Low-dose CT screening among never-smokers with or without a family history of lung cancer in Taiwan: a prospective cohort study.

BACKGROUND: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer. METHODS: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing. FINDINGS: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis. INTERPRETATION: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer. FUNDING: Ministry of Health and Welfare of Taiwan.

Low-Dose Computed Tomography Screening in Relatives With a Family History of Lung Cancer.

INTRODUCTION: The role of a family history of lung cancer (LCFH) in screening using low-dose computed tomography (LDCT) has not been prospectively investigated with long-term follow-up. METHODS: A multicenter prospective study with up to three rounds of annual LDCT screening was conducted to determine the detection rate of lung cancer (LC) in asymptomatic first- or second-degree relatives of LCFH. RESULTS: From 2007 to 2011, there were 1102 participants enrolled, including 805 and 297 from simplex and multiplex families (MFs), respectively (54.2% women and 70.0% never-smokers). The last follow-up date was May 5, 2021. The overall LC detection rate was 4.5% (50 of 1102). The detection rate in MF was 9.4% (19 of 202) and 4.4% (4 of 91) in never-smokers and in those who smoked, respectively. The corresponding rates for simplex families were 3.7% (21 of 569) and 2.7% (6 of 223), respectively. Of these, 68.0% and 22.0% of cases with stage I and IV diseases, respectively. LC diagnoses within a 3-year interval from the initial screening tend to be younger, have a higher detection rate, and have stage I disease; thereafter, more stage III-IV disease and 66.7% (16 of 24) with negative or semipositive nodules in initial computed tomography scans. Within the 6-year interval, only maternal (modified rate ratio = 4.46, 95% confidence interval: 2.32-8.56) or maternal relative history of LC (modified rate ratio = 5.41, 95% confidence interval: 2.84-10.30) increased the risk of LC. CONCLUSIONS: LCFH is a risk factor for LC and is increased with MF history, among never-smokers, younger adults, and those with maternal relatives with LC. Randomized controlled trials are needed to confirm the mortality benefit of LDCT screening in those with LCFH.

Bladder Distention Demonstrating Vesicourachal Diverticulum on 18 F-FDG PET/CT Images of a Lung Cancer Patient.

ABSTRACT: A 58-year-old man with lung cancer was referred for an 18 F-FDG PET/CT scan for pretreatment staging. The FDG PET/CT scan revealed focal uptakes in the lower abdomen. We differentiated the etiology of the lesions by performing a delayed scan with urine retention and bladder distension. The delayed scan demonstrated a tubular, radioactivity-filled structure arising above the urinary bladder. Combining the FDG PET/CT scan, clinical findings, and ultrasonography, we made the diagnosis of vesicourachal diverticulum.

Pulmonary Recruitment Prior to Intraoperative Multiple Pulmonary Ground-Glass Nodule Localization Increases the Localization Accuracy-A Retrospective Study.

The standard treatment for early-stage lung cancer is complete tumor excision by limited resection of the lung. Preoperative localization is used before video-assisted thoracoscopic surgery (VATS) to improve the accuracy of pulmonary nodule excision. However, lung atelectasis and hypoxia resulting from controlling apnea during the localization procedure may affect the localization accuracy. Pre-procedural pulmonary recruitment may improve the respiratory mechanics and oxygenation during localization. In this study, we investigated the potential benefits of pre-localization pulmonary recruitment prior to pulmonary ground-glass nodule localization in a hybrid operating room. We hypothesized that pre-localization pulmonary recruitment would increase the localization accuracy, improve oxygenation, and prevent the need for re-inflation during the localization procedure. We retrospectively enrolled patients with multiple pulmonary nodule localizations before surgical intervention in our hybrid operating room. We compared the localization accuracy between patients who had undergone pre-procedure pulmonary recruitment and patients who had not. Saturation, re-inflation rate, apnea time, procedure-related pneumothorax, and procedure time were also recorded as secondary outcomes. The patients who had undergone pre-procedure recruitment had better saturation, shorter procedure time, and higher localization accuracy. The pre-procedure pulmonary recruitment maneuver was effective in increasing regional lung ventilation, leading to improved oxygenation and localization accuracy.

Association of smoking and ALK tyrosine-kinase inhibitors on overall survival in treatment-naïve ALK-positive advanced lung adenocarcinoma.

Introduction: Anaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world. Methods: This retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data. Results: Among the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively. Conclusions and relevance: For patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed.

Migrating hook wire that travels to the heart via the bloodstream: A case report.

RATIONALE: This report documents the intracardiac migration of a hook wire in a 47-year-old male patient after computed tomography (CT)-guided percutaneous hook wire localization of pulmonary ground-glass opacities. PATIENT CONCERNS: The patient underwent CT-guided hook wire localization before video-assisted thoracoscopic surgery (VATS) wedge resection for a pulmonary nodule in the right upper lung field. However, the hook wire was not found in the specimen obtained from the wedge resection. A right upper lobectomy was performed to locate the hook wire; however, it was not found. DIAGNOSIS: A transesophageal echocardiogram was performed, and the hook wire was found in the left ventricle (LV). INTERVENTIONS: The patient subsequently underwent exploratory cardiotomy to remove the foreign body. The patient was admitted to the intensive care unit for postoperative care. OUTCOMES: Postoperatively, no complications were observed, and the patient was discharged from the hospital 7 days postoperatively. He received standard lung cancer treatment afterwards. LESSONS: The present case was unique because the hook wire migrated through the bloodstream from the pulmonary vein to the left atrium, before finally reaching the LV. Based on the patient preoperative CT images, the ground glass opacities were proximal to a 2.5 mm wide vein, which drained into the pulmonary vein. The proximity of the hook wire to a blood vessel was reportedly attributed to an increased risk of hook wire migration through the bloodstream. Hematogenous hook wire migration into the heart can result in fatal complications. Early diagnosis and timely removal of the hook wire are recommended to prevent the worsening of this complication.

Adjuvant chemotherapy compared with observation in patients with T2aN0 stage IB lung adenocarcinoma.

Introduction: For patients with T2aN0 stage IB lung adenocarcinoma, benefits of adjuvant chemotherapy remain controversial. Here, we aimed to evaluate such benefits. Methods: This retrospective cohort study was conducted on the database of the National Taiwan Cancer Registry. We analyzed patients with T2aN0 stage IB lung adenocarcinoma (re-classified by AJCC 8th edition) diagnosed during the period from January 2011 to December 2017. They were divided into two groups: (1) group 1: tumor <=3 cm with visceral pleural invasion (VPI); (2) group 2: tumor >3 cm, but <=4 cm. Overall survival (OS) and cancer specific survival (CSS) were evaluated. Risk factors for survival were determined. Results: A total of 2,100 patients with T2aN0 stage IB lung adenocarcinoma (1,265 in group 1 and 835 in group 2) were enrolled for study. The proportions of patients receiving adjuvant chemotherapy in group 1 and 2 were 39.1% and 68.6%, respectively. Amongst group 1 patients, adjuvant chemotherapy was not an independent risk factor for OS and CSS. Amongst group 2 patients, high-grade histologic findings and receiving sublobar resection were two risk factors for poorer survival. Adjuvant chemotherapy was also associated with an OS (adjusted hazard ratio (aHR), 0.52; 95% confidence interval (CI), 0.38-0.72; P<0.001) and CSS (aHR, 0.54; 95% CI, 0.37-0.78; p=0.001) benefit regardless of the presence or absence of risk factors. Conclusion: For patients with T2aN0 stage IB lung adenocarcinoma, adjuvant chemotherapy improved OS and CSS in those with tumors >3 cm, but <=4 cm.For patients with tumors <=3 cm with VPI, adjuvant chemotherapy had no survival benefit.

Challenges of the eighth edition of the American Joint Committee on Cancer staging system for pathologists focusing on early stage lung adenocarcinoma.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer adopts new criteria for tumor size, and for determining pTis, pT1a(mi), and pT1a. The latter is based on the size of stromal invasion. It is quite challenging for lung pathologists. METHODS: All patients who had undergone surgical resection for pulmonary adenocarcinoma (ADC) at Chung Shan Medical University Hospital between January 2014 and April 2018 were reviewed, and restaged according to the eighth AJCC staging system. The clinical characteristics and survival of patients with tumor stage 0 (pTis), I or II were analyzed. RESULTS: In total, 376 patients were analyzed. None of the pTis, pT1a(mi), or pT1a tumors recurred during the follow-up period up to 5 years, but pT1b, pT1c, pT2a, and pT2b tumors all had a few tumor recurrences (p < 0.0001). In addition, 95.2%, 100%, and 77.5% of pTis, pT1a(mi), and pT1a tumors, respectively, had tumor sizes ≤1.0 cm by gross examination. All pTis, pT1a(mi), and pT1a tumors exhibited only lepidic, acinar, or papillary patterns histologically. CONCLUSIONS: This study demonstrated excellent survival for lung ADC patients with pTis, pT1a(mi), and pT1a tumors when completely excised. To reduce the inconsistencies between pathologists, staging lung ADC with tumors of ≤1 cm in size grossly as pTis, pT1a(mi), or pT1a may not be necessary when the tumors exhibit only lepidic, acinar, or papillary histological patterns. A larger cohort study with sufficient follow-up data is necessary to support this proposal.

Spontaneous pneumothorax with pulmonary Langerhans cell histiocytosis (PLCH) in an adult heavy cigarette smoker-A case report.

Pulmonary Langerhans cell histiocytosis is a rare disease caused by the proliferation of CD1a-positive histiocyte-like cells infiltrating the lung's interstitial layer. Most cases affect young to middle-aged persons, especially adult heavy cigarette smokers. A 49-year-old male heavy smoker (40 pack-year), with non-productive cough, dyspnoea and desaturation, presented with a right-sided pneumothorax on chest x-ray with total atelectasis. Chest computed tomography (CT) revealed bilateral multiple thick-walled infiltrated cysts and multiple ground-glass nodules throughout the entire lung. Surgery with minimal invasive thoracoscopic lung biopsy and pleurodesis was performed. Pathology showed histiocyte-like cells aggregates in the pulmonary parenchyma. Immunohistochemical stain demonstrated CD1a(+), S100(+) and CD68(+). After 3 months of smoking cessation, clear improvement was evidenced with a chest CT showing bilateral multiple thin-walled rounded cysts and multiple ground-glass nodules that are smaller in size and decreased in numbers. Early minimal invasive thoracoscopic lung biopsy and pleurodesis can also be a choice if the development of secondary spontaneous pneumothorax occurs.

Association of Smoking With Patient Characteristics and Outcomes in Small Cell Lung Carcinoma, 2011-2018.

Importance: Small cell lung carcinoma (SCLC) is uncommon in individuals who have never smoked (never-smokers). The related epidemiologic factors and prognosis remain unclear. Objective: To assess the epidemiologic factors, clinical characteristics, and outcomes of SCLC in never-smokers. Design, Setting, and Participants: A retrospective cohort study was conducted using data from the national Taiwan Cancer Registry, which was inaugurated in 1979 and maintains standardized records of patients' characteristics and clinical information for all individuals with cancer. Patients with cytologically or pathologically proven lung cancer were included for analysis. The study obtained data on patients from January 1, 1996, to December 31, 2018; data analysis was conducted from January 1, 1996, to December 31, 2019. Exposures: Clinical characteristics and outcomes of smokers and never-smokers with SCLC. Main Outcomes and Measures: Clinical characteristics for comparison included age at diagnosis, sex, performance status, tumor stage, and treatment. The main outcome parameter was overall survival of patients with SCLC from 2011 to 2018. Results: From 1996 to 2018, a total of 225 788 patients had diagnosed lung cancer; 141 654 patients (62.7%) were men; mean (SD) age was 67.55 (12.58) years. The numbers of both patients with newly diagnosed lung cancer and those with SCLC increased until 2009 by 111.5% for lung cancer and 118.5% for SCLC. Thereafter, lung cancer cases grew in number, but SCLC cases did not; hence, the percentage of patients with SCLC decreased from 9.3% in 2009 to 6.3% in 2018. From 2011 to 2018, the percentage of never-smokers increased significantly among all patients with lung cancers (from 49.9% in 2011 to 60.2% in 2018) and among those with lung adenocarcinomas (from 64.1% in 2011 to 70.9% in 2018) (both P < .001). However, the percentage of never-smokers appeared to vary little in the SCLC population: 15.5% in 2011 and 16.1% in 2018 (P = .28). The median overall survival was significantly longer in patients with adenocarcinoma vs SCLC (adjusted hazard ratio, 0.32; 95% CI, 0.31-0.33; P < .001). Compared with smokers with SCLC, never-smokers with SCLC tended to include more older patients (age ≥70 years: 492 [57.3%] vs 2242 [44.8%]), more women (274 [31.9%] vs 322 [6.4%]), more individuals with a poor performance status (Eastern Cooperative Oncology Group performance status ≥2: 284 [33.1%] vs 1261 [25.2%]) and stage IV cancer (660 [76.9%] vs 3590 [71.8%]), and more patients without treatment (203 [23.7%] vs 626 [12.5%]). Furthermore, never-smokers, particularly men, experienced a shorter survival rate (adjusted hazard ratio, 1.10; 95% CI, 1.00-1.20; P = .04) compared with the other groups. Conclusions and Relevance: The findings of this cohort study suggest that the decrease in the percentage of patients with SCLC was associated with increased lung cancers of other histologic types, with no substantial decrease in the number of those with SCLC.

Differential contribution of protein phosphatase 1α to cell transformation of different cell types.

Protein phosphorylation plays roles in cell transformation. Numerous protein kinase enzymes actively participate in the formation of various types of cancer by phosphorylating downstream substrates. Aurora­A is a widely known Serine/Threonine (Ser/Thr) oncogenic kinase, which is upregulated in more than twenty types of human cancer. This enzyme phosphorylates a wide range of substrates. For example, Aurora­A induces cell transformation by phosphorylating hepatoma upregulated protein (HURP) at four serine residues, which in turn decreases the phosphorylated levels of cell­growth suppressive Jun N­terminal kinase (p­JNK). Various protein phosphatase enzymes are considered tumor suppressors by the dephosphorylation and consequent inactivation of their oncogenic substrates. Protein phosphatase 1α (PP1α), for instance, acts on Aurora­A by dephosphorylating its substrates. However, the role of PP1α in cancer progression remains ambiguous. PP1α is overexpressed in several cancer tissues, and induces cell apoptosis and differentiation or it inhibits tumor formation in other types of cells. In addition, positive and negative correlations between PP1α expression and lung cancer development have been documented. These observations suggest the differential regulation of PP1α in various cancer tissues, or propose an ambiguous contribution of PP1α to lung cancer development. In order to investigate these contradictory conclusions, it was reported that the chromosomal region covering the PP1α locus was subjected to DNA alterations, such as gain or loss in various human cancer types by a study based on literature search. Upregulation of PP1α was noted in a collection of lung cancer tissues, and was required for the cell transformation of the lung cancer cell line A549. In contrast to this finding, overexpression of ectopic PP1α inhibited cell proliferation in 293T cells. Mechanistic studies revealed that PP1α activated AKT in A549 cells, whereas it further inactivated AKT and disrupted the HURP/JNK signaling cascade in 293T cells. Collectively, the data indicated that PP1α exerted an oncogenic function in lung cancer, while exhibiting various effects on cell transformation in different types of cells via distinct or opposite mechanisms.

Overexpression of Aurora-A bypasses cytokinesis through phosphorylation of suppressed in lung cancer.

Mitosis is a complicated process by which eukaryotic cells segregate duplicated genomes into two daughter cells. To achieve the goal, numerous regulators have been revealed to control mitosis. The oncogenic Aurora-A is a versatile kinase responsible for the regulation of mitosis including chromosome condensation, spindle assembly, and centrosome maturation through phosphorylating a range of substrates. However, overexpression of Aurora-A bypasses cytokinesis, thereby generating multiple nuclei by unknown the mechanisms. To explore the underlying mechanisms, we found that SLAN, a potential tumor suppressor, served as a substrate of Aurora-A and knockdown of SLAN induced immature cytokinesis. Aurora-A phosphorylates SLAN at T573 under the help of the scaffold protein 14-3-3η. The SLAN phosphorylation-mimicking mutants T573D or T573E, in contrast to the phosphorylation-deficiency mutant T573A, induced higher level of multinucleated cells, and the endogenous SLAN p573 resided at spindle midzone and midbody with the help of the microtubule motor MKLP1. The Aurora-A- or SLAN-induced multiple nuclei was prevented by the knockdown of 14-3-3η or Aurora-A respectively, thereby revealing a 14-3-3η/Aurora-A/SLAN cascade negatively controlling cytokinesis. Intriguingly, SLAN T573D or T573E inactivated and T573A activated the key cytokinesis regulator RhoA. RhoA interacted with SLAN np573, i.e., the nonphosphorylated form of SLAN at T573, which localized to the spindle midzone dictated by RhoA and ECT2. Therefore, we report here that SLAN mediates the Aurora-A-triggered cytokinesis bypass and SLAN plays dual roles in that process depending on its phosphorylation status.

EGFR-activating mutations, DNA copy number abundance of ErbB family, and prognosis in lung adenocarcinoma.

In this study, EGFR-activating mutation status and DNA copy number abundances of members of ErbB family were measured in 261 lung adenocarcinomas. The associations between DNA copy number abundances of ErbB family, EGFR-activating mutation status, and prognosis were explored. Results showed that DNA copy number abundances of EGFR, ERBB2, ERBB3, and ERBB4 had associations with overall survival in lung adenocarcinoma with EGFR-activating mutations. In the stratification analysis, only ERBB2 showed significant discrepancy in patients carrying wild type EGFR and other members of ErbB family in patients carrying EGFR-activating mutation. This indicated that CNAs of ErbB family had effect modifications of EGFR-activating mutation status. Findings of this study demonstrate potential molecular guidance of patient management of lung adenocarcinoma with or without EGFR-activating mutations.

EGFR mutation and lobar location of lung adenocarcinoma.

The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment-naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis.

R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability.

PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.

Identification of five driver gene mutations in patients with treatment-naïve lung adenocarcinoma in Taiwan.

BACKGROUND: It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. METHODS: This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). RESULTS: From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. CONCLUSION: This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.

The involvement of nuclear factor-κappaB in the nuclear targeting and cyclin E1 upregulating activities of hepatoma upregulated protein.

Hepatoma upregulated protein (HURP) is originally isolated during the search for the genes associated with hepatoma. HURP is upregulated in many human cancers. Culture cells exhibit transformed and invasive phenotype when ectopic HURP is introduced, revealing HURP as an oncogene candidate. Our previous studies demonstrated that Aurora-A regulated the cell transforming activities of HURP by phosphorylating HURP at four serines. To unravel how the Aurora-A/HURP cascade contributes to cell transformation, we firstly noticed that HURP shuttled between cytoplasm and nucleus. The nuclear localization activity of HURP was promoted or abolished by overexpression or knockdown of Aurora-A. Similarly, the HURP phosphorylation mimicking mutant 4E had higher nuclear targeting activity than the phosphorylation deficient mutant 4A. The HURP 4E accelerated G1 progression and upregulated cyclin E1, and the cyclin E1 upregulating and cell transforming activities of HURP were diminished when the nuclear localization signal (NLS) was removed from HURP. Furthermore, HURP employed p38/nuclear factor-κB (NF-κB) cascade to stimulate cell growth. Interestingly, NF-κB trapped HURP in nucleus by interacting with HURP 4E. At last, the HURP/NF-κB complex activated the cyclin E1 promoter. Collectively, Aurora-A/HURP relays cell transforming signal to NF-κB, and the HURP/NF-κB complex is engaged in the regulation of cyclin E1 expression.

Methylosome protein 50 promotes androgen- and estrogen-independent tumorigenesis.

Methylosome protein 50 (MEP50) is a component of methylosome where MEP50 binds protein substrates and activates the oncogenic protein arginine methyl transferase 5 (PRMT5). MEP50 is also a coactivator for androgen receptor (AR) and estrogen receptor (ER), and transforms cells in the presence of androgen or estrogen. To extend the understanding of how MEP50 transforms cells, we investigated whether MEP50 could transform cells independent of AR and ER, and clarified whether PRMT5 could contribute to the MEP50-caused tumor formation. Microarray and Western blot analyses revealed the association of MEP50 with many human cancers including lung cancer. Knockdown of MEP50 retarded cell growth and migration in selected lung cancer cell lines, which expressed very low level of AR and ER and were insensitive to inhibitors of AR and ER. Moreover, overexpression of Myc-MEP50 enhanced cell transforming activities of 293T cells which are known lack of expression of AR and ER. Mechanistic analyses showed that MEP50 controlled G2 progression, upregulated cyclin-dependent kinase 1(CDK1)/cyclin B1, and activated the survival cascade Phosphoinositide 3-kinase (PI3K)/AKT. MEP50 promoted cell migration, and activated the cell migration pathways such as Ras-related C3 botulinum toxin substrate 1 (Rac1)/vasodilator-stimulated phosphoprotein (VASP), and forkhead box protein A2 (FOXA2)/slug/cadherin cascades. Further analyses revealed that MEP50 activated the survival factor PI3K through PRMT5-catalyzed dimethylation of PI3K. Collectively, it is concluded that MEP50 can transform cells independent of AR and ER, and PRMT5 has partial contribution to that process.

Pulmonary sequestration-differences in diagnosis and treatment in a single institution.

BACKGROUND: Pulmonary sequestration (PS) is a rare congenital lung malformation. In this study, we evaluated the diagnosis and treatment of PS in 31 adult patients at a single institution. METHODS: A retrospective review of all patients 16 years of age and older with PS in a single institution between January 1985 and January 2011 was conducted. The following data were analyzed for all patients: major symptoms, diagnostic procedures, operative findings, operative techniques, postoperative complications, and outcome. RESULTS: Our study involved 31 patients, 17 male and 14 female, with an average age of 32.1 (17-57) years, who underwent surgical intervention for PS. The preoperative symptoms of these patients included cough, hemoptysis, fever, pneumonia, and chest pain. Thirty (96.8%) patients were diagnosed by thoracic computed tomography. Of the 31 patients, 29 were diagnosed with intralobar pulmonary sequestration and two had extralobar pulmonary sequestration. Surgical procedures for intralobar pulmonary sequestration included lobectomy in 22 patients (including one thoracoscopic lobectomy), segmentectomy in six, and wedge resection in one of the patients. Thoracoscopic simple mass excision was performed on the two patients with extralobar pulmonary sequestration. Two patients had a postoperative complication (prolonged air leak in 1 patient and postoperative hemothorax in the other). The average hospital stay for all study patients was 6.4 (4-18) days, and there was no mortality. CONCLUSION: Diagnostic tools may enable the clinician to obtain a definitive diagnosis in patients where there is a strong suspicion of PS via a noninvasive procedure. Computed tomography angiography may be the diagnostic imaging method of choice for optimal evaluation of the sequestrated lung and its vascular supply.