Primary Lung Research Articles

Transbronchial Microwave Ablation of Peripheral Lung Tumors: The NAVABLATE Study.

Image-guided thermal ablation is a minimally invasive local therapy for lung malignancies. NAVABLATE characterized the safety and performance of transbronchial microwave ablation (MWA) in the lung. The prospective, single-arm, 2-center NAVABLATE study (NCT03569111) evaluated transbronchial MWA in patients with histologically confirmed lung malignancies ≤30mm in maximum diameter who were not candidates for, or who declined, both surgery and stereotactic body radiation therapy. Ablation of 1 nodule was allowed per subject. The nodule was reached with electromagnetic navigation bronchoscopy. Cone-beam computed tomography was used to verify the ablation catheter position and to evaluate the ablation zone postprocedure. The primary end point was composite adverse events related to the transbronchial MWA device through 1-month follow-up. Secondary end points included technical success (nodule reached and ablated according to the study protocol) and technique efficacy (satisfactory ablation based on 1-month follow-up imaging). Thirty subjects (30 nodules; 66.7% primary lung, 33.3% oligometastatic) were enrolled from February 2019 to September 2020. The pre-procedure median nodule size was 12.5mm (range 5 to 27mm). Procedure-day technical success was 100% (30/30), with a mean ablative margin of 9.9±2.7mm. One-month imaging showed 100% (30/30) technique efficacy. The composite adverse event rate related to the transbronchial MWA device through 1-month follow-up was 3.3% (1 subject, mild hemoptysis). No deaths or pneumothoraces occurred. Four subjects (13.3%) experienced grade 3 complications; none had grade 4 or 5. Transbronchial microwave ablation is an alternative treatment modality for malignant lung nodules ≤30mm. There were no deaths or pneumothorax. In all, 13.3% of patients developed grade 3 or above complications.

Prolonged Effect of Repetitive Erector Spinae Plane Block in Reducing Thoracic Pain Caused by Lung Cancer.

Pain significantly affects the quality of life of lung cancer patients. We aimed to evaluate the effect of the erector spinae plane block (ESPB) on pain in these patients. We reviewed the medical records of patients with primary lung and bronchial cancer who experienced refractory pain in the thoracic region and underwent repeated ESPBs (three blocks at 24-hour intervals) between 2019 and 2020 in this single-center retrospective study. Visual analog scale (VAS) scores recorded before the procedure and on the first day (first day after the third block) and the first and third months of follow-up in 43 patients were analyzed. Results: The study population consisted of 31 male and 12 female patients, with a mean age of 56.7 years. The mean pre-procedure VAS score was 8.9±0.8, which showed a significant decrease on the first day (2.9), first month (3.6), and third month (4.6) of the follow-up. Four patients experienced minor complications (pain at the procedure site and hypotension); however, no major complications were observed. We observed a prolonged effect of repeated ESPBs for ≥3 months. The block efficacy decreased with time; however, an approximately 50% reduction in the VAS score persisted even in the third month. Repetitive ESPBs may be regarded as a straightforward, safe, and replicable intervention to complement medical treatment and diminish the need for opioids in managing lung cancer-related pain.

Primary Lung and Pleural Malignancies in Children: Imaging of a Case Series

Primary Lung and Pleural Malignancies in Children: Imaging of a Case Series

Effects of Semisupervised Exercise Training on Health Outcomes in People With Lung or Head and Neck Cancer: Protocol for a Randomized Controlled Trial.

Lung or head and neck cancers are known for their high prevalence and mortality rates. Chemotherapy and radiotherapy are usually recommended as cancer treatment for these malignancies; however, they can negatively impact both the physical and mental status of patients. Hence, it is reasonable to consider resistance and aerobic exercise training to prevent these negative health outcomes. Further, several factors prevent patients from attending outpatient exercise training programs, and, therefore, a semisupervised home-based exercise training program may be seen as a well-accepted alternative. The aim of this study will be to investigate the effects of a semisupervised home-based exercise training program on physical performance, body composition, and self-reported outcomes; changes in the initial cancer treatment dose prescribed; number of hospitalizations at 3, 6, and 9 months; and 12-month survival in people with primary lung or head and neck cancer. Participants will be randomly allocated to the training group (TG) or control group (CG). The TG will undergo semisupervised home-based resistance and aerobic exercise training throughout their cancer treatment. The resistance training will be performed using elastic bands (TheraBand) twice a week. The aerobic training (ie, brisk walk) will be performed for at least 20 minutes per day outdoors. The equipment and tools used during the training sessions will be provided. This intervention will start the week before treatment commencement, will be performed throughout the duration of the treatment, and will continue for 2 weeks after treatment completion. The CG will undergo usual care (ie, cancer treatment with no formal exercise prescription). Assessments will take place 2 weeks before the beginning of the usual cancer treatment and 2 weeks after treatment completion. The measures of physical function (peripheral muscle strength, functional exercise capacity, and physical activity), body composition, and self-reported outcomes (symptoms of anxiety and depression, health-related quality of life, and symptoms related to the disease and treatment) will be collected. We will report on any change in the initial cancer treatment dose prescribed; number of hospitalizations at 3, 6, and 9 months; and 12-month survival. In February 2021, the clinical trial registration was approved. Recruitment and data collection for the trial are ongoing (as of April 2023, 20 participants had already been randomized), and findings of this study are likely to be published late in 2024. This exercise training as a complementary treatment for patients with cancer is likely to promote positive effects on the health outcomes assessed, over and above any change in the CG, and prevent the reduction of initial cancer treatment dose prescribed. If these positive effects are shown, they will likely impact long-term outcomes such as hospitalizations and 12-month survival. Brazilian Clinical Trials Registry (ReBEC) RBR-5cyvzh9; https://ensaiosclinicos.gov.br/rg/RBR-5cyvzh9. PRR1-10.2196/43547.

Performance of [18F]FDG-PET/CT Imaging in First Recurrence of Invasive Lobular Carcinoma.

Invasive lobular carcinoma accounts for 10 to 15% of all breast cancers. The first objective of this retrospective study was to assess the diagnostic performance of FDG-PET/CT scanning in women previously treated for invasive lobular carcinoma with suspected first recurrence. The secondary objectives were to evaluate the impact of PET/CT in a change in treatment and its prognostic value on specific survival. Patients in whom a PET/CT scan was performed from January 2011 to July 2019 in our Cancer Research Center were enrolled. Recurrence was suspected based on clinical symptoms, abnormal findings on conventional imaging, and/or elevated tumor markers. The diagnosis of recurrence was established by the oncologist after integration of all clinical, biological, histological, imaging, and follow-up data. Prognostic factors of recurrence as predicted by PET were determined using univariate logistic regression. KI67, mitotic index, or grade of mitosis were tested. Survival curves were compared using the log-rank test. Sixty-four patients (mean age: 60.3; SD = 12.4 years) were enrolled. The average time from initial diagnosis of the primary tumor to suspicion of recurrence was 5.2 ± 4.1 years. Forty-eight patients (75%) were judged to have recurrence by the oncologist: 7 local and 41 metastatic, with mainly bone (n = 24), lymph node (n = 14) and liver (n = 10) metastases. Sensitivity, specificity, and positive and negative predictive values of PET/CT to predict recurrence were, respectively: 87%, 87%, 95%, and 70%. SUVmax at recurrence sites was generally high (mean: 6.4; SD = 2.9). False negative PET/CT results occurred with local (n = 2), peritoneal (n = 2), meningeal (n = 1), or bladder (n = 1) recurrences. In 40 patients with available histopathological data from suspected sites of recurrence, 30 PET/CT were true positive. In four patients, primary lung (n = 1) or gastric (n = 1) tumors or lymphomas (n = 2) were found. The detection of a recurrence resulted in a change in treatment in 44/48 patients (92%). No association between recurrence predicted by PET and biological biomarkers was found. Median specific survival appears shorter in patients with metastatic recurrence versus patients with local or no recurrence on PET/CT (p = 0.067). FDG-PET/CT is an effective and reliable tool for the detection of invasive lobular carcinoma recurrence, although certain recurrence sites specific to this histological type can impair its diagnostic performance.

Abstract 2474: Uncovering a new therapeutic vulnerability for preventing brain metastases

Abstract INTRO: Patients with brain metastases (BM) face a 90% mortality rate within one year of their diagnosis and they lack targeted therapeutic options, particularly preventative or interceptional ones. METHODS: The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from patient-derived BM from primary lung and breast cancers and melanoma. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective metastatic cascades and allowed characterization of a “premetastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but present a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RESULTS: Targeting premetastatic BM cells is a feasible interceptional strategy to block BM, but druggable targets are still very limited. Here, we applied RNA sequencing of premetastatic BM cells to reveal a unique deregulated transcriptomic profile that is specific to premetastatic cells regardless of primary tumor origin. Subsequent Connectivity Map analysis revealed compounds that we biologically characterized in vitro for selective anti-BMIC phenotypes. This effort led us to identify a tool compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Follow up preclinical studies showed that treatment with this tool compound reduces the tumor burden of mice compared to placebo, while providing a significant survival advantage. Mass spectrometry-based metabolomics and CRISPR knock-out studies directly validated our tool compound’s target, Target X, as a targetable therapeutic vulnerability in BM, where pharmacological and genetic perturbation of Target X attenuates BM cell proliferation both in vitro and in vivo. We have now begun a large-scale medicinal chemistry campaign to develop a novel, brain penetrant Target X-inhibitor with a drug-like pre-clinical profile validated by our in vivo experimental models. This advanced drug candidate will be ready for later stage preclinical development and subsequent clinical development. CONCLUSION: This potential first-in-class anti-metastatic therapy may provide an alternative interceptional treatment strategy for patients experiencing BM that are otherwise limited to palliation. Our work provides a new model for target discovery and validation to develop more effective preventative therapeutic strategies for patients with metastatic disease. Citation Format: Agata M. Kieliszek, Daniel Mobilio, Blessing I. Bassey-Archibong, Jarrod Johnson, Nikoo Aghaei, William Gwynne, Dillon McKenna, Minomi K. Subapanditha, Chitra Venugopal, Jakob Magolan, Sheila K. Singh. Uncovering a new therapeutic vulnerability for preventing brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2474.

Association between radiotherapy for surgically treated oral cavity cancer and secondary lung cancer.

There is limited research on the incidence of secondary lung cancer (SLC) after radiotherapy (RT) for oral cavity cancer (OCC). Therefore, we investigated the association between RT for OCC and the risk of SLC and the overall survival of these patients. Patients diagnosed with OCC between 1975 and 2015 were selected from the Surveillance, Epidemiology, and End Results database. The cumulative incidence of SLC, relative risk (RR) of RT vs. no RT (NRT), standardized incidence ratios (SIR), and survival outcomes were assessed. A total of 10,936 patients with OCC were included. Of these, 429 (3.92%) patients developed SLC, where 136 (5.02%) received RT and 293 (3.56%) did not. The cumulative incidence of SLC during follow-up was 6.89% and 4.84% in the RT and NRT patients, respectively. RT was associated with a higher risk of SLC. In the subset analysis, the results showed that a higher risk of developing SLC among patients with index OCC in most subgroups. Dynamic RR and SIR revealed a decreased risk of SLC with increasing latency time. No difference was observed in the 10-year survival rates for patients with SLC who received RT or not or compared with primary lung cancer. RT was associated with a higher risk of SLC, and patients diagnosed with OCC could be followed for 5-10 years after diagnosis.

Evaluating Current Prognostic Factors for Brain Metastases of Patients with Primary Lung and Breast Cancer Receiving Cranial Radiotherapy - A Single Center Study

Evaluating Current Prognostic Factors for Brain Metastases of Patients with Primary Lung and Breast Cancer Receiving Cranial Radiotherapy - A Single Center Study

Epidemiological trends, prognostic factors, and survival outcomes of synchronous brain metastases from 2015 to 2019: a population-based study.

Brain metastases (BM) constitute a significant cause of oncological mortality. Statistics on the incidence of BM are limited because of the lack of systematic nationwide reporting. We report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015 to 2019 using National Cancer Institute's (NCI's) Surveillance, Epidemiology, and End Results Program database. We identified 1,872,057 patients with malignancies diagnosed between 2015 and 2019 from the SEER 17 Registries database, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Kaplan-Meier curves and a multivariate Cox regression model were used to investigate survival. The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest incidence of sBM (5.18 to 5.64 per 100,000), followed by melanoma (0.30 to 0.34 per 100,000) and breast cancers (0.24 to 0.30 per 100,000). In children, renal tumors had the highest sBM incidence. sBM were associated with poorer survival than extracranial metastases only (hazard ratio [HR]: 1.40 [95% CI: 1.39-1.42], P < .001). We observed better survival in white patients relative to nonwhite patients with sBM (HR: 0.91 [95% CI: 0.90-0.94], P < .001). The incidence rate of sBM has remained similar to rates reported over the last 9 years, with the majority associated with primary lung and bronchus cancers. sBM represent a national healthcare burden with tremendous mortality in pediatric and adult populations. This population may benefit from improved screening and treatment strategies.

Surgical and Oncological Outcomes of En-Bloc Resection for Malignancies Invading the Thoracic Spine.

There is still limited data in the literature concerning the survival of patients with tumors of the thoracic spine. In this study, we analyzed clinical features, perioperative and long-term outcomes in patients who underwent vertebrectomy for cancer. Furthermore, we evaluated the survival and surgical complications. We retrospectively reviewed all cases of thoracic spinal tumors treated by the same team between 1998 and 2018. We divided them into three groups according to type of tumor (primary vertebral, primary lung and metastases) and compared outcomes. For each patient, Overall Survival (OS) and Cumulative Incidence of Relapse (CIR) were estimated. Complications and survival were analyzed using a logistic model. Seventy-two patients underwent thoracic spine surgery (40 in group 1, 16 in each group 2 and 3). Thirty patients died at the end of the observation at a mean follow up time of 60 months (41%). The 5-year overall survival was 72% (95% CI: 0.52-0.84), 20% (95% CI: 0.05-0.43) and 27% (95% CI: 0.05-0.56) for each group, respectively. CIR of group 3 was higher (HR 2.57, 95% CI: 1.22-5.45, p = 0.013). The logistic model revealed that age was related to complications (p = 0.04), while surgery for a type 3 tumor was related to mortality (p = 0.02). Although the cohort size was limited, primary vertebral tumors displayed the best 5-y-OS with an acceptable complications rate. The indication of surgery should be advised by a multidisciplinary team and only for selected cases. Finally, the use of a combined approach does not increase the risk of complications.

Differentiating Primary Tumors for Brain Metastasis with Integrated Radiomics from Multiple Imaging Modalities

Objectives To differentiate the primary site of brain metastases (BMs) is of high clinical value for the successful management of patients with BM. The purpose of this study is to investigate a combined radiomics model with computer tomography (CT) and magnetic resonance imaging (MRI) images in differentiating BMs originated from lung and breast cancer. Methods Pretreatment cerebral contrast enhanced CT and T1-weighted MRI images of 78 patients with 179 BMs from primary lung and breast cancer were retrospectively analyzed. Radiomic features were extracted from contoured BM lesions and selected using the Mann–Whitney U test and the least absolute shrinkage and selection operator (LASSO) logistic regression. Binary logistic regression (BLR) and support vector machine (SVM) models were built and evaluated based on selected radiomic features from CT alone, MRI alone, and combined images to differentiate BMs originated from lung and breast cancer. Results A total of 10 and 6 optimal radiomic features were screened out of 1288 CT and 1197 MRI features, respectively. The mean area under the curves (AUCs) of the BLR and SVM models using fivefolds cross-validation were 0.703 vs. 0.751, 0.718 vs. 0.754, and 0.781 vs. 0.803 in the training dataset and 0.708 vs. 0.763, 0.715 vs. 0.717, and 0.771 vs. 0.805 in the testing dataset for models with CT alone, MRI alone, and combined CT and MRI radiomic features, respectively. Conclusions Radiomics model based on combined CT and MRI features is feasible and accurate in the differentiation of the primary site of BMs from lung and breast cancer.

Development and validation of MRI-based radiomics signatures as new markers for preoperative assessment of EGFR mutation and subtypes from bone metastases

BackgroundThis study aimed to develop and externally validate contrast-enhanced (CE) T1-weighted MRI-based radiomics for the identification of epidermal growth factor receptor (EGFR) mutation, exon-19 deletion and exon-21 L858R mutation from MR imaging of spinal bone metastasis from primary lung adenocarcinoma.MethodsA total of 159 patients from our hospital between January 2017 and September 2021 formed a primary set, and 24 patients from another center between January 2017 and October 2021 formed an independent validation set. Radiomics features were extracted from the CET1 MRI using the Pyradiomics method. The least absolute shrinkage and selection operator (LASSO) regression was applied for selecting the most predictive features. Radiomics signatures (RSs) were developed based on the primary training set to predict EGFR mutations and differentiate between exon-19 deletion and exon-21 L858R. The RSs were validated on the internal and external validation sets using the Receiver Operating Characteristic (ROC) curve analysis.ResultsEight, three, and five most predictive features were selected to build RS-EGFR, RS-19, and RS-21 for predicting EGFR mutation, exon-19 deletion and exon-21 L858R, respectively. The RSs generated favorable prediction efficacies for the primary (AUCs, RS-EGFR vs. RS-19 vs. RS-21, 0.851 vs. 0.816 vs. 0.814) and external validation (AUCs, RS-EGFR vs. RS-19 vs. RS-21, 0.807 vs. 0.742 vs. 0.792) sets.ConclusionsRadiomics features from the CE MRI could be used to detect the EGFR mutation, increasing the certainty of identifying exon-19 deletion and exon-21 L858R mutations based on spinal metastasis MR imaging.

MiRNAs in Serum Exosomes for Differential Diagnosis of Brain Metastases.

Simple SummaryCurrent methods for the detection of brain malignancies often display low sensitivity and specificity. Noninvasive biomarkers can complement imaging techniques to improve the diagnosis of these tumors. The aim of this study was to identify circulating miRNAs in serum exosomes useful in all phases of the diagnostic and therapeutic path of patients with malignant brain lesions. Our data show a signature of exosomal miRNAs useful for the differential diagnosis of brain metastases and for monitoring tumor evolution over time.Circulating miRNAs are increasingly studied and proposed as tumor markers with the aim of investigating their role in monitoring the response to therapy as well as the natural evolution of primary or secondary brain tumors. This study aimed to evaluate the modulation of the expression of three miRNAs, miR-21, miR-222 and miR-124-3p, in the serum exosomes of patients with high-grade gliomas (HGGs) and brain metastases (BMs) to verify their usefulness in the differential diagnosis of brain masses; then, it focused on their variations following the surgical and/or radiosurgical treatment of the BMs. A total of 105 patients with BMs from primary lung or breast cancer, or melanoma underwent neurosurgery or radiosurgery treatment, and 91 patients with HGGs were enrolled, along with 30 healthy controls. A significant increase in miR-21 expression in serum exosomes was observed in both HGGs and BMs compared with healthy controls; on the other hand, miR-124-3p was significantly decreased in BMs, and it was increased in HGGs. After the surgical or radiosurgical treatment of patients with BMs, a significant reduction in miR-21 was noted with both types of treatments. This study identified a signature of exosomal miRNAs that could be useful as a noninvasive complementary analysis both in the differential diagnosis of BMs from glial tumors and in providing information on tumor evolution over time.

Combined whole-lesion radiomic and iodine analysis for differentiation of pulmonary tumors

Quantitative radiomic and iodine imaging features have been explored for diagnosis and characterization of tumors. In this work, we invistigate combined whole-lesion radiomic and iodine analysis for the differentiation of pulmonary tumors on contrast-enhanced dual-energy CT (DECT) chest images. 100 biopsy-proven solid lung lesions on contrast-enhanced DECT chest exams within 3 months of histopathologic sampling were identified. Lesions were volumetrically segmented using open-source software. Lesion segmentations and iodine density volumes were loaded into a radiomics prototype for quantitative analysis. Univariate analysis was performed to determine differences in volumetric iodine concentration (mean, median, maximum, minimum, 10th percentile, 90th percentile) and first and higher order radiomic features (n = 1212) between pulmonary tumors. Analyses were performed using a 2-sample t test, and filtered for false discoveries using Benjamini–Hochberg method. 100 individuals (mean age 65 ± 13 years; 59 women) with 64 primary and 36 metastatic lung lesions were included. Only one iodine concentration parameter, absolute minimum iodine, significantly differed between primary and metastatic pulmonary tumors (FDR-adjusted p = 0.015, AUC 0.69). 310 (FDR-adjusted p = 0.0008 to p = 0.0491) radiomic features differed between primary and metastatic lung tumors. Of these, 21 features achieved AUC ≥ 0.75. In subset analyses of lesions imaged by non-CTPA protocol (n = 72), 191 features significantly differed between primary and metastatic tumors, 19 of which achieved AUC ≥ 0.75. In subset analysis of tumors without history of prior treatment (n = 59), 40 features significantly differed between primary and metastatic tumors, 11 of which achieved AUC ≥ 0.75. Volumetric radiomic analysis provides differentiating capability beyond iodine quantification. While a high number of radiomic features differentiated primary versus metastatic pulmonary tumors, fewer features demonstrated good individual discriminatory utility.

Prognostic significance of 4R lymph node dissection in patients with right primary non-small cell lung cancer

BackgroundTo investigate the prognostic significance of station 4R lymph node (LN) dissection in patients who underwent operations for right primary non-small cell lung cancer (NSCLC).MethodsWe performed a retrospective study involving patients with right primary NSCLC who received lobotomy or pneumonectomy with mediastinal LN dissection between January 2011 and December 2017. Propensity score matching was performed. Disease-free survival (DFS) and overall survival (OS) were compared between patients with and without station 4R dissection.ResultsOur study included 2070 patients, with 207 patients having no station 4R dissection (S4RD− group) and 1863 patients having station 4R dissection (S4RD+ group). The 4R LN metastasis rate was 13.4% (142/1748), higher than that for other mediastinal LN metastases. Compared with the S4RD− group, the S4RD+ group had higher 5-year DFS (48.1% vs. 39.1%, P = 0.009) and OS (54.4% vs. 42.8%, P = 0.025). Station 4R dissection was an independent risk factor for DFS (odds ratio, OR, 1.28, 95% confidence interval, CI, 1.08–1.64, P = 0.007) and OS (OR 1.31, 95% CI 1.04–1.63, P = 0.018). Patients with adjuvant chemotherapy had a better prognosis after station 4R dissection than those without adjuvant chemotherapy (57.4% vs. 52.3%, P = 0.006). The 5-year OS in the station 4R metastasis group was lower than that in the station 4R non-metastasis group (26.9% vs. 44.3%, P = 0.006) among N2 patients. The 5-year OS of the single-station 4R metastasis group was lower than that of the single-station 7 metastasis group (15.7% vs. 51.6%, P = 0.002).ConclusionsStation 4R metastasis was the highest among all the mediastinal station metastases in right primary NSCLC patients. Station 4R dissection can improve the prognosis and should be recommended as a routine procedure for these patients.

Sequential bronchoplastic upper lobectomy as a surgical component of multimodal treatment for synchronous bilateral multiple primary non-small cell lung cancer

Relevance. Lung cancer (LC) is the leading cause of cancer-related death worldwide including Russia. Surgery remains the standard of care for early non-small cell lung cancer (NSCLC). However, as the disease progresses, the risk of metastasis increases, and the effectiveness of surgical intervention decreases. The treatment strategy for patients presenting with a single NSCLC has long been developed. However, for patients with two or more tumors, especially in both lungs, the correct choice is determined by many additional factors. Currently, the view on the surgical treatment for synchronous multiple primary NSCLC has changed dramatically. However, patients with locally advanced synchronous NSCLC often receive conservative treatment, and for those who do undergo surgery, the prognostic factors are unclear. The disease prognosis in patients after surgical treatment for bilateral synchronous multiple primary NSCLC has now been proven to be favorable. Pneumonectomy is believed to have no any negative effect on survival; however, several authors reported on a 1.5-2-fold increase in postoperative mortality in a series of surgeries for synchronous NSCLC. Case description. We herein report a case in which extended bronchoplastic upper lobectomy was successfully applied in the treatment of a patient with bilateral synchronous NSCLC. Our experience demonstrates that the sequential application of modern therapeutic modalities results in satisfactory long-term outcomes in the treatment of locally advanced LC.Conclusion. Due to its uniqueness, this clinical case will be useful for developing treatment strategy for synchronous locally advanced NSCLC as well as for improving the quality of life of patients and increasing their survival.

Abstract 3794: Comprehensive clonal and molecular profiling of primary tumors and distant lung metastases in an amputation model of osteosarcoma

Abstract An important feature of osteosarcoma is relapse which occurs in more than 30% of patients and metastasis to the lungs. It has been revealed that the metastatic ability and resistance to chemotherapy might be due to the presence of a subset of cells within the intra-tumorally heterogeneous population. However, tracking the rare genetic subpopulations that play a critical role in cancer recurrence, metastasis and resistance and the lack of a defined in vivo model to recapitulate clonal evolution has been a challenge. To further understand clonal dynamics and intra-tumoral heterogeneity a new barcoded PDX (OS17) derived cell line was established by stably transducing the cell line with a lentiviral vector-based system. The highly complex barcode library of ten million enabled labelling each of the cells with a unique molecular identifier and clonally tracking more than one million cells in vitro. Following seventeen passages in vitro and transplant for three generations in vivo, flow cytometry, nested PCR and next generation sequencing showed that the barcoded cells retained the sequence in vitro and in vivo suggesting that it was possible to track cell populations and their clonal lineages both at the genomic DNA and RNA level. The barcoded M17 PDX cells were injected in 25 SCID and NSG mice intratibially to monitor tumor growth and clonally track the cells in both the primary tumors and the lungs. Seventeen (68%) of the mice developed primary tumors. Tumor latency and growth was 61.82 ±34.5 and 51.24 ± 23 days respectively. Seven (35%) of the primary tumor bearing mice had lung metastasis. Limb amputations were performed in 5 mice with 2 surviving the surgery. The results not only show a diversity in clonal subpopulations between the mice injected on different dates but also the primary tumor and matched lung metastatic samples. An in-depth clonal characterization further revealed a high degree of similarity in the subclonal populations between the lung nodules and the primary tumor samples. In vitro, a proportion of the barcodes were very reduced or lost in the early six passages however, these slowly expanded in the late passages suggesting that in a more favorable environment in vivo, these clones can maintain tumorigenic potential. These results suggest a clonal evolutionary dynamic model where pre-existing clones have a fitness for persistence and dissemination. This advantage might include long term tumorigenic and proliferative potential and the ability to grow in different micro-environments. Conclusion: It has been demonstrated that the barcoded PDX models have inter and intra-tumoral heterogeneity of osteosarcoma both in vitro and in vivo and can potentially be used in tracking tumor colonization at the primary and metastatic sites. Using this model will therefore advance our understanding of osteosarcoma lung metastasis which is the critical clinical challenge for these patients. Citation Format: Sylvester Jusu, Sankaranarayanan Kannan, Sahil Seth, Michael D. Peoples, Zhongting Zhang, Wendong Zhang, Zhaohui Xu, Yifei Wang, Xin Zhou, Yizheng Tu, Giuseppe Longo, Michael Roth, Jonathan B. Gill, Richard Gorlick. Comprehensive clonal and molecular profiling of primary tumors and distant lung metastases in an amputation model of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3794.

Abstract 5442: LP-184, a tumor site activated small molecule synthetic lethal therapeutic, is effective in central nervous system cancers

Abstract Blood-brain barrier (BBB) permeable agents effective against recurrent, chemotherapy-resistant central nervous system (CNS) tumors are urgently needed, particularly in Glioblastoma multiforme (GBM) and atypical teratoid/rhabdoid tumors (ATRT). These represent 2 extremely aggressive and lethal types of CNS malignancies sharing a median overall survival of 12-18 months and 5-year survival rate of 5 to 30% in the US. LP-184 has received orphan drug designation for the treatment of malignant gliomas. LP-184 is activated to a highly labile metabolite by Prostaglandin Reductase 1 (PTGR1) and has potential to be a potent therapeutic as a single agent for PTGR1-expressing malignancies. LP-184 was found to have nanomolar range potency (IC50 30-400 nM) against multiple human GBM cell lines and patient-derived neurospheres in vitro. Intravenous LP-184 induced complete and durable regression of pre-established subcutaneous U87 and M1123 GBM xenografts and prolonged survival of mice bearing orthotopic U87 and M1123 xenografts (p&amp;lt;0.0001). Activated LP-184 creates covalent DNA adducts (e.g. N3 of adenine) that are selectively repaired via ERRC-dependent nucleotide excision repair or by homologous recombination. Consistent with this, we observed 2-5X increase in cytotoxicity in U87, Mayo39, M1123 GBM cells treated with LP-184 in combination with the ERCC3 inhibitor Spironolactone relative to LP-184 alone. This supports LP-184’s function as a synthetic lethal agent in the presence of DNA repair deficiencies. &amp;gt; 50% of newly diagnosed GBMs fail to respond to standard of care temozolomide (TMZ) due to MGMT expression (i.e.unmethylated mgmt promoter) and essentially all GBMs ultimately develop TMZ resistance. Our in silico analyses and type of DNA adduct generated by LP-184 indicate that sensitivity to LP-184 is independent of MGMT expression and potentially higher in MGMT unmethylated cancers. This is supported by in vitro toxicity assays showing LP-184 IC50s of 46 nM in LN-18 (unmethylated mgmt) and 203 nM in U87 (hypermethylated mgmt) cell lines. Analysis of genes associated with LP-184 sensitivity in solid tumor cell lines revealed that expression of SMARCB1 is significantly anti-correlated to LP-184 sensitivity, suggesting that LP-184 will be effective in ATRTs and other tumors with SMARCB1 loss. LP-184 treatment induced tumor regression in mice implanted with SMARCB1 deficient CHLA06 ATRT subcutaneous xenografts, with 2 of 10 treated mice being virtually tumor-free after 2 cycles over 22 days. Pharmacokinetic analyses showed favorable in vivo BBB permeability (mouse brain/blood ratio=0.112) comparable to that reported for TMZ. LP-184 was also active in vitro against models of brain metastases from primary lung and breast cancers. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations. Citation Format: Aditya Kulkarni. LP-184, a tumor site activated small molecule synthetic lethal therapeutic, is effective in central nervous system cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5442.

Abstract 976: Interrogating the pre-metastastic gene signature to block brain metastases

Abstract BACKGROUND: The incidence of brain metastases (BM) is tenfold higher than that of primary brain tumors. BM predominantly originate from primary lung, breast, and melanoma tumors with a 90% mortality rate within one year of diagnosis, posing a large unmet clinical need to identify novel therapies against BM. The goal of this work is to uncover the molecular factors that drive the formation of BM and investigate whether we can slow down and ultimately block BM formation. METHODS: The Singh lab has generated a large in-house biobank of patient-derived BM cell lines that are established from BM patient tumor samples. We use these BM cell lines to generate murine orthotopic xenograft models of BM and interrogate the biological processes that lead to BM. These models have successfully recapitulated all the stages of their respective BM cascades and additionally captured a “pre-metastatic” population of BM cells that have just seeded the brains of mice before forming mature, clinically detectable tumors. Pre-metastatic cell populations are impossible to detect in human patients but represent a therapeutic window wherein metastasizing cells can be targeted and eradicated before establishing clinically detectable and difficult to treat brain tumors. RESULTS: RNA sequencing of pre-metastatic BM cells revealed a unique deregulated transcriptomic profile that is specific to pre-metastatic cells despite the tumor of origin. Subsequent Connectivity Map analysis revealed compounds that we biologically characterized in vitro for selective anti-BMIC phenotypes. This effort led to a lead compound that exhibits anti-BM activity in vitro, while remaining ineffective against normal brain cell controls. Preliminary in vivo work has shown that following both orthotopic and intracardiac injection of BM cells, treatment with this lead compound reduces the tumor burden compared to mice being treated by a vehicle control, while providing a significant survival advantage. Ongoing mechanistic investigations aim to delineate the protein target of this compound in the context of the observed selective anti-BM phenotype. CONCLUSION: Identification of novel small molecules that target premetastatic BM cells could slow or prevent the formation of BM and dramatically improve the prognosis of at-risk cancer patients. Citation Format: Agata Kieliszek, Blessing Bassey-Archibong, Chitra Venugopal, Sheila Singh. Interrogating the pre-metastastic gene signature to block brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 976.

Abstract 5983: Gene profile analysis of breast cancer lung metastasis, liver metastasis, brain metastasis and primary tumor

Abstract Background: The incidence of male breast cancer (MBC) is lower than female breast cancer (FBC), representing 1% of all breast cancer worldwide. The difference with FBC may affect the treatment strategy of MBC, but the necessary precondition is that we should know more about the difference between FBC and MBC. However, Because of its low incidence that the relevant data about MBC is relatively scarce. Here we report some data about gene mutation of MBC, and compared it with FBC. Methods: Blood or tumor Tissue samples of breast cancer were collected and subjected to NGS in a College of American Pathologists (CAP)-certified and Clinical Laboratory Improvement Amendments (CLIA)-accredited lab for gene mutation analysis (3D Medicines Inc.,Shanghai, China). Statistical analysis was performed using GraphPad Prism (version 7.01) and SPSS version 21.0 (SPSS,Inc.). Results: Approximately 182 samples were analyzed, among which, exist 82 samples were from primary tissue, 66 samples were breast cancer liver metastases, 20 were lung metastases and 14 were brain metastases. High genomic heterogeneity was found among primary breast cancer tissue, breast cancer liver metastases, lung metastases, brain metastases, that is at least 20 gene mutations were found in these BC samples, while different gene mutations were showed among primary and different metastases tissues. The top five mutated gene in primary tumor tissue were TP53(80.49%), PIK3CA(53.66%), FGF19(30.49%), ERBB2(26.83%), MYC(23.17%); in liver metastases tissues were TP53(54.55%), FGF19(39.39%), PIK3CA(37.88%), ERBB2(21.21%), CCND1(19.70%); in lung metastases tissues were TP53(70.00%), PIK3CA(55.00%), ERBB2,MCL1(25.00%), CDKN2A/2B(20.00%), CCND1, NF1, CDK12(15.00%), CCND2, MYC, PTEN, GNAS, FGF19, PTK2, FGFR1(10.00%); in brain metastases tissues were TP53(42.86%), PIK3CA(28.57%), ZNF703, PREX2, JAK3, MYC, FGFR1(14.29%). Besides, levels of TMB were also different among primary tissue, liver, lung and brain metastases tissues. Higher TMB level were showed in liver and brain metastases tissue than primary and lung metastases tissues (p&amp;lt;0.001). Conclusions: Different metastases of breast cancer were different in gene mutation landscape, this imply these patients should be managed differently. Citation Format: Yanman Fang, Hushan Zhang, Jiali Zou, Fulin Zhou, Xuejie Tang, Yi Yang, Li Luo, Yu Ding. Gene profile analysis of breast cancer lung metastasis, liver metastasis, brain metastasis and primary tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5983.