Emerging trends in the coexistence of primary lung Cancer and hematologic malignancy: a comprehensive analysis of clinicopathological features and genetic abnormalities.

BACKGROUND: The incidence of multiple primary cancers (MPC), especially involving primary lung cancer (PLC) and primary hematologic malignancies (PHM), is rising. This study aims to analyze clinicopathological features, gene abnormalities, and prognostic outcomes in individuals diagnosed with PLC-PHM MPC. METHODS: A retrospective analysis included 89 patients diagnosed with PLC-PHM MPC at the Respiratory or Hematology Departments of Ruijin Hospital from 2003 to 2022 (a total of 842,047 people). Next-generation sequencing (NGS) assessed lung cancer specimens, while Polymerase Chain Reaction (PCR) and NGS were used for hematologic malignancy specimens. Statistical analysis involved survival analysis and Cox regression. RESULTS: PLC-PHM MPC incidence surged from 1.67 per year (2011-2013) to 16.3 per year (2020-2022). The primary demographic for PLC-PHM MPC consists predominantly of elderly (average age 66 years) males (59.6%), with a high prevalence of metachronous MPC (89.9%). The prevailing histological types were lung adenocarcinoma (70.8%) in lung cancer (LC) and mature B-cell lymphomas (50.6%) in hematologic malignancies (HM). Notably, in a molecular testing cohort of 38 LC patients, 84.2% of lung cancer cases exhibited driver mutations, in which EGFR mutations frequence prevalent was 74.2%. In total group of 85 cases achieved a median overall survival (mOS) of 46.2 months, with a 5-year survival rate of 37.9% and advanced LC patients with LC gene mutations achieved a mOS was 52.6 months, with a 5-year OS rate of 30.6%. The median progression-free survival (PFS) following first-line treatment of 11 advanced patients with lung cancer-associated driver gene mutations is 26.6 months. Multivariate Cox regression revealed a favorable OS associated with surgery for LC, favorable PS score, adenocarcinoma pathology of LC, and the presence of genetic abnormalities associated with HM. CONCLUSION: PLC-PHM MPC incidence is rising, characterized by a significant proportion of lung adenocarcinoma and a high prevalence of positive driver genes, especially in EGFR. Despite suffering from two primary tumors, the PLC-PHM MPC patients had superior data of both PFS and OS, suggesting an inherently intricate background of genetic abnormalities between the two kinds of tumors.

International expert consensus on diagnosis and treatment of lung cancer complicated by chronic obstructive pulmonary disease.

Background: Lung cancer combined by chronic obstructive pulmonary disease (LC-COPD) is a common comorbidity and their interaction with each other poses significant clinical challenges. However, there is a lack of well-established consensus on the diagnosis and treatment of LC-COPD. Methods: A panel of experts, comprising specialists in oncology, respiratory medicine, radiology, interventional medicine, and thoracic surgery, was convened. The panel was presented with a comprehensive review of the current evidence pertaining to LC-COPD. After thorough discussions, the panel reached a consensus on 17 recommendations with over 70% agreement in voting to enhance the management of LC-COPD and optimize the care of these patients. Results: The 17 statements focused on pathogenic mechanisms (n=2), general strategies (n=4), and clinical application in COPD (n=2) and lung cancer (n=9) were developed and modified. These statements provide guidance on early screening and treatment selection of LC-COPD, the interplay of lung cancer and COPD on treatment, and considerations during treatment. This consensus also emphasizes patient-centered and personalized treatment in the management of LC-COPD. Conclusions: The consensus highlights the need for concurrent treatment for both lung cancer and COPD in LC-COPD patients, while being mindful of the mutual influence of the two conditions on treatment and monitoring for adverse reactions.

SDH mutations, as potential predictor of chemotherapy prognosis in small cell lung cancer patients.

PURPOSE: Small cell lung cancer (SCLC) is an aggressive and rapidly progressive malignant tumor characterized by a poor prognosis. Chemotherapy remains the primary treatment in clinical practice; however, reliable biomarkers for predicting chemotherapy outcomes are scarce. METHODS: In this study, 78 SCLC patients were stratified into "good" or "poor" prognosis cohorts based on their overall survival (OS) following surgery and chemotherapeutic treatment. Next-generation sequencing was employed to analyze the mutation status of 315 tumorigenesis-associated genes in tumor tissues obtained from the patients. The random forest (RF) method, validated by the support vector machine (SVM), was utilized to identify single nucleotide mutations (SNVs) with predictive power. To verify the prognosis effect of SNVs, samples from the cbioportal database were utilized. RESULTS: The SVM and RF methods confirmed that 20 genes positively contributed to prognosis prediction, displaying an area under the validation curve with a value of 0.89. In the corresponding OS analysis, all patients with SDH, STAT3 and PDCD1LG2 mutations were in the poor prognosis cohort (15/15, 100%). Analysis of public databases further confirms that SDH mutations are significantly associated with worse OS. CONCLUSION: Our results provide a potential stratification of chemotherapy prognosis in SCLC patients, and have certain guiding significance for subsequent precise targeted therapy.

The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC.

Chemotherapy for advanced non-small-cell lung cancer (NSCLC) remains the first treatment choice. Angiogenesis inhibitors are effective for lung cancer treatment. This study explored whether chemotherapy combined with angiogenesis inhibitors could achieve better efficacy in NSCLC. The zebrafish A549 xenograft model was used to investigate the combined effect of apatinib and chemotherapeutic agents in NSCLC. Apatinib combined with pemetrexed demonstrated the highest antitumor effect compared with apatinib combined with gemcitabine or paclitaxel in vitro. In the zebrafish A549 xenograft model, apatinib and pemetrexed, alone or in combination, showed significant inhibition of tumor growth. Co-treatment with apatinib and pemetrexed demonstrated the best antitumor effects, suggesting that the combination of apatinib and pemetrexed might be a promising alternative therapy for patients with lung cancer. Apatinib combined with pemetrexed had enhanced antitumor effects compared with either one alone in the zebrafish model of NSCLC.

Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial.

INTRODUCTION: In CameL phase 3 study (ClinicalTrials.gov: NCT03134872), addition of camrelizumab to first-line chemotherapy significantly improved the progression-free survival in patients with stages IIIB to IV nonsquamous NSCLC. Here, we present outcomes after a minimum follow-up of 43.9 months since last patient randomization. METHODS: Eligible patients were randomized 1:1 to 4 to 6 cycles of camrelizumab plus carboplatin and pemetrexed or chemotherapy alone every 3 weeks, followed by maintenance camrelizumab plus pemetrexed or pemetrexed only (n = 205 and 207, respectively). Total camrelizumab exposure was up to 2 years. RESULTS: As of January 31, 2022, camrelizumab plus chemotherapy exhibited substantially improved overall survival over chemotherapy alone (median, 27.1 versus 19.8 mo; hazard ratio = 0.72 [95% confidence interval: 0.57-0.92]). In the chemotherapy-alone group, 95 patients (45.9%) crossed over to camrelizumab monotherapy. After adjustment for crossover, the survival benefit with camrelizumab plus chemotherapy was more pronounced (adjusted hazard ratio = 0.55 [95% confidence interval: 0.42-0.71]). In camrelizumab plus chemotherapy group, 33 patients completed 2 years of camrelizumab. Objective response rate was 97.0%, with ongoing responses in 17 of the 32 responses (53.1%), and 93.9% (31 of 33) of the patients were alive at data cutoff. Safety profiles were consistent with the previous report, and no obvious evidence of cumulative toxicity was found with long exposure to camrelizumab. CONCLUSIONS: Camrelizumab plus carboplatin and pemetrexed provides long-term survival benefit over chemotherapy, with manageable toxicity and remarkable and durable response in patients receiving 2 years of camrelizumab, further supporting camrelizumab combination as first-line treatment for advanced nonsquamous NSCLC.

Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).

PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Risk factors and prognostic role of renal adverse event in patients receiving immune checkpoint inhibitor therapy: analysis of data from a retrospective cohort study.

Background: Along with the widespread use of immune checkpoint inhibitors (ICIs), there has been a surge in immune-related adverse events which can limit the efficacy of ICIs. However, to date, there is a paucity of reports on renal adverse events (RAEs) related to ICIs. Therefore, this study reports the incidence, risk factors, pathological features of RAEs in patients receiving ICI therapy and its association with overall survival. Methods: The medical records of patients who received at least 1 cycle of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) monoclonal antibody (mAb) between January 1st 2018 and July 31th 2021 were retrospectively reviewed. All available serum creatinine data were extracted and used to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and RAEs were defined as a 25% decrease in eGFR from baseline. Logistic regression was used to analyze the risk factors for RAEs. The Kaplan-Meier method was used to compare the survival among patients with and without RAEs. Results: A total of 328 patients receiving ICI therapy were enrolled and 42 developed RAEs. Patients with RAEs had a lower median baseline acute monocyte count (AMC), higher median baseline ratio of lymphocyte and monocyte (LMR), were more likely to have hypertension, coronary heart disease, and distant metastasis, and were more likely to be receiving more cycles of ICI therapy. Multivariate analysis revealed that RAEs were associated with distant metastasis and the number of cycles of ICI therapy. RAEs were not associated with baseline creatinine, eGFR, ICI type, nor the line of ICI therapy. Regardless of whether patients were receiving first-line ICI therapy or non-first line ICI therapy, patients with RAEs had lower survival rates compared to patients without RAEs. Of the patients with RAEs, 2 received renal biopsies and were pathologically confirmed with acute interstitial nephritis (AIN). Conclusions: RAEs were not a rare complication in patients receiving ICIs treatment. Distant metastasis and the number of cycles of ICI therapy were associated with RAEs. Patients who developed RAEs were associated with worse survival.

Efficacy, prognosis and safety analysis of anti-PD-1/PD-L1 inhibitor rechallenge in advanced lung cancer patients: a cohort study.

Background: The rechallenge of immune checkpoint inhibitors (ICI) is now an optional strategy for patients who discontinued ICI due to immune-related adverse events (irAEs) or disease progression. However, little data is available for the prognosis and prognostic factors of patients receiving ICI rechallenge treatment in advanced lung cancer patients. Our study aimed to explore the efficacy, prognosis and safety of patients who received anti-programmed cell death-1/programmed cell death ligand 1 (anti-PD-1/PD-L1) inhibitor rechallenge. Methods: In our retrospective cohort study, data of advanced lung cancer patients who received anti-PD-1/PD-L1 inhibitor and discontinued due to irAEs or disease progression were collected from December 2016 to August 2021. Enrolled patients were categorized into two groups: rechallenge group (R group) and non-rechallenge group (NR group). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety data were analyzed. Cox model and subgroup analysis were analyzed according to baseline characteristics, ICI type, the reason for discontinuing ICI, etc. According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), evaluation was performed routinely every 6-8 weeks after initiating treatment with the PD-1/PD-L1 inhibitor. The last follow-up in the study was on September 20, 2021. Results: Eighty-one patients who met our inclusion criteria were enrolled. In the whole cohort, the R group achieved better OS than the NR group [hazard ratio (HR) =0.176; 95% confidence interval (CI): 0.065-0.477; P=0.001). In the irAEs group, the survival analyses showed a trend toward improved OS in the rechallenge subgroup (HR =0.287; 95% CI: 0.081-1.025; P=0.055), and a promising DCR of 75% after an ICI rechallenge. Additionally, the exploration of safety outcomes indicated an acceptable recurrence rate (22.5%) of irAEs and an early onset of irAEs after an ICI rechallenge. In the disease progression group, the rechallenge subgroup did not improve OS (HR =0.214; 95% CI: 0.027-1.695; P=0.144), and the DCR of the rechallenge subgroup was 40% after ICI rechallenge. Conclusions: ICI rechallenge might be an attractive option for patients who discontinue treatment due to irAEs. For patients with disease progression, further research should be conducted. The recurrence of irAEs and their early onset during the second round of ICI should be considered.

PIV and PILE Score at Baseline Predict Clinical Outcome of Anti-PD-1/PD-L1 Inhibitor Combined With Chemotherapy in Extensive-Stage Small Cell Lung Cancer Patients.

Objectives: The objective of this study is to evaluate whether PIV (Pan-Immune-Inflammation Value) and PILE [a score derived from PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)] can predict clinical outcome of anti-PD-1/PD-L1 inhibitor combined with chemotherapy in patients with extensive-stage (ES) small cell lung cancer (SCLC). Methods: A total of 53 patients with ES-SCLC in the control group of clinical trial (NCT03041311) were included in this study. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE scores were composited based on PIV, LDH levels, and ECOG PS. The Kaplan-Meier method and Cox hazards regression models were used for survival analyses. Moreover, the predictive ability of PIV and PILE was validated in an independent real-world group consisting of 84 patients. Results: Patients in the low PIV group (PIV < median) had longer progression-free survival (PFS) and overall survival (OS) than those in the high PIV group (PIV ≥ median), along with the HR, which was 2.157 and 2.359, respectively (PFS HR 95% CI: 1.181-3.940, p = 0.012; OS HR 95% CI: 1.168-4.762, p = 0.020). High PILE score was observed relating to worse treatment efficacy (disease control rate (DCR): 84.21% vs. 100%, p = 0.047; durable clinical benefit (DCB) rate: 10% vs. 48.5%, p = 0.060) and poor clinical outcome (median PFS: 4.75 vs. 5.53 m, p = 0.043; median OS: 7.13 vs. 15.93 m, p = 0.002). Similar results were obtained about the predictive and prognostic abilities of PIV and PILE scores in the validation group. Conclusions: High PIV and high PILE were correlated with worse clinical outcomes in ES-SCLC patients treated with anti-PD-1/PD-L1 inhibitor combined with chemotherapy, reflecting that PIV and PILE might be useful to identify patients unlikely to benefit from anti-PD-1/PD-L1 therapy.

Two severe adverse events triggered by an anti-PD-1 immune checkpoint inhibitor in an advanced lung cancer patient: a case report and review of the literature.

Anti-programmed death 1 (PD-1) immune checkpoint inhibitors have produced robust tumor responses in several solid tumors including lung cancer by enhancing the antitumor activity of the immune system. In general, the adverse events triggered by anti-PD-1/PD-L1 mAbs appear to be less severe when compared with traditional chemotherapy. However, a subgroup of patients will experience various autoimmune adverse events, such as skin, gastrointestinal, pulmonary, hepatic, renal, and endocrine events, among others. In previous studies, only one irAE was reported in a patient who received immunotherapy. However, in this report, we presented an advanced non-small cell lung cancer patient who was positive for PD-L1 in 20% of tumor cells and negative for actionable molecular markers such as KRAS, EGFR, ALK, MET, and ROS1 alterations. He received a PD-1 inhibitor combined with chemotherapy according to the guidelines of the Chinese Society of Clinical Oncology (CSCO) non-small cell lung cancer [2020] and experienced severe hepatitis and pneumonitis successively, which were recovered after the treatment of systemic glucocorticoids. This situation increased the difficulty of diagnosis and treatment of immune-related adverse events (irAEs). This case illustrates the potential toxicity caused by immunotherapy, and more attention should be paid to its prevention, treatment, and association with antitumor efficacy. Multidisciplinary discussions should be undertaken to improve patient prognosis.

Genomic landscape and evolution of arm aneuploidy in lung adenocarcinoma.

For lung adenocarcinoma, arm aneuploidy landscape among primary and metastatic sites, and among different driver and frequently mutated gene groups have not been previously studied. We collected the largest cohort of LUAD patients (n=3533) to date and analyzed the profiles of chromosome arm aneuploidy (CAA), and its association with different metastatic sites and mutated gene groups. Our results showed distant metastasis (bone, brain, liver) were characterized by high CAA burden and biased towards arm losses compared to regional metastasis (pleura, chest) and primary tumors. Moreover, EGFR, MET, PIK3CA, PKHD1 and RB1 mutant groups were found to have high CAA burden, while those with BRAF, ERBB2 and KRAS mutations belonged to the low CAA burden group. Comparing EGFR L858R and EGFR 19del mutants, distinct CAA co-occurrences were observed. Network-based stratification with population based genomic evolution analysis revealed two distinct subtypes of LUAD with different CAA signatures and unique CAA order of acquisition. In summary, our study presented a comprehensive characterization of arm aneuploidy landscape and evolutionary trajectories in lung adenocarcinoma, which could provide basis for both biological and clinical investigations in the future.

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study.

INTRODUCTION: Some ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC. METHODS: The exploratory study was a phase 2, single-arm, multicenter design (NCT03608007). Patients with ROS1-positive NSCLC with a previous chemotherapy line number of less than or equal to 1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary end point was objective response rate evaluated by an investigator per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From June 2018 to July 2019, a total of 59 patients were enrolled at 23 centers in the People's Republic of China. At the time of data cutoff, the median follow-up was 19.8 months (range: 0.8-22.5). The median objective response rate was 27.0 % (95 % confidence interval [CI]: 13.8-44.1) with 10 partial responses. Median duration of response was 4.8 months (95 % CI: 1.8-10.8). The median progression-free survival was 4.6 months (95 % CI: 4.0-6.4). The median overall survival was not estimable (95 % CI: 14.9-not estimable). Of four patients with brain metastases, intracranial disease control was reported in three (75.0 %, 95 % CI: 19.4-99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. Most of the TRAEs were of grades 1 to 2, and incidence of grade greater than or equal to 3 TRAEs was 25.4 %. CONCLUSIONS: Ensartinib had a modest efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.

Efficacy and Safety of Niraparib as Maintenance Treatment in Patients With Extensive-Stage SCLC After First-Line Chemotherapy: A Randomized, Double-Blind, Phase 3 Study.

INTRODUCTION: ZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage SCLC (ES-SCLC). METHODS: Patients with complete response (CR) or partial response (PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥ 77 kg, platelet count ≥ 150,000/µL] or 200 mg) once daily until progression or unacceptable toxicity. Primary end points were progression-free survival (PFS) (blinded independent central review) and overall survival (sample size planned: 591 patients). Secondary end points included investigator-evaluated PFS and safety. RESULTS: ZL-2306-005 was terminated early owing to ES-SCLC treatment landscape changes (data cutoff: March 20, 2020). During July 2018-February 2020, a total of 185 of 272 patients screened were randomized (niraparib: n = 125 [CR = 1, PR = 124]; placebo: n = 60 [CR = 1, PR = 59]). Median (95% confidence interval [CI]) PFS (blinded independent central review) was 1.54 months (1.41-2.69, niraparib) and 1.36 months (1.31-1.48, placebo); hazard ratio (HR) = 0.66 (95% CI: 0.46-0.95, p = 0.0242). Median overall survival was 9.92 months (9.33-13.54, niraparib) and 11.43 months (9.53-not estimable, placebo); HR = 1.03 (95% CI: 0.62-1.73, p = 0.9052). Median investigator-evaluated PFS was 1.48 months (1.41-2.56, niraparib) and 1.41 months (1.31-2.00, placebo); HR = 0.88 (95% CI: 0.61-1.26; p = 0.4653). Grade greater than or equal to 3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients. CONCLUSIONS: ZL-2306-005 did not reach primary end points. Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.

EGFR/BRAF/MEK co-inhibition for EGFR-mutated lung adenocarcinoma patients with an acquired BRAFV600E mutation: a case report and review of literature.

Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), most advanced non-small-cell lung cancers (NSCLCs) progress eventually due to therapeutic resistance. V-Raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs. In the presented case, BRAFV600E mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib (a third-generation EGFR-TKI). The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAFV600E mutation, consistent with the review of the literature (eight cases). Additionally, our case highlights the important role of sample type, method, and platform of gene detection in patient management, life quality, and prognosis, as well as the understanding of acquired resistance mechanism.

Case Report: A 91-Year-Old Patient With Non-Small Cell Lung Cancer Harboring MET Y1003S Point Mutation.

BACKGROUND: The Y1003S point mutation in exon 14 of mesenchymal-epithelial transition (MET) is a rare mutation that can lead to oncogenic transformation. Few data are available on the characteristics of this mutation. This report presents an elderly patient with non-small cell lung cancer (NSCLC) and a Y1003S mutation in MET detected by next-generation sequencing (NGS). CASE REPORT: In October 2020, a 91-year-old male was admitted to the Department of Respiratory and Critical Care Medicine, Ruijin Hospital because of an increased carcinoembryonic antigen. Imaging revealed highly suspicious lesions in the right upper lobe of the lung, right apex, and left upper lobe with traction of the adjacent pleura. The patient was histologically confirmed as having adenocarcinoma and the MET Y1003S mutation was detected by the NGS subsequently. After evaluation, the patient started crizotinib treatment in December 2020. In the first assessment of tumor response, a chest CT scan in January 2021 showed a partial response. The patient experienced a pulmonary embolism and an abnormal liver function during the treatment and recovered after symptomatic treatment. He maintained a partial response in the last available assessment in July 2021, with the right upper lung lesion being 26 × 9 mm. CONCLUSION: The MET Y1003S mutation was detected in this case, and the patient achieved a partial response using crizotinib. This case highlighted the role of NGS in detecting a rare mutation. Successful remission of complications in such an elderly patient necessitates careful and timely management.

A detrimental mutation on USP40 unlocks the tumorigenesis in a rare case of lung cancer.

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer. Previous research has shown heterogeneity in lung cancer, with the parallel existence of multiple subclones characterized by their own specific mutational landscape. The aim of our study was to gain insight into the evolutionary pattern of lung cancer by investigating the genomic heterogeneity between a nodule and its distant tumor. Luckily, we obtained nodule and tumor samples derived from surgery and a blood sample from a single patient. The samples are very unique, for tissues with the same genetic background from nodules to malignant tumors are rarely available and require precise micro-cutting. In this study, we performed whole-genome sequencing of these two samples, to identify novel candidate driver genes associated with LUAD. The nodule and tumor were found to have common significant ubiquitin-specific protease 40 (USP40) mutations, indicating an important driver role for the gene. Moreover, we also observed the two novel candidate driver genes ASCL5 and CAPNS1 in the LUAD sample. In summary, we pinpoint the predominant mutations in LUAD by WES, highlighting the substantial genetic alterations contributing to LUAD tumorigenesis. This may provide a better understanding of the clonal evolution during tumor development.

Monitoring antiangiogenesis of bevacizumab in zebrafish.

Bevacizumab, which is a humanized anti-VEGF antibody, has been successfully applied in clinics since 2004. Bevacizumab in combination with chemotherapy showed high safety and has been applied to solid tumors. However, studies on the insight into the mechanism about the antiangiogenesis activity of bevacizumab were mostly done on mice models, and so there are no visual and intuitive models to observe the process of antiangiogenesis. Here, we first used a zebrafish model to investigate the angiogenesis suppressing behavior of bevacizumab. Our results showed that bevacizumab inhibited formation of zebrafish subintestinal veins, which mimics the process of tumor angiogenesis in vivo. Meanwhile, bevacizumab caused specific vasculature formation defects in subintestinal veins but not in the trunk. Our study also indicated that bevacizumab could inhibit zebrafish retinal angiogenesis with therapeutic potential.

Imperatorin Targets MCL-1 to Sensitize CD133+ Lung Cancer Cells to γδ-T Cell-Mediated Cytotoxicity.

BACKGROUND/AIMS: CD133+ cancer cells display low sensitivity to anti-cancer treatment; thus, combination treatment with adjuvant drugs is required to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of imperatorin, a linear furanocoumarin compound, on γδ T cell-mediated cytotoxicity against CD133+ lung cancer cells. METHODS: CD133+ and CD133- subgroups from A549 and PC9 lung cancer cells were sorted by using flow cytometry. The cytotoxicity of γδ T cells against cancer cells was evaluated by measuring lactate dehydrogenase release. The concentration of tumor necrosis factor-related apoptosis-inducing ligand in the co-culture system was determined by using an enzyme-linked immunosorbent assay. Mitochondrial membrane potential, expression of death receptor 4 (DR4) and DR5 on the cell surface, and rate of apoptosis were measured by flow cytometry. Cytochrome c release and cellular protein expression were detected by western blot analysis. RESULTS: Compared with CD133- cells, CD133+ cells were resistant to γδ T cell-mediated cytotoxicity. However, imperatorin significantly increased the sensitivity of CD133+ lung cancer cells to γδ T cell treatment in vitro and in vivo. Mechanically, we found that myeloid cell leukemia 1 (MCL-1), an important anti-apoptotic protein belonging to the Bcl-2 family, was overexpressed in CD133+ A549 and PC9 cells compared to their corresponding CD133- cells. Co-treatment with imperatorin and γδ T cells suppressed the expression of MCL-1, and thus promoted the mitochondrial apoptosis mediated by γδ T cells in CD133+ A549 and PC9 lung cancer cells. CONCLUSION: Up-regulated MCL-1 in CD133+ lung cancer cells is responsible for their resistance to γδ T cells. Furthermore, the combination of γδ T cells with imperatorin sensitized CD133+ lung cancer cells to γδ T cell-mediated cytotoxicity by targeting MCL-1.

Significance of NLDA, the commixed index of inflammation, immune responses, hemostasis, and nutrition, for predicting metastatic non-small cell lung cancer prognosis and metastases.

PURPOSE: This study aimed to take a comprehensive review of the hematological indexes and discover a novel, comprehensive, and economical index for prognostic prediction. RESULTS: The predictive prognostic model revealed that an elevated value of NLDA (NLDA = neutrophil count/lymphocyte count × D-dimer count/albumin) was an independent risk factor for one-year adverse prognosis (hazard ratio = 3.038; 95% confidence interval [CI], 1.959-4.712; P < 0.001). The C-indexes of internal and external validation in nomogram were 0.738 (95% CI, 0.686-0.79) and 0.731 (95% CI, 0.631-0.831), respectively. The areas under the curves of the NLDA values in retrospective and prospective studies were 0.700 (95% CI, 0.631-0.769; P < 0.001) and 0.692 (95% CI, 0.535-0.822; P = 0.005), respectively. The cut-off value of NLDA was 0.15. NLDA was positively associated with M stage (P = 0.032), organ metastasis counts (P = 0.006), liver metastases (P = 0.019), and vertebrae metastases (P = 0.013). MATERIALS AND METHODS: This was a retrospective and prospective study. The clinicopathological characteristics and hematological parameters of stage IV non-small cell lung cancer patients were analyzed retrospectively and prospectively to establish a valid predictive prognostic model. The primary endpoint was the 1-year overall survival. The predictive prognostic model was established and validated by Cox Regression and nomogram. The cut-off and predictive prognostic values of the novel indexes were calculated through the receiver operating characteristic curves. The chi-square test was used to explore the correlation between the new prognostic hematological index and metastatic characteristics. CONCLUSIONS: In this study, NLDA, a new, comprehensive and economic parameter, was found to be an independent adverse prognostic factor for stage IV non-small cell lung cancer patients, and was positively associated with organ metastases.