Treatment strategies for malignant pulmonary nodule: beyond lobectomy. Point-counterpoint.

PURPOSE OF REVIEW: Technological advancement in low-dose computed tomography resulted in an increased incidental discovery of early-stage lung cancer and multifocal ground glass opacity. The demand for parenchyma-preserving treatment strategies is greater now than ever. Pulmonary ablative therapy is a groundbreaking technique to offer local ablative treatment in a lung-sparing manner. It has become a promising technique in lung cancer management with its diverse applicability. In this article, we will review the current development of ablative therapy in lung and look into the future of this innovative technique. RECENT FINDINGS: Current literature suggests that ablative therapy offers comparable local disease control to other local therapies and stereotactic body radiation therapy (SBRT), with a low risk of complications. In particular, bronchoscopic microwave ablation (BMWA) has considerably fewer pleural-based complications due to the avoidance of pleural puncture. BMWA can be considered in the multidisciplinary treatment pathway as it allows re-ablation and allows SBRT after BMWA. SUMMARY: With the benefits which ablative therapy offers and its ability to incorporate into the multidisciplinary management pathway, we foresee ablative therapy, especially BMWA gaining significance in lung cancer treatment. Future directions on developing novel automated navigation platforms and the latest form of ablative energy would further enhance clinical outcomes for our patients.

Radiation Principles, Protection, and Reporting for Interventional Pulmonology: A World Association of Bronchology and Interventional Pulmonology White Paper.

The use and availability of diverse advanced X-ray based imaging and guidance systems in the field of interventional pulmonology are rapidly growing. This popularity links inextricably to an increase in ionizing radiation use. Knowing ionizing radiation is hazardous, knowledge and competent use of X-ray imaging and guidance systems are important. The globally implemented As Low As Reasonably Achievable (ALARA) principle demands careful attention to minimize radiation exposure while achieving the precise goals of the intervention and imaging therein. To allow careful and targeted weighing of risk against reward while using X-ray based equipment, proper background knowledge of physics as well as imaging system aspects are needed. This white paper summarizes the principles of ionizing radiation which are crucial to enhance awareness and interpretation of dosimetric quantities. Consecutively, a consensus on standards for reporting radiation exposure in interventional pulmonology procedures is indicated to facilitate comparisons between different systems, approaches and results. Last but not least, it provides a list of practical measures, considerations and tips to optimize procedural imaging as well as reduce radiation dose to patients and staff.

Radical Minimally Invasive Surgery After Immuno-chemotherapy in Initially-unresectable Stage IIIB Non-small cell Lung Cancer.

INTRODUCTION: Use of neoadjuvant immunotherapy agent in advanced stage NSCLC is controversial. Herein, we aim to report on a case series of successful conversion from initial unresectable stage cIIIB NSCLC to radical minimally invasive surgery through immunochemotherapy; with particular attention given to surgical outcomes and survival benefit of surgery. METHODS: Fifty-one patients with initial stage cIIIB NSCLC who received PD-1 agents plus platinum-based chemotherapy between May, 2018 to August, 2020 were retrospectively identified. Surgical and oncological outcomes of enrolled patients were collected. RESULTS: Of 31 patients who underwent subsequent resection, 23 (74.2%) patients underwent lobectomy, 1 (3.2%) underwent pneumonectomy, 5 (16.1%) underwent sleeve lobectomy, and 2 (6.5%) with bilobectomy. The median surgical time was 205 minutes (range, 100-520). The average blood loss was 185 (range: 10-1100) ml. Dense adhesions or fibrosis was noted in 15 cases. The median postoperative hospital stay was 6 (range: 3-13) days. No surgical-related mortality was recorded, only 5 patients (16.1%) experienced any postoperative morbidity (no grade 3 complications). Ten patients (32.3%) had major pathological response, with mediastinal down-staging been observed in 22/31 (71.0%) patients. With a median after up of 15.4 months, thirty-one patients that had surgery had relatively longer median DFS/PFS compared to that of either non-responders or responders that without surgery (27.5 vs. 4.7 vs. 16.7 months, respectively). CONCLUSIONS: Radical surgery after chemoimmunotherapy in initial unresectable stage IIIB NSCLC seems to be safe with low surgical-related mortality and morbidity, and was favorably associated with longer DFS/PFS compared to those without surgery.

Electromagnetic Navigation Bronchoscopy Triple Contrast Dye Marking for Lung Nodule Localization.

Small pulmonary lesions can be difficult to localize during video-assisted thoracoscopic surgery. Electromagnetic navigation bronchoscopy (ENB) dye marking of the lesion, particularly when guided by cone beam computed tomography in the hybrid operating room (HOR), is an emerging approach. However, issues with confirmation of dye injection and intraoperative visualization of the colored dye can be unpredictable and challenging. To address these uncertainties, we present our technique of ENB dye marking localization of lung nodule using the triple-contrast dye method in the HOR.

Mutation Profile of Resected EGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing.

BACKGROUND: The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed. RESULTS: Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. CONCLUSION: Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. IMPLICATIONS FOR PRACTICE: The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

A Nomogram for Predicting Cancer-Specific Survival of TNM 8th Edition Stage I Non-small-cell Lung Cancer.

BACKGROUND: Models for predicting the survival outcomes of stage I non-small-cell lung cancer (NSCLC) defined by the newly released 8th edition TNM staging system are scarce. This study aimed to develop a nomogram for predicting the cancer-specific survival (CSS) of these patients and identifying individuals with a higher risk for CSS. METHODS: A total of 30,475 NSCLC cases were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified and integrated the risk factors to build a nomogram. The model was subjected to bootstrap internal validation with the SEER database, and external validation with a multicenter cohort of 1133 patients from China. The difference in the impact of adjuvant chemotherapy on model-defined high- and low-risk patients was examined using the National Cancer Database (NCDB). RESULTS: Eight independent prognostic factors were identified and integrated into the model. The calibration curves showed good agreement. The concordance index (C-index) of the nomogram was higher than that of the staging system (IA1, IA2, IA3, and IB) (internal validation set 0.63 vs. 0.56; external validation set 0.66 vs. 0.55; both p < 0.01). Specifically, 21.7% of stage IB patients (7.5% of all stage I) were categorized into the high-risk group (score > 30). There was a significant interaction effect between the adjuvant chemotherapy and risk groups in the NCDB cohort (p = 0.003). CONCLUSIONS: We established a practical nomogram to predict CSS for 8th edition stage I NSCLC. A prospective study is warranted to determine its role in identifying adjuvant chemotherapy candidates.

Assessment of programmed cell death ligand-1 expression by 4 diagnostic assays and its clinicopathological correlation in a large cohort of surgical resected non-small cell lung carcinoma.

Immune checkpoint blockade targeting the PD-1/PD-L1 axis has recently demonstrated efficacy and promise in cancer treatment. Appropriate biomarker selection is therefore essential for improving treatment efficacy. However, the establishment of PD-L1 assay in pathology laboratories is complicated by the presence of multiple testing platforms using different scoring systems. Here we assessed the PD-L1 expression in 713 consecutive non-small cell lung carcinomas by four commercially available PD-L1 immunohistochemical assays, namely, 22C3, 28-8, SP142 and SP263. The analytical performances of the four assays and diagnostic performances across clinically relevant cutoffs were evaluated. The prevalence of PD-L1 (22C3) expression was 21% with a ≥50% cutoff and 56% with a ≥1% cutoff. High PD-L1 expression (using a ≥50% cutoff) was significantly associated with male sex (P = 0.001), ever smoking history (P < 0.001), squamous cell carcinoma (P = 0.001), large cell carcinoma (P < 0.001), lymphoepithelioma-like carcinoma (P = 0.006), sarcomatoid carcinoma (P < 0.001), mutant KRAS (P = 0.005) and wild-type EGFR (P = 0.003). Elevated PD-L1 expression was also significantly associated with shorter survival in patients with adenocarcinoma (log-rank P = 0.026) and remained an independent prognostic factor by multivariable analysis. Among the four assays, 22C3, 28-8 and SP263 were highly concordant for tumor cell scoring. With a cutoff of ≥50% (i.e., the threshold for first-line patient selection), inter-rater agreement was high among the three assays with percentage agreement >97%. In conclusion, three PD-L1 assays showed good analytical performance and a high agreement with each other, but not all cases were correctly classified using the same clinical cutoff. Further studies comparing the predictive value of these assays are required to address the interchangeability of these assays for clinical use.

FOXP3 promotes tumor growth and metastasis by activating Wnt/ß-catenin signaling pathway and EMT in non-small cell lung cancer.

BACKGROUND: The role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC). METHODS: One hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results. RESULTS: NSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial-mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/ß-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with ß-catenin and TCF4 to enhance the functions of ß-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction. CONCLUSIONS: FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.

Single-Port Video-Assisted Thoracoscopic Major Lung Resections: Experience with 150 Consecutive Cases.

Background Video-assisted thoracic surgery (VATS) for major lung resection has undergone major changes from three or four-port approach to the recently possible single-port VATS approach. Outcomes following single-port VATS major lung resection are analyzed to determine safety and efficacy. Methods A prospective database of 150 consecutive patients who underwent single-port VATS major lung resection between March 2012 and January 2014 was reviewed. Patient demographics, perioperative parameters, histopathology, and outcomes up to follow-up of 2 years were analyzed by descriptive and Kaplan-Meier survival statistics. Results Single-port VATS major lung resection was successfully performed in 142 patients (conversion rate 5.3%) for both malignant and benign diseases of the lung. Overall, 130 patients (87%) had nonsmall-cell lung carcinoma (NSCLC), 9 (6%) had other types of primary lung cancer, and the remaining for secondary malignancies and benign diseases. Among the 130 patients with NSCLC, 93 (71.5%) were stage I, 28 were stage II (21.5%), and 9 (7%) were stage III or greater. There was no intraoperative or 30-day mortality. However, one perioperative death occurred on day 49, and another on day 60 postoperatively due to infective causes. The overall 2-year mortality rate for all patients was 3%. The disease-free survival rate for subgroups, stage I NSCLC, and stage II or greater NSCLC were 96 and 83%, respectively. Conclusions Single-port VATS major lung resection for malignant and benign lung diseases is associated with low perioperative morbidity and mortality. Disease-free survival rates for NSCLC are acceptable and comparable with conventional VATS.

Antineoplastic effects of 15(S)-hydroxyeicosatetraenoic acid and 13-S-hydroxyoctadecadienoic acid in non-small cell lung cancer.

BACKGROUND: Previous studies have shown that the levels of 15-lipoxygenase 1 (15-LOX-1) and 15-LOX-2 as well as their metabolites 13-S-hydroxyoctadecadienoic acid (13(S)-HODE) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) are significantly reduced in smokers with non-small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen-induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC. METHODS: NSCLC cells were treated with exogenous 13(S)-HODE and 15(S)-HETE, and then the ways in which they affected cell function were examined. 15-LOX-1 and 15-LOX-2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)-HODE and 15(S)-HETE before cell function was assessed. RESULTS: The application of exogenous 13(S)-HODE and 15(S)-HETE significantly enhanced the activity of peroxisome proliferator-activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15-LOX-1 and 15-LOX-2 obviously promoted the endogenous levels of 13(S)-HODE and 15(S)-HETE, which were demonstrated to be more effective in the inhibition of NSCLC. CONCLUSIONS: This study has demonstrated that exogenous or endogenous 13(S)-HODE and 15(S)-HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15-LOX activity to increase the production of endogenous 15(S)-HETE and 13(S)-HODE may offer a novel research direction for molecular targeting treatment of smoking-related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands.

The traditional vs "1:1:1" approach debate on massive transfusion in trauma should not be treated as a dichotomy.

Traditional transfusion guidelines suggest that fresh frozen plasma (FFP) should be given based on laboratory or clinical evidence of coagulopathy or acute loss of 1 blood volume. This approach tends to result in a significant lag time between the first units of erythrocytes and FFP in trauma requiring massive transfusion. In severe trauma, observational studies have found an association between increased survival and aggressive use of FFP and platelets such that FFP:platelet:erythrocyte ratio approaches 1:1:1 to 2 from the first units of erythrocytes given. There are considerable concerns over either approach, and no randomized controlled trials have been published comparing the 2 approaches. Nowadays, trauma clinicans are incorporating the strenghts of both approaches and are no longer treating them as a dichotomy. Specifically, "1:1:1" proponents have devised 1:1:1 activation criteria to minimize unnecessary FFP and platelet transfusion and are prepared to deactivate the protocol as soon as patient is stabilized. Similarly, 1:1:1 skeptics are more mindful of the need to be proactive about trauma coagulopathy and the inherent delays in FFP administration in trauma patients.

Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis.

Peritoneal carcinomatosis (PC) represents a significant clinical challenge for which there are few treatment options. Oncolytic viruses are ideal candidates for PC treatment because of their high tumor specificity, excellent safety profile and suitability for peritoneal delivery. Here, we described the use of vvDD-SR-RFP, a recombinant vaccinia virus, in xenograft and syngeneic models of colorectal PC. Colorectal cancer cell lines were highly susceptible to vvDD-SR-RFP replication and cytotoxicity. Intraperitoneal delivery of vvDD-SR-RFP on Day 12 to mice with colorectal carcinomatosis significantly improved survival whereas survival was not improved following virus treatment on Day 8, when tumors were smaller. Immunohistochemistry revealed early tumors had a poorly distributed network of blood vessels and lower proliferation index compared to later tumors. Virus infection was also restricted to tumor rims following Day 8 treatment, whereas it was disseminated in tumors treated on Day 12. Additionally, direct infection of tumor endothelium was observed and virus infection correlated with a loss of endothelial staining and induction of cell death. Our results demonstrate that tumor vasculature has a critical role in virus delivery and tumor response. This will have significant implications in the clinical setting, both in understanding timing of therapies and in designing combination treatment strategies.

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

BACKGROUND: 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. METHODS: The prospective, single-arm, 2-center NAVABLATE study (NCT03569111) evaluated transbronchial MWA in patients with histologically confirmed lung malignancies ≤30 mm 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). RESULTS: 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 12.5 mm (range 5 to 27 mm). Procedure-day technical success was 100% (30/30), with a mean ablative margin of 9.9±2.7 mm. 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. CONCLUSION: Transbronchial microwave ablation is an alternative treatment modality for malignant lung nodules ≤30 mm. There were no deaths or pneumothorax. In all, 13.3% of patients developed grade 3 or above complications.

Safety and feasibility of transbronchial microwave ablation for subpleural lung nodules.

BACKGROUND: Transbronchial microwave ablation in treating lung nodules is gaining popularity. However, microwave ablation in subpleural lung nodules raised concerns about pleural-based complications due to the proximity between the pleura and the ablation zone. METHODS: Patients who underwent transbronchial microwave ablation between March 2019 and November 2022 were included in this analysis. The lung nodules were categorized into the subpleural group-less than 5 mm distance to the nearest pleural surface; the deep nodule group-larger or equal to 5 mm distance to the nearest pleural surface. A review of the safety profile of subpleural lung nodule ablation was conducted. RESULTS: Eighty-two lung nodules (n = 82) from 77 patients were treated. The mean nodule size was 14.2 ± 5.50 mm. The technical success rate was 100%. The mean procedural time was 133 min. No statistically significant differences were detected in the complication rate and the length of stay between the subpleural and deep nodule groups. Complications occured in 21 nodules (25.6%). No minor pneumothorax was reported. Total five cases of pneumothorax required drainage were observed (6.06% in subpleural nodules [n = 2] vs. 6.12% in deep nodules [n = 3], p = 0.991). Total seven cases of pleuritic chest pain were observed (12.1% in subpleural nodules [n = 4] vs. 6.12% in deep nodules [n = 3], p = 0.340). CONCLUSIONS: This single-center retrospective analysis found no significant difference in the safety outcomes between subpleural and nonsubpleural lung nodule ablation. The overall rate of complications was low in the cohort. This demonstrated that transbronchial microwave was feasible and safe for most lung nodules.

Neuroendocrine Lesions Arising From Mediastinal Teratoma-A Case Report and Literature Review.

Background. Neuroendocrine lesions arising from mediastinal teratomas are rare tumors with only small number of patients reported in literature. The behavior of these lesions appears to be different from traditional neuroendocrine neoplasms. A comprehensive review will be valuable for histologic assessment and treatment planning for similar cases. Case presentation. We present an example of a 57-year-old man who presented with cough. Subsequent work-up revealed an anterior mediastinal mass of 2.1 cm on computed tomography. The patient underwent robot-assisted thoracoscopic thymectomy. Histological examination revealed a mature cystic teratoma with a neuroendocrine component consisting of clusters of tumor cells with round to oval nuclei and a "salt-and-pepper" chromatin pattern. The tumor cells were immunoreactive to cytokeratin, synaptophysin, chromogranin, and INSM1, with a Ki-67 proliferative index of 4%. A histological diagnosis was mature teratoma with well-differentiated low-grade neuroendocrine tumor (carcinoid) was made. The patient was well and without disease after complete surgical excision at 10 months. Literature review. Literature reviewed yielded 13 examples of neuroendocrine lesions arising from mediastinal teratomas. No disease-related mortality was reported, even in lesions with high-grade neuroendocrine, carcinomatous, or immature teratomatous components. Conclusions. Surgical removal is the mainstay of treatment of these lesions, and the presence of a neuroendocrine component does not appear to negatively affect prognosis.

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage-Myofibroblast Transition in Non-Small-Cell Lung Carcinoma.

Macrophage-myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro-tumoral cancer-associated fibroblasts (CAFs) in non-small cell lung carcinoma (NSCLC) in a TGF-ß1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor-associated macrophage at single-cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT-specific TGF-ß1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT-derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage-specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage-specific genetic deletion and systemic pharmacological inhibition of TGF-ß1/Smad3/Runx1 signaling effectively prevent MMT-driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.

SMARCA4 deficiency and mutations are frequent in large cell lung carcinoma and are prognostically significant.

SMARCA4 mutation has emerged as a marker of poor prognosis in lung cancer and has potential predictive value in cancer treatment, but recommendations for which patients require its investigation are lacking. We comprehensively studied SMARCA4 alterations and the clinicopathological significance in a large cohort of immunohistochemically-subtyped non-small cell lung cancer (NSCLC). A total of 1416 patients was studied for the presence of SMARCA4 deficiency by immunohistochemistry (IHC). Thereafter, comprehensive sequencing of tumours was performed for 397 of these patients to study the mutational spectrum of SWI/SNF and SMARCA4 aberrations. IHC evidence of SMARCA4 deficiency was found in 2.9% of NSCLC. Of the sequenced tumours, 38.3% showed aberration in SWI/SNF complex, and 9.3% had SMARCA4 mutations. Strikingly, SMARCA4 aberrations were much more prevalent in large cell carcinoma (LCC) than other histological tumour subtypes. SMARCA4-deficient and SMARCA4-mutated tumours accounted for 40.5% and 51.4% of all LCC, respectively. Multivariable analyses confirmed SMARCA4 mutation was an independent prognostic factor in lung cancer. The immunophenotype of a subset of these tumours frequently showed TTF1 negativity and HepPAR1 positivity. SMARCA4 mutation or its deficiency was associated with positive smoking history and poor prognosis. It also demonstrated mutual exclusion with EGFR mutation. Taken together, the high incidence of SMARCA4 aberrations in LCC may indicate its diagnostic and prognostic value. Our study established the necessity of SMARCA4 IHC in the identification of SMARCA4-aberrant tumours, and this may be of particular importance in LCC and tumours without known driver events.

Review on endobronchial therapies-current status and future.

There is a growing demand for lung parenchymal-sparing localized therapies due to the rising incidence of multifocal lung cancers and the growing number of patients who cannot undergo surgery. Lung cancer screening has led to the discovery of more pre-malignant or early-stage lung cancers, and the focus has shifted from treatment to prevention. Transbronchial therapy is an important tool in the local treatment of lung cancers, with microwave ablation showing promise based on early and mid-term results. To improve the precision and efficiency of transbronchial ablation, adjuncts such as mobile C-arm platforms, software to correct for computed tomography (CT)-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy are useful. Other forms of energy such as steam vapor therapy, pulsed electric field, and photodynamic therapy are being intensively investigated. In addition, the future of transbronchial therapies may involve the intratumoral injection of novel agents such as immunomodulating agents, gene therapies, and chimeric antigen receptor T cells. Extensive pre-clinical and some clinical research has shown the synergistic abscopal effect of combination of these agents with ablation. This article aims to provide the latest updates on these technologies and explore their most likely future applications.

Protocol to study immunodynamics in the tumor microenvironment using a tyramide signal amplification-based immunofluorescent multiplex panel.

Immunodynamics in the tumor microenvironment can be precisely examined by using multiple antigen identification approaches. Here, we present a protocol for capturing expression levels of multiple target proteins in the same specimen at single-cell resolution using a tyramide signal amplification-based immunofluorescent multiplexing system. We describe steps for tumor tissue microarray preparation, multiplex immunohistochemistry staining, image acquisition, and quantification. This protocol can quantify immune cells in tissues from patients or experimental disease models at a protein level. For complete details on the use and execution of this protocol, please refer to Chung et al. (2023),1 Tang et al. (2022),2 and Tang et al. (2022).3.

Impact of lymphadenectomy extent on immunotherapy efficacy in postresectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study.

BACKGROUND: Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel 'immunotherapy-driven' LN dissection strategy. MATERIALS AND METHODS: The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification. RESULTS: A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7-13); 66 had a DLN count greater than 16 (median, IQR: 23, 19-29). With a median follow-up time of 14.3 months (95% CI: 11.0-17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1-11.7) months, 11.7 (95% CI: 7.9-15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1-6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07-0.89), P =0.03]; [validation cohort: HR=0.46 (95% CI: 0.22-0.96), P =0.04]; [entire cohort: HR=0.53 (95% CI: 0.32-0.89), P =0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065-0.845, P =0.027). CONCLUSIONS: An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.