Recursive Partitioning Analysis Classification and Graded Prognostic Assessment for Non-Small Cell Lung Cancer Patients with Brain Metastasis:A Retrospective Cohort Study

Objective：To assess prognostic factors and validate the effectiveness of recursive partitioning analysis （RPA） classes and graded prognostic assessment （GPA） in 290 non-small cell lung cancer （NSCLC） patients with brain metastasis （BM）.Methods：From Jan 2008 to Dec 2009,the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation,systemic chemotherapy and tyrosine kinase inhibitors （TKIs） in two institutes were analyzed.Survival was estimated by Kaplan-Meier method.The differences of survival rates in subgroups were assayed using log-rank test.Multivariate Cox＇s regression method was used to analyze the impact of prognostic factors on survival.Two prognostic indexes models （RPA and GPA） were validated respectively.Results：All patients were followed up for 1-44 months,the median survival time after brain irradiation and its corresponding 95% confidence interval （95% CI） was 14 （12.3-15.8） months.1-,2-and 3-year survival rates in the whole group were 56.0%,28.3%,and 12.0%,respectively.The survival curves of subgroups,stratified by both RPA and GPA,were significantly different （P0.001）.In the multivariate analysis as RPA and GPA entered Cox＇s regression model,Karnofsky performance status （KPS） ≥ 70,adenocarcinoma subtype,longer administration of TKIs remained their prognostic significance,RPA classes and GPA also appeared in the prognostic model.Conclusion：KPS ≥70,adenocarcinoma subtype,longer treatment of molecular targeted drug,and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.

Surgery Versus Stereotactic Radiosurgery for Single Synchronous Brain Metastasis from Non-Small Cell Lung Cancer

Objective： The aim of this study is to compare the effectiveness of surgery with stereotactic radiosurgery （SRS） for patients with a single synchronous brain metastasis from successfully treated non-small cell lung cancer. Methods： Between 1995 and 2002, 53 patients underwent resection of both primary non-small cell lung cancer and the associated single brain metastasis. There were 33 men and 20 women with a mean age of 57 years （range, 32-85 years）. At the time of diagnosis, 42 patients experienced lung cancer related symptoms, whereas 11 patients experienced brain metastases-related symptoms. 42 patients had received thoracic surgery first, and 11 patients had undergone neurosurgery or radiosurgery first. Pneumonectomy was performed in 9 out of 42 patients （21.4%）, lobectomies in 30 （71.4%）, and wedge resection in 3 （7.2%）. 48 patients （90.5%） underwent complete lymphadenectomy. 35 patients underwent brain metastasectomy. 18 underwent SRS. Results： There was no postoperative mortality and severe complications after either lung or brain surgery. Histology showed 34 adenocarcinomas, 16 squamous cell carcinomas, and 3 large cell lung cancers. 15 patients （28.3%） had no evidence of lymph node metastases （No）, 20 patients （37.7%） had hilar metastases （N1）, and 18 patients （34%） had mediastinal metastases （N2）. The 1-, 2-, 3- and 5-year overall survival rates were 49%, 19%, 10%, and 5%, respectively. The corresponding data for neurosurgery group were 55%, 17%, 11%, and 6%, respectively. The median survival time was 13 months. For SRS group the corresponding data were 44.8%, 20.9% 10.5%, and 2%, respectively. The median survival time was 14 months. The differences between the two groups were not significant （P〉0.05）. In lymph node negative patients （No）, the overall 5-year survival rate was 10%, as compared with a 1% survival rate in patients with lymph node metastases （N1-2）. The difference was significant （P〈0,01）. For adenocarcinomas, the 5-year survival rate was 5%. The correspondent data for squamous cell lung cancers was 3%. The difference was not significant （P〉0.05）. Conclusion： Although the overall survival rate for patients who have brain metastases from NSCLC is poor, surgical resection or radiosurgery may be beneficial in a select group of patients with synchronous brain metastases and lung cancer without lymph node metastases.

Implications of the autophagy core gene variations on brain metastasis risk in non-small cell lung cancer treated with EGFR-TKI

Objective The brain is the main site of failure in cancer patients with epidermal growth factor receptor(EGFR)mutations undergoing treatment.However,identifying patients who may develop brain metastases(BM)is difficult.Autophagy is critical for cancer initiation and progression.We hypothesized that genetic variants in autophagy core genes might contribute to BM risk of non-small cell lung cancer(NSCLC)following treatment with EGFR tyrosine kinase inhibitor(EGFR-TKIs).Methods We systematically examined 16 potentially functional genetic polymorphisms in seven autophagy core genes among 105 TKI-treated NSCLC patients.Kaplan-Meier curves were plotted to assess the cumulative BM probability.Univariate and multivariate Cox proportional hazard regression analyses were utilized to calculate hazard ratios(HRs)and 95%confidence intervals(CIs).We evaluated the potential associations of these genes with subsequent BM development.Results We found that ATG16L1:rs2241880,ATG10:rs10036653,rs3734114,and ATG3:rs7652377 are significantly associated with NSCLC treated with EGFR-TKIs(all P<0.05).BM developed more often in patients with ATG3 rs7652377 CC genotype(33%),ATG10 rs10036653 AA genotype(43%),ATG10:rs3734114 CT/CC genotype(46%),and ATG16L1 rs2241880 AA genotype(37%)compared to patients with AA genotypes at rs7652377(12%),AT/TT genotypes at rs10036653(16%),the TT genotype at rs3734114(13%),or AG/GG genotypes at rs2241880(17%).Conclusion These associations may be critical for understanding the role of autophagy in BM risk.Future prospective studies are needed to determine if prophylactic cranial irradiation(PCI)could offer a survival benefit in this group of patients.

A Phase Ⅰ trial of dose escalation of topotecan combined with whole brain radiotherapy for brain metastasis in lung cancer

Objective The aim of this study was to define the maximum-tolerated dose (MTD) and observe the toxicity of escalating topotecan combined whole brain radiotherapy for brain metastasis in lung cancer.

Therapy for non-small-cell lung cancer patients with brain metastasis

Brain metastasis is a major cause of poor prognosis and high mortality for non-small cell lung cancer patients. The prognosis of non-small-cell lung cancer(NSCLC) patients with brain metastasis is generally poor and more effective treatment is required to improve their prognosis. Whole-brain radiotherapy, surgery, stereotactic radiosurgery, chemotherapy and targeted therapy are the main treatment for brain metastasis. This review focuses on the five therapeutic strategy and in particular, on targeted therapy.

Estrogen Receptor β of Host Promotes the Progression of Lung Cancer Brain Metastasis of an Orthotopic Mouse Model

Estrogen receptors (ERα and ERβ) in the brain play critical roles in maintaining brain tissue homeostasis and in tissue repair after injury. Growth of cancer metastasis in the brain is a constant damaging process. The role of ERs of the host in the progression of cancer brain metastasis is unknown. To determine the role of ERβ of host in the progression of lung cancer brain metastasis, we used an isogenic murine lung cancer cell line, Lewis lung carcinoma cells (3LL), to produce orthotopic lung cancer brain metastases in wild type and ERβ knockout (ERβ-/-) mice. In the wild type mice, we found that ERα and ERβ appeared in the tumor associated reactive astrocytes at 24hr after injection of tumor cells, and ERβ remained thereafter while ERα disappeared after 1 week. The metastasis bearing ERβ-/- mice survived significantly longer than the wild type mice. To further test the role of ERβ of reactive astrocytes in the survival of cancer cells, we knocked down ERβ in cultured actrocytes using shRNA and performed 3D co-culture with 3LL cells in the presence/absence of chemotherapeutic agents, oxaliplatin and 5-fluorouracil. We found that loss of ERβ in astrocytes significantly reduced the survivability of 3LL cells co-cultured with astrocytes. It is concluded that ERβ of host, especially ERβ in reactive astrocytes, promotes the progression of lung cancer brain metastasis and ERβ might be a potential therapeutic target for lung cancer brain metastasis.

Predictive Factors of Intracranial Response of Immune Checkpoint Inhibitors in Patients with Brain Metastasis from Non-Small Cell Lung Cancer

Background: Immune checkpoint inhibitors (ICI)s were recently approved for the treatment of advanced non-small cell lung cancer (NSCLC). Whereas brain metastases (BM) are frequent in NSCLC patients, data are missing regarding ICIs intracranial efficacy and tolerance in patients with BM from NSCLC. Methods: This retrospective study was performed in the Multidisciplinary Oncology and Therapeutic Innovation department, Marseille, France between April 2013 and February 2016. Data from patients with NSCLC with at least one BM, and treated with ICIs (anti-PD1, anti-PDL1 or anti-CTL4) were analyzed. Clinical, biological data and outcomes were retrieved from electronic patients’ records. We assessed ICIs intracranial efficacy and tolerance. Results: Data from 55 patients were analyzed. Objective Response Rate (ORR) and Disease Control Rate (DCR) were respectively of 1.8 and 36.4%. Median overall survival was 17.2 months and median progression free survival was 2.9 months. Intracranial ORR (icORR) and intracranial DCR (icDCR) were respectively 16.4% and 45.5%. Both were independent of smoking status, intracranial treatment, performance status, pathology, molecular profile and the presence or number of BM at diagnosis. However, there was a trend towards an association between icORR and ECOG PS (p = 0.05), tobacco status (p = 0.057) and intracranial treatment. Adverse events were seen in 38.2% patients without identified predictive factor. Neurological symptoms appeared in 5.5% patients during immunotherapy and improved in 3.63% patients. Conclusions: ICIs can be used safely on patients with BM from NSCLC. However, intracranial response is heterogeneous in such patients and we showed ECOG PS, tobacco smoking and intracranial treatment to be associated with an improved icORR. This is the first study looking for predictive factors of intracranial response of ICIs in patients with BM from NSCLC.

Unusual Cystic and Papillary Appearance of Brain Metastasis from Papillary Lung Adenocarcinoma on MRI. Radiologic-Pathologic Correlations in Two Similar Cases

We report two cases of brain metastasis from a lung adenocarcinoma. Magnetic Resonance Imaging (MRI) appearance was closely correlated with the macroscopic and microscopic findings that showed multiples nodules of a well-differentiated papillary adenocarcinoma with secreting tubules, surrounded by mucoid fluid.

Relationship between HER-2 overexpression and brain metastasis in esophageal cancer patients

AIM:To study if HER-2 overexpression by locally advanced esophageal cancers increase the chance of brain metastasis following esophagectomy.METHODS:We retrospectively reviewed the medical records of esophageal cancer patients who underwent esophagectomy at University of Iowa Hospitals and Clinics between 2000 and 2010.Data analyzed consisted of demographic and clinical variables.The brain metastasis tissue was assayed for HER-2 overexpression utilizing the FDA approved DAKO Hercept Test.RESULTS:One hundred and forty two patients were reviewed.Median age was 64 years(36-86 years).Eighty eight patients(62%) received neoadjuvant chemoradiotherapy.Pathological complete and partial responses were achieved in 17(19%) and 71(81%) patients.Cancer relapsed in 43/142(30%) patients.The brain was the first site of relapse in 9/43 patients(21%,95% CI:10%-36%).HER-2 immunohistochemistry testing of the brain metastasis tissue showed that 5/9(56%) cases overexpressed HER-2(3+ staining).CONCLUSION:HER-2 overexpression might be associated with increased risk of brain metastasis in esophageal cancer patients following esophagectomy.Further studies will be required to validate this observation.

Chemotherapy combined with bevacizumab for small cell lung cancer with brain metastases:A case report

BACKGROUND Small cell lung cancer(SCLC)is a common and aggressive subtype of lung cancer.It is characterized by rapid growth and a high mortality rate.Approximately 10%of patients with SCLC present with brain metastases at the time of diagnosis,which is associated with a median survival of 5 mo.This study aimed to summarize the effect of bevacizumab on the progression-free survival(PFS)and overall survival of patients with brain metastasis of SCLC.CASE SUMMARY A 62-year-old man was referred to our hospital in February 2023 because of dizziness and numbness of the right lower extremity without headache or fever for more than four weeks.The patient was diagnosed with limited-stage SCLC.He received 8 cycles of chemotherapy combined with maintenance bevacizumab therapy and achieved a PFS of over 7 mo.CONCLUSION The combination of bevacizumab and irinotecan effectively alleviated brain metastasis in SCLC and prolonged PFS.

Gastric metastasis of small cell lung carcinoma:Three case reports and review of literature

BACKGROUND Small cell lung carcinoma(SCLC)is highly susceptible to metastasis in the early stages of the disease.However,the stomach is an uncommon site of metastasis in SCLC,and only a few cases of this type of metastasis have been reported.Therefore,SCLC gastric metastases have not been systematically characterized and are easily missed and misdiagnosed.CASE SUMMARY We report three cases of gastric metastasis from SCLC in this article.The first patient presented primarily with cough,hemoptysis,and epigastric fullness.The other two patients presented primarily with abdominal discomfort,epigastric distension,and pain.All patients underwent gastroscopy and imaging examinations.Meanwhile,the immunohistochemical results of the lesions in three patients were suggestive of small cell carcinoma.Finally,the three patients were diagnosed with gastric metastasis of SCLC through a comprehensive analysis.The three patients did not receive appropriate treatment and died within a short time.CONCLUSION Here,we focused on summarizing the characteristics of gastric metastasis of SCLC to enhance clinicians'understanding of this disease.

Tumor microenvironment in lung cancer-derived brain metastasis

Brain metastasis(BM)is the leading cause of mortality in lung cancer patients.The process of BM(from initial primary tumor development,migration and intravasation,dissemination and survival in the bloodstream,extravasation,to colonization and growth to metastases)is a complex process for which few tumor cells complete the entire process.Recent research on BM of lung cancer has recently stressed the essential role of tumor microenvironment(TME)in assisting tumor cells in the completion of each BM step.This review summarizes recent studies regarding the effects of TME on tumor cells in the entire process of BM derived from lung cancer.The identification of vulnerable targets in the TME and their prospects to provide novel therapeutic opportunities are also discussed.

Abemaciclib-induced lung damage leading to discontinuation in brain metastases from breast cancer: A case report

BACKGROUND This case report addresses the dearth of effective therapeutic interventions for central nervous system metastases in patients with HER2-negative breast cancer.It presents a unique case of a woman with estrogen receptor-positive,HER2-negative breast cancer who developed brain metastasis.The report highlights her initial favorable response to abemaciclib and letrozole therapy prior to the discon-tinuation due to drug-induced lung damage(DILD).CASE SUMMARY In this comprehensive case summary,we present the clinical course of a woman in her 60s,who 11 years following primary breast cancer surgery,was diagnosed with multiple brain metastases.As a third-line systemic therapy,she underwent treatment with abemaciclib and letrozole.This treatment approach yielded a near-partial response in her metastatic brain lesions.However,abemaciclib adminis-tration ceased due to the emergence of DILD,as confirmed by a computed tomography scan.The DILD improved after 1 mo of cessation.Despite ongoing therapeutic efforts,the patient’s condition progressively deteriorated,ultimately resulting in death due to progression of the brain metastases.CONCLUSION This case underscores the challenge of managing adverse events in responsive brain metastasis patients,given the scarcity of therapeutic options.

Combined Therapy of Brain Metastasis in Lung Cancer

In order to confirm the anti-carcinoma effect of 10 % Brucea javanica emulsion, 68 casesof brain metastasis as a complication of lung cancer were randomly divided into 2 groups. One group wastreated with radiotherapy alone, the other was treated with a combination of radiotherapy and intravenousinjection of 10 % Brucea javanica emulsion. The results showed that the median survival duration (15months in the test group, 10 months in the control group) and the quality of life of the patients in the com-bined (test) group was much better than in the radiotherapy alone (control) group. The results suggest the10 % Brucea javanica emulsion exhibits a synergic action with the radiotherapy in the treatment of brain-metastasis as a complication of lung cancer.

Unusual magnetic resonance imaging findings of brain and leptomeningeal metastasis in lung adenocarcinoma:A case report

BACKGROUND Metastatic tumors are the most common malignancies of central nervous system in adults,and the frequent primary lesion is lung cancer.Brain and leptomeningeal metastases are more common in patients with non-small-cell lung cancer harboring epidermal growth factor receptor mutations.However,the coexist of brain metastasis with leptomeningeal metastasis(LM)in isolated gyriform appearance is rare.CASE SUMMARY We herein presented a case of a 76-year-old male with an established diagnosis as lung adenocarcinoma with gyriform-appeared cerebral parenchymal and leptomeningeal metastases,accompanied by mild peripheral edema and avid contrast enhancement on magnetic resonance imaging.Surgical and pathological examinations confirmed the brain and leptomeningeal metastatic lesions in the left frontal cortex,subcortical white matter and local leptomeninges.CONCLUSION This case was unique with respect to the imaging findings of focal gyriform appearance,which might be caused by secondary parenchymal brain metastatic tumors invading into the leptomeninges or coexistence with LM.Radiologists should be aware of this uncommon imaging presentation of tumor metastases to the central nervous system.

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials:a trend over decades

Aim:To investigate the frequencies and trends of brain metastases(BMs)as exclusion criteria in extensive-stage small cell lung cancer(ES-SCLC)trials.Methods:We conducted a comprehensive search to identify prospective clinical trials in patients with ES-SCLC.PubMed searches were conducted with the key words“small cell lung cancer”and“extensive”.The online archives of 20 oncology journals were also searched.Recent review articles in ES-SCLC were also investigated for additional articles.Eligible studies must have enrolled primarily ES-SCLC and been published in English.Studies involving brain/chest radiation and brain metastasis-specific trials were excluded.Studies were categorized into allowed/undefined,conditional,or complete exclusion of BM.Results:In total,491 published studies were identified by PubMed(240),journal websites(198),and review articles(53).Early publication year(1970-1999)and first-line/maintenance setting were associated with higher incidence of complete exclusion of cases with BMs(P<0.0001 and 0.0233,respectively).Incidence of complete exclusion was 27%in the 1990s,and then decreased to 12%in the 2000s and 8%in the 2010s.Conclusion:A significant number of ES-SCLC trials continues to exclude patients with BM.Future studies need to ease eligibility regarding BM according to ASCO/Friends recommendations.

Risk factors and treatments for brain metastasis in patients with adenocarcinoma of the lung: a retrospective analysis of 373 patients

Background: Risk factors and treatments for brain metastasis (BM) in patients with adenocarcinoma have not been fully profiled in previous studies because of the enrolment of patients with tumours of mixed histology. Thus, we specifically addressed the issue in patients with adenocarcinoma. Methods: Clinical data for 373 patients with pathologically confirmed adenocarcinoma were studied retrospectively. Factors including age (≤60 vs.＞60), gender (male vs. female), stage at diagnosis, T status (T1-2 vs. T3-4), N status (N0-1 vs. N2-3), epidermal growth factor receptor (EGFR) mutation status (wild-type vs. mutant) and smoking status (never vs. current) were analyzed. Results: In multivariate analysis, age (P=0.006) and N status (P=0.041) were independent risk factors for BM. In patients with BM, adding systemic therapy to local therapy improved median post-brain-metastasis survival (mPBMS) (P=0.02). However, if stratification was conducted according to the recursive partitioning analysis (RPA) classification or graded prognostic assessment (GPA) scoring, only patients in RPA class Ⅱ (P=0.020) or with GPA score 1.5-2.5 (P=0.032) could benefit from local plus systemic therapy. Those who received both pemetrexed and tyrosine kinase inhibitors (TKIs) as systemic therapies had a longer mPBMS than those who received TKIs alone, regardless of whether local therapy was applied. In patients with EGFR-sensitive mutations, TKIs therapy led to a longer mPBMS than conventional chemotherapy (P=0.002). Conclusions: Adenocarcinoma patients who were younger than 60 years of age and those with N2-3 disease have a significantly higher risk of BM. The addition of systemic therapy to local therapy can significantly prolong mPBMS, but the survival benefit confined in certain populations. Patients with opportunity to receive both pemetrexed and TKIs had the longest mPBMS.

Updates in the management of brain(leptomeningeal) metastasis of lung cancer

Brain(leptomeningeal) metastasis is one of the most common and severe complications of lung cancer. This article interprets expert consensus on the treatment advice for brain(leptomeningeal) metastasis of lung cancer, expounding on its epidemiology, diagnostic standards, efficacy assessment, treatment advice, and other aspects.

Risk factors of brain metastasis of lung squamous cell carcinoma:a retrospective analysis of 188 patients from single center

Background:To explore risk factors and the efficacy of treatment strategies for brain metastasis (BM) in squamous cell carcinoma (SCC) of the lung.Methods:The clinical data of 188 pathologically confirmed as squamous cell carcinoma or adenosquamous carcinoma patients were studied retrospectively. Factors including age (<60 vs.≥60), gender, stage at diagnosis, T status (T1-2 vs. T3-4), N status (N0-1 vs. N2-3), histology (squamous vs. adenosquamous), smoking history (non-smoker vs. currentsmoker) and serum tumor markers (normal vs. elevated) were analyzed.Results:The incidence of BM was 19.1％(36/188) in our cohort. Patients who were female (p=0.005), had advanced disease at diagnosis (p<0.001), had adenosquamous carcinoma histology (p=0.033) or had elevated serum level of CEA at diagnosis (p<0.001) had significantly higher incidence of BM. In multivariate analysis, female (p=0.034, HR=18.874) and elevated serum level of CEA at diagnosis (p=0.009, HR=19.824) were independent risk factors of BM. BM patients who received additional systemic therapy after local therapy had significantly longer post-BM survival than those who received local therapy only (p=0.004, HR=0.058). Gemcitabine/platinum-containingregimen (GP) and taxans/platinum-containing regimen (TP) led to comparable brain-metastasis-free survival (BMFS) (p=0.10).Conclusions:Females and patients with elevated serum level of CEA at diagnosis had a higher risk of developing BM. The following systemic therapy after local therapy prolonged the survival of BM patient, but the efficacy of GP and TP was comparable in terms of preventing BM.

A CLINICOPATHOLOGICAL STUDY OF MEDIASTINAL LYMPH NODE METASTASIS OF LUNG CANCER

Objective: To investigate pathologically the characteristics of lung cancer metastasis by mediastinal lymph node ways (N2). Methods: Of 398 lung cancer patients who underwent radical pulmonectomy and extensive lymph node dissection, 160 patients were diagnosed as with N2 metastasis, their 352 groups of mediastinal lymph nodes invaded were subject to the pathological study. Results: Evidences showed that the N2 metastasis of lung cancer was very active. It appears as single group or multi-group or jumping-form metastasis, rating 41.2%, 58.8% and 29.3% respectively. In addition, the extension of N2 metastasis was large, the most concentrated site was the 7th group lymph node (48.8%), then the 4th, 3rd and 5th group, rating 45.6%, 31.3% and 25.6% respectively. The occurrence of N2 metastasis was highly correlated with the site, size, histopathological type and the grade of differentiation of the cancer. An another feature of N2 metastasis was the invasion of metastasized lymph node into the bronchial wall, especially in adenocarcinoma. Conclusion: In order to achieve the radical removal of tumor, it is necessary to dissect the lymph nodes of the hilar and upper and lower mediastinum at the homolateral thoracic cavity actively and completely; beside, attention may be paid to the bronchial wall invasion caused by the lymph nodes metastasized.