Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.

BACKGROUND: Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells. METHODS: We investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model. RESULTS: High expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells. CONCLUSIONS: Our findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.

Rational application of EGFR-TKI adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant NSCLC: a systematic review and meta-analysis of 11 randomized controlled trials.

PURPOSE: To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC). METHOD: Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30-0.63, P < 0.001) and 2- and 3-year DFS rates, but also improve OS (HR 0.72, 95% CI, 0.54-0.96, P = 0.024), compared with chemotherapy or the placebo. Further subgroup analyses indicated prolonged OS from first-generation EGFR-TKI adjuvant therapy in stage III patients, compared with chemotherapy or the placebo (HR for OS, 0.34; 95% CI, 0.18-0.63; P = 0.001). Of note, osimertinib adjuvant therapy led to the OS benefit expanding from stage III to stage II-III patients, with significantly improved DFS and a lower risk of brain recurrence, compared with the placebo. A 2-year treatment duration with EGFR-TKI adjuvant therapy showed a significantly lower recurrence risk than a ≤ 1-year duration. CONCLUSION: The DFS advantage from first-generation EGFR-TKI adjuvant therapy can translate into an OS benefit in stage III NSCLC patients. Osimertinib might be more suitable for adjuvant therapy than first-generation EGFR-TKIs, because of the lower recurrence rate and the potential OS benefit even in early-stage patients. The optimal treatment duration for EGFR-TKIs at different stages of disease needs to be validated.

Short-term outcomes and safety of radiotherapy for immediate breast reconstruction with autologous flap transfer following breast-conserving surgery.

BACKGROUND: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer. METHOD: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. RESULTS: In total, 84 breast cancer patients were enrolled, with 32 patients in the RT group and 52 in the non-RT group. At a median follow-up time of 33.3 months, no significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P = 1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P < 0.001). No significant difference in the reduction of flap size was observed at any timepoint between the two groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P > 0.05). Additionally, no grade 3 or greater RT-associated adverse events occurred during or after RT. CONCLUSION: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.

Clinical option of pemetrexed-based versus paclitaxel-based first-line chemotherapeutic regimens in combination with bevacizumab for advanced non-squamous non-small-cell lung cancer and optimal maintenance therapy: evidence from a meta-analysis of randomized control trials.

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.

Meta-analysis Exploring the Effectiveness of S-1-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer.

S-1 is a new oral fluoropyrimidine formulation that comprises tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate. S-1 is designed to enhance antitumor activity and to reduce gastrointestinal toxicity. Several studies have demonstrated that both S-1 monotherapy and S-1 combination regimens showed encouraging efficacies and mild toxicities in the treatment of lung squamous cell carcinoma and adenocarcinoma. However, it is unclear whether S-1 can be used as standard care in advanced non-small cell lung cancer (NSCLC). The purpose of this meta-analysis was to assess the efficacy and safety of S-1-based chemotherapy, compared with standard chemotherapy, in patients with locally advanced or metastatic NSCLC. Thirteen randomized controlled trials (RCTs) involving 2,134 patients with a similar ratio of different pathological types were included. In first-line or second-line chemotherapy, compared with standard chemotherapy, S-1-based chemotherapy showed similar efficacy in terms of median overall survival (mOS), median progression free survival (mPFS), and objective response rate (ORR) (all P > 0.1), and significantly reduced the incidence of grade ≥ 3 hematological toxicities. In patients with locally advanced NSCLC receiving concurrent chemoradiotherapy, compared with standard chemoradiotherapy, significantly improved survival in the S-1-based chemotherapy was noted in terms of mOS and mPFS (risk radio [RR] = 1.289, P = 0.009; RR = 1.289, P = 0.000, respectively) with lower incidence of grade ≥ 3 neutropenia (RR = 0.453, P = 0.000). The present meta-analysis demonstrates that S-1-based chemotherapy shows similar benefits in advanced NSCLC and improves survival in locally advanced NSCLC, compared with standard treatment.

Meta-analysis comparing higher and lower dose radiotherapy for palliation in locally advanced lung cancer.

The purpose of this meta-analysis was to compare higher dose (≥30 Gy) and lower dose (<30 Gy) radiotherapy (RT) on palliation of symptoms and survival in patients with locally advanced lung cancer. A search of PubMed and Google Scholar was conducted on 10 June 2013 using combinations of the search terms: radiotherapy, non-small-cell lung carcinoma, palliative, supportive, symptom relief. Inclusion criteria were: (i) palliative thoracic RT; (ii) randomized controlled trial; (iii) English language; and (iv) compared outcomes between higher dose (≥30 Gy) and lower dose (<30 Gy) RT. The primary outcome was palliation of symptoms (cough, chest pain, hemoptysis), and 1- and 2-year overall survival. Tests of heterogeneity, sensitivity, and publication bias were performed. Five randomized controlled trials with a total of 1730 patients with lung cancer were included in the meta-analysis. There were 925 patients treated with a higher RT dose (≥30 Gy) and 805 treated with a lower RT dose (<30 Gy). The combined odds ratios (ORs) indicated no significant difference in palliation of cough, chest pain, and hemoptysis between the higher dose and lower dose RT groups (combined ORs = 0.88, 1.83, 1.39, respectively). The 1- and 2-year OS rates were similar between the high and low dose RT groups (combined ORs = 1.09 and 1.38, respectively). This meta-analysis indicates that high dose (≥30 Gy) and lower dose (<30 Gy) RT provide similar symptom palliation and 1- and 2-year OS in patients with locally advanced lung cancer.

The influence of mtDNA deletion on lung cancer cells under the conditions of hypoxia and irradiation.

PURPOSE: This study was to evaluate the influence of mtDNA deletion on the lung cancer cells under the conditions of hypoxia or irradiation. METHOD: The treatment conditions of lung cancer cell lines with (A549) and without mtDNA (ρ0A549: obtained by inducing from A549) included 2 h of hypoxia and 4 Gy irradiation (group 1: without treatment; group 2: 2 h of hypoxia; group 3: 4 Gy irradiation; group 4: 2 h of hypoxia plus 4 Gy irradiation). The Human OneArray™ microarray was used to hybridize with the Cy5-labeled aRNA in microarray sample preparation. Differentially expressed genes (DEGs) between the lung cancer cells with and without mtDNA were identified using NOISeq package in R. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using the online tool of DAVID. RESULT: In the KEGG pathway analysis of down-regulated DEGs, nineteen pathways were simultaneously enriched in the four groups, which were mainly metabolism- and biosynthesis-related pathways. Nine lung cancer-related pathways were enriched in group 4, and more cancer-associated DEGs, such as MYC, MAX, and E2F1 were found in group 4 than in the other groups. CONCLUSION: The mtDNA deletion could inhibit the biosynthesis and metabolism of lung cancer cells and promote the effect of hypoxia and radiation on lung cancer cells. MYC might be the key gene of the cooperation of hypoxia and radiation and MYC, MAX, and E2F1 might play roles in hypoxia- and radiation-induced cell death in lung cancer cells without mtDNA.

Expert consensus on the use of third-generation EGFR-TKIs in EGFR-mutated advanced non-small cell lung cancer with various T790M mutations post-resistance to first-/second-generation EGFR-TKIs.

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have emerged as the mainstay of treatment for advanced EGFR-mutant advanced non-small cell lung cancer (NSCLC), effectively overcoming the problems of acquired threonine-to-methionine (T790M) mutations associated with the first- or second-generation TKIs. Evidence from several studies suggests that these agents, including osimertinib and aumolertinib, also show potential benefits in T790M-negative or unknown populations, particularly those with brain metastases, where the high permeability of the blood-brain barrier allows effective control of intracranial lesions. Despite the encouraging results, further high-quality research, including prospective trials, is warranted to fully elucidate the efficacy profiles of these third-generation TKIs in T790M-negative or unknown NSCLC patients after first- or second-line TKI failure. The present expert consensus highlights the evolving role of third-generation EGFR-TKIs in overcoming therapeutic resistance and optimizing patient outcomes.

Experts agree on treating lung cancer with specific gene changes using advanced medicines Newer medicines called third-generation EGFR inhibitors have become key treatments for a type of advanced lung cancer that has specific genetic changes. These drugs, such as osimertinib and aumolertinib, solve a problem encountered with older drugs: resistance caused by a mutation known as T790M. They're especially promising for patients whose cancer has spread to the brain, because they can pass through the brain's protective barrier and help control tumors there. While current evidence suggests these new drugs can help even when the T790M mutation isn't present or hasn't been tested for, more research is needed to fully understand how well they work in these situations. After other treatments have stopped being effective, using these advanced medicines may offer new hope by tackling treatment resistance and improving patients' chances. This expert agreement outlines how these newer drugs are changing the way we overcome therapy challenges and enhance patient care.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433-0.973) and 0.682 (95% CI: 0.464-0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511-1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14-3.4) and PFS 2.13 (95% CI: 1.28-3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Impact of Drp1-regulated changes in T cell activity on the combined antitumor effects of PARPi and PD-1 inhibitors.

This study aimed to investigate the influence of dynamin-related protein 1 (Drp1)-regulated T cells on the antitumor effects of poly (ADP-ribose) polymerase inhibitors (PARPi) combined with programmed cell death protein 1 (PD-1) inhibitors to identify potential targets for enhancing immunotherapy efficacy. We found that T cells with high expression of Drp1 promoted the inhibitory and killing effects of the PARPi and PD-1 inhibitor combination on lung cancer cells in vivo and in vitro. This synergistic mechanism involves Drp1-regulated promotion of activation, migration, and intratumor infiltration of effector T cells; inhibition of negative immunomodulatory cells in the tumor microenvironment; and suppression of PARPi-induced upregulation of PD-L1 expression in tumor cells. These findings suggest that Drp1 could serve as a new target for comprehensively improving the tumor microenvironment, enhancing immunotherapy efficacy, and reversing immunotherapy resistance.

The Optimal First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer Based on Liver Metastasis Status: A Network Meta-Analysis and Systematic Review.

PURPOSE: To compare the efficacy of first-line regimens based on programmed cell death (or ligand) [PD-(L)1] blockade in extensive-stage small-cell lung cancer (ES-SCLC) patients with or without liver metastases (LM), and to identify optimal treatment strategies. METHODS: Network meta-analysis of randomized controlled trials (RCTs) comparing chemo-immunotherapy (CIT) and chemotherapy (CT) in ES-SCLC patients stratified by LM. Overall survival (OS) and progression-free survival (PFS) were evaluated using hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Seven RCTs involving 3658 ES-SCLC patients (1243 with LM, 2415 without LM) were analyzed. For patients with LM, the combination therapies of anti-PD-1 + CT (HR, 0.67; 95% CI, 0.54%-0.82%; p < 0.001) and anti-PD-L1 + CT + anti-angiogenesis (HR, 0.84; 95% CI, 0.71%-0.99%; p = 0.042) demonstrated superior efficacy in prolonging OS compared to CT alone. The anti-PD-1 + CT regimen had the highest cumulative probability of 91.6% for extending OS in patients with LM. For patients without LM, all CIT regimens resulted in improved OS compared to CT alone, with the regimen of anti-angiogenesis + anti-PD-L1 + CT ranking first and having the highest cumulative probability of 95.5% for prolonging OS. CONCLUSIONS: CIT is effective for ES-SCLC patients regardless of LM status. For patients with LM, PD-1 blockade combined with CT is the best option. For patients without LM, the most beneficial regimen is the combination of anti-angiogenesis, PD-L1 blockade, and CT.

Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial.

This single-arm, multicenter, phase 2 trial (NCT04106180) investigated the triple combination of sintilimab (anti-PD1 antibody), stereotactic body radiotherapy (SBRT) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic non-small cell lung cancer (NSCLC). With a median follow-up of 32.1 months, 18 (36.7%, 90% CI 25.3%-49.5%) of the 49 evaluable patients had an objective response, meeting the primary endpoint. Secondary endpoints included out-of-field (abscopal) response rate (ASR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). The ASR was 30.6% (95% CI 18.3%-45.4%). The median PFS and OS were 5.9 (95% CI 2.5-9.3) and 18.4 (95% CI 9.7-27.1) months, respectively. Any grade and grade 3 TRAEs occurred in 44 (86.3%) and 6 (11.8%) patients, without grade 4-5 TRAEs. Moreover, in pre-specified biomarker analyses, SBRT-induced increase of follicular helper T cells (Tfh) in unirradiated tumor lesions and patient's blood, as well as of circulating IL-21 levels, was found associated with improved prognosis. Taken together, the triple combination therapy was well tolerated with promising efficacy and Tfh may play a critical role in SBRT-triggered anti-tumor immunity in metastatic NSCLC.

Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to investigate the clinical benefit and necessity of neoadjuvant programmed cell death (or ligand) (PD-(L)1) blockades in resectable non-small cell lung cancer (NSCLC) patients with negative PD-L1 expression. MATERIALS AND METHODS: Randomized control trials (RCTs) that compared event-free survival (EFS), overall survival (OS), major pathological response (MPR), and/or pathological complete response (pCR) between neoadjuvant chemo-immunotherapy (nCIT) and neoadjuvant chemotherapy (nCT) for patients with resectable NSCLC stratified by PD-L1 expression were eligible for inclusion in the study. Data regarding the pathological response and EFS were evaluated by the odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) using random and fixed models. RESULTS: A total of six RCTs involving 3,194 patients with resectable NSCLC with or without neoadjuvant immunotherapy were included. Compared with nCT alone, nCIT significantly improved pCR (18.3 % vs. 3.0 %; OR, 5.64; 95 % CI, 3.22-9.89; P < 0.001), MPR (38.9 % vs. 15.5 %; OR, 3.57; 95 % CI, 2.10-6.05; P < 0.001), and EFS (HR, 0.75; 95 % CI, 0.62-0.90; P = 0.002) in PD-L1 <1 % NSCLC patients. In addition, PD-L1 ≥1 % was associated with higher rates of pCR (32.8 % vs. 18.3 %; OR, 2.28; 95 % CI, 1.40-3.73; P = 0.001) and MPR (53.9 % vs. 38.9 %; OR, 1.84; 95 % CI, 1.22-2.79; P = 004) and longer EFS (HR, 0.44 vs. 0.75) in the setting of nCIT compared with PD-L1 <1 %. nCIT improved only OS in NSCLC patients with PD-L1 ≥1 % but not in patients with PD-L1 <1 %. CONCLUSIONS: The use of nCIT should be recommended for resectable NSCLC patients with negative PD-L1 expression, as nCIT significantly improved the pathological response and EFS in these patients. The benefit to PD-L1-negative patients treated with nCIT on OS remains to be validated.

Pretreatment pulmonary tumor necrosis is a promising prognostic imaging biomarker for first-line anti-PD-1/PD-L1 therapy in advanced lung squamous cell carcinoma: a multi-institutional, propensity score-matching cohort analysis.

Background: Tumor necrosis (TN) is a common feature in lung squamous cell carcinoma (LSCC), which could provide useful predictive and prognostic information. Objectives: This study aimed to investigate the effect of pretreatment pulmonary TN (PTN) on the prognosis of first-line anti-programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitor in advanced LSCC. Design: We conducted a retrospective study to analyze the association between the presence of PTN and clinical outcomes in advanced LSCC patients treated with anti-PD-1/PD-L1 inhibitors. Methods: Data from 240 eligible patients were collected from 27 hospitals across China between 2016 and 2020. The presence of PTN was assessed using contrast-enhanced chest computed tomography (CT) imaging at baseline. We utilized the Cox proportional-hazards regression model to analyze the association between PTN and clinical outcomes. In addition, to account for potential confounding factors and ensure comparability between groups, we employed propensity score-matching (PSM) analysis. Results: In the overall patient cohort, the presence of PTN was 39.6%. The median follow-up duration was 20.3 months. The positive PTN group exhibited a notably inferior median progression-free survival (PFS; 6.5 months vs 8.6 months, p = 0.012) compared to the negative PTN group. Within the Cox proportional-hazards regression model, PTN emerged as an independent predictor of unfavorable PFS (hazard ratio (HR) = 1.354, 95% confidence interval (CI): 1.002-1.830, p = 0.049). After PSM, the median PFS for the positive PTN group (6.5 months vs 8.0 months, p = 0.027) remained worse than that of the negative PTN group. Multivariate analyses also further underscored that the presence of PTN independently posed a risk for shorter PFS (HR = 1.494, 95% CI: 1.056-2.112, p = 0.023). However, no statistically significant difference in overall survival was observed between the two groups. Conclusion: Our study suggests that the presence of PTN on baseline contrast-enhanced chest CT is a potential negative prognostic imaging biomarker for the outcome of anti-PD-1/PD-L1 inhibitor therapy in advanced LSCC. Further studies are warranted to validate these findings and explore the underlying mechanisms.

Predicting anti-PD-1/PD-L1 inhibitor treatment outcomes: pulmonary tumor necrosis in lung squamous cell carcinoma Our study focused on lung squamous cell carcinoma (LSCC) patients receiving first-line anti-PD-1/PD-L1 therapy. We explored the impact of a feature called pretreatment pulmonary tumor necrosis (PTN) on their prognosis. PTN was identified in 39.6% of patients using baseline chest CT scans. Results revealed that patients with PTN had a shorter time without disease progression (median PFS of 6.5 months compared to 8.6 months) and a higher risk of unfavorable outcomes. This suggests that PTN may serve as a negative prognostic imaging marker for anti-PD-1/PD-L1 therapy in advanced LSCC. Further research is needed to confirm and understand these findings better.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Clinical definition of secondary resistance to immunotherapy in non-small cell lung cancer.

Immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 blockade) have revolutionized the treatment landscape in non-small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO-IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Concordant KRAS mutations in primary and metastatic colorectal cancer tissue specimens: a meta-analysis and systematic review.

A meta-analysis was performed to compare KRAS gene mutations in colorectal cancer tissue samples with primary and metastatic colorectal cancers. A total of 19 publications with 986 paired primary and distant metastases and 171 paired primary and lymph node metastases showed that KRAS genotype was highly concordant in primary and distant metastatic tumors, indicating that either type of tumor tissue could be useful as a source to detect KRAS mutations for selection of anti-EGFR therapy. However, lymph-node-metastatic tumors might not be suitable for diagnostic analysis of KRAS mutations due to an obvious discordant rate between primary and lymph-node-metastatic tumors.

Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer.

OBJECTIVE: Exon 19 deletion (19del) is a sensitive mutation of epidermal growth factor receptor (EGFR) observed in non-small cell lung cancer (NSCLC), and consists of a large number of variants. It remains unclear whether 19del subtype impacts clinical outcomes following EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: We systematically searched web databases and identified eligible studies comparing the clinical outcomes of various EGFR 19del subtypes with EGFR-TKIs. The hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS),as well as the risk ratio (RR) for objective response rate and the frequency of acquired T790M mutation were used as study endpoints. RESULTS: A total of eleven retrospective studies and one prospective study involving 1,630 NSCLC patients with EGFR 19del were included in this meta-analysis. Most of studies were from Asia, and the 19del subtypes in these studies were grouped differently. Patients harboring deletions starting from E746 had significantly longer OS than those with deletions starting from L747 (HR, 0.79; 95% CI: 0.65 to 0.96, P = 0.019), and relatively but not significantly longer PFS (HR, 0.86; 95% CI: 0.69 to 1.06, P = 0.160). Patients with E746_A750del, the most common 19del subtype, had a significantly higher frequency of acquired T790M mutation when treated with first- or second-generation EGFR-TKIs compared to those with other 19del subtypes (RR, 0.76; 95% CI: 0.64-0.89, P = 0.001). There were no differences in PFS between the E746_A750del group and the uncommon group, or between the 15-nucleotide deletion group and other patients. CONCLUSION: This is the first meta-analysis to present survival outcomes and acquired T790M mutation frequency in the context of EGFR 19del subtype with EGFR-TKI therapy. Patients with a deletion starting from E746 show better OS than those with other subtypes, and patients with E746_A750del subtype have a higher frequency of acquired T790M mutation.

Impact of Drp1-Mediated Mitochondrial Dynamics on T Cell Immune Modulation.

In recent years, various breakthroughs have been made in tumor immunotherapy that have contributed to prolonging the survival of tumor patients. However, only a subset of patients respond to immunotherapy, which limits its use. One reason for this is that the tumor microenvironment (TME) hinders the migration and infiltration of T cells and affects their continuous functioning, resulting in an exhausted phenotype. Therefore, clarifying the mechanism by which T cells become exhausted is of significance for improving the efficacy of immunotherapy. Several recent studies have shown that mitochondrial dynamics play an important role in the immune surveillance function of T cells. Dynamin-related protein 1 (Drp1) is a key protein that mediates mitochondrial fission and maintains the mitochondrial dynamic network. Drp1 regulates various activities of T cells in vivo by mediating the activation of a series of pathways. In addition, abnormal mitochondrial dynamics were observed in exhausted T cells in the TME. As a potential target for immunotherapy, in this review, we describe in detail how Drp1 regulates various physiological functions of T cells and induces changes in mitochondrial dynamics in the TME, providing a theoretical basis for further research.