed the clinical model in stratifying the risk for survival with statistical significance. In predicting 1-year survival, the radiomics model and the composite model also achieved better predicting accuracies compared to the clinical model. (4) Conclusions: Robust PET radiomics analysis successfully facilitated the stratification of patient risk for survival outcomes and predicted 1-year survival in stage IVB NSCLC.

Effect of heterozygosity loss of HLA-I on immune evasion and promotion of non-small cell lung cancer brain metastasis and immunotherapy resistance.

209 Background: HLA-I play a crucial role in T cell recognition and killing of tumor cells as well as in PD-1/PD-L1 immunotherapy. Loss of heterozygosity (LOH) of HLA-I alleles has been found to be common in lung cancer patients and influences immune escape during tumor evolution. This study aims to explore the incidence of HLA-I LOH in intracranial metastases of advanced non-small cell lung cancer patients with brain metastasis and its impact on the efficacy of immunotherapy. Methods: A total of 29 patients with non-small cell lung cancer brain metastasis were included in this study. All enrolled patients underwent either percutaneous biopsy or surgical resection of intracranial metastases and had tissue specimens from the primary lung lesions. Whole-exome sequencing was performed on all primary/metastatic lesions to determine HLA-I typing/LOH and calculate tumor mutation burden (TMB). Additionally, we assessed the expression levels of CD8 T cells in the tumor immune microenvironment. Among the enrolled patients, 20 received PD-1/PD-L1 treatment. Results: Among the enrolled patients, 82.8% (24/29) had heterozygous HLA-I typing, with HLA-I LOH present in 25% (6/24) of patients' primary lesions and 58.3% (14/24) in brain metastatic lesions. Analysis of TMB in different lesions revealed a median TMB of 7.8 mut/Mb in lesions with intact HLA-I and 11.4 mut/Mb in lesions with HLA-I LOH. Notably, the median TMB in brain metastatic lesions with HLA-I LOH was 13.2 mut/Mb, higher than that in HLA-I LOH primary lung lesions (10.1 mut/Mb). Immunohistochemistry demonstrated that CD8 T cell expression levels were lowest in brain metastatic lesions with HLA-I LOH and highest in intact HLA-I primary lung lesions. Among patients who received immunotherapy, four cases exhibited inconsistent lesion responses, with stable or regressing primary lesions but progressive intracranial metastases. Survival analysis revealed that patients with HLA-I LOH in brain metastases had significantly lower PFS compared to those without (4.1 months vs. 6.9 months, P < 0.05), with no significant difference in OS. Conclusions: This study indicates that the incidence of HLA-I LOH in brain metastases of lung cancer is higher than that in primary lung lesions, accompanied by higher TMB, possibly due to the ineffective presentation of tumor antigens resulting in the accumulation of mutations in lost HLA-I. Moreover, tumors with HLA-I LOH have reduced levels of CD8 T cell infiltration, suggesting impaired tumor antigen presentation impedes immune cytotoxicity. These phenomena contribute to the poorer efficacy of immunotherapy in such patients. In conclusion, HLA-I LOH may be one of the important mechanisms of immune escape in lung cancer brain metastases.

Autocontouring of primary lung lesions and nodal disease for radiotherapy based only on computed tomography images

Background and purposeIn many clinics, positron-emission tomography is unavailable and clinician time extremely limited. Here we describe a deep-learning model for autocontouring gross disease for patients undergoing palliative radiotherapy for primary lung lesions and/or hilar/mediastinal nodal disease, based only on computed tomography (CT) images. Materials and methodsAn autocontouring model (nnU-Net) was trained to contour gross disease in 379 cases (352 training, 27 test); 11 further test cases from an external centre were also included. Anchor-point-based post-processing was applied to remove extraneous autocontoured regions. The autocontours were evaluated quantitatively in terms of volume similarity (Dice similarity coefficient [DSC], surface Dice coefficient, 95th percentile Hausdorff distance [HD95], and mean surface distance), and scored for usability by two consultant oncologists. The magnitude of treatment margin needed to account for geometric discrepancies was also assessed. ResultsThe anchor point process successfully removed all erroneous regions from the autocontoured disease, and identified two cases to be excluded from further analysis due to ‘missed’ disease. The average DSC and HD95 were 0.8 ± 0.1 and 10.5 ± 7.3 mm, respectively. A 10-mm uniform margin-distance applied to the autocontoured region was found to yield “full coverage” (sensitivity > 0.99) of the clinical contour for 64 % of cases. Ninety-seven percent of evaluated autocontours were scored by both clinicians as requiring no or minor edits. ConclusionsOur autocontouring model was shown to produce clinically usable disease outlines, based on CT alone, for approximately two-thirds of patients undergoing lung radiotherapy. Further work is necessary to improve this before clinical implementation.

683: Patterns of CT lung injury after SABR for primary or secondary lung lesions

683: Patterns of CT lung injury after SABR for primary or secondary lung lesions

A NSCLC patient with novel ALK fusion responded to crizotinib therapy after alectinib-induced interstitial lung disease.

A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in our hospital. Immunohistochemistry (Ventana D5F3 antibody) result showed the presence of ALK rearrangement; and next-generation sequencing assay (NGS) indicated EML4-ALK fusion (E6:A20) with concurrent CCDC148-ALK (C1:A20), PKDCC-ALK (Pintergenic:A20)and VIT-ALK (V15:A20) fusions. After 32 weeks of alectinib treatment, the patient complained cough and exertional chest distress but had no sign of infection. Computed tomography (CT) showed bilateral diffuse ground glass opacities, suggesting a diagnosis of alectinib-related interstitial lung disease (ILD). Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged in the regular follow-up. The administration of a first-generation ALK inhibitor crizotinib was then initiated and the disease was stable for 25 months without recurrence of ILD.

Early Stereotactic Body Radiotherapy to the Primary Lung Lesion for Patients with Advanced NSCLC Treated with First-Line Systemic Therapy

Although adding consolidative stereotactic body radiotherapy (SBRT) to systemic therapy improves survival in advanced non-small cell lung cancer (NSCLC), the optimal timing of SBRT remains unclear. This study aimed to explore the clinical outcome of early and delayed SBRT to primary lung lesions of advanced NSCLC patients treated with first-line systemic therapy. We identified patients with advanced NSCLC who were suitable to receiveSBRT for the primary lung tumors after first-line systemic therapy. All eligible patients were treated with first-line systemic therapy and SBRT for their primary lung lesions. Early SBRT group was defined as patients who received SBRT for their primary lung tumor at the maximal response of systemic therapy. Delayed SBRT group was defined as patients who received SBRT after the occurrence of oligoprogression in primary lung tumor. The primary endpoints were progression-free survival 1 (PFS1, time from start of first-line systemic therapy to disease progression) and PFS2 (time from start of first-line systemic therapy to disease progression after SBRT). Overall survival (OS) and adverse effects (AEs) were secondary endpoints. A two-sided P value of 0.05 was considered statistically significant. All of the statistical analyses were performed with statistical software. A total of184 patients with advanced NSCLC treated with SBRT for primary tumors were screened, and 49 patients were eligible for enrollment in this study. The median age of the entire cohort was 66 years (range, 37-80 years), and 34 (69.4%) patients were male. Thirty-four patients (69.4%) were treated by target therapy and 15 (30.6%) were treated by chemotherapy and immunotherapy. Of the 49 eligible patients, 28(57.1%) received early SBRT to lung primary tumor and 21(42.9%) received delayed SBRT to lung primary tumor. The early SBRT group showed a significantly prolonged PFS1 as compared with the delayed SBRT group (mPFS1: 30 months vs. 8 months, P<0.001). The median PFS2 of the early SBRT group was longer than that of the delayed SBRT group, but the difference between the two groups did not achieve a statistical significance (mPFS2: 42 months vs. 23 months, P = 0.303). Median OS of both groups has not reached. No severe toxicities (≥grade 3) were observed in early SBRT group and only one patient in the delayed SBRT group experienced grade 3 radiation pneumonitis. Early SBRT to the primary lung lesion significantly improved PFS and is a new potentially effective and tolerable treatment option for patients with advanced NSCLC who had stable disease during first-line systemic therapy.

Toxicity of Patients with Ultra-Central Thoracic Tumors Treated with Stereotactic Body Radiotherapy (SBRT) with Dose of 50 Gy in 5 Fractions

The ideal regimen for stereotactic body radiotherapy (SBRT) in ultra-central lung tumors is still to be defined, mostly due to the risk of unacceptable or fatal toxicity. There is not much information on outcomes after SBRT for this group of patients. We summarize here our experience with ultra-central lung cancer patients treated with the dose of 50 Gy delivered in 5 fractions. This study is a retrospective review of all cases of ultra-central thoracic tumors treated with SBRT with the dose of 50 Gy in 5 fractions, delivered every other day, at our institution. In all cases, as we defined ultra-central lung tumor, the PTV overlapped or touched one or more of the following structures: bronchial tree, trachea, great vessels, heart, and esophagus. Metastatic and primary lung lesions were included. The volumes of treatment were defined by 4D-CT to consider breathing motion. Normal organs constraints followed the recommendations of the RTO 0813 trial as follows: Spinal cord: max 30 Gy. Lung right or lung left: V13 Gy[cc] < 1500. Esophagus: max 52 Gy and nonadjacent esophagus: V27.5 Gy[cc] < 5. Heart: V32 Gy[cc] < 15; max 52 Gy. Great vessels: max 52 Gy and non-adjacent great vessels V47 Gy[cc] < 10. Trachea plus bronchus: max 52 Gy and non-adjacent V18 Gy[cc] < 4. Follow-up, at the discretion of the treating MD, included periodic CT scans of the thorax after SBRT and assessment of radiation-induced toxicity scored with CTCv3.0. Between December 2015 and February 2022, 86 patients were eligible for this review. Median follow-up was 17 months (range: 1-76 months); the median age was 74 years (range: 37-98 years). Histology was as follows: 50 patients had biopsy proved NSCLC, 16 had no biopsy, and 20 had metastatic non-lung primaries. Overlapped structures were as follows: with great vessels in 46 cases, heart in 20 cases, trachea/branchial tree in 18 cases, and esophagus in 2 cases. In 16 patients the overlap was present in more than one structure. Overall, 68.6% did not report acute toxicity. The most common acute side effects were fatigue (15.1%), coughing (8.1%), shortness of breath (6.9%), esophagitis (2.3%), and dysphagia (1.1%). No grade 3 or more significant toxicity was described. As acute side effects, many patients had exacerbations of the previous condition, such as shortness of breath (16 pts) or coughing (4 pts) during follow-up. Pneumonitis was found as a late side effect in four cases. One patient had empyema associated with a fistula in the non-irradiated lung, where the patient had previous surgery, but in the irradiated lung no severe complication was detected. There were no deaths attributed to the SBRT treatment. 67.5% of 86 patients were alive at the time of the review; 87.2% had local control, and 65.1% had metastases-free survival. In this cohort of patients, no death or even severe acute or chronic toxicity was attributed to SBRT. SBRT seems safe for ultra-central lesions using the regimen of 50 Gy in 5 fractions with the constraints of the RTOG 0813 trial.

Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain metastases

IntroductionWithout the clear immunophenotyping of brain metastases (BrMs), the optimal treatment strategy based on PD-1/PD-L1 inhibitor for patients with non-small-cell lung cancer (NSCLC) and BrMs remains unknown.Methods308 patients with NSCLC received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy were retrospectively identified. Kaplan-Meier curves with log-rank tests were used to determine the treatment outcomes differences. Transcriptomic analysis of paired primary lung lesions and BrMs were performed to dissect the specific tumor immune microenvironment (TIME) of BrMs.ResultsThe presence of BrMs was associated with significantly inferior PFS (2.5 vs. 3.7 months; P = 0.0053) and OS (8.3 vs. 15.4 months; P = 0.0122) in monotherapy group, while it was only associated with poorer PFS (4.6 vs. 7.0 months; P = 0.0009) but similar OS (22.8 vs. 21.0 months; P = 0.9808) in combination treatment group. Of patients with BrMs, PD-1/PD-L1 inhibitor plus antiangiogenic therapy was associated with longest PFS (7.7 vs. 3.2 vs. 2.5 months; P = 0.0251) and OS (29.2 vs. 15.8 vs. 8.3 months; P = 0.0001) when compared with PD-1/PD-L1 inhibitor plus chemotherapy or anti-PD-1/PD-L1 monotherapy. Multivariate analyses suggested that combination treatment was independently correlated with significantly longer PFS (P = 0.028) and OS (P < 0.001) in patients with BrMs. Transcriptomic analysis showed a suppressive TIME in BrMs with decreased CD4+ T cells and M1 macrophages but increased M2 macrophages infiltration.ConclusionNSCLC with BrMs obtained barely satisfactory overall benefit from anti-PD-1/PD-L1 monotherapy, partly due to its immunosuppressive TIME. PD-1/PD-L1 inhibitor-based combination treatment, especially anti-PD-1/PD-L1 plus anti-angiogenic treatment, could significantly improve the clinical outcomes of patients with NSCLC and BrMs.

Biopsy Method and Needle Size on Success of Next-Generation Sequencing in NSCLC: A Brief Report

IntroductionNext-generation sequencing (NGS) is essential to the care of patients with NSCLC. Nevertheless, NGS is dependent on adequate material from biopsy. We evaluated the impact of biopsy method and needle gauge necessary for optimizing success in tissue NGS. MethodsA total of 1660 formalin-fixed, paraffin-embedded samples were submitted to Caris Life Sciences from 2007 to 2022 for tumor profiling. The results of NGS assays were linked with retrospective biopsy data for patients with lung cancer treated at USC/Norris Cancer Center to create a database with the following parameters: demographics, biopsy method, tumor location (lung mass versus lymph node versus metastasis), needle gauge, number of needle passes, complications, tumor volume, DNA content, and status of NGS. Fisher’s exact test and analysis of variance were performed to determine the impact of biopsy method and needle gauge (G). ResultsIn total, 77 computed tomography (CT)-guided transthoracic core needle (CT-TTCN) biopsies, 74 endobronchial ultrasound (EBUS)-guided transbronchial needle aspirations (TBNAs), 27 bronchial forceps biopsies, and 107 surgical resections were included. Furthermore, 41 of 77 CT-TTCN biopsies (53.2%), 43 of 74 EBUS-TBNAs (58.1%), 22 of 27 bronchial forceps biopsies (81.5%), and 105 of 107 surgical resections (98.1%) underwent successful NGS assays. The probability of successful NGS completion for lung cancers was highest in surgical resections and bronchial forceps biopsies. Needle-based biopsies were more successful when a needle larger than 20G was used. Complication rates were higher for CT-TTCN biopsies compared with EBUS-TBNA (p < 0.0001). Overall, the DNA yield was significantly higher in EBUS-TBNA compared with CT-TTCN biopsies in primary lung sites (p = 0.0002). EBUS-TBNA was found to have higher success rates in NGS compared with CT-TTCN for both primary lung lesions (p = 0.023) and lymph node targets (p = 0.035). ConclusionsThe less invasive EBUS-TBNAs had higher success rates in NGS than CT-TTCN biopsies and resulted in higher DNA concentrations. In CT-TTCN biopsies, use of 20G or smaller needles is associated with a higher risk of obtaining an inadequate specimen regardless of the number of passes taken. Surgical and bronchial forceps biopsies had highest success in achieving NGS.

Genetic trajectory and clonal evolution of multiple primary lung cancer with lymph node metastasis

Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis haven’t been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p = 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.

99mTc-3PRGD2 SPECT/CT Imaging for Diagnosing Lymph Node Metastasis of Primary Malignant Lung Tumors.

To evaluate 99mtechnetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (99mTc-3PRGD2) single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging for diagnosing lymph node metastasis of primary malignant lung neoplasms. We prospectively enrolled 26 patients with primary malignant lung tumors who underwent 99mTc-3PRGD2 SPECT/CT and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT imaging. Both imaging methods were analyzed in qualitative (visual dichotomous and 5-point grades for lymph nodes and lung tumors, respectively) and semi-quantitative (maximum tissue-to-background radioactive count) manners for the lymph nodes and lung tumors. The performance of the differentiation of lymph nodes with and without metastasis was determined at the per-lymph node station and per-patient levels using histopathological results as the reference standard. Total 42 stations had metastatic lymph nodes and 136 stations had benign lymph nodes. The differences between metastatic and benign lymph nodes in the visual qualitative and semiquantitative analyses of 99mTc-3PRGD2 SPECT/CT and 18F-FDG PET/CT were statistically significant (all P < 0.001). The area under the receiver operating characteristic curve (AUC) in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT was 0.908 (95% confidence interval [CI], 0.851-0.966), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.86 (36/42), 0.88 (120/136), 0.69 (36/52), and 0.95 (120/126), respectively. Among the 26 patients (including two patients each with two lung tumors), 15 had pathologically confirmed lymph node metastasis. The difference between primary lung lesions in patients with and without lymph node metastasis was statistically significant only in the semi-quantitative analysis of 99mTc-3PRGD2 SPECT/CT (P = 0.007), with an AUC of 0.807 (95% CI, 0.641-0.974). 99mTc-3PRGD2 SPECT/CT imaging may notably perform in the direct diagnosis of lymph node metastasis of primary malignant lung tumors and indirectly predict the presence of lymph node metastasis through uptake in the primary lesions.

Assessing Treatment Response after Lung SABR: An Evaluation of the Predictive Value of RECIST Criteria

<h3>Purpose/Objective(s)</h3> Response Evaluation Criteria In Solid Tumors (RECIST) – version 1.1 is a commonly used framework to assess treatment response. However, response assessment after lung stereotactic ablative radiotherapy (SABR) can be difficult due to radiation-induced lung changes. The goal of this study was to assess how frequently lung lesions treated with SABR triggered RECIST criteria for recurrence and to correlate RECIST findings with actual treatment outcomes. <h3>Materials/Methods</h3> We reviewed patients who were treated with lung SABR between 2010-2015. Prescribed dose was 54-60 Gy in 3-8 fractions. Both primary lung and metastatic lesions were included. All lesion measurements were based on maximum diameter on CT axial slices. After treatment, progressive disease (PD) by RECIST was based on strict RECIST criteria and defined as: 1) increase of ≥ 20% compared to post-treatment minimum and 2) ≥ 5 mm absolute increase. The final assessment of recurrence was based on subsequent changes in lesions size after PD by RECIST and, when available, PET scan and/or pathology. When assessing subsequent changes in lesion size, stability (≤ 20% change) in size for at least one year or a decrease (> 20%) in size indicated no recurrence, while subsequent growth (> 20%) indicated recurrence. The assessment of lesion response by the treating radiation oncologist (RO) in the clinical record was also recorded when available. <h3>Results</h3> A total of 85 patients, with 88 lesions, met inclusion criteria. 75 of these lesions were lung primaries, the remainder were metastases. Median patient age was 79 years (IQR: 73-85) and mean lesion size was 2.1 ± 0.9 cm. Median follow-up was 52 months (IQR: 33-68). 66% (58/88) of treated lesions met criteria for PD by RECIST. However, on final assessment only 10% (9/88) were found to have recurrence. The positive predictive value (PPV) of RECIST criteria was 0.16. In the subset of patients with primary lung tumors only, 64% (48/75) were classified as PD by RECIST, but only 12% (9/75) were categorized as recurrence on final assessment. PPV was 0.19. The predictive value of RECIST was lower when PD by RECIST was triggered ≤ 12 vs. > 12 months post-treatment (PPV 0.08 vs. PPV 0.21). Median time to PD by RECIST was 19 months (IQR: 12-27) for those with recurrence vs. 15 months (IQR: 8-24) for those without recurrence on final assessment (p=0.13). Assessment by treating RO was only available for 57% (50/88) of cases, but concordance with final study assessment was 0.85, translating to an overall predictive accuracy of 94% (47/50). <h3>Conclusion</h3> Using strict RECIST criteria, two-thirds of patients treated with lung SABR met criteria for PD. However, on further follow-up only a minority of these patients were felt to have recurrence, leading to a poor PPV for RECIST criteria in this setting. Further work is needed to develop validated criteria for designation of recurrence after lung SABR.

Ethanol Ablation Therapy Drives Immune-Mediated Antitumor Effects in Murine Breast Cancer Models.

Simple SummaryTumor ablation is the process of directly destroying tumor tissue by injecting a cytotoxic substance, in this case, ethanol ethylcellulose. In this report, we characterized the effect of ablation on local and systemic immunologic markers known to impact disease progression in several mouse models. Ablation improved overall survival in poorly invasive breast cancer models and was notable for demonstrating an increase in tumor infiltrating lymphocytes. However, in a metastatic breast cancer model, the response to ablation was more nuanced: the growth of the primary tumor was only modestly slowed compared to controls, and there was a reduction in pro-tumor granulocytic myeloid derived suppressor cells (gMDSCs) with a reduction in metastatic disease. A single ablation reduced circulating granulocytic colony stimulating factor, tumoral gMDSCs, splenic gMDSCs, and pulmonary gMDSCs, as well as the suppressive ability of MDSCs on CD4 and CD8 T cells. The immunomodulation incited by tumor ablation was utilized to recover response to checkpoint inhibitors, resulting in increased overall survival compared to checkpoint inhibitors alone, demonstrating a proof-of-concept for using ethanol ablation as an adjuvant immunomodulatory therapy. Ethanol ablation is a minimally invasive, cost-effective method of destroying tumor tissue through an intratumoral injection of high concentrations of cytotoxic alcohol. Ethyl-cellulose ethanol (ECE) ablation, a modified version of ethanol ablation, contains the phase-changing polysaccharide ethyl-cellulose to reduce ethanol leakage away from the tumor. Ablation produces tissue necrosis and initiates a wound healing process; however, the characteristic of the immunologic events after ECE ablation of tumors has yet to be explored. Models of triple-negative breast cancer (TNBC), which are classically immunosuppressive and difficult to treat clinically, were used to characterize the immunophenotypic changes after ECE ablation. In poorly invasive TNBC rodent models, the injury to the tumor induced by ECE increased tumor infiltrating lymphocytes (TILs) and reduced tumor growth. In a metastatic TNBC model (4T1), TILs did not increase after ECE ablation, though lung metastases were reduced. 4T1 tumors secrete high levels of granulocytic colony stimulating factor (G-CSF), which induces a suppressive milieu of granulocytic myeloid-derived suppressor cells (gMDSCs) aiding in the formation of metastases and suppression of antitumor immunity. We found that a single intratumoral injection of ECE normalized tumor-induced myeloid changes: reducing serum G-CSF and gMDSC populations. ECE also dampened the suppressive strength of gMDSC on CD4 and CD8 cell proliferation, which are crucial for anti-tumor immunity. To demonstrate the utility of these findings, ECE ablation was administered before checkpoint inhibitor (CPI) therapy in the 4T1 model and was found to significantly increase survival compared to a control of saline and CPI. Sixty days after tumor implant no primary tumors or metastatic lung lesions were found in 6/10 mice treated with CPI plus ECE, compared to 1/10 with ECE alone and 0/10 with CPI and saline.

Clinical use of 18F-FDG PET/CT in the differential diagnosis of patients with primary and secondary adenoid cystic carcinoma of the lung: a retrospective cohort study.

BackgroundAdenoid cystic carcinoma (ACC) of the lung (ACCL) is a rare malignancy and includes primary ACCL (PACCL) and secondary ACCL (SACCL) metastasized from the ACC of the head and neck. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been shown to be useful in the differential diagnosis between primary and metastatic lung lesions. This study retrospectively investigated the role of 18F-FDG PET/CT in combination with clinicopathological findings in the management of patients with primary or secondary ACCL.MethodsClinicopathological characteristics and 18F-FDG PET/CT metabolic parameters of 29 patients with PACCL and 11 patients with SACCL with pathological confirmation as gold standard were retrospectively collected. The association between PET/CT metabolic parameters and clinicopathological features was explored. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal maximum standard uptake value (SUVmax) cut-off value to distinguish PACCL from SACCL. The prognostic value of PET/CT metabolic parameters and clinicopathological features was evaluated by Cox regression analysis.ResultsSACCL patients more often presented with multiple ACC lesions in the peripheral lung (81.8% vs. 17.2%, P<0.05) and tended to be asymptomatic compared to patients with PACCL (72.7% versus 27.6%, P<0.05). The SUVmax was significantly higher in PACCL patients compared to SACCL patients (median 4.4 vs. 2.8, P<0.05). Furthermore, at a cut-off value of 3.2 for SUVmax, the sensitivity and specificity of 18F-FDG PET/CT in distinguishing PACCL from SACCL were 82.8% and 72.7%, respectively. Higher SUVmax of ACCL was observed in patients with clinical symptoms, fewer ACC lesions, or larger tumor size (P<0.05). The median PFS of ACCL patients was 71.1 months, and the 12- and 24-month PFS rates were 96.1% and 91.6%, respectively. Univariate Cox regression analysis showed that SACCL from metastasis, lesions located at the peripheral lung or multiple ACC lesions present in the lung, were associated with poorer PFS (P<0.05). However, multivariate Cox regression analysis showed that none of the variables examined were independent predictors of prognosis.ConclusionsThe use of 18F-FDG PET/CT in combination with assessment of clinicopathological features was helpful in distinguishing PACCL from SACCL, which could provide guidance for clinical decision making.

Improved Survival With Surgical Treatment of Primary Lung Lesions in Non-Small Cell Lung Cancer With Brain Metastases: A Propensity‐Matched Analysis of Surveillance, Epidemiology, and End Results Database

ObjectivesNon-small cell lung cancer (NSCLC) with Brain metastases (BM) is an advanced disease with poor prognosis and low survival rate. Our study evaluated the survival benefit of primary lung resection with mediastinal lymph node dissection in NSCLC patients with BM using Surveillance, Epidemiology, and End-result (SEER) databases.MethodsAll cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with BM of NSCLC from 2010 to 2016 was retrospectively analyzed. Patients (N=203) patients who underwent radical surgical treatment for primary lung lesions and patients (N=15500) who did not undergo surgery were compared. We successfully analyzed patients using propensity score matching (PSM). Kaplan‐Meier and Cox‐ regression analyses were applied to assess prognosis.ResultsThe median survival in the surgery group was longer than in the control group (27 months vs 5 months; P < 0.001) in the overall sample, 21 months longer compared to the control group (27 months vs 6 months; P<0.001) in a PSM cohort. Cox regression analysis showed that underwent surgery patients in the propensity-matched sample had a significantly lower risk of mortality (HR:0.243, 95%CI: 0.162-0.365, P < 0.001) compared with untreated patients. Multivariate analysis identified the following as independent risk factors for NSCLC with BM: no primary resection surgery, age >65 years, worse differentiation, squamous cell carcinoma, lymphatic metastasis, no systemic therapy. Subgroup analysis revealed that radical resection of the primary lung provided a survival benefit regardless of marital status, tumor size, tumor grade, tumor T stage, and mediastinal lymph node metastasis after PSM.ConclusionRadical resection of primary lung can improve the survival of NSCLC patients with BM. Male, age>65years, poorly differentiated tumor, tumor size>5cm, and mediastinal lymph node metastasis were factors for poor survival.

Accuracy of Chest Computed Tomography in Distinguishing Cystic Pleuropulmonary Blastoma From Benign Congenital Lung Malformations in Children

The ability of computed tomography (CT) to distinguish between benign congenital lung malformations and malignant cystic pleuropulmonary blastomas (PPBs) is unclear. To assess whether chest CT can detect malignant tumors among postnatally detected lung lesions in children. This retrospective multicenter case-control study used a consortium database of 521 pathologically confirmed primary lung lesions from January 1, 2009, through December 31, 2015, to assess diagnostic accuracy. Preoperative CT scans of children with cystic PPB (cases) were selected and age-matched with CT scans from patients with postnatally detected congenital lung malformations (controls). Statistical analysis was performed from January 18 to September 6, 2020. Preoperative CT scans were interpreted independently by 9 experienced pediatric radiologists in a blinded fashion and analyzed from January 24, 2019, to September 6, 2020. Accuracy, sensitivity, and specificity of CT in correctly identifying children with malignant tumors. Among 477 CT scans identified (282 boys [59%]; median age at CT, 3.6 months [IQR, 1.2-7.2 months]; median age at resection, 6.9 months [IQR, 4.2-12.8 months]), 40 cases were extensively reviewed; 9 cases (23%) had pathologically confirmed cystic PPB. The median age at CT was 7.3 months (IQR, 2.9-22.4 months), and median age at resection was 8.7 months (IQR, 5.0-24.4 months). The sensitivity of CT for detecting PPB was 58%, and the specificity was 83%. High suspicion for malignancy correlated with PPB pathology (odds ratio, 13.5; 95% CI, 2.7-67.3; P = .002). There was poor interrater reliability (κ = 0.36 [range, 0.06-0.64]; P < .001) and no significant difference in specific imaging characteristics between PPB and benign cystic lesions. The overall accuracy rate for distinguishing benign vs malignant lesions was 81%. This study suggests that chest CT, the current criterion standard imaging modality to assess the lung parenchyma, may not accurately and reliably distinguish PPB from benign congenital lung malformations in children. In any cystic lung lesion without a prenatal diagnosis, operative management to confirm pathologic diagnosis is warranted.

Therapeutic effects and clinical outcomes of immune checkpoint inhibitors on bone metastases in lung cancer.

e21118 Background: In recent years, advanced lung cancer patients who received immune checkpoint inhibitors (ICIs) reportedly had a more prolonged overall survival (OS) than those treated with conventional anticancer drugs. However, the therapeutic effect of ICIs on bone metastases remains unclear. The purpose of this study was to investigate the therapeutic effects of ICIs on advanced lung cancer with bone metastasis. Methods: This retrospective study included 58 lung cancer patients (42 men and 16 women; mean age, 66.2±7.8 years) who had been diagnosed with bone metastasis before the initiation of ICI treatment between 2016 and 2019, and the mean follow-up period was 23.2 months. The clinical data such as content of chemotherapy including the bone-modifying agent (BMA), skeletal-related events (SREs), and immune-related adverse events (irAEs) were investigated. The therapeutic effects of ICIs on the primary lung lesions and bone metastases were evaluated by the response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson criteria, respectively. To assess the influence of ICI treatment on prognosis, OS from the diagnosis of bone metastases was compared to the prognostic prediction of Katagiri's score. Results: The most used ICI was pembrolizumab in 27 cases (46.6%). BMA was used in 38 cases (65.6%), and denosumab was used in 31 cases (81.6%). SREs and irAEs were observed in three cases (5.2%) and 13 cases (22.4%), respectively. In the primary lung lesions, the response rate (RR) and disease control rate (DCR) of ICIs were 14.3% and 38.1%, respectively, including one case in CR and 5 cases in PR. In the bone metastatic lesions, the RR and DCR were 38.6% and 75.0%, respectively, including 3 cases in CR and 14 cases in PR. In 17 cases that ICIs responded to bone metastases, nine cases were treated with pembrolizumab (52.9%), and all cases whose evaluations were CR had been treated with concomitant therapy of pembrolizumab and denosumab. The median survival time was 28.1 months and the 2-year OS rate was 51.7%. The 6-, 12-, and 24-month OS rates in this study were more favorable than the prognostic prediction of the Katagiri's score. Conclusions: ICI treatment showed favorable responses to bone metastases in NSCLC and better prognoses than conventional predictive prognosis. Particularly, pembrolizumab may be the most effective, and the therapeutic effect was enhanced by the concomitant use of denosumab.[Table: see text]

OC-0421 MR-Guided SBRT/Hypofractionated RT for Metastatic and Primary Ultracentral and Central Lung Lesions

OC-0421 MR-Guided SBRT/Hypofractionated RT for Metastatic and Primary Ultracentral and Central Lung Lesions

The Therapeutic Effect and Clinical Outcome of Immune Checkpoint Inhibitors on Bone Metastasis in Advanced Non-Small-Cell Lung Cancer.

IntroductionIn advanced non-small-cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) have been reported a better treatment outcome on primary lesions, however, the therapeutic effect on bone metastases has not been clarified. This study investigates the therapeutic effect of ICIs on bone metastases in advanced NSCLC.MethodsThe data of patients with advanced NSCLC, treated with ICIs from 2016 to 2019 at our hospital, were analyzed. The therapeutic effects of ICIs on primary lung and metastatic bone lesions, concomitant use of bone modifying agents (BMA), treatment outcomes, and frequency of immune-related adverse events (irAEs) and skeletal-related events (SREs) were investigated.ResultsA total of 29 patients were included (19 men and 10 women; mean age, 64.2 years). Among the ICIs, pembrolizumab was the most used (55.2%), and concomitant use of BMA was prevalent in 21 patients (zoledronic acid=1, denosumab=20). The therapeutic effect was partial response (PR) in 10.3% (n=3) on primary lung lesions by RECIST 1.1, complete response (CR) in 6.9% (n=2) and PR in 17.2% (n=5) on bone metastatic lesions by MDA criteria. ICIs suppressed the progression of bone metastasis in 21 cases (72.4%). All patients in CR and PR were treated with pembrolizumab and denosumab. SREs and irAEs were developed in 3.4% (n=1) and 20.7% (n=6), respectively. The median survival time after treatment with ICIs was 11.0 months. Concomitant therapy with ICIs and denosumab significantly prolonged the overall survival compared to ICI-only therapy (16.0 months vs. 2.5 months, p<0.01).ConclusionsThis study showed that treatment with ICIs may successfully suppress the progression of bone metastasis in advanced NSCLC. Pembrolizumab with denosumab had the highest therapeutic effect on both primary lung lesions and bone metastases. Systemic treatment with this combination and conservative treatment of bone metastasis could be one of the options in the treatment of advanced NSCLC.

Integrated genomic and DNA methylation analysis of patients with advanced non-small cell lung cancer with brain metastases

BackgroundBrain metastasis is a common and lethal complication of non-small cell lung cancer (NSCLC). It is mostly diagnosed only after symptoms develop, at which point very few treatment options are available. Therefore, patients who have an increased risk of developing brain metastasis need to be identified early. Our study aimed to identify genomic and epigenomic biomarkers for predicting brain metastasis risk in NSCLC patients.MethodsPaired primary lung tumor tissues and either brain metastatic tissues or cerebrospinal fluid (CSF) samples were collected from 29 patients with treatment-naïve advanced NSCLC with central nervous system (CNS) metastases. A control group comprising 31 patients with advanced NSCLC who died without ever developing CNS metastasis was also included. Somatic mutations and DNA methylation levels were examined through capture-based targeted sequencing with a 520-gene panel and targeted bisulfite sequencing with an 80,672 CpG panel.ResultsCompared to primary lung lesions, brain metastatic tissues harbored numerous unique copy number variations. The tumor mutational burden was comparable between brain metastatic tissue (P = 0.168)/CSF (P = 0.445) and their paired primary lung tumor samples. Kelch-like ECH-associated protein (KEAP1) mutations were detected in primary lung tumor and brain metastatic tissue samples of patients with brain metastasis. KEAP1 mutation rate was significantly higher in patients with brain metastasis than those without (P = 0.031). DNA methylation analysis revealed 15 differentially methylated blocks between primary lung tumors of patients with and without CNS metastasis. A brain metastasis risk prediction model based on these 15 differentially methylated blocks had an area under the curve of 0.94, with 87.1% sensitivity and 82.8% specificity.ConclusionsOur analyses revealed 15 differentially methylated blocks in primary lung tumor tissues, which can differentiate patients with and without CNS metastasis. These differentially methylated blocks may serve as predictive biomarkers for the risk of developing CNS metastasis in NSCLC. Additional larger studies are needed to validate the predictive value of these markers.