Spatial distribution of immune checkpoint proteins in histological subtypes of lung adenocarcinoma

The most prevalent histological type of non-small cell lung cancer (NSCLC) is adenocarcinoma. The WHO classifies this tumor into subtypes according to the predominant growth pattern such as lepidic, acinar, papillary, solid or micropapillary, each harboring specific molecular features. NSCLC adenocarcinoma heterogeneity is discussed to be a reason for therapy failure using targeted therapy or immune checkpoint inhibitors. For successful therapy of immune checkpoint inhibitors the expression and distribution of the involved immune checkpoint proteins is essential. Therefore, we aimed to investigate the distribution of five prominent immune checkpoint proteins in regard of the histological growth patterns of lung adenocarcinoma. We performed immunohistochemical staining of 84 tumor segments from 22 resected tumor samples to evaluate the expression of PD-L1, PD-1, Nectin-2, PVR, and TIGIT in distinct growth patterns of lung adenocarcinoma. We determined a distinct heterogeneity between and within different tumor segments regarding morphological growth patterns. Furthermore, expression of immune checkpoint proteins varied between different growth pattern areas as well as within one distinct growth pattern. Expression of PVR was significantly higher in solid compared to acinar growth pattern (p= 0.00736). Of note, we detected TIGIT not only on tumor infiltrating lymphocytes but also on tumor cells, whereas non-neoplastic lung tissue was consistently TIGIT-negative. The immune checkpoint protein distribution in histologic subtypes of pulmonary adenocarcinoma displays an considerable intra- and intertumoral heterogeneity implying the requirement of either a multiregion or an adjusted analysis when determining the expression status of PD-1:PD-L1 and the TIGIT:PVR/Nectin-2 checkpoint proteins as predictive markers.     

甲孕酮联合长春瑞滨顺铂治疗晚期非小细胞肺癌临床观察

目的：观察甲孕酮合并NP方案（长春瑞滨＋顺铂）化疗及单用NP方案化疗治疗晚期非小细胞肺癌患者的疗效及不良反应。方法：75例接受化疗的晚期非小细胞肺癌患者随机分为单用化疗组（对照组）36例及化疗并用甲孕酮组（治疗组）39例,治疗周期均为21天,2个周期后评价疗效。结果：治疗组、对照组有效率（CR＋PR）分别为43.59%（17/39例）,41.67%（15/36例）,中位疾病进展期分别为4.0、3.6个月,中位生存期分别为9.1、8.9个月;1年生存率分别为38.5%、38.9%;差异无统计学意义（P〉0.05）;主要不良反应是Ⅲ～Ⅳ度骨髓抑制、恶心呕吐。治疗组的白细胞减少（7.69%）、血红蛋白下降（0）、血小板减少（7.69%）发生率与对照组（25.00%、19.44%、13.89%）比较差异有统计学意义（P〈0.05）;治疗组的恶心呕吐发生率为0,显著低于对照组（13.89%）。化疗后治疗组生活质量改善明显并优于对照组,差异具有统计学意义（P〈0.05）。结论：甲孕酮合用长春瑞滨联合顺铂治疗晚期NSCLC疗效较高,毒副反应轻,患者耐受良好。     

Immunohistochemistry-detected microscopic tumor spread affects outcome in en-bloc resection for T3-chest wall lung cancer

Objective: This study is aimed at analyzing the effect of immunohistochemistry-detected microscopic tumor spread on long-term survival after en-bloc lung and chest wall resection for T3-chest wall non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed 47 patients (mean age 64.4 ± 7.1 years, range 48–77) who underwent radical en-bloc lung and chest wall resection for NSCLC between 1987 and 2000. Resection margins, invasion depth, and lymph nodes were re-assessed by immunohistochemistry with AE1/AE3 anti-cytokeratin and anti-CEA monoclonal antibodies. Results: Operative mortality and morbidity were 2.1% and 34%, respectively. At immunohistochemistry analysis, five patients (10.6%) revealed microinfiltration of the resection margins that was significantly correlated with the development of local recurrence (p < 0.005). Nodal micrometastases were found in 4 out of 33 N0 patients (12.1%), and correlated with distant relapse (p < 0.001). Overall and disease-free survivals were significantly influenced by N-status (p < 0.001), especially after re-evaluation of micrometastases (p < 0.0001), and resection margins microinfiltration (p < 0.0001) being these last two the only significant prognostic factors at Cox regression analysis. Five-year overall survival in radically resected patients was 73%. Conclusions: In this study immunohistochemical analysis allowed to identify patients at higher risk of recurrence following en-bloc resection for T3-chest wall NSCLC.     

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies.     

吉非替尼对晚期非小细胞肺癌患者生活质量的改善

Objective  

The aim of this study was to evaluate the effect of gefitinib on improvement of quality of life (QoL) of patients with advanced non-small cell lung cancer (NSCLC).     

Front-line treatment of advanced non-small-cell lung cancer with MTA (LY231514, Pemetrexed disodium, ALIMTATM) and cisplatin: A multicenter phase II trial

Background:To evaluate the activity of MTA plus cisplatin inchemotherapy-naïve patients with non-small cell lung cancer (NSCLC). Patients and methods:Thirty-six chemotherapy-naïve patientswith NSCLC received 500 mg/m² MTA plus 75 mg/m²cisplatin every 21 days, with 4 mg dexamethasone orally twice daily on the daybefore, of, and after MTA administration. Results:Median age was 58 years. WHO performance status was0–2. Eighteen patients each had stage IIIB and IV disease. Seventeenpatients each had squamous-cell and adenocarcinoma; two had undifferentiateddisease. Fourteen patients (39%; 95% confidence interval:23%–57%) showed partial response; seventeen (47%)had stable disease. Median survival was 10.9 months. Twenty-one patients(59%) experienced grade 3 or 4 granulocytopenia without fever orinfection. Five (14%) and six (17%) patients experienced grade3 anemia and grade 3 or 4 thrombocytopenia, respectively. Nonhematologicaltoxicities included grade 3 nausea in two patients (6%), and grade 3and 4 diarrhea in one patient (3%) each. One patient each experiencedgrade 4 ALT and grade 3 bilirubin and AST elevations. Conclusions:MTA plus cisplatin is well tolerated and activeagainst NSCLC. Further studies of this combination are warranted.     

Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non–Small-Cell Lung Cancer: Study Protocol

The treatment outcome has been unsatisfactory for patients with non–small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer.