Clinical characteristics associated with ALK rearrangements in never-smokers with pulmonary adenocarcinoma

Objectives

Anaplastic lymphoma kinase (ALK) rearrangement is a validated predictive marker to define patients with non-small cell lung cancer (NSCLC) who can benefit from selective ALK inhibitors. Therefore, accurate assessment of its prevalence and clinical characteristics is increasingly important in the treatment of NSCLC. Also, this ALK rearrangement was previously reported to be more common in patients with no smoking history or those with adenocarcinoma.

Patients and methods

Never-smokers with completely resected pulmonary adenocarcinoma were screened for ALK rearrangements using Nanostring's gene expression platform. Clinicopathologic data, such as information about epidermal growth factor receptor (EGFR) and KRAS mutation status were retrospectively reviewed.

Results

Of 231 tumors screened, 20 (9%) had an ALK rearrangement and all were confirmed to be positive with immunohistochemical and fluorescent in situ hybridization analysis. Of the tumors with available data on the EGFR/KRAS mutation status, EGFR and KRAS mutation rates were 64% (69/108) and 5% (5/102), respectively. Amongst the tumors that were free of EGFR and KRAS mutations, the proportion of ALK rearrangements reached up to 33%. At the time of data cut-off, total of 68 tumors were recurred. Although the recurrence rate was similar between the ALK-positive and negative groups (30% vs. 29%), there was a tendency for ALK-positive tumors to recur more frequently in the pleural space (15% vs. 5%). The five-year disease-free survival (61%) and overall survival rates (79%) in the ALK-positive group were similar to those in the ALK-negative group (51% and 83%, respectively). Even after excluding two patients treated with crizotinib after disease recurrence, overall survival was similar between the two groups.

Conclusion

In an NSCLC subpopulation based on smoking history, histology, and EGFR and KRAS mutation status, the prevalence of ALK rearrangements is considerably high. However, ALK rearrangement status itself has no prognostic relevance in patients with completely resected NSCLC.     

Invasive adenocarcinoma of the lung is associated with the upper lung regions

Objectives

We postulated that ventilation–perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior–inferior regional distribution, and associated variables such as emphysema.

Materials and Methods

One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema.

Results

The majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P = 0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P = 0.008, compared to lower region), whereas lobar location of tumor was not (P = 0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (P = 0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P = 0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P = 0.217).

Conclusion

Invasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.     

The characteristics and failure pattern of gefitinib responders with postoperative recurrence of pulmonary adenocarcinoma

Aims

Gefitinib shows prominent anti-tumor activity against advanced or recurrent non-small cell lung cancer (NSCLC). However, most gefitinib-responsive patients ultimately relapse. We reviewed postoperatively recurrent NSCLC patients who received gefitinib treatment, and analyzed both the clinical features and manifestations of treatment failure in patients who initially responded to gefitinib.

Methods

From 2002 to 2006, gefitinib was administered to in 34 postoperative recurrent lung adenocarcinoma patients. There were 13 men and 21 women with a mean age of 65 years. Twenty patients had never smoked while 14 were former smokers. Epidermal growth factor receptor (EGFR) gene mutation was measured using surgical specimens of the primary tumor.

Results

The study group showed 1 complete response, 16 partial responses, 7 stable diseases and 8 progressive diseases. Mutations of EGFR gene were detected in 20 of 34 patients. Only the presence of EGFR gene mutations was significantly associated with the clinical response of gefitinib in our limited study (p = 0.036). In 9 of 12 responders, gefitinib treatment failed due to the appearance of new lesions.

Conclusions

Gefitinib was significantly effective for patients with mutations of the EGFR gene and most responders failed due to the appearance of new lesions without progression of the pre-existent target lesions.     

High mesothelin expression in advanced lung adenocarcinoma is associated with KRAS mutations and a poor prognosis

Mesothelin is a cell surface glycoprotein which is highly expressed in several epithelial cancers and may have a role in cell adhesion and metastases. In this study, we used prospectively obtained clinical and pathological data to characterize mesothelin expression in advanced lung adenocarcinoma. Tissue was obtained from patients who underwent molecular profiling of potentially actionable genes on a trial of molecular profiling and targeted therapies in advanced thoracic malignancies. We immunohistochemically evaluated the intensity, and the percentage of cells expressing mesothelin in 93 advanced lung adenocarcinomas. The evaluation was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. 53% of advanced lung adenocarcinomas expressed mesothelin to some degree; high mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with inferior survival (median 18.2 months vs. 32.9 months; P = 0.014). High mesothelin expression was strongly associated with mutant KRAS (P < 0.0001) and wild-type EGFR (P = 0.002). Our results provide strong rationale to explore anti-mesothelin targeted therapies in advanced lung adenocarcinoma especially in the KRAS-mutant subgroup.     

代谢综合征与肺腺癌患者临床分期的相关性研究

目的:探讨代谢综合征（metabolic syndrome,MS）与肺腺癌临床分期的相关性。方法:2018年1月至2019年1月由华北理工大学附属医院首次确诊为肺腺癌的患者135例。57例被诊断为代谢综合征合并肺腺癌患者纳入病例组,78例为单纯肺腺癌患者纳入对照组。收集病例人口学信息、首次生化检查结果、临床症状及肺腺癌临床分期,SPSS 23.0用于数据分析。结果:经多元Logistic回归分析发现MS并不会导致肺腺癌临床症状的改变（P均大于0.05）,但是却与肺腺癌患者的临床分期相关（P=0.019）,与单纯肺腺癌患者相比,MS合并肺腺癌的患者肿瘤临床分期为晚期的概率上升了51.8%。结论:MS与肺腺癌患者的肿瘤临床分期存在相关性,MS可能是导致肺腺癌临床分期严重程度的独立危险因素。     

A Phase II Study with Teniposide (VM26) in Patients with Progressed or Relapsed Small Cell Lung Cancer (SCLC)

Summary

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m², i.v. days 1-5, every 3 weeks until further progression.

The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P<0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P< 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.     

Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma

Recent studies have reported increased podoplanin expression by cancer cells and stromal cells, but little is known about its expression and biological significance in adenocarcinoma of the lung. We examined podoplanin expression by both cancer cells and stromal cells in 177 consecutive lung adenocarcinoma cases and analyzed relations between podoplanin expression and both clinicopathological factors and outcome. Podoplanin expression was observed on the apical membrane of the cancer cells in only 9 of the 177 (5.1%) cases. By contrast, cancer-associated fibroblasts (CAFs) were found to express podoplanin in 54 cases (30.5%). Podoplanin (+) CAFs were found only in invasive adenocarcinoma and none were found in noninvasive adenocarcinoma. Conventional prognostic factors were significantly correlated with podoplanin expression by CAFs. The univariate analyses and log-rank test showed that podoplanin expression was significantly associated with shorter survival time (p < 0.001 and p < 0.001, respectively). We divided the cases into 3 groups according grade based on the proportion of CAFs expressing podoplanin [a grade 0 group (n = 123), a grade 1 group (n = 36) and a grade 2 group (n = 18)]. The result showed that conventional prognostic factors were significantly correlated with the grade of podoplanin expression by CAFs. Furthermore, the grade 2 group tended to have a shorter survival time than the grade 1 group (p = 0.092). The results of this study highlight the importance of podoplanin expression by CAFs and provide new insights into the biology of the cancer microenvironment in adenocarcinoma of the lung.     

Metastatic lung adenocarcinoma in a 20-year-old patient

Lung cancer is rare disease in patients under 25 years of age. It typically occurs in older patients with a history of tobacco use. This case concerns a 20-year-old man with no history of tobacco use who complained of several months of cough and lower back pain and an 11.3-kg weight loss. He was treated for pneumonia after a chest radiograph showed total opacification of the right lung. Computed tomography imaging subsequently revealed a superior right hilar mass and mediastinal lymphadenopathy. Further imaging studies showed diffuse metastatic disease. Mediastinal biopsy showed poorly differentiated epithelioid tumour with desmoplastic stromal reaction, neutrophil infiltration, and squamous differentiation. Tissue immunostaining confirmed a non-small-cell lung cancer. Unfortunately, despite aggressive therapy, the patient’s disease progressed, and he died within 9 months. In this paper, we hope to illustrate the unique challenges in diagnosing and treating young patients with metastatic lung cancer.     

肺癌相关血清学肿瘤标志物研究进展

肿瘤生物标志物近年来一直是肿瘤基础和临床研究的一个十分活跃的领域.尽管迄今尚未找到肺癌特异性抗原,国内外研究人员已发现多种有潜力用于肺癌早期诊断、临床分型和分期、预后判断和疗效观察等的肿瘤生物标志.本文以癌胚抗原、神经元特异性烯醇化酶、细胞角蛋白19片段抗原、碳水化合物抗原242、粘蛋白1抗原、神经细胞粘附分子、组织多肽特异性抗原、干细胞因子、血管内皮生长因子、肝细胞生长因子、肺癌相关抗原和磷脂酰肌醇蛋白聚糖等为例,对肺癌相关血清学肿瘤生物标志物的研究进展作一综述.     

Cushing's paraneoplastic syndrome as first manifestation of an adenocarcinoma of unknown origin

Small cell lung cancer is the most common cause of paraneoplastic Cushing's syndrome. The definitive treatment consists in surgical removal of the tumour, which is not possible in most of these cases (they are often diagnosed at advanced stages), and therefore it is frequently necessary adding the drug ketoconazol. We hereby present the case of a patient diagnosed with a metastatic carcinoma of unknown origin associated with two paraneoplastic syndromes: a Cushing's syndrome and a sensitive-motor axonal neuropathy, a very uncommon association.     

Proliferation genes in lung development associated with the prognosis of lung adenocarcinoma but not squamous cell carcinoma

There are many similarities between embryonic development and tumorigenesis, and gene expression profiles show that certain correlations exist between the gene signature during development and the clinical phenotypes of different cancers. Our group previously reported the gene expression profiles of human lung development, and the expression of one group of proliferation‐related genes (PTN1 genes) steadily decreased during lung development. Here, we examined the prognostic value of PTN1 genes in 5 independent lung adenocarcinoma (ADC) and 5 lung independent squamous cell carcinoma (SCC) microarray datasets and found that the expression levels of PTN1 genes were associated with survival in lung ADC but not lung SCC. All of the lung ADC datasets contained a set of highly correlated genes from PTN1 genes, but the lung SCC datasets had no similar set of genes. We identified 63 unique core genes from the PTN1 genes in the 5 lung ADC datasets: 17 of these core genes appeared in at least 4 of the lung ADC datasets, and the 17 corresponding proteins clearly interacted more strongly with each other in lung ADC than in lung SCC. Moreover, 16 of the 17 core genes play major roles in the G₂/M phase of the cell cycle. These data indicate that proliferation‐related genes in lung development have a significant prognostic value for lung ADC; the synergistic effects of the 17 core genes play an important role in lung ADC prognosis. These genes may have significant clinical implications for the treatment and prognosis of lung ADC.     

MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration

Brain metastasis (BM) can affect ～ 25% of nonsmall cell lung cancer (NSCLC) patients during their lifetime. Efforts to characterize patients that will develop BM have been disappointing. microRNAs (miRNAs) regulate the expression of target mRNAs. miRNAs play a role in regulating a variety of targets and, consequently, multiple pathways, which make them a powerful tool for early detection of disease, risk assessment, and prognosis. We investigated miRNAs that may serve as biomarkers to differentiate between NSCLC patients with and without BM. miRNA microarray profiling was performed on samples from clinically matched NSCLC from seven patients with BM (BM+) and six without BM (BM-). Using t-test and further qRT-PCR validation, eight miRNAs were confirmed to be significantly differentially expressed. Of these, expression of miR-328 and miR-330-3p were able to correctly classify BM+ vs. BM- patients. This classifier was used on a validation cohort (n = 15), and it correctly classified 12/15 patients. Gene expression analysis comparing A549 parental and A549 cells stably transfected to over-express miR-328 (A549-328) identified several significantly differentially expressed genes. PRKCA was one of the genes over-expressed in A549-328 cells. Additionally, A549-328 cells had significantly increased cell migration compared to A549 cells, which was significantly reduced upon PRKCA knockdown. In summary, miR-328 has a role in conferring migratory potential to NSCLC cells working in part through PRKCA and with further corroboration in additional independent cohorts, these miRNAs may be incorporated into clinical treatment decision making to stratify NSCLC patients at higher risk for developing BM.     

Colonic adenocarcinoma associated with the acquired immune deficiency syndrome

Colonic adenocarcinoma developed in an intravenous drug abuser with the acquired immune deficiency syndrome (AIDS) that was diagnosed by the presence of antibodies to the human immunodeficiency virus (HIV), generalized lymphadenopathy, and biopsy proven esophageal candidiasis. The colon cancer presented atypically at a young age with no known risk factors and with a bulky primary tumor and a local fistula. AIDS and AIDS risk factors have been associated with Kaposi's sarcoma, lymphomas, and anal and oropharyngeal carcinoma. This report suggests a possible association between colonic adenocarcinoma and AIDS.     

肺动脉成形肺叶切除治疗非小细胞肺癌

目的　总结肺动脉成形肺叶切除在非小细胞肺癌的治疗经验 ,了解该术式的治疗应用价值。方法　 12例非小细胞肺癌施行了肺动脉成形肺叶切除术 ,回顾治疗及病理特征。结果　所有手术病人无早期死亡 ,1年、3年、5年生存率分别为 83.3% ,5 0 .1% ,35 .2 %。结论　本组资料表明 ,肺动脉成形肺叶切除术与常规手术相比无明显不同 ,只要解剖条件允许可减少全肺切除 ,保留肺功能。