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Objective: Despite the promising potential of neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC), there is limited consensus on the optimal treatment strategy for potentially resectable NSCLC. This study aimed to evaluate the efficacy and safety of neoadjuvant chemoimmunotherapy (neoCT/IO) with planned surgery versus definitive concurrent chemoradiation followed by immunotherapy (cCRT + IO) in potentially resectable stage III NSCLC., Methods: This retrospective study analyzed data from patients with potentially resectable stage III NSCLC who underwent neoCT/IO with planned surgery or cCRT + IO between March 2020 and June 2023. Propensity score matching (PSM) was used to balance heterogeneity between groups. Efficacy outcomes, safety profiles and patterns of disease recurrence were assessed., Results: A total of 308 eligible patients were included in this study, of whom 195 (63.3%) underwent neoCT/IO and 113 (36.7%) received cCRT + IO. The neoCT/IO group consisted of patients who underwent neoCT/IO + Surgery and neoCT/IO + Radiotherapy. After 1:1 PSM, each group consisted of 105 patients. The median progression-free survival (PFS) was 25.9 months in the cCRT + IO group and not reached (NR) in the neoCT/IO group (hazard ratio: 2.91, 95% confidence interval: 1.77-4.78; p < 0.001). Median overall survival (OS) was NR in either group, with 3-year OS rates of 87.5% in the neoCT/IO group and 75.0% in the cCRT + IO group (p = 0.22). The incidence of grade 3/4 treatment-related adverse events was similar in both groups, except for a higher incidence of grade 3/4 hematological toxicity in the cCRT + IO group., Conclusions: For patients with potentially resectable stage III NSCLC, neoCT/IO appears to be a safe approach and may offer better survival outcomes compared with cCRT + IO. Prospective randomized trials are needed to further validate these findings., Competing Interests: Declarations. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethical approval: The study was approved by all participating institutions. The study was conducted in accordance with the Declaration of Helsinki and International Good Clinical Practice Guidelines. The need for informed consent was waived by the Ethics Committee of Shandong Cancer Hospital and Institute, because of the retrospective nature of the study., (© 2025. The Author(s).)

Background: Pulmonary sarcomatoid carcinoma (PSC) is a highly aggressive malignancy with a significant risk of recurrence even after surgical intervention, leading to a dismal prognosis. In recent years, perioperative immunotherapy has demonstrated promising results in resectable non-small cell lung cancer (NSCLC). However, there is a lack of studies reporting the efficacy of perioperative immunotherapy in PSC., Case Presentation: We report the clinical outcomes of four patients diagnosed with locally advanced PSC who underwent neoadjuvant immunotherapy in combination with chemotherapy from 2021 to 2023 in our hospital. Prior to surgery, these patients received 2 to 4 cycles of neoadjuvant treatment. Post-treatment imaging assessments indicated a partial response (PR) in all cases, and each patient successfully achieved R0 resection. Pathological evaluations demonstrated significant pathological responses: one patient attained Pathological Complete Response (PCR), two patients exhibited Major Pathological Response (MPR), and one patient showed PR. Currently, all four patients remain alive without evidence of tumor progression. Notably, the patient who achieved PCR has maintained a disease-free survival (DFS) exceeding 32 months post-surgery, while their event-free survival (EFS) has surpassed 36 months., Conclusions: Neoadjuvant immunotherapy in combination with chemotherapy has provided new promise for the treatment of locally advanced PSC with surgical potential. But these findings still need to be verified by further prospective researches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guo, Wang, Li, Wang, Zhu and Guo.)

Background: This study aimed to identify a specific SCLC population that would benefit from surgery., Methods: This study utilized patient data retrieved from the Surveillance, Epidemiology, and End Results (SEER) database spanning 2010 to 2017. To mitigate clinical biases, the propensity score matching (PSM) technique was employed. Separate cohorts were aligned using PSM according to the AJCC 8th edition TNM classification. The Kaplan-Meier method and a competing risk model were applied to evaluate overall survival (OS) and lung cancer-specific survival (LCSS), respectively., Outcomes: Among the 3394 patients with potentially resectable SCLC included in the study, 3062 underwent chemoradiotherapy and 332 underwent surgical treatment with adjuvant chemotherapy. Surgery was associated with better OS (median OS: 49 months; 95% CI: 35-63 months vs. 27 months; 95% CI: 21-33 months, p < 0.001) and LCSS (SHR, 0.578; 95% CI: 0.411-0.815, p < 0.001) in stage I patients after PSM. However, there was no significant difference in OS and LCSS between the surgery and nonsurgery groups in stage II and III patients after PSM. In the entire cohort, lobectomy was associated with improved OS (median OS: 48.6 vs. 28.7 months, p < 0.0001), but not LCSS (SHR, 0.696; 95% CI: 0.466-1.040, p = 0.078) compared with sublobar resection after PSM., Conclusion: Surgery with adjuvant chemotherapy significantly improved the survival prognosis of patients with early-stage SCLC. However, surgical treatment should be carefully considered in patients with stage II/III disease. Lobectomy is oncologically equal to sublobar resection., (© 2024 The Author(s). The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7-78.9%) and the DCR was 76% (95% CI: 54.9-90.6%). The mPFS was 6.0 months (95% CI: 5.4-9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response., (© 2024. The Author(s).)

Brain metastases (BMs) are the most common sites of metastasis in patients with non-small cell lung cancer (NSCLC). However, BMs are not responsive to immunotherapy because of the blood-brain barrier. This is because intracranial immune cells such as M2 tumor-associated macrophages (TAMs) accumulate, creating an immunosuppressive tumor microenvironment. In this study, we focused on irradiated tumor cell-released microparticles (RT-MPs) that can cross the blood-brain barrier and influence the intracranial immune microenvironment. Using animal models of BMs, we observed that RT-MPs could penetrate the blood-brain barrier and be swallowed by TAMs. Then the microenvironment of TAMs is shifted from the M2 phenotype to the M1 phenotype, thereby modulating the interactions between TAMs and tumor cells. Single-cell sequencing analysis demonstrated that TAMs, after internalizing RT-MPs, active chemokine signaling pathways and secrete more chemokines, such as CCL5, CXCL2, CXCL1, CCL3, CCL4, and CCL22, attracting more CD4 + T cells and CD8 + T cells, improving immune-mediated killing, and enhancing subsequent combination anti-PD-1 therapy. These findings provide a preclinical foundation for exploring alternative treatments for patients with immunoresistant NSCLC BMs., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2024. Published by Elsevier B.V.)

Background: Naïve CD4 + T cells and their differentiated counterparts play a significant regulatory role in the tumor immune microenvironment, yet their effects on lung adenocarcinoma (LUAD) are not fully understood., Methods: We utilized Mendelian randomization to assess the causal association between naïve CD4 + T cells and LUAD. Employing a modified single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm with The Cancer Genome Atlas (TCGA) database, we determined the infiltration levels of naïve CD4 + T cells and their differentiation subtypes and investigated their correlation with clinical characteristics. Potential regulatory pathways of T helper cells were identified through Mantel tests and Kyoto Encyclopedia of Genes and Genomes (KEGG) database enrichment analysis., Results: Mendelian randomization analysis revealed an inhibitory effect of naïve CD4 + T cells on LUAD (false discovery rate < 0.05), which was corroborated by observational experiments using TCGA database. Specifically, T helper cell type 2 demonstrated a promotive effect on LUAD in terms of overall, disease-free, and progression-free survival (p < 0.05). Moreover, regulatory T cells exhibited a protective effect on LUAD in terms of disease-specific survival (p < 0.01). Concurrently, we explored the overall impact of naïve CD4 + T cell differentiation subtypes on LUAD, revealing upregulation in pathways such as neutrophil degranulation, MAPK family signaling pathways, and platelet activation, signaling, and aggregation., Conclusion: Naïve CD4 + T cells and their differentiated counterparts play essential regulatory roles in the tumor immune microenvironment, demonstrating bidirectionality in their effects.Thus, elucidating the mechanisms and developing novel cell differentiation-inducing agents will benefit anti-cancer therapy., (© 2024. The Author(s).)

Background: First-line chemotherapy combined with bevacizumab is one of the standard treatment modes for patients with advanced non-small cell lung cancer (NSCLC). Thoracic radiotherapy (TRT) can provide significant local control and survival benefits to patients during the treatment of advanced NSCLC. However, the safety of adding TRT has always been controversial, especially because of the occurrence of radiation pneumonia (RP) during bevacizumab treatment. Therefore, in this study, we used an expanded sample size to evaluate the incidence of RP when using bevacizumab in combination with TRT., Patients and Methods: Using an institutional query system, all medical records of patients with NSCLC who received TRT during first-line chemotherapy combined with bevacizumab from 2017 to 2020 at Shandong Cancer Hospital and Institute were reviewed. RP was diagnosed via computed tomography and was classified according to the RTOG toxicity scoring system. The risk factors for RP were identified using univariate and multivariate analyses. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS)., Results: Ultimately, 119 patients were included. Thirty-eight (31.9%) patients developed Grade ≥ 2 RP, of whom 27 (68.1%) had Grade 2 RP and 11 (9.2%) had Grade 3 RP. No patients developed Grade 4 or 5 RP. The median time for RP occurrence was 2.7 months (range 1.2-5.4 months). In univariate analysis, male, age, KPS score, V 20  > 16.9%, V 5  > 33.6%, PTV (planning target volume)-dose > 57.2 Gy, and PTV-volume > 183.85 cm 3 were correlated with the occurrence of RP. In multivariate analysis, male, V 20  > 16.9%, and PTV-volume > 183.85 cm 3 were identified as independent predictors of RP occurrence. The mPFS of all patients was 14.27 (95% CI, 13.1-16.1) months. The one-year and two-year PFS rates were 64.9% and 20.1%, respectively. The mOS of all patients was 37.09 (95% CI, 33.8-42.0) months. The one-year survival rate of all patients was 95%, and the two-year survival rate was 71.4%., Conclusions: The incidence of Grade ≥ 2 RP in NSCLC patients who received both bevacizumab and TRT was 31.9%. Restricting factors such as V 20 and PTV will help reduce the risk of RP in these patients. For patients who receive both bevacizumab and TRT, caution should be exercised when increasing TRT, and treatment strategies should be optimized to reduce the incidence of RP., (© 2024. The Author(s).)

Background: The superior efficacy of concurrent thoracic radiotherapy (TRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been proven in locally advanced and advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, the high incidence of radiation pneumonitis (RP) reduced by concurrent TRT and TKIs has attracted widespread attention. Thus, this study was designed to investigate the rate and risk factors for RP in EGFR-positive NSCLC patients simultaneously treated with aumolertinib and TRT., Methods: We retrospectively evaluated stage IIIA-IVB NSCLC patients treated with concurrent aumolertinib and TRT between May 2020 and December 2022 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed by two senior radiologists and then graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events v5.0. All risk factors were evaluated by univariate and multivariate logistic regression analyses., Results: A total of 49 patients were included, the incidence of grade ≥ 2 RP was 42.9%. Grade 2 and 3 RP were observed in 28.6% and 14.3% of patients, respectively. Grade 4 to 5 RP were not observed. the gross total volume (GTV) ≥ 21 ml and ipsilateral lung V20 ≥ 25% were risk factors for RP. The median progression-free survival (PFS) in the first-line therapy group and second-line therapy group were 23.5 months and 17.2 months, respectively (p = 0.10)., Conclusions: Better local control is achieved with concurrent TRT and aumolertinib, and special attention should be given to controlling ipsilateral lung V20 and GTV to reduce the risk of RP., (© 2024. The Author(s).)

Background: In first/second generation EGFR-TKIs, strong PD-L1 expression contributes to primary resistance, significantly affecting patient prognosis. The relationship between PD-L1 expression levels and third-generation TKIs remains unclear. Methods: This study analyzed advanced NSCLC who received third-generation EGFR-TKIs as first-line systemic therapy from March 2019 to June 2022. The EGFR and PD-L1 status of the patients was also assessed. Results: Overall, 150 patients were included in this study. PD-L1 expression was negative (PD-L1 tumor proportion score <1%) in 89 cases, weak (1-49%) in 42 cases, and strong (≥50%) in 19 cases. mPFS for patients with negative, weak and strong PD-L1 expressions was 23.60, 26.12 and 16.60 months, respectively. The mPFS for strong PD-L1 expression was significantly shorter than that for with weak PD-L1 expression but was not associated with negativity. The same conclusions were shown in subgroup analyses of mutation types and TKI kinds. In addition, Relative to PD-L1-negative patients, resistance to TKIs may be associated with early progression for patients with strong PD-L1 expression. Conclusion: PD-L1 expression in tumor cells influenced the clinical outcomes of patients with advanced NSCLC treated with third-generation EGFR-TKIs. Stronger PD-L1 expression in TKIs-treated patients with advanced first-line EGFR-mutated NSCLC was associated with worse PFS.

Background: Immunotherapy (IO) has demonstrated promising results in treating extensive-stage small cell lung cancer (ES-SCLC), and the management of ES-SCLC brain metastases (BMs) is now receiving significant clinical attention. The objective of this study was to evaluate the role of IO in the clinical management of BMs., Methods: Between January 2020 and December 2021, the study included the records of 250 patients who were diagnosed with ES-SCLC. Overall survival (OS), progression-free survival, intracranial progression-free survival, and the cumulative incidence of BMs were calculated using the Kaplan-Meier method and were compared using the log-rank test. In addition, the Cox regression model was used to analyze prognostic factors., Results: In the entire group, 85 patients had baseline BMs (IO plus chemotherapy [IO + ChT], n = 38; ChT alone, n = 47), and 165 patients (IO + ChT, n = 86; ChT alone, n = 79) did not have BMs at the time of initial diagnosis. The median follow-up was 22.4 months. The OS benefit with first-line antiprogrammed death ligand 1 therapy was maintained regardless of whether patients had BMs (with BMs, 17.97 vs. 13.14 months [p = .03]; without BMs, 18.46 vs. 15.05 months [p = .047]). However, in patients without BMs, IO did not delay the median time to developing brain progression (10.84 vs. 10.74 months; p = .84), and it did not significantly reduce the risk of developing intracranial metastases (the 2-year actuarial risk of developing BMs was 57.0% vs. 50.6%, respectively)., Conclusions: Antiprogrammed death ligand 1 therapy improved OS regardless of the presence of BMs. However, IO did not delay the median time to brain progression or reduce the risk of intracranial metastasis in patients without baseline BMs. The findings of this study have important clinical implications for the future management of BMs from ES-SCLC., (© 2023 American Cancer Society.)

Rationale: Many studies have shown that first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. The efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors is still under investigation. Although new targeted tyrosine kinase inhibitors and monoclonal antibody-based agents have made significant advances in the treatment of epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) mutation, the efficacy of these novel agents is not quite satisfactory. Platinum- and pemetrexed-based chemotherapy remains the standard first-line treatment for patients harboring EGFR ex20ins mutation., Patient Concerns: We report for the first time 2 Chinese patients diagnosed with advanced lung adenocarcinoma with EGFR ex20ins mutations after analysis of the αC-helix sequence by next-generation sequencing. Both patients were treated with furmonertinib as the first-line therapy., Interventions: The first case included a 38-year-old female who had an EGFR ex20ins mutation (p.S768&#95;D770dupSVD). After 1 month of treatment with furmonertinib, her symptoms of pain and cough were significantly alleviated. She achieved a partial response according to response evaluation criteria in solid tumors.[1] The final progression-free survival was 8.13 months. The second case included a 40-year-old male who had an EGFR ex20ins mutation (p.N771&#95;P772insVal). He had a good response to furmonertinib and exhibited stable disease according to response evaluation criteria in solid tumors with a progression-free survival of 10.90 months., Outcomes: Both patients experienced significant improvement in symptoms and prolonged survival after furmonertinib was used as first-line treatment. Side effects were limited but manageable., Conclusion: The present study indicates that furmonertinib may be a first-line treatment option for patients with non-small cell lung cancer harboring EGFR ex20ins mutation., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (lung-molGPA) index provide more accurate survival prediction for patients diagnose with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). Given that the value of cranial radiotherapy (CRT) is still controversial for NSCLC patients with BM, this retrospective study aimed to evaluate the value of CRT and optimal timing in NSCLC patients with initial BM after stratified with lung-molGPA index., Methods: This study screened NSCLC patients with initial BM in our cancer center from February 2012 to July 2018. The prognosis value of CRT and optimal timing was evaluated with Kaplan-Meier survival analysis and the patients were classified into lung-molGPA0-2 and lung-molGPA2.5-4 group. Upfront CRT was defined as received CRT within 3 months after initial diagnosis and without BM progression, other CRT was classified into deferred CRT., Results: Overall, 288 patients were enrolled in our study, 156 patients received CRT. The median follow-up time was 47 months. In the entire cohort, the median PFS and OS were 9.2 and 17.0 months, respectively. In the lung-molGPA2.5-4 group, CRT can bring significantly overall survival benefit for NSCLC patients with initial BM (HR: 0.48, 95% CI: 0.34-0.68, P < 0.0001), and the upfront CRT can further expand this survival benefits compared with deferred CRT (HR: 0.49, 95% CI: 0.27-0.89, P = 0.0026). But this phenomenon was not observed in lung-molGPA0-2 group patients., Conclusion: Upfront CRT could bring significantly overall survival benefit for these patients with lung-molGPA2.5-4 but not for patients with lung-molGPA0-2., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

As one of the common complications of radiotherapy, radiation pneumonia (RP) limits the prognosis of patients. Therefore, better identifying the high-risk factors that lead to RP is essential to effectively prevent its occurrence. However, as lung cancer treatment modalities are being replaced and the era of immunotherapy has arrived, literature that reviews the parameters and mode of radiotherapy, chemotherapy drugs, targeted drugs and current hot immune checkpoint inhibitors related to RP is lacking. This paper summarizes the risk factors for radiation pneumonia by retrieving and analysing previously published literature and the results of large clinical trials. The literature primarily included retrospective analyses, including clinical trials in different periods and a part of the literature review. A systematic literature search of Embase, PubMed, Web of Science, and Clinicaltrials.gov was performed for relevant publications up to 6 Dec. 2022. Search keywords include, but are not limited to, "radiation pneumonia", "pneumonia", "risk factors", "immunotherapy", etc. The factors related to RP in this paper include physical parameters of radiotherapy, including V 5 , V 20 , and MLD; chemoradiotherapy mode and chemotherapy drugs, including paclitaxel and gemcitabine; EGFR-TKI; ALK inhibitors; antiangiogenic drugs; immune drugs and the underlying disease of the patient. We also introduce the possible mechanism of RP. In the future, we hope that this article not only sounds the alarm for clinicians but also helps to identify a method that can effectively intervene and reduce the occurrence of RP, significantly improve the quality of life and prognosis of patients, and more effectively improve the therapeutic effect of radiation therapy., (© 2023. The Author(s).)

Purpose: The objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitors in small cell lung cancer patients with brain metastases., Methods: We retrospectively reviewed the records of small cell lung cancer patients with brain metastases treated with chemotherapy and radiotherapy for brain metastases with or without immune checkpoint inhibitors at our institution from January 2019 to January 2021. Patients were divided into two groups. In Group A, patients received chemotherapy and radiotherapy for brain metastases. In Group B, patients received chemotherapy, radiotherapy for brain metastases and at least four cycles of immunotherapy. Overall survival and intracranial progression-free survival were assessed using Kaplan-Meier estimates and Cox regression models., Results: A total of 282 patients were enrolled in our study. At the end of the study (May 12, 2021), the median overall survival was 13.3 months among 218 patients in Group A and 33.4 months among 64 patients in Group B (hazards ratio [HR] 0.320, 95% confidence interval [CI], 0.189-0.545, P < 0.001). Both univariate and multivariate analyses suggested that two factors were significantly correlated with overall survival: the inclusion of immunotherapy in the regimen and the presence of extracranial metastases. The median intracranial progression-free survival was 6.93 months in Group A and 10.73 months in Group B (HR = 0.540, 95% CI, 0.346-0.841, P = 0.006). The intracranial objective response rate of Group B was greater than that of Group A, but the intracranial disease control rate was similar between the groups., Conclusion: Immunotherapy plus chemotherapy and radiotherapy for brain metastases showed promising efficacy for small cell lung cancer patients with brain metastases., (© 2022. The Author(s).)

Purpose: Although immune checkpoint inhibitor monotherapy has been used as a second-line treatment in advanced non-small cell lung cancer (NSCLC), the improvement in progression-free survival (PFS) remains unsatisfactory. We investigated the feasibility of sintilimab plus chemotherapy as a second-line treatment in advanced NSCLC., Methods: This was a phase II, single-arm, prospective study in advanced NSCLC patients who had failed standard platinum-based chemotherapy (ChiCTR1900027634, Registered 22 November 2019). Eligible patients received docetaxel 75 mg/m 2 (day 1) plus sintilimab 200 mg (day 3) Q3W. Those did not progress after 4-6 cycles received sintilimab 200 mg Q3W as maintenance treatment. The primary endpoint was PFS., Results: Forty patients were enrolled between October 2019 and October 2020. With a median follow-up of 12.2 months, the median PFS was 5.8 months, and the PFS rates at 6 and 12 months were 48% and 30%, respectively. The median overall survival (OS) was 12.6 months, with a 12-month OS rate of 62.0%. The overall response rate was 32.4%, and the disease control rate was 89.2%. The incidence of all and ≥ grade 3 treatment-related adverse events (TRAEs) were 65% (26/40) and 17.5% (7/40), respectively. No TRAEs-related permanent treatment discontinuation or death occurred. bTMB reduction at 6 weeks was associated with a longer PFS (NR vs 3.0 months, P < 0.0001)., Conclusion: This prospective phase II study in China suggested that sintilimab plus docetaxel might improve PFS and tumor response with good tolerability for Chinese patients with previously treated advanced NSCLC. bTMB reduction at 6 weeks could serve as a potential predictive biomarker for this regimen., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: To explore whether immune checkpoint inhibitors (ICIs) increase the incidence of radiation-induced brain injury in lung cancer patients with brain metastases. Methods: According to whether they received ICIs within 6 months before and after cranial radiotherapy (CRT), all patients were divided into two groups: ICIs + CRT group and CRT + non-ICIs group. Results: The incidence of radiation necrosis (RN) in the CRT + ICIs group was 14.3%, while that in the CRT + non-ICIs group was 5.8% (p = 0.090). If ICIs were used within 3 months of CRT, there was statistical significance. A maximum diameter of brain metastasis >3.3 cm and cumulative radiation dose of metastatic lesions >75.7 Gy were risk factors for RN. Conclusion: ICIs could increase the risk of RN, especially when used within 3 months of CRT.

Purpose: No definite conclusion has yet to be reached for the first-line treatment combined with chemotherapy for advanced adenocarcinoma NSCLC patients with negative driver genes. This study sought to compare the clinical outcomes of Beva+ChT and IO+ChT as first-line treatment for this population and investigated whether the statuses of BM, PD-L1 expression, and KRAS and TP53 mutations could influence the results., Patients and Methods: The clinical data of patients with adenocarcinoma NSCLC who received first-line therapy were retrospectively collected and the patients were assigned to the IO+ChT and Beva+ChT groups. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated between the two groups. The survival effects of BM, PD-L1 expression, and KRAS and TP53 mutations were also evaluated., Results: From April 2018 to October 2020, a total of 105 patients with first-line therapy were included in our analysis; 54 (51.4%) patients were included in the IO+ChT group and 51 (48.6%) patients were included in the Beva+ChT group. The results showed that OS (NR vs. 18.3 m, p = 0.011) and PFS (14.9 m vs. 6.3 m, p < 0.001) were superior in patients in the IO+ChT group than in patients in the Beva+ChT group. Further analysis revealed that the OS (median OS: NR vs. 14.7 months, p = 0.039) and PFS (median PFS: 18.5 vs. 5.5 months, p < 0.001) advantages of the IO+ChT group were also seen in the PD-L1 > 1% subgroup but were not seen in the PD-L1 < 1%, BM or KRAS mutation subgroups., Conclusions: ICIs combined with ChT improved clinical outcomes over Beva combined with ChT as first-line therapy for adenocarcinoma patients without driver gene alterations, especially in patients with PD-L1 ≥ 1%., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients., Methods: A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m 2 , day 3, every 3 weeks) for 4-6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated., Results: Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005)., Conclusion: ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients., Competing Interests: Competing interests: XD, FG, ZH, and CZ were employed by Amoy Diagnostics. No other potential conflicts of interest relevant to this article were reported., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We comprehensively investigated the morphology patterns of lung cancers associated with cystic airspaces. Our goal was to determine the predictive value of imaging features in a clinical environment., Methods: We collected information about patients with resected lung cancers associated with cystic airspaces from January 2010 to December 2019. Radiological features, clinicopathological characteristics, gene mutations and survival data were analysed comprehensively., Results: A total of 384 resected lung cancers associated with cystic airspaces were identified and categorized as 4 types: I, thin-wall type (n = 31, 8.1%); II, thick-wall type (n = 113, 29.4%); III, cystic airspace with a nodule type (n = 162, 42.1%) and IV, mixed type (n = 78, 20.3%). There were 27 (7.0%) adenocarcinomas in situ/minimally invasive adenocarcinomas; 237 (61.7%) lung adenocarcinomas; 115 (29.9%) squamous cell carcinomas; and 5 (1.3%) other tumours. The epidermal growth factor receptor mutation rate for type III was the highest (68.4%, P = 0.004). Pre-/minimally invasive adenocarcinomas were commonly featured as thin, pure ground-glass wall-surrounded cystic airspaces with smooth inner surfaces and margins. For patients with lung adenocarcinomas associated with cystic airspaces, type III (odds ratio 2.10; 95% confidence interval 0.55-8.06; P = 0.028) was an independent factor associated with a worse differentiation level. Type I was associated with excellent survival and type II, with the worst prognosis (P &lt; 0.001). Type II (hazard ratio 2.29; 95% confidence interval 1.30-4.04; P = 0.004) was an independent prognostic factor for overall survival., Conclusions: Morphological patterns could be predictors for gene mutations, invasive status, pathological differentiation and postoperative prognosis for lung adenocarcinomas associated with cystic airspaces., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Anti-programmed cell death-ligand 1 (Anti-PD-L1) blockades have become the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) from CASPIAN and IMpower133 trials. SCLC has a high incidence of brain metastasis (BM) and brain radiotherapy (BRT) is the main local treatment method, but there is limited data on the BRT-immunotherapy scheme. The aim of the retrospective study is to investigate the clinical efficacy and safety of the first-line anti-PD-L1 blockades combined with BRT in ES-SCLC with BM., Methods: Patients with newly diagnosed ES-SCLC with baseline BMs at Shandong Cancer Hospital and Research Institute between 2017 and 2021 were selected. Patients were divided into the anti-PD-L1+BRT group and BRT group. We also assessed the leukoencephalopathy in both groups., Results: A total of 46 patients were selected. Fifteen were divided into anti-PD-L1+BRT group and 31 to BRT group. The median overall survival (OS) was not reached (NR) vs 15.9 m (P = 0.172). Progression-free survival (PFS) was numerically prolonged with anti-PD-L1 blockades, but the significance was not reached (median: 9.4 m vs 7.4 m, P = 0.362). The median intracranial PFS was not improved, neither (median: 8.2 m vs 8.9 m, P = 0.620). Objective response rate (ORR) in the two groups was 73.33% vs 77.42% (P = 0.949) and disease control rate (DCR) was both 100%. Intracranial ORR and DCR were 53.33% vs 70.97% (P = 0.239) and 73.33% vs 80.65% (P = 0.855), respectively. There was no significant difference in leukoencephalopathy incidence between the two groups., Conclusion: The combination of first-line anti-PD-L1 blockades with BRT did not confer a significant survival benefit in ES-SCLC with BM, without enhancing cranial neurotoxicity., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Unlike non-small-cell lung cancer (NSCLC), the progression of small-cell lung cancer (SCLC) is slow. Extensive-stage SCLC (ES-SCLC) is a serious threat to human health, with a 5-year survival rate of <7%. Chemotherapy has been the first-line treatment for the past 30 years. The anti-PD-L1 checkpoint blockades durvalumab and atezolizumab have greatly prolonged overall survival and have become the standard first-line therapy for ES-SCLC since the CASPIAN and IMpower133 trials. In the era of chemotherapy, radiation therapy (RT), including thoracic radiation therapy (TRT) and brain radiation therapy (BRT), has shown clinical effects in randomized and retrospective studies on ES-SCLC. RT-immunotherapy has shown exciting synergistic effects in NSCLC. For ES-SCLC, the clinical effects of combining TRT/BRT with immunotherapy have not yet been systematically explored. In this review, we found that studies on RT-immunotherapy in ES-SCLC are relatively few and limited to early phase studies focusing on toxicity. The efficacy and safety profiles of early phase studies encourage prospective clinical trials. In this review, we discuss the best population, optimum TRT dose, proper TRT time, and strategies for reducing radiation-induced neurotoxicity. Furthermore, we suggest that biomarkers and patient performance status should be fully assessed before RT-immunotherapy treatment. Prospective trials are needed to provide more evidence for RT-immunotherapy applications in ES-SCLC., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Bevacizumab, an anti-VEGF monoclonal antibody, has significantly improved the clinical outcomes of patients with advanced non-squamous NSCLC (ns-NSCLC). However, the safety and efficacy of bevacizumab for elderly patients with advanced NSCLC require further investigation. Thus, 59 patients were included in the present retrospective study, 22 patients in the bevacizumab plus pemetrexed and platinum (B + PP) group, and 37 patients in the pemetrexed and platinum (PP) group. For the entire cohort of patients, the median OS was 33.3 months, and the 1-year and 2-year overall survival rates were 88.5% and 67.8%, respectively. The median OS and 1-year and 2-year OS rates were 20.5 months, 70.3% and 0%, respectively, in the B + PP group and 33.4 months, 97.0% and 89.4%, respectively, in the PP group (P < 0.001). The incidence of grade ⩾ 3 adverse events was higher in the B + PP group than in the PP group (27.3% vs. 10.8%, respectively; P = 0.204). Univariate and multivariate analyses suggested that the receipt of ⩾ 5 cycles of first-line chemotherapy was an independent favorable prognostic factor for OS, whereas the addition of bevacizumab was an unfavorable prognostic factor. With increased toxicities, the addition of bevacizumab to PP does not improve the overall survival of elderly patients with advanced ns-NSCLC., (© 2022. Higher Education Press.)

Data in 2020 show that lung cancer is the second most common cancer with the highest morbidity and mortality in the world, among which small cell lung cancer (SCLC) accounts for about 15% of the total number of lung cancers, but the number of deaths accounts for 25% of lung cancers. SCLC is an aggressive malignancy disease with a high recurrence rate and poor prognosis. The survival rate of small cell lung cancer is lower than other types of lung cancer and the prognosis is very poor. At present, there is still a lack of effective therapeutic options for SCLC after the failure of second-line treatment. However, studies have shown that anti-vascular therapy and programmed death-1 (PD-1) inhibitors are effective in SCLC. In the present case, a combination therapy of camrelizumab, a PD-1 inhibitor, and anlotinib (an anti-angiogenic drug) was administered to treat a 58-year-old male patient with programmed cell death-Ligand 1 (PD-L1) negative metastatic SCLC accompanied by primary tongue cancer. A total of 28 cycles were used from March 2020 to November 2021. Until November 2021, the survival time of the patient is 31 months; he has survived for 19 months with no disease progression, and is currently classified as complete response (CR). Our study demonstrates that camrelizumab plus anlotinib may be a promising treatment option for patients with metastatic SCLC.

Radiation recall pneumonitis (RRP) is described as an unpredictable acute inflammatory reaction within the previously irradiated lung site during the administration of systematic therapy after radiotherapy. Here, we reported a case of a 54-year-old woman with non-small lung cancer (NSCLC), who had pneumonitis at 3 and 10 months after radiotherapy regarded as radiation pneumonitis (RP) and RRP induced by anti-PD-1 sintilimab, respectively. This unique patient with double pneumonitis (RP and RRP) has drawn attention to the identification of immune or radiation pneumonitis, its potential mechanism, and further treatment strategy after the emergence of RRP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Xu and Zhu.)

Background: We aimed to clarify the benefits of the addition of rh-endostatin into concurrent chemoradiotherapy (CCRT) versus CCRT alone for locally advanced non-small cell lung cancer (NSCLC) by a meta-analysis., Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, Wanfang and Chinese National Knowledge Infrastructure (CNKI) were systematically screened from inception to November 2020 using the prespecified terms. Prospective trials (evaluating or) comparing the efficacy of endostar combined with CCRT and CCRT for locally advanced NSCLC were included. The primary endpoints were risk ratios (RRs) for objective response rate (ORR) and disease control rate (DCR). The secondary endpoints were RRs for overall survival (OS) and adverse events (AEs)., Results: Ten studies with 716 patients were included in this meta-analysis. Endostar combined with CCRT significantly improved ORR and DCR compared with CCRT. The RRs of ORR and DCR for endostar combined with CCRT versus CCRT were 1.263 (95% CI: 1.137-1.403, p < 0.001) and 1.274 (95% CI: 1.124-1.444, p < 0.001), respectively. Endostar combined with CCRT significantly improved one-year survival rate compared with CCRT with pooled RR = 1.113 (95% CI: 1.006-1.231, p = 0.038). Endostar combination treatments had similar incidences of main adverse events compared with CCRT (p > 0.05)., Conclusion: Endostar combined with CCRT is associated with significantly higher ORR, DCR and survival rate than CCRT with similar incidences of main adverse events in NSCLC., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background US has proven valuable in the diagnosis of subpleural pulmonary lesions (SPLs); however, existing US indicators have limitations. Purpose To propose and validate a revised contrast-enhanced (CE) US indicator for differential diagnosis of benign and malignant SPLs and to compare its performance with existing CE US diagnostic criteria. Materials and Methods This prospective study (Chinese clinical trial registry, ChiCTR1800019828) enrolled patients with SPLs between May 2019 and August 2020. They were divided into a developmental cohort (DC) and a validation cohort (VC). In the DC, the optimal indicator was selected from five CE US indicators. In the VC, the selected indicator was compared with existing CE US diagnostic criteria using the area under the receiver operating characteristic curve (AUC). Pathologic analysis, microbial evidence, and clinical follow-up were used as reference standards for all SPLs. Results A total of 902 participants (DC, 424 participants; VC, 478 participants) with SPLs (mean age, 56 years ± 17; 593 men) were evaluated. The arrival time (AT) difference ratio proved to be the optimal indicator to distinguish benign from malignant SPLs. In the overall (regardless of lesion size), large (vertical diameter >3 cm), and small (vertical diameter ≤3 cm) lesion groups, the cutoff values of the AT difference ratio were 43%, 42%, and 50% and the AUCs obtained from the VC were 0.91 (95% CI: 0.88, 0.93), 0.97 (95% CI: 0.94, 0.98), and 0.77 (95% CI: 0.71, 0.83) respectively, which were higher than those of lesion-lung AT difference greater than 2.5 seconds (0.81 [ P < .001], 0.85 [ P < .001], and 0.7 [ P = .005], respectively), lesion AT greater than 7.5 seconds (0.65 [ P < .001], 0.64 [ P < .001], and 0.63 [ P < .001], respectively), and lesion AT greater than 10 seconds (0.67 [ P < .001], 0.68 [ P < .001], and 0.64 [ P < .001] respectively). Conclusion The US contrast agent arrival time difference ratio enables better differentiation of benign and malignant subpleural lesions when compared with existing diagnostic criteria. Online supplemental material is available for this article . Published under a CC BY 4.0 license.

Purpose: To investigate the predictive performance of the maximum standardized uptake value (SUV max ) and mean standardized uptake value (SUV mean ) of primary lesions based on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) for EGFR mutation status in patients with non-small cell lung cancer (NSCLC)., Methods: The PubMed/Medline, Embase, Cochrane Library and Web of Science databases were searched as of January 1, 2021. Studies whose reported data could be used to construct contingency tables were included. Study characteristics were extracted, and methodological quality assessment was conducted by two separate reviewers using the Quality Assessment of Diagnostic Accuracy Studies. The pooled sensitivity, specificity and area under the summary receiver operating characteristic curve (AUROC) were calculated. The possible causes of heterogeneity were analysed by meta-regression., Results: The 18 included studies had a total of 4024 patients. The majority of the studies showed a low to unclear risk of bias and concerns of applicability. For differentiating EGFR-mutant NSCLC from wild-type NSCLC, the pooled sensitivity and specificity were 71 % and 60 % for SUV max and 64 % and 63 % for SUV mean , respectively. The summary AUROCs of SUV max and SUV mean were 0.69 (95 % CI, 0.65-0.73) and 0.68 (95 % CI, 0.64-0.72), respectively. The meta-regression analysis indicated that blindness to EGFR mutation test results, the number of readers and the number of PET/CT scanners were possible causes of heterogeneity., Conclusions: Our meta-analysis implied that SUV max and SUV mean of primary lesions from 18 F-FDG PET/CT harboured moderate predictive efficacy for the EGFR mutation status of NSCLC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors can cause immune-related toxicity in various systems, and myocarditis is the most serious life-threatening toxicity. This report introduces diagnosis and treatment of two cases which developed myocarditis after receiving PD-1 inhibitors therapy. The first case was a 77-year-old male with chordoma, who was treated by third-line sintilimab combined with anlotinib, and presented with symptoms of chest tightness, shortness of breath and upper eyelid ptosis three weeks later. He was diagnosed as immune-checkpoint-inhibitors-related myocarditis and myositis-myasthenia-gravis overlap syndrome based on his clinical symptoms, serum biomarkers, electrocardiogram, echocardiogram, and characteristic findings on cardiac 18F-FDG PET-MRI. Methylprednisolone was given 480 mg/d initially and was gradually reduced to 40 mg/d in 4 weeks, with the myocardial injury biomarkers declined in the same time. The second case was a 69-year-old female with advanced non-small cell lung cancer, who was treated by pemetrexed combined with bevacizumab and camrelizumab, and presented with palpitations 20 days later. She was diagnosed as immune-checkpoint-inhibitors-related myocarditis based on her clinical symptoms, serum biomarkers, electrocardiogram and echocardiogram. Methylprednisolone was given 240 mg/d initially and was gradually reduced to 40 mg/d with good response of myocardial injury biomarkers decline. However, the patient developed fatal myasthenia gravis afterwards, with little response to all treatments. These two cases revealed that, early detection and timely intervention, including discontinuation of immune checkpoint inhibitors and initiation of adequate steroid therapy, can reduce morbidity and mortality and improve prognosis.

Perioperative adjuvant treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). In particular, the success of immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, in patients with lung cancer has increased our expectations for the success of these therapeutics as neoadjuvant immunotherapy. Neoadjuvant therapy is widely used in patients with resectable stage IIIA NSCLC and can reduce primary tumor and lymph node stage, improve the complete resection rate, and eliminate microsatellite foci; however, complete pathological response is rare. Moreover, because the clinical benefit of neoadjuvant therapy is not obvious and may complicate surgery, it has not yet entered the mainstream of clinical treatment. Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancellation of surgery, additional illness, and even death, and have therefore attracted much attention. In this article, we draw on several sources of information, including (i) guidelines on adverse reactions related to immune checkpoint inhibitors, (ii) published data from large-scale clinical studies in thoracic surgery, and (iii) practical experience and published cases, to provide clinical recommendations on adverse events in NSCLC patients induced by perioperative immunotherapy., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The exact rate and relevant risk factors of radiation pneumonitis (RP) for non-small-cell cancer (NSCLC) patients treated with the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and thoracic radiotherapy have not been reported. Thus, this study aimed to investigate the rate and risk factors of RP for EGFR-positive NSCLC patients simultaneously treated with first-generation EGFR-TKI and TRT., Patients and Methods: We retrospectively evaluated NSCLC patients simultaneously treated with first-generation EGFR-TKI and thoracic radiotherapy between January 2012 and December 2019 at Shandong Cancer Hospital and Institute, Shandong, China. RP was diagnosed via computed tomography and was classified according to the Common Terminology Criteria for Adverse Events v5.0. The risk factors of RP were identified using uni- and multivariate analyses., Results: Of the 67 patients included, 44.78% (30/67) developed grade ≥ 2 RP. Grade ≥ 2 RP occurred within a median of 3.48 (range 1.07-13.6) months. The EGFR-TKI icotinib, ipsilateral lung V30 > 34%, and overlap time of > 20 days between EGFR-TKI and thoracic radiotherapy were identified to be independent predictive factors of grade ≥ 2 RP., Conclusions: Grade ≥ 2 RP is highly frequent in NSCLC patients simultaneous treated with first-generation EGFR-TKI and thoracic radiotherapy. Icotinib, ipsilateral lung V30 ≤ 34%, and overlap time of ≤ 20 days for EGFR-TKI and thoracic radiotherapy will be helpful to lower the risk of RP in these patients. The addition of thoracic radiotherapy should be cautious, and the treatment strategies can be optimized to reduce the rate of RP for patients treat with simultaneous EGFR-TKI and thoracic radiotherapy.

A 56-year-old male was diagnosed with right lung upper lobe squamous cancer with right hilar and mediastinum lymph node metastasis. After four cycles of neoadjuvant immunochemotherapy, reexamination by computed tomography showed progressive disease of the primary lesion. Then, the patient underwent a right lung upper lobectomy, and hilar and mediastinum lymph node dissection. Surgical pathology showed a partial response to immunochemotherapy. Single-cell RNA sequencing was used to characterize the infiltrating immune cell atlas after neoadjuvant immunochemotherapy; the most common infiltrating immune cell types were cytotoxic CD8+ T cells, monocyte-derived dendritic cells, and macrophages. Imaging mass cytometry revealed a transformation from cold to hot tumor after neoadjuvant immunochemotherapy. In this case study, we are the first to report a case of neoadjuvant immunochemotherapy pseudoprogression, proved by surgical pathology, single-cell RNA sequencing, and imaging mass cytometry. Both single-cell RNA sequencing and imaging mass cytometry revealed an activated immune microenvironment after neoadjuvant immunochemotherapy., Competing Interests: FT and QL were employed by BGI-Qingdao. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jia, Zhu, Gao, Sun, Tan, Liu, Guo and Yu.)

Background: Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown., Methods: Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD., Results: We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation., Conclusions: Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

Immune checkpoint blockades (ICBs) have changed the standard of care of squamous and adenocarcinoma non-small cell lung cancer (NSCLC). Whereas detailed researches regarding ICBs in the two major histological subtypes are rare. In order to uncover the clinical efficacy differences between squamous and adenocarcinoma NSCLC and better understand the underlying immune-regulatory mechanisms, we compared the survival benefits of ICBs between the two subtypes by revealing phase 3 randomized trials and attempted to uncover the immune-regulatory discrepancy. Generally, compared with nonsquamous NSCLC, squamous NSCLC benefited more from ICBs in Keynote 024, CheckMate 026, CheckMate 227 and CheckMate 017 and similar in OAK, but less in Keynote 010 and PACIFIC. We revealed that the tumor mutation burden (TMB) level, the programmed cell death ligand 1 (PD-L1) expression, tumor infiltrating lymphocytes (TILs) in the tumor microenvironment (TME), chemokines, and oncogenic driver alterations within the two subtypes may contributed to the clinical outcomes of ICBs. We prospected that the combinations of ICBs with chemotherapy, radiation therapy, and antiangiogenic therapy could be promising strategies to re-immunize the less immunogenic tumors and further enhance the efficacy of ICBs., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Our study is the first to report an especially high rate of grade 2 or worse radiation pneumonitis in patients treated with thoracic radiotherapy and simultaneous Osimertinib, despite total lung V5, V20 and MLD seeming unlikely to induce radiation pneumonitis., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Prognostic biomarkers that can reliably predict early disease progression of non-small cell lung cancer (NSCLC) are needed for identifying those patients at high risk for progression, who may benefit from more intensive treatment. In this work, we aimed to identify an imaging signature for predicting progression-free survival (PFS) of locally advanced NSCLC. Methods : This retrospective study included 82 patients with stage III NSCLC treated with definitive chemoradiotherapy for whom both baseline and mid-treatment PET/CT scans were performed. They were randomly placed into two groups: training cohort (n=41) and testing cohort (n=41). All primary tumors and involved lymph nodes were delineated. Forty-five quantitative imaging features were extracted to characterize the tumors and involved nodes at baseline and mid-treatment as well as differences between two scans performed at these two points. An imaging signature was developed to predict PFS by fitting an L1-regularized Cox regression model. Results : The final imaging signature consisted of three imaging features: the baseline tumor volume, the baseline maximum distance between involved nodes, and the change in maximum distance between the primary tumor and involved nodes measured at two time points. According to multivariate analysis, the imaging model was an independent prognostic factor for PFS in both the training (hazard ratio [HR], 1.14, 95% confidence interval [CI], 1.04-1.24; P = 0.003), and testing (HR, 1.21, 95% CI, 1.10-1.33; P = 0.048) cohorts. The imaging signature stratified patients into low- and high-risk groups, with 2-year PFS rates of 61.9% and 33.2%, respectively ( P = 0.004 [log-rank test]; HR, 4.13, 95% CI, 1.42-11.70) in the training cohort, as well as 43.8% and 22.6%, respectively ( P = 0.006 [log-rank test]; HR, 3.45, 95% CI, 1.35-8.83) in the testing cohort. In both cohorts, the imaging signature significantly outperformed conventional imaging metrics, including tumor volume and SUV max value (C-indices: 0.77-0.79 for imaging signature, and 0.53-0.73 for conventional metrics). Conclusions : Evaluation of early treatment response by combining primary tumor and nodal imaging characteristics may improve the prediction of PFS of locally advanced NSCLC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Immune checkpoint inhibitors (ICIs) are new and promising therapeutic agents for non-small cell lung cancer (NSCLC). However, along with demonstrating remarkable efficacy, ICIs can also trigger immune-related adverse events. Checkpoint inhibitor pneumonitis (CIP) has been reported to have a morbidity rate of 3% to 5% and a mortality rate of 10% to 17%. Moreover, the incidence of CIP in NSCLC is higher than that in other tumor types, reaching 7% to 13%. With the increased use of ICIs in NSCLC, CIP has drawn extensive attention from oncologists and cancer researchers. Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events. In this review, the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease, prior thoracic irradiation, and combinations with other drugs. Our review also explored potential mechanisms closely related to CIP, including increased T cell activity against associated antigens in tumor and normal tissues, preexisting autoantibodies, and inflammatory cytokines., Competing Interests: *These authors contributed equally to this work., (Copyright: © 2020, Cancer Biology & Medicine.)

Background: Immune checkpoint inhibitors have dramatically changed the landscape of therapeutic management of non-small-cell lung cancer (NSCLC). Tumor mutation burden (TMB) is an important biomarker of the response to cancer immunotherapy. We investigated the relationship between TMB and the imaging, histologic, and genetic features in NSCLC., Materials and Methods: We evaluated the associations between the semantic imaging features (7 quantitative or semiquantitative imaging features and 13 qualitative features that reflect the tumor characteristics) and TMB and built an imaging signature for TMB using logistic regression. Finally, we integrated the imaging signature, histologic type, and TP53 genotype into a composite model., Results: Among 89 patients, 37 (41.6%) had low TMB and 52 (58.4%) had high TMB. Tumors with high TMB were more prevalent in squamous cell carcinoma (P = .017) and those with a TP53 mutation (P < .0001). The absence of concavity was significantly associated with higher TMB (P = .008). An imaging signature containing 5 features, including concavity, border definition, spiculation, thickened adjacent bronchovascular bundle and size, achieved good discrimination between tumors with low and high TMB (area under the curve [AUC], 0.79; 95% confidence interval [CI], 0.69-0.89). The composite model integrating the imaging signature, histologic type, and TP53 genotype improved the classification (AUC, 0.89; 95% CI, 0.82-0.95) compared with the imaging signature alone using the DeLong test (P = .012). The composite model achieved a high sensitivity of 95% and a specificity of 62%., Conclusion: Specific computed tomography features are associated with TMB in NSCLC, and the integration of imaging, histologic, and genetic information might allow for accurate prediction of TMB., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The coexistence of lung cancer and pulmonary tuberculosis (PTB) is uncommon in young patients. We report a case of 22-year-old man who presented with a one-month history of chest pain, cough, slight haemoptysis and weight loss. Following two acid fast bacilli positive sputum samples, a diagnosis of TB was concluded. However, his response to anti-TB therapy was inadequate. A CT scan and further laboratory tests assisted the final diagnosis as c-ros oncogene 1 (ROS1) rearranged lung adenocarcinoma and PTB. Despite severe comorbidities, the patient achieved clinical remission following treatment with the anti-cancer drug, crizotinib and anti- TB therapy. Clinicians should be aware that this comorbidity can occur in all age groups and the clinical and radiological symptoms of the two diseases are similar.

Background: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented., Methods: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded., Results: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy., Conclusions: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC., (© 2019 American Cancer Society.)

Purpose: This study aimed to assess the effect of nanoparticle albumin-bound paclitaxel (nab-PTX) chemotherapy regimens in elderly patients (≥70 years old) with advanced squamous non-small-cell lung cancer (NSCLC)., Patients and Methods: The clinical records of elderly patients aged ≥70 years with advanced squamous NSCLC were reviewed retrospectively. All of these patients received nab-PTX, with or without combination of chemotherapy in Shandong Cancer Hospital and Institute between 1 July 2012 and 30 June 2017. We analyzed the toxicity profiles, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR)., Results: Totally, 52 elderly patients with squamous NSCLC were included in the analysis. For all patients, the ORR was 34.6%, the DCR was 80.8%, median PFS was 5.9 months (95% confidence interval [CI]: 4.0-7.8 months), and median OS was 14.3 months (95% CI: 11.0-17.8 months). Combination with chemotherapy significantly prolonged OS (19.3 vs 11.2 months, P = .016), despite a nonsignificant improvement in PFS (7.1 vs 4.2 months, P = .060) vs monotherapy. For patients who received nab-PTX as first-line treatment, the median PFS and OS were 6.7 months and 17.2 months, respectively, and the median OS in combination therapy subgroup was significantly higher than that in monotherapy group (20.3 vs 11.2 months, P = .013). Meanwhile, the median PFS and OS of patients with nab-PTX as second- or later-line treatment were 4.4 months and 13.3 months, respectively, but no survival benefit was achieved by the combination chemotherapy when compared with single-agent chemotherapy. Hematologic toxicities were the most common adverse events (AEs), which include grade 3 or 4 neutropenia (13.7%), thrombocytopenia (4.1%), and anemia (6.8%). The main nonhematologic toxicities were peripheral sensory neuropathy (39.7%), followed by anorexia and nausea/vomiting., Conclusion: In elderly advanced squamous NSCLC patients, the treatment of nab-PTX was effective and well tolerated., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

To investigate the predictive value of methylthioadenosine phosphorylase (MTAP) on treatment response and survival in advanced lung adenocarcinoma. MTAP expression was detected by immunohistochemistry. Treatment response and survival were compared according to MTAP expression level. The results indicated MTAP-low expression was observed in 61.2% (101/165) of all patients. The objective response rate and disease control rate improved in the MTAP-low group (64.4% vs 46.9%, p = 0.035; 92.1% vs. 79.7%, p = 0.03; respectively). The median progression-free survival and survival time in the MTAP-low group were significantly lower than that in the MTAP-high group (8.1 vs. 13.1 months, p = 0.002; 22 vs. 32 months, p = 0.044). Multivariate analysis demonstrated that brain metastasis (HR 1.55, p = 0.046), thoracic radiation (HR 0.52, p = 0.026), and MTAP-low expression (HR 1.36, p = 0.038) were independent factors on survival. It is concluded that MTAP-low expression could predict improved treatment response but worsened survival in advanced lung adenocarcinoma.

Background: To date, there is no effective treatment for thromboangiitis obliterans (TAO). Anlotinib, as a third-line therapy, is recommended for patients with refractory advanced non-small cell lung cancer (NSCLC). We presented a case report of a patient suffering from right lung squamous cell carcinoma combined with thromboangiitis obliterans, and analyzed the treatment dilemma, which provided a new idea for the treatment of these two diseases., Methods: A patient of right lung squamous cell carcinoma complicated with TAO was admitted to the department of respiratory and critical care medicine of the Shanghai General Hospital in August 2018. The diagnosis and treatment was retrospectively analyzed, and the literature was reviewed., Results: The 73-year-old male patient complained of cough and sputum for 5 months and was diagnosed with NSCLC (T4N2M0, stage IIIb, performance status score 2) in right upper lung by tracheoscopy biopsy. Pigmentation in both lower extremities accompanied by weakened pulse of dorsal foot artery was confirmed. He had a history of smoking, and suspected vascular intermittent claudication and wandering phlebitis for more than one year. Ultrasound indicated multiple arterial occlusion in both upper and lower extremities and deep venous thrombosis in lower extremities. TAO was diagnosed. Peripherally inserted central catheter (PICC) implantation and intravenous infusion post implantation failed and he could not receive chemotherapy. Vascular endothelial growth factor (VEGF) signal pathway dysfunction is also involved in TAO. Anlotinib (12 mg qd po) was selected for treatment NSCLC and TAO, accordingly. He had partial response (PR) and the cancer kept stable for 14 months. At the same time, TAO improved., Conclusions: Anlotinib effectively controlled the growth of NSCLC and improved TAO related symptoms. Anlotinib maybe normalize disordered growth of blood vessels through the VEGF signaling pathway, rather than simply inhibiting angiogenesis.

Background: Immunosuppression caused by tumorigenesis may promote tumor progress and invasion. Here, we investigated whether the characteristics of circulating T lymphocyte subtypes in patients with extensive small cell lung cancer (ED-SCLC) can be used as an alternative marker of tumor progression., Methods: This study included 36 newly diagnosed ED-SCLC patients before treatment and the patients were followed up. 22 age and sex-matched healthy volunteers were selected as control. The percentages and proliferation potential of T lymphocyte subpopulations from peripheral blood were measured., Results: CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) were elevated in ED-SCLC patients compared with healthy controls (p = 0.0083). In contrast, the percentages of CD3 + and CD3 + CD4 + T cells were significantly lower in SCLC patients (p < 0.001; p = 0.0014). The proliferation (%divided) of CD8 + T cells of SCLC patients was suppressed compared with healthy controls (p = 0.0058), but not of CD4 + T cells (p = 0.1611). Multivariate analyses showed that the %divided of CD8 + T cells is an independent predictor for PFS (HR: 4.342, 95% CI 1.324-14.245; p = 0.015). The percentages of peripheral Tregs and the degree of chemotherapy or radiotherapy induced lymphopenia negatively correlated with the proliferation of CD8 + T cells (p = 0.0225, r = - 0.379; p = 0.0003, r = - 0.464)., Conclusion: The present study indicates that SCLC patients have impaired immunity in peripheral blood, and the proliferation potential of circulating CD8 + T cells is a significant predicator for PFS.

Introduction: The aim of the present study was to investigate the value of incorporation 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) maximum standardized uptake value (SUVmax) and neutrophil-to-lymphocyte ratio (NLR) for improving prediction of clinical outcomes of patients with locally advanced non-small-cell lung cancer (LA NSCLC)., Materials and Methods: We retrospectively enrolled 138 patients with unresectable LA NSCLC at our institution from July 2010 to August 2017. Spearman correlation analyses were used to estimate the correlations between SUVmax and NLR level. The univariate and multivariate Cox survival analyses were used to evaluate the prognostic indicators, including the incorporation of SUVmax and NLR. We defined the SUVmax and NLR grade (SNG = 0, 1, or 2) score as the number of risk factors among (1) SUVmax > 11.95 and (2) NLR > 3.82. The SNG score prognostic value was evaluated for overall survival (OS) and progression-free survival (PFS)., Results: Univariate analysis showed that tumor stage, SUVmax, SUVmean, NLR, and SNG score were significantly associated with OS and PFS in patients with LA NSCLC. Kaplan-Meier analysis and log-rank test demonstrated significant differences in both OS and PFS among patients in SNG score (OS, P < .001; PFS, P < .001). Spearman correlation analyses showed that SUVmax had a correlation with the NLR (r = 0.237; P = .005). In subgroup analyses for patients with tumor pathologic stage IIIA/IIIB, we found that the SNG score was significantly associated with OS and PFS in each subgroup (P < .001, P < .001 for OS and P = .027, P < .001 for PFS, respectively). Multivariate analysis showed that the SNG score was a significantly independent prognostic factor for OS (hazard ratio, 1.612; 95% confidence interval, 1.157-2.246; P = .005) and PFS (hazard ratio, 2.241; 95% confidence interval, 1.486-3.379; P < .001)., Conclusion: Incorporation of the SUVmax and NLR improves prediction of clinical outcomes in patients with LA NSCLC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We reported a case of carotid artery stenosis with stroke symptoms detected in a patient with lung cancer after radiotherapy. The patient was a 58-year-old male with a complaint of \"a single episode of temporary amaurosis in the right eye for 10 minutes". The clinical diagnosis at admission, after consideration of the patient's age, medical history, and auxiliary examination results, was as follows: lung cancer; right common carotid artery stenosis; left common carotid artery stenosis; left vertebral artery stenosis; and right subclavian artery occlusion with right subclavian steal syndrome (Grade 3). Carotid angioplasty and stenting (CAS) were subsequently performed. During the 6-month follow-up, we observed no episode of temporary vision loss or other signs of stroke. Clinicians should pay great attention to delayed radiation-induced carotid stenosis. It is recommended that patients with a history of radiotherapy should undergo regular color Doppler ultrasound examination of the cervical region to diagnose, prevent, and treat RICS in an expedient fashion. This approach should improve survival rate and quality of life.

Background: Noninvasive prognostic biomarkers are needed for advanced non-small cell lung cancer (NSCLC) patients with different histological types to identify cases with poor survival. Here, we investigated the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28- T cells in advanced NSCLC patients treated with chemo(radio)therapy and the impact of histological type on them., Methods: Of 232 registered advanced NSCLC patients, 101 treatment-naïve individuals were eligible and included in our study. Flow cytometry was used to evaluate CD8+CD28+ T cells, CD8+CD28- T cells, CD4+ CD25 hi T cells, B cells, natural killer cells, γδT cells, and natural killer T cells in patients' peripheral blood., Results: The median follow-up time was 13.6 months. Fifty-nine (58.4%) patients died by the end of our study. Fifty-three of the 101 advanced NSCLC cases selected for our study were adenocarcinomas (ADs), and 48 were squamous cell carcinomas (SCCs). Multivariate analyses showed that increased levels of CD8+CD28+ T cells independently predicted favorable overall survival (OS) [hazard ratio (HR): 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.021] and progression-free survival (PFS) (HR: 0.66, 95% CI 0.37-0.93, P = 0.038) in ADs, but the prediction in SCCs was not statistically significant. In contrast, high levels of CD8+CD28- T cells independently predicted unfavorable OS (HR: 1.41, 95% CI 1.17-3.06, P = 0.035) and PFS (HR: 2.01, 95% CI 1.06-3.85, P = 0.029) in SCCs, but the prediction in ADs was not statistically significant. ADs had higher levels of CD4+CD25 hi T cells and CD8+CD28- T cells and lower NK cells (all P < 0.05) than SCCs., Conclusions: Our findings uncovered the prognostic values of peripheral CD8+CD28+ T cells and CD8+CD28- T cells in advanced NSCLC patients treated with chemo(radio)therapy, which could help to identify patients with poor outcomes and refine treatment strategies.

Objectives: Current evidence suggests that microorganisms are associated with neoplastic diseases; however, the role of the airway microbiome in lung cancer remains unknown. To investigate the taxonomic profiles of the lower respiratory tract (LRT) microbiome in patients with lung cancer., Materials and Methods: BALF samples were collected in a discovery set comprising 150 individuals, including 91 patients with lung cancer, 29 patients with nonmalignant pulmonary diseases and 30 healthy subjects, and an independent validation set including 85 participants. The samples were assessed by metagenomics analysis. Random forest regression analysis was performed to select a diagnostic panel., Results: In the discovery set, richness was reduced in lung cancer patients compared with that in healthy subjects, and the microbiome of patients with nonmalignant diseases resembled that of patients with lung cancer. Interestingly, Bradyrhizobium japonicum was only found in patients with lung cancer, whereas Acidovorax was found in patients with cancer and nonmalignant pulmonary diseases. A microbiota-related diagnostic model consisting of age, pack year of smoking and eleven types of bacteria was built, and the area under the curve (AUC) for discriminating the patients with cancer was 0.882 (95%CI: 0.807-0.957) in the training set and 0.796 (95%CI: 0.673-0.920) in the independent validation set., Conclusion: Our study demonstrates that the LRT microbiome richness is diminished in lung cancer patients compared with that in healthy subjects and that microbiota-specific biomarkers may be useful for diagnosing patients for whom lung biopsy is not feasible., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Leptomeningeal metastasis (LM) is a devastating and terminal complication of advanced non-small-cell lung cancer (NSCLC), especially in patients harboring epidermal growth factor receptor (EGFR) mutations. The role of whole brain radiation therapy (WBRT) in the treatment of EGFR-mutant NSCLC patients with LM is not conclusive. Therefore, we conducted a retrospective study to evaluate the therapeutic effect of WBRT in this setting., Methods: EGFR-mutant NSCLC patients with LM, who had previously received treatment at the Shandong Cancer Hospital and Institute from July 2014 to March 2018 were reviewed retrospectively. LM was diagnosed by positive CSF cytology and/or leptomeningeal-enhanced magnetic resonance imaging (MRI). Survival was estimated using the Kaplan-Meier method., Results: In total, 51 EGFR-mutated NSCLC patients with LM were eligible for analysis, subdivided into 26 in the WBRT group and 25 in the non-WBRT group. No significant differences were observed in intracranial ORR (15.4% vs. 16%, p = 0.952) and DCR (34.7% vs. 28%, p = 0.611) between the two groups. The median iPFS LM and OS LM for the entire cohort were 3.3 months (95% CI: 2.77-3.83) and 12.6 months (95% CI: 9.66-15.54), respectively. No difference in iPFS LM was observed between the WBRT and non-WBRT groups (median 3.9 vs. 2.8 months; HR = 0.506, p = 0.052). The median OS LM was 13.6 months in the WBRT group, compared with 5.7 months in the non-WBRT group (HR = 0.454, p = 0.022). Multivariate analyses of OS LM showed that KPS ≥ 80 at the time of LM diagnosis (HR = 0.428, 95% CI: 0.19-0.94; p = 0.034) and the administration of EGFR-TKIs (HR = 0.258, 95% CI: 0.11-0.58; p = 0.001) were independent predictors of survival, but WBRT (HR = 0.49, 95% CI: 0.24-1.01; p = 0.54) was not. Toxicities associated with WBRT or other treatment were rare., Conclusion: For EGFR-mutated NSCLC patients with LM, WBRT did not improve intracranial treatment response and survival statistically.

Small cell lung cancer (SCLC) is one of the deadliest cancer types in the world. Despite the high response rate to frontline platinum-containing doublets, relapse is inevitable for the majority of patients and the prognosis is poor. Topotecan, which has limited efficacy, has remained the standard second-line therapy for approximately three decades. Although SCLC has a high mutation burden, the clinical efficacy of immune checkpoint blockades (ICBs) in SCLC is far less pronounced than that in non-small cell lung cancer (NSCLC). Only atezolizumab in combination with chemotherapy improved overall survival over chemotherapy alone in the phase III CheckMate 133 trial and has recently received FDA approval as first-line therapy. Most studies concerning ICBs in SCLC are limited to early-phase studies and found that ICBs were not superior to traditional chemotherapy. Why is there such a large difference between SCLC and NSCLC? In this review, comparative analyses of previous studies indicate that SCLC is even more immunodeficient than NSCLC and the potential immune escape mechanisms in SCLC may involve the low expression of PD-L1 and the downregulation of major histocompability complex (MHC) molecules and regulatory chemokines. In consideration of these immune dysfunctions, we speculate that chemotherapy and radiotherapy prior to immunotherapy, the combination of ICBs with antiangiogenic treatment, and selecting tumor mutation burden in combination with PD-L1 expression as biomarkers could be promising strategies to improve the clinical efficacy of immunotherapy for SCLC.

Background: Leptomeningeal metastasis (LM) is a detrimental complication of advanced non-small-cell lung cancer (NSCLC), and the optimal therapeutic approach for LM patients is in shortage. This retrospective study aimed to investigate the clinical features and prognostic factors of NSCLC patients with LM., Methods: We retrospectively reviewed the medical records of NSCLC patients with LM at the Shandong Cancer Hospital and Institute between July 2014 and March 2018. Identified cases had pathology-proven NSCLC with either positive cerebrospinal fluid cytology or leptomeningeal enhancement by MRI., Results: One hundred and thirty-six NSCLC patients (58 men, 78 women) with LM were enrolled in the retrospective study; median age was 55 years (range, 29-89 years). Fifty-one patients harbored EGFR mutations, ALK rearrangement was detected in 6 patients. Treatment for LM consisted of EGFR-TKIs alone in 11 patients, whole brain radiotherapy (WBRT) alone in 19 patients, Chemotherapy (ChT) alone in 12 patients, EGFR-TKIs plus WBRT in 30 patients, WBRT plus ChT in 25 patients, and EGFR-TKIs plus ChT in 24 patients. The median progression-free survival was 3.9 months (95% confidence interval [CI]: 3.178-4.622), and the median overall survival (OS LM ) was 9.8 months (95% CI:7.5-12.1). Thirty patients who received WBRT plus EGFR-TKIs achieved longer survival than those who only received WBRT (median 13.6 vs 8.8 months; P = 0.027), but did not add any survival benefit than those only received EGFR-TKIs (median 13.6 vs 13.9 months; P = 0.352). A multivariate analysis indicated that KPS ≥ 80 (hazard ratio [HR] = 0.592, 95% CI:0.369-0.95; P = 0.03) and EGFR-TKIs (HR = 0.507, 95% CI:0.283-0.908; P = 0.022) after LM diagnosis were independent favourable predictors of survival, whereas smoking (HR = 1.181, 95% CI:1.009-3.246; P = 0.047) was an independent predictor of poor survival., Conclusions: Our results suggest that patients with good performance statuses, non-smoking patients, and the administration of EGFR-TKIs might improve clinical outcomes in NSCLC patients with LM., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)