Does denosumab offer survival benefits? —Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). Denosumab is a humanized monoclonal antibody to RANK ligand used to prevent skeletal-related events of bone metastases in solid tumors. We are reporting the clinical outcomes in our NSCLC patients who received RANKL inhibitor in combination with ICIs.MethodsThis observational study used retrospective data from a tertiary cancer center from 2015–2020. Stage IV non-small cell lung cancer patients who received denosumab within 30 days of ICIs (pembrolizumab, nivolumab, atezolizumab, ipilimumab) were included. Kaplan-Meier curves were obtained for survival analysis.ResultsWe identified 69 patients and all had skeletal metastases, and 37.7% had brain metastases. Median OS was 6.3 months and median PFS was 2.8 months, with overall response rate (ORR) of 18.8% and disease control rate (DCR) of 40.6%. Median OS in patients with concomitant denosumab and ICIs more than 3 months was 11.5 months, comparing to 3.6 months in patients with <3 months of concomitant therapy (P=0.0005). OS and PFS did not differ with respect to brain metastases or number of skeletal metastases. However, the duration of ICIs and denosumab overlap was associated with improved OS and PFS. Among the 18.8% of patients who achieved complete response (CR) and partial response (PR), six-month survival rate was 100% and one-year survival rate was 69.2%. Most of the patients tolerated denosumab well, and hypocalcemia was the most commonly reported side effect.ConclusionsPatients receiving combination therapy did not perform poorly comparing to published studies despite of poor prognostic features such as brain metastases and numerous skeletal metastases. Although we did notice potential benefit of the longer duration of concomitant use of ICI and denosumab, future prospective clinical trials are needed to evaluate the synergistic effect of RANKL inhibitors/ICI and if duration of RANKL inhibitors matters.     

Bone metastases in non-small cell lung cancer: a narrative review

Background and ObjectiveBone metastases are common in patients with non-small cell lung cancer (NSCLC) and remain a significant source of morbidity, mortality, and diminished quality of life, despite the considerable progress made in the overall management of patients with metastatic NSCLC over the last decade. Understanding the molecular pathogenesis of bone metastases is critical to improving survival, preserving function, and managing symptoms in this patient population. The objective of our review is to provide a comprehensive review of the pathophysiology, clinical presentation, management, and factors predicting the development and prognosis of patients with NSCLC with bone metastases.MethodsAn online electronic search was performed on PubMed and Google Scholar of all English-language literature using combinations of the following keywords: bone metastases, non-small cell lung cancer, pathophysiology, skeletal related events, response to therapy, predictive factors, and immunotherapy. Bibliographies of identified papers were reviewed for additional articles of interest. Observational cohort, retrospective studies, randomized controlled trials (RCTs), meta-analyses, and review articles were examined for this review.Key Content and FindingsBone metastases in lung cancer patients remain a common occurrence, impacting morbidity, mortality, and quality of life. Patients with skeletal related events (SREs) have worse prognosis. There is data supporting use of bisphosphonates and/or denosumab, and these should be considered in all patients with bone metastases. Novel studies comparing the genomic alterations of skeletal metastases and primary tumors are needed. As therapy for patients with advanced disease evolves, more studies are needed to evaluate the interplay between immunotherapy and bone metastases, and in determining the response to treatment in bone.ConclusionsPredicting development and progression of bone metastases could allow earlier and targeted therapy in patients with bone metastases. Predicting and evaluating response to conventional chemotherapy and immune checkpoint inhibitors in NSCLC patients with bone metastases remains an unmet need and merits further study.     

Efficacy and safety of apatinib combined with whole-brain radiation therapy with a simultaneous integrated boost for brain metastases from non-small cell lung cancer: a multicenter retrospective study

BackgroundBrain metastases (BMs) develop in 20–65% of non-small cell lung cancer (NSCLC) patients and are associated with a poor prognosis. Apatinib, a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor 2, is safe and significantly prolongs the survival of chemotherapy-refractory gastric cancer patients. This retrospective study evaluated the safety and efficacy of apatinib combined with concurrent brain radiotherapy in NSCLC patients with BMs.MethodsThis trial enrolled patients with non-recurrent BM from histologically-confirmed NSCLC without any limits regarding the BM size/quantity. Eligibility criteria were patients 18–75 years old with measurable BM from histologically-confirmed NSCLC (including both newly-diagnosed and previously treated NSCLC) and expected survival time greater than 3 months. Oral apatinib (500 or 250 mg/day) was started within 1 week prior to commencing whole brain radiotherapy with simultaneous integrated boost (WBRT-SIB) and continued until one week after radiotherapy completion. In addition to toxicities, analyzed outcomes included intracranial overall response rate (iORR), intracranial disease control rate (iDCR), intracranial progression free survival (iPFS), and overall survival (OS).ResultsFrom July 2016 to January 2020, 16 patients were enrolled in this retrospective study. After 3 months of brain radiotherapy, the iORR was 75%, the iDCR was 100%, and the brain edema index (EI) was significantly reduced compared to that before brain radiation therapy (4.2 vs. 1.9; P=0.02). The median iPFS was 16.5 months [95% confidence interval (CI): 15.1–37.4 months]. The median OS was 26 months (95% CI: 17.0–54.0 months). Most of the patients tolerated apatinib well, but 7 patients had side effects, most commonly grade 1 or 2. Only 2 patients experienced grade 3 adverse events (hypertension and oral mucositis), and no grade 4 or 5 toxicities were observed.ConclusionsApatinib combined with WBRT-SIB appears to be safe and effective in treating BMs in NSCLC patients.     

WBRT for brain metastases from non-small cell lung cancer: for whom and when?—Contemporary point of view

The incidence of brain metastases (BM) is estimated between 20% and 40% of patients with solid cancer. The most common cause of this failure is lung cancer, and in locally advanced non-small cell lung cancer (NSCLC) BM represent a common site of relapse in 30–55% cases. The basic criteria of therapeutic decision-making are based on the significant prognostic factors which are components of prognostic scores. The standard approach to treatment of BM from NSCLC include whole brain radiotherapy (WBRT) which is used as adjuvant modality after local therapy (surgery or stereotactic radiosurgery) or as primary treatment and it remains the primary modality of treatment for patients with multiple metastases. WBRT is also used in combination with systemic therapy. The aim of presented review of literature is trying to answer which patients with BM from NSCLC should receive WBRT and when it could be omitted. There were presented the aspects of application of WBRT in relation to (I) choice between WBRT or the best supportive care and (II) employment of WBRT in combination with local treatment modalities [surgical resection or stereotactic radio-surgery (SRS)] and/or with systemic therapy. According to data from literature we concluded that the most important factor that needs to be considered when assessing the suitability of a patient for WBRT is the patient’s prognosis based on the Lung-molGPA score. WBRT should be applied in treatment of multiple BM from lung cancer in patients with favourable prognosis and in in patients with presence of EML4-ALK translocation before therapy with crizotinib. Whereas WBRT could be omitted in patients with poor prognosis and after primary SRS.     

LDA-SVM-Based EGFR Mutation Model for NSCLC Brain Metastases: An Observational Study

Epidermal growth factor receptor (EGFR) activating mutations are a predictor of tyrosine kinase inhibitor effectiveness in the treatment of non–small-cell lung cancer (NSCLC). The objective of this study is to build a model for predicting the EGFR mutation status of brain metastasis in patients with NSCLC.Observation and model set-up.This study was conducted between January 2003 and December 2011 in 6 medical centers in Southwest China.The study included 31 NSCLC patients with brain metastases.Eligibility requirements were histological proof of NSCLC, as well as sufficient quantity of paraffin-embedded lung and brain metastases specimens for EGFR mutation detection. The linear discriminant analysis (LDA) method was used for analyzing the dimensional reduction of clinical features, and a support vector machine (SVM) algorithm was employed to generate an EGFR mutation model for NSCLC brain metastases. Training-testing-validation (3 : 1 : 1) processes were applied to find the best fit in 12 patients (validation test set) with NSCLC and brain metastases treated with a tyrosine kinase inhibitor and whole-brain radiotherapy.Primary and secondary outcome measures: EGFR mutation analysis in patients with NSCLC and brain metastases and the development of a LDA-SVM-based EGFR mutation model for NSCLC brain metastases patients.EGFR mutation discordance between the primary lung tumor and brain metastases was found in 5 patients. Using LDA, 13 clinical features were transformed into 9 characteristics, and 3 were selected as primary vectors. The EGFR mutation model constructed with SVM algorithms had an accuracy, sensitivity, and specificity for determining the mutation status of brain metastases of 0.879, 0.886, and 0.875, respectively. Furthermore, the replicability of our model was confirmed by testing 100 random combinations of input values.The LDA-SVM-based model developed in this study could predict the EGFR status of brain metastases in this small cohort of patients with NSCLC. Further studies with larger cohorts should be carried out to validate our findings in the clinical setting.     

Local ablative therapy of brain metastasis from non-small cell lung cancer: benefits and limitations

Brain metastases (BMs) are the most common intracranial tumors and non-small cell lung cancer (NSCLC) are responsible for BM more than any other solid tumor. Its frequency is increasing due to of the availability of new imaging techniques, earlier diagnosis and improvement in treatment techniques and survival rates. NSCLC patients with BM represent heterogeneous prognostic group. The possibility of better prognostic stratification associated with more systemic therapy options and imaging and radiation technology advances have led to an increment of evaluation and indication of local ablative radiotherapy. The definite increment in quality of life and the potential overall survival (OS) benefit of its indication must be balanced with eventual higher risk of brain disseminated disease when whole brain irradiation is postponed. Therefore, a multidisciplinary evaluation is recommended to refine and personalize the therapeutic approach. The development of clinical nomograms or evaluation of circulating tumor cells/tumoral DNA that predict the survival free of new lesions may be the tools that will warranty further optimization of the treatment of NSCLC patients with BM. In this review, we report the main aspects of diagnosis, prognosis and therapeutic options and dilemmas evolving local ablative radiotherapy essentially based on seminal, updated prospective studies and ongoing trials.     

High expression of cell adhesion molecule 2 unfavorably impacts survival in non-small cell lung cancer patients with brain metastases

BackgroundLung cancer is one kind of malignant tumor with a high risk for morbidity and mortality compared to other solid organ malignancies. Brain metastases occur in 30–55% of non-small cell lung cancer (NSCLC) patients. Prognosis of NSCLC patients with brain metastases is very poor. Our previous study showed that cell adhesion molecule 2 (CADM2) could regulate the development of brain metastasis in NSCLC cells. Therefore, the objective of the study is to evaluate the effect of CADM2 on the prognosis of NSCLC patients with brain metastases.MethodsThe expression of CADM2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in the tissue of the primary tumor. Patients were followed up and overall survival (OS) was calculated. The relationships between CADM2 and clinicopathological features were analyzed using the chi-square test. Kaplan-Meier analysis was carried out to demonstrate the influence of CADM2 on the OS of patients. Univariate and multivariate Cox analyses were used to determine the prognosis of NSCLC patients with brain metastases.ResultsA total of 139 NSCLC patients with brain metastases from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University, treated between January 2015 and December 2017 were evaluated retrospectively. The expression level of CADM2 in patients ranged from 1 to 17.2677, with a median of 6.0772. Chi-square analysis showed that CADM2 gene expression level was not significantly associated with gender, age, tumor location, histological subtype, tumor T stage, extracranial metastasis, or smoking status. However, CADM2 expression was notably associated with risk for lymph node metastasis. The results of the Kaplan-Meier analysis showed that high expression [CADM2 messenger RNA (mRNA) ≥6.0772] of CADM2 was markedly associated with poor prognosis. Univariate and multivariate Cox analyses demonstrated that CADM2 was an independent risk factor for survival in NSCLC patients with brain metastases (P<0.05).ConclusionsCADM2 expression is up-regulated and closely associated with disease progression and poor prognosis in NSCLC patients with brain metastases. CADM2 expression warrants special consideration given its potential prognostic significance that might help inform clinical decision making.     

Clinical efficacy of crizotinib in Chinese patients with ALK-positive non-small-cell lung cancer with brain metastases

Background

Crizotinib has been associated with intracranial disease control in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients with brain metastases. Continued crizotinib treatment has also been used for prolonged disease control in patients experiencing isolated central nervous system (CNS) failure. However, there are few studies of crizotinib efficacy in ALK-positive Chinese patients. Thus, we retrospectively investigated the clinical efficacy of crizotinib in Chinese ALK-positive NSCLC patients with brain metastases at baseline, and evaluated the clinical benefit of continuing crizotinib beyond CNS failure.

Methods

A total of 120 advanced ALK-positive NSCLC patients treated with crizotinib were enrolled with 38 having brain metastases at baseline. The objective response rate (ORR) and progression-free survival (PFS) were compared between patients with and without brain metastases at baseline. A subset of patients who developed CNS failure continued crizotinib treatment beyond progressive disease (PD), and the second PFS from the time of the first progression was also evaluated.

Results

The ORR of crizotinib was similar between patients with and without brain metastases at baseline (68.4% vs. 69.5%, P=0.904). However, the patients without brain metastases at baseline experienced a longer median PFS [10.0 months, 95% confidence interval (CI), 7.6-12.5 vs. 7.0 months, 95% CI, 6.4-7.6; P=0.021]. Among 88 patients with PD defined Response Evaluation Criteria in Solid Tumors (RECIST), 33 developed CNS failure. A total of 24 patients who developed CNS failure continued crizotinib treatment beyond PD, and they achieved a second median PFS of 6.3 months (95% CI, 2.9-9.7).

Conclusions

Chinese ALK-positive NSCLC patients with brain metastases achieved a similar response to crizotinib and significantly shorter PFS compared to those without brain metastases at baseline. Continuous administration of crizotinib beyond PD in patients developing CNS failure appeared to be a valid treatment strategy.     

Immune checkpoint inhibitors in neoadjuvant therapy of non-small cell lung cancer: a systematic review and meta-analysis

BackgroundOur objective was to explore the safety and feasibility of immune checkpoint inhibitors (ICIs) in the neoadjuvant treatment of non-small cell lung cancer (NSCLC).MethodsEmbase, PubMed and Web of Science were systematically searched from 1^st January 2018 to 1^st August 2021 for studies with data on the treatment-related adverse reactions (TRAE), immune-related adverse events (irAE), perioperative information, major pathological response (MPR), pathologic complete remission (pCR) and objective response rate (ORR). The QUADAS-2 tool was used to assess the quality of the studies, then the data were transformed for meta-analysis. Review Manager 5.3 (Cochrane) was used for statistical analyses with a P value of <0.05 considered significant.ResultsThirteen studies with 358 patients were included in this meta-analysis, of which, 218 patients received ICI and chemotherapy-containing regimens and 140 patients received neoadjuvant ICIs only. The 157 (72.0%) patients who received combined neoadjuvant therapy showed a higher incidence of TRAEs, while only 37 (26.4%) patients who received neoadjuvant ICIs experienced TRAEs. Grade 3 or higher irAEs were observed in 92 (25.7%) patients, of which, 81 patients belonged to the neoadjuvant immunochemotherapy subgroup. The surgical resection rate was between 38.5–100%, with only two patients experiencing a delay in surgery. Complication rates were between 3.6–100% in the 8 studies that reported postoperative complications, with more postoperative complications [35 (18.9%)] identified in the neoadjuvant immunochemotherapy subgroup. Of which 176 patients achieved MPR, 126 received ICI and chemotherapy combined neoadjuvant therapy. Seventy-one of 95 patients who had achieved pCR had undergone ICI and chemotherapy. Compared with the neoadjuvant immunotherapy group, patients undergoing ICI and chemotherapy achieved more radiological response [118 (54.1%)] than patients undergoing ICIs [25 (17.9%)] only. The odds ratio (OR) value of the MPR/pCR/ORR rate in the neoadjuvant immunochemotherapy group was higher [OR =0.55/0.32/0.39, 95% confidence interval (CI): 0.44–0.66/0.22–0.44/0.26–0.53, P=0.0004/0.14/<0.0001] after transformation.DiscussionNeoadjuvant immunotherapy shows lower toxicity and fewer perioperative complications. ICI combined chemotherapy can achieve more pathological relief and clinical benefits in the neoadjuvant treatment of NSCLC but is associated with increased irAE and perioperative complications. However, the small sample size limits the reliability of the research.     

Initial rapidity of tumor growth as a prognostic factor for the therapeutic effect of immune-checkpoint inhibitors in patients with non-small cell lung cancer: evaluation for linear and non-linear correlation

BackgroundImmune-checkpoint inhibitors (ICIs) have been increasingly used for non-small cell lung cancer (NSCLC) treatment in recent years. Although insufficient, the rate of programmed death-ligand 1 expression has been adopted as a predictor of ICI efficacy. We evaluated tumor growth rate as a clinically easy-to-use predictor of the therapeutic effect of ICIs.MethodsThis study is a single-institution retrospective study in Japan. NSCLC patients treated with nivolumab, pembrolizumab, or atezolizumab at Saitama Medical Center from January 1, 2016 to December 31, 2018 were enrolled, and followed until December 31, 2020. We defined and calculated the initial rapidity of tumor progression (IRP) as: the increase in the sum of the diameters of intrathoracic tumors and lymph nodes on two series of chest computed tomography (CT) scans (one obtained at an initial checkup and the other obtained immediately before the first treatment) divided by the number of days between these CT scans. Two coefficients were calculated: the maximal information coefficient (MIC) between IRP and time to treatment failure (TTF) using the Python package with minepy library, and the Spearman’s rank correlation coefficient.ResultsA total of 55 patients (median age, 70 years; 47 men) were enrolled. The median TTF with ICIs was 126 days, and four patients continued to receive ICI treatment at the end of the follow-up. The MIC between IRP and TTF was 0.302 with weak correlation, and the Spearman’s rank correlation coefficient was −0.347 (P=0.00938).ConclusionsThe initial tumor growth rate had a negative linear correlation with the therapeutic effect of ICIs.     

影响非小细胞肺癌脑转移患者放射治疗后生存的临床相关因素分析

目的 探讨非小细胞肺癌（NSCLC）脑转移患者放射治疗后的预后转归及影响患者生存期的相关因素.方法 回顾性分析2004年1月至2010年11月在我院诊治的NSCLC脑转移放疗后103例患者的资料.采用Kaplan-Meier法进行生存分析,以Log-Rank检验比较各亚组生存率差异,采用风险比例模型（COX模型）进行多因素生存相关危险因素分析.结果 103例NSCLC脑转移放疗后患者总体生存期为1～68个月;中位生存期为10个月（95％CI：7.231～ 12.769个月）,1年生存率为46.0％,2年生存率为22.0％;COX多因素分析结果 显示：体能状态评分（ECOG）、分级预后评估指数（GPA）是影响患者生存率的独立预后因素（P =0.024,P=0.000）.Log-Rank检验行GPA亚组分析显示,4组间生存曲线有显著性差异（P=0.000）.结论 ECOG评分、GPA是影响NSCLC脑转移放疗后患者生存率的独立预后因素;GPA指数模型可以反映放射治疗后NSCLC脑转移患者的预后.     

Durable response to immunotherapy plus chemotherapy in a patient with untreated,brain-metastatic,EGFR exon 20 insertion mutation lung adenocarcinoma: A case report

Rational:Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion.Patient concerns:A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis.Diagnosis:Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y).Interventions:The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019.Outcomes:The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment.Lessons:This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.     

肺癌免疫治疗预测指标在非小细胞肺癌免疫治疗中的预测价值

目的:探索由中性粒细胞淋巴细胞比率(NLR)联合乳酸脱氢酶(LDH)得出的新型肺癌免疫治疗预测指标(IOPI)在非小细胞肺癌(NSCLC)免疫检查点抑制剂治疗中的预测价值。方法:对2018年1月至2019年7月来自空军军医大学第一附属医院和空军军医大学第二附属医院共5个科室的88例使用PD-1/PD-L1抑制剂的NSC...     

Immune checkpoint inhibitor-related interstitial lung disease in patients with advanced non-small cell lung cancer: systematic review of characteristics,incidence, risk factors,and management

BackgroundImmune checkpoint inhibitors (ICIs) are widely used in cancers with or without other treatments. Immune-related adverse events (irAEs) have been reported as side effects of ICIs and involve various organs. Pneumonitis, which is also called ICI-related interstitial lung disease (ILD), is one of the life-threatening adverse events. In this report, we reviewed the safety of ICIs and risk factors for ICI-related ILD in non-small cell lung cancer (NSCLC) patients.MethodsDatabases (The National Center for Biotechnology Information, PubMed, Cochrane Library, Google Scholar, and Embase) were searched for the literature on pulmonary adverse events and immunotherapy following PRISMA guidelines. All studies published in English between January 2016 and June 2021 were included.ResultsOne-hundred twenty-five articles were included at final. Pre-existing ILD as well as asthma and chronic obstructive lung disease (COPD) were associated with high risk for the development of ICI-related ILD, however, it did not affect the prognosis. The treatment of ICI-related ILD is different according to the severity grades, which includes discontinuation of ICI, corticosteroids, and for steroid-refractory ILD, other immunosuppressants. Rechallenging of ICI should be carefully considered in selected patients.DiscussionPatients with pre-existing lung disease and poor lung function need more attention for the development of ICI-related ILD. It is necessary to be aware of clinical manifestation of ICI-related ILD with prompt management.     

COX-2-related tumor immune microenvironment in non-small cell lung cancer: a novel signature to predict hot and cold tumor

BackgroundAt present, non-small cell lung cancer (NSCLC) remains a great threat to the health of people worldwide. Immune checkpoint inhibitors (ICIs) have shown positive results in the treatment of advanced NSCLC. However, the treatment response of ICIs is not stable and unpredictable. We used a bioinformatics analysis to determine a novel signature to diagnose the hot and cold tumor in NSCLC which may guide the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) therapeutic strategy.MethodsThe RNA-seq dataset and clinical data of 485 lung adenocarcinoma (LUAD) and 473 lung squamous cell carcinoma (LUSC) samples from The Cancer Genome Atlas (TCGA) database. Tumor infiltrating immune cells was calculated by CIBERSORT algorithm and ConsensusClusterPlus was used to classify the hot and cold tumor. Least absolute shrinkage and selection operator (LASSO) regression, Support Vector Machine (SVM) and Gaussian Mixture Model (GMM) were performed to determine the diagnostic area under curve (AUC) of novel signature of ICIs treatment. Overall survival (OS) analysis was based on the Kaplan-Meier statistical method.ResultsIn this study, we found that the expression of PD-1/PD-L1 is associated with COX2 (PTGS2) expression. We identified novel signatures [STMN3, KIRREL1, SH2D3C, VCL, PDCD1, CD274, PTGS2, combined diagnostic (AUC) =0.838], in order to diagnose the hot and cold tumor subtype to indicate the treatment response of PD-1/PD-L1 inhibitor in NSCLC. Furthermore, we found that in hot tumor subtype, high PDCD1 expression group had worse OS than low PDCD1 expression group (P=0.047); high SH2D3C expression group had worse OS than low SH2D3C expression group either (P=0.003). SH2D3C was correlated to PD-1 expression in NSCLC samples (R=0.49, P<0.001). We speculated that SH2D3C likely plays a crucial role in PD-1-related immunotherapy in NSCLC patients. Pathway enrichment showed that the focal adhesion (P=0.005) and actin cytoskeleton (P=0.022) pathways were associated with OS.ConclusionsThis study aimed to identify the classification of hot and cold tumors, and develop a novel signature to predict the ICI treatments response for PD-1/PD-L1 high expression NSCLC patients.     

Camrelizumab plus zoledronic acid showed sustained efficacy in a patient with cranial and spinal metastases from lung adenocarcinoma

The role of anti-programmed cell death protein-1 (PD-1) antibody camrelizumab in brain metastases (BMs) from lung adenocarcinoma is uncertain. Herein, for the first time, we report the efficacy of camrelizumab in a patient with chemotherapy-refractory BMs from lung adenocarcinoma. A 49-year-old male non-smoker was admitted with cough and back pain. Primary lung adenocarcinoma with brain and spinal metastases was diagnosed. The specimen from CT-guided lung biopsy showed positive expression of PD-L1 (~20%). The BMs were enlarged after first-line intravenous pemetrexed/cisplatin and zoledronic acid; whereas second-line camrelizumab demonstrated impressive complete remission of the BMs. The intracranial progression-free survival and overall survival of the patient since immunotherapy were more than 12 months and 20 months, respectively. In addition, we searched PubMed for relevant studies from inception to May 2020, and a total of 23 reports enrolling 1187 patients also indicated the promising efficacy of immunotherapy for BMs from lung cancer. However, more and better evidence are still needed before a definite conclusion could be drawn.     

ICI 182,780 penetrates brain and hypothalamic tissue and has functional effects in the brain after systemic dosing

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg.d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 alpha-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg.d) dose dependently inhibited this effect. ICI (3.0 mg/kg.d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg.d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg.d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.     

Radiotherapy for brain metastases from small-cell lung cancer in distinct clinical indications and scenarios

Management of brain metastases (BM) from small-cell lung cancer (SCLC) is complex and not supported by a strong evidence from prospective clinical trials. Owing to the different clinical and pathological characteristics of SCLC, patients with this histology were not included in the prospective studies on the value of whole-brain radiotherapy (WBRT) and local surgical or ablative radiation treatment like stereotactic radiosurgery (SRS). Chemotherapy also represents a major part of the armamentarium against BM from SCLC due to the well-recognized chemoresponsiveness of this cancer and the frequent presentation of BM with extracranial progression. WBRT in combination with chemotherapy has long been a standard approach in this setting. However, data on the neurocognitive toxicity and the lack of documented impact on overall survival of WBRT in the management of BM from other solid tumors, as well as the increasing availability of the stereotactic radiotherapy technologies, has led to the increasing use of SRS with omission of WBRT also in SCLC. In the current review the use of different modalities of radiotherapy and ways of combining radiotherapy with chemotherapy for BM from SCLC will be presented for distinct clinical situations: presentation of BM synchronous with primary, metachronous presentation of BM—without previous prophylactic cranial irradiation (PCI) vs. after PCI, and asymptomatic BM found at the staging before PCI.     

A meta-analysis comparing hyperfractionated vs. conventional fractionated radiotherapy in non-small cell lung cancer

Background

Lung cancer is the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) accounts for most lung cancer and carries a 5-year survival rate of 15%. The squamous cell carcinoma, large cell carcinoma, and adenocarcinoma are the most common types of NSCLC. The data on long term use of hyperfractionated radiotherapy (HRT) in NSCLC treatment is lacking. We performed a meta-analysis, based on published randomized trials to compare HRT [continuous hyperfractionated accelerated radiotherapy (CHART)/continuous hyperfractionated accelerated radiotherapy weekend less (CHARTWEL)] vs. conventional fractionated (CF) radiotherapy in the treatment of NSCLC.

Methods

A systematic search through the bibliographic databases, PubMed, Google Scholar and Cochrane Library was performed till December 2013.

Results

Of 63 studies identified, 3 studies were analyzed. All were randomized studies and included 1,005 patients in total. The pooled results of the studies showed that HRT did not improve overall survival (OS) of patients suffering from NSCLC compared to CF after 2 years (OR, 1.29; 95% CI, 0.98-1.71; P=0.16) and 3 years (OR, 0.55; 95% CI, 0.34-0.87; P=0.22) which was statistically significant. HRT was no better than CF in controlling tumour (OR, 1.40; 95% CI, 1.03-1.91). No significant difference in metastasis free survival (OR, 1.08; 95% CI, 0.83-1.39) and late dysphagia (OR, 1.48; 95% CI, 0.75-2.92) were observed between the two groups.

Conclusions

The results of the present meta-analysis showed that HRT was not significantly better to conventional radiotherapy in NSCLC treatment.