Angiopoietin-2 is associated with metabolic syndrome in chronic kidney disease.

BACKGROUNDS: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. METHODS: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. RESULTS: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3-41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). CONCLUSION: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Polygenic Risk Score in Predicting Esophageal, Oropharyngeal, and Hypopharynx Cancer Risk among Taiwanese Population.

Esophageal cancer shares strong associations with oropharyngeal and hypopharyngeal cancers, primarily due to shared risk factors like excessive tobacco and alcohol use. This retrospective study at Taichung Veterans General Hospital involved 54,692 participants, including 385 with squamous cell carcinoma (SCC) of the esophagus, oropharynx, or hypopharynx. Using a polygenic risk score (PRS) derived from 8353 single-nucleotide polymorphisms, researchers aimed to assess its correlation with cancer incidence and prognosis. The study found a 1.83-fold higher risk of esophageal, oropharyngeal, and hypopharyngeal SCCs in participants with a high PRS (Q4) compared to the low-PRS group (Q1). Esophageal cancer risk demonstrated a significant positive association with the PRS, as did hypopharyngeal cancer. Clinical parameters and staging showed limited associations with PRS quartiles, and the PRS did not significantly impact recurrence or mortality rates. The research highlighted that a higher PRS is linked to increased susceptibility to esophageal and hypopharyngeal cancer. Notably, a specific polygenic risk score, PGS001087, exhibited a discernible association with SCC risk, particularly in specific subtypes and advanced disease stages. However, it was not significantly linked to clinical cancer staging, emphasizing the multifactorial nature of cancer development. This hospital study reveals that a higher PRS correlates with increased susceptibility to esophageal and hypopharyngeal cancers. Notably, PGS001087 shows a discernible association with SCC risk in specific subtypes and advanced stages, although not significantly linked to clinical cancer staging. These findings enhance our understanding of genetic factors in upper aerodigestive tract cancers, particularly esophageal SCC, guiding future research and risk assessment strategies.

Loss of TIMP-3 promotes tumor invasion via elevated IL-6 production and predicts poor survival and relapse in HPV-infected non-small cell lung cancer.

Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNA (cytosine-5-)-methyltransferase 1 (DNMT1) expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer.

Cytoplasmic Ape1 expression elevated by p53 aberration may predict survival and relapse in resected non-small cell lung cancer.

BACKGROUND: Subcellular localization of apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ape1) has been demonstrated to promote lung tumor malignancy via NF-κB activation. We hypothesized that increased cytoplasmic Ape1 expression might cause NF-κB activation by p53 aberration, and result in poor outcome in non-small cell lung cancer (NSCLC). METHODS: Herein, knockdown of E6 or p53 and overexpression of E6 were performed in various lung cancer cells to test whether cytoplasmic Ape1 expression could be elevated by p53 aberration. To examine whether cytoplasmic Ape1 could be associated with patients' outcome, 125 lung tumors from patients with NSCLC were collected to determine Ape1 protein and mRNA expression by immunohistochemistry and real-time RT-PCR. RESULTS: Our data showed that cytoplasmic Ape1 decreased in E6-knockdown TL-1 cells and increased in E6-overexpressed TL-4 and p53-knockdown H520 cells; and cell invasion capability was dependent on the presence of cytoplasmic Ape1. Increases in cytoplasmic Ape1 by p53 aberration may be through activation of Ape1 transcription and S-nitrosation of Ape1 protein. Kaplan-Meier and Cox models showed that patients with high cytoplasmic Ape1 had shorter cancer-specific survival (CSS) and relapse-free survival (RFS) periods than did those with low cytoplasmic Ape1. CONCLUSIONS: We suggest that cytoplasmic Ape1 expression elevated by p53 aberration may be used to predict poor survival and relapse in patients with NSCLC.

Comparison of wide and narrow gastric conduit in esophageal cancer surgery.

BACKGROUND: Gastric conduit is most widely used method for esophageal reconstruction. Despite its popularity, certain complications, such as anastomotic leakage and strictures, remain to be resolved. In the present study, we reviewed the outcomes of narrow gastric conduit compared to wide gastric conduit reconstruction. METHODS: We retrospectively reviewed 493 patients with esophageal cancer who received esophagectomy with reconstruction in Taichung Veteran General Hospital, Taiwan between January 2010 and December 2019. We performed gastric conduit reconstruction with two different methods, narrow gastric conduit made of multistaples (more than four staples) and wide gastric conduit made of two or three staples. Among the 493 patients, 170 patients underwent wide gastric conduit formation and 323 patients underwent narrow gastric conduit. After propensity score matching, 140 patients from each group were matched by 1:1. RESULTS: The average anastomotic leakage rate is 80 of 493 (16.23%). The leakage rate, length of hospital stay, intensive care unit (ICU) admission, and ICU stay were significantly lower in the narrow gastric conduit group than in the wide gastric conduit group. The need for postoperation dilatation was significantly higher in wide gastric conduit group (19.41% vs 11.76%, p = 0.0217), and the time to first dilatation was similar in both groups ( p = 0.9808). Similar results were observed even after propensity score matching. In univariate analysis, the narrow gastric conduit, circular stapler, video-assisted thoracic surgery, and laparoscopic surgery were associated with a reduced risk of anastomotic leakage. However, these factors are not statistically significant in a multivariate logistic regression analysis. CONCLUSION: The narrow gastric conduit is not inferior to the wide gastric conduit and can be considered an alternative option for gastric conduit preparation.

XPC mRNA level may predict relapse in never-smokers with non-small cell lung cancers.

BACKGROUND: Disease recurrence and distant metastasis are the major causes of death in resected non-small cell lung cancer (NSCLC). The prognostic marker for never-smokers with this disease remains to be identified. To improve patient outcome, establishing an adjacent molecular marker to predict relapse of NSCLC in never-smokers is needed. METHODS: Three hundred two lung tumors from NSCLC patients and normal lung tissues from 68 noncancer subjects were enrolled to evaluate XPC (xeroderma pigmentosum group C) mRNA expression by quantitative real-time reverse transcriptase polymerase chain reaction. Receiver operating characteristic curve analysis was used to search for a feasible cutoff point of XPC mRNA levels for predicting recurrence-free survival. Of the 326 patients, 214 were confirmed as only receiving surgical resection. Kaplan-Meier and multivariate Cox regression analysis were used to assess the prognostic value of XPC mRNA level in lung tumors from patients who only received surgical resection. RESULTS: Receiver operating characteristic curve analysis indicated 30.28 as a cutoff point, and thus 150 and 64 tumors with low- and high-XPC mRNA expression were categorized in this study population. Low-XPC mRNA appeared with more frequency in never-smokers and in late-stage (stage II-III) disease than smokers and early-stage disease (stage I). Kaplan-Meier analysis indicated that patients with low-XPC mRNA had shorter recurrence-free survival than that found in never-smokers (P = 0.002), but not in smokers (P = 0.296). Cox regression analysis further revealed that low-XPC mRNA may independently predict relapse in lung cancer of never-smokers (hazard ratio 2.34, 95% confidence interval 1.21-4.51, P = 0.011). CONCLUSIONS: Low-XPC mRNA may predict relapse in lung cancer patients who are never-smokers.

Understanding the adoption of the mask-supply information platforms during the COVID-19.

Since late 2019, coronavirus disease 2019 (COVID-19) has led to a significant increase in the demand for medical resources. To publish data on face mask supplies, the Taiwanese government collaborated with program developers to construct a mask-supply information transitional platform (MITP). To comprehend the adoption of MITP, the study proposes a research model that integrates the health behavior model (HBM) and IS/IT continuance model for examining the factors affecting intention to use an MITP. Survey data collected from 524 respondents indicated that (1) intention to use an MITP is directly influenced by perceived threat of COVID-19 and beliefs toward using the MITP; (2) cues to action directly influence the perceived threat of COVID-19; and (3) perceived ease of use of MITP is a significant determinant of perceived usefulness of MITP. These results provide practical guidelines for health authorities and government to develop health information systems and strategies to control pandemics.

A dimedone-phenylalanine-based fluorescent sensor for the detection of iron (III), copper (II), L-cysteine, and L-tryptophan in solution and pharmaceutical samples.

The development of fluorescence molecules for the fast and effective detection of L-tryptophan (L-Trp) has attracted a lot of attention because it is an important amino acid for baby growth, nitrogen equilibrium in adults, improving sleep, and mood regulation. A dimedone-phenylalanine-based chiral sensor (SDPA) was synthesized and exhibited a strong fluorescence quenching by Fe3+ and Cu2+ in a water/DMSO (3/7) solution with a detection limit of 2.29 × 10-6 M and 6.37 × 10-6 M, respectively. The factors affecting fluorescence sensings, such as the pH and competing cations, were studied. The sensor can be reused at least five times after being treated with EDTA. The Job plot, ESI-MS spectra, 1H NMR spectra, absorbance, and fluorescence titration experiments were investigated to study the mechanism of SDPA-Fe3+ and SDPA-Cu2+ complexation. The SDPA-Cu2+ complex can detect L-tryptophan and L-cysteine at trace levels by turn-on fluorescence with a detection limit of 9.35 × 10-6 M and 8.86 × 10-6 M, respectively. Moreover, applying the SDPA-Cu2+ complex for quantitative analysis of L-tryptophan in real sleep-improving capsules resulted in good recovery. The L-tryptophan level of the Elining capsule was determined at 190.8 ± 10.5 mg/g (mg L-tryptophan/g medicine), which is close to the announced quantity of 180 mg/g. Besides, the SDPA-Cu2+ complex can selectively detect free L-Try molecules and L-Try residues in proteins.

Naked-eye colorimetric and turn-on fluorescent Schiff base sensor for cyanide and aluminum (III) detection in food samples and cell imaging applications.

A new efficient Schiff base sensor SB3 for fluorescent and colorimetric "naked-eye" "turn-on" sensing of cyanide anion (CN-) with excellent sensitivity and selectivity was developed. The 4,4'-(perfluoropropane-2,2-diyl)bisphenol group and two phenyl groups were covalently linked by two C = N bonds to extend the conjugation length. The four hydroxyl groups can improve the water solubility of the SB3 sensor. The SB3 sensor exhibited high specificity towards CN- by interrupting its intramolecular charge transfer, resulting in a color change and remarkable "turn-on" green fluorescence emission. The sensing mechanism is caused by the nucleophilic addition of CN- toward imine groups of the SB3 sensor, leading to breaks of the conjugation, fluorescent spectral changes, and color change. It was confirmed by 1H NMR titration and Mass spectra. The detection limits for CN- and Al3+obtained by fluorescence spectrum are 0.80 µM and 0.25 µM, respectively. The SB3 sensor can act as an efficient chemical sensor for detecting the CN- and Al3+ ions under common environmental and physiological conditions (pH 5-12). Besides, the sensor can also detect CN- in food materials (such as sprouting potatoes and cassava flour) and imaging CN-in living cells with strong "turn-on" fluorescence at 490 nm. SB3 is an excellent CN- sensor that exhibits some advantages, including easy synthesis, distinct fluorescence and color change, high selectivity, low detection limit, and good anti-interference ability to analyze solution and food samples, together with fluorescence cell imaging.

An aniline trimer-based multifunctional sensor for colorimetric Fe3+, Cu2+ and Ag+ detection, and its complex for fluorescent sensing of L-tryptophan.

The detection of metal ions and amino acids by the aniline oligomer-based receptor has not been reported yet, to the best of our knowledge. In this study, an efficient multifunctional cation-amino acid sensor (CAS) with aniline moiety and chiral thiourea binding site was synthesized by the reaction of aniline trimer and (S)-(+)-1-phenyl ethyl isothiocyanate. CAS can sense Fe3+, Cu2+, Ag+ ions, and L-tryptophan. These results can be recognized by the naked eye. The appropriate pH range for the quantitative analysis of Fe3+, Cu2+, and Ag+ by CAS in DMSO/water (30 vol% water) was evaluated. The interaction between CCS and metal ions was analyzed by 1H NMR titration. The detection limits of CAS for the Cu2+, Ag+, and Fe3+ were 0.214, 0.099, and 0.147 µM, respectively. Moreover, the CASCu2+ complex can act as a turn-on fluorescence sensor for L-tryptophan. On the contrary, there is no response upon the addition of other amino acids, such as L-histidine, L-proline, L-phenylalanine, L-threonine, L-methionine, L-tyrosine, and L-cystine to CASCu2+ complex.

Molecular profiling of thymoma with myasthenia gravis: Risk factors of developing myasthenia gravis in thymoma patients.

OBJECTIVE: Thymoma is a rare epithelial tumor arising from the thymus in the anterior mediastinum. Nearly 50% of patients with thymoma develop myasthenia gravis, which is an indication of a poor long-term prognosis. Here, we identified specific and effective molecular markers for predicting in the development of myasthenia gravis patients with thymoma. MATERIAL AND METHODS: We investigated molecular profiling based on RNA-sequencing (RNA-seq) for myasthenia gravis development in patients with thymoma. RNA was extracted from 34 patients with thymoma, 16 of whom had myasthenic and 18 of whom did not, and transcriptome profiles were analyzed through next-generation sequencing. RESULTS: We discovered 140 differential expressed genes associated with myasthenia gravis in thymoma patients. The four genes, hypoxia-inducible factor 3 alpha (HIF3A), insulin-like growth factor-binding protein 1, pyruvate dehydrogenase kinase, and Krüppel-like factor 15 were differentially expressed in patients with thymoma who has myasthenia gravis and were validated by quantitative polymerase chain reaction. HIF3A expression was significantly higher in patients with myasthenia gravis than in those without. CONCLUSION: HIF3A is aberrantly expressed in patient with thymoma who has myasthenia gravis and may be involved in the development of myasthenia gravis in thymoma patient.

MAP4K3/GLK Promotes Lung Cancer Metastasis by Phosphorylating and Activating IQGAP1.

Overexpression of the serine/threonine kinase GLK/MAP4K3 in human lung cancer is associated with poor prognosis and recurrence, however, the role of GLK in cancer recurrence remains unclear. Here, we report that transgenic GLK promotes tumor metastasis and cell migration through the scaffold protein IQ motif-containing GTPase-activating protein 1(IQGAP1). GLK transgenic mice displayed enhanced distant metastasis. IQGAP1 was identified as a GLK-interacting protein; two proline-rich regions of GLK and the WW domain of IQGAP1 mediated this interaction. GLK and IQGAP1 colocalized at the leading edge including filopodia and lamellipodia of migrating cells. GLK directly phosphorylated IQGAP1 at Ser-480 enhancing Cdc42 activation and subsequent cell migration. GLK-induced cell migration and lung cancer metastasis were abolished by IQGAP1 depletion. Consistently, human NSCLC patient tissues displayed increased phospho-IQGAP1, which correlated with poor survival. Collectively, GLK promotes lung cancer metastasis by binding to, phosphorylating, and activating IQGAP1. SIGNIFICANCE: These findings show the critical role of the GLK-IQGAP cascade in cell migration and tumor metastasis, suggesting it as a potential biomarker and therapeutic target for lung cancer recurrence.

Surgical treatment of endobronchial leiomyosarcoma with right main bronchus total obstruction: a case report.

Endobronchial leiomyosarcoma is an unusual tumor of the respiratory tract. Clinically, patients may present with intermittent coughing, chest pain, dyspnea, hemoptysis, and fever until late in the course of the disease because of total obstruction of the main airway. In this paper, we report the case of a 51-year-old male with endobronchial leiomyosarcoma who presented with acute respiratory distress as a result of total obstruction of the right main bronchus and suffocation after massive hemoptysis. After intraoperative bronchoscopic assessment and bronchotomy, an elongated endobronchial tumor was found that arose from the right middle lobe (RML) bronchus with intraluminal extension upward into the right main bronchus. He underwent RML and right lower lobe (RLL) bilobectomy and had a rapid and uneventful recovery.

Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Patients With Stage I Non-Small-Cell Lung Cancer: A Competing Risks Analysis.

Purpose To perform competing risks analysis and determine short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who had undergone resection for stage I non-small-cell lung cancer (NSCLC). Patients and Methods Of 5,371 consecutive patients who had undergone curative-intent resection of primary lung cancer at our institution (2000 to 2011), 2,186 with pathologic stage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were included in the analysis, specifically, Charlson comorbidity index, predicted postoperative (ppo) diffusing capacity of the lung for carbon monoxide, and ppo forced expiratory volume in 1 second. Cause-specific mortality analysis was performed with competing risks analysis. Results Of 2,186 patients, 1,532 (70.1%) were ≥ 65 years of age, including 638 (29.2%) ≥ 75 years of age. In patients < 65, 65 to 74, and ≥ 75 years of age, 5-year lung cancer-specific cumulative incidence of death (CID) was 7.5%, 10.7%, and 13.2%, respectively (overall, 10.4%); noncancer-specific CID was 1.8%, 4.9%, and 9.0%, respectively (overall, 5.3%). In patients ≥ 65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer-specific CID; the higher noncancer-specific, early-phase mortality was enhanced in patients ≥ 75 years of age than in those 65 to 74 years of age. Multivariable analysis showed that low ppo diffusing capacity of lung for carbon monoxide was an independent predictor of severe morbidity ( P < .001), 1-year mortality ( P < .001), and noncancer-specific mortality ( P < .001), whereas low ppo forced expiratory volume in 1 second was an independent predictor of lung cancer-specific mortality ( P = .002). Conclusion In patients who undergo curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with an increasing impact as patient age increases.

GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer.

Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of total lung cancers; 40% to 60% of NSCLC patients die of cancer recurrence after cancer resection. Since GLK (also named MAP4K3) induces activation of NF-κB, which contributes to tumor progression, we investigated the role of GLK in NSCLC. GLK protein levels of 190 samples from pulmonary tissue arrays and 58 pulmonary resection samples from stage I to stage III NSCLC patients were studied using immunohistochemistry or immunoblotting. High levels of GLK proteins were detected in pulmonary tissues from NSCLC patients. Elevated GLK protein levels were correlated with increased recurrence risks and poor recurrence-free survival rates in NSCLC patients after adjusting for pathologic stage, smoking status, alcohol status, and EGFR levels. Thus, GLK is a novel prognostic biomarker for NSCLC recurrence.

Tumoral CD10 expression correlates with high-grade histology and increases risk of recurrence in patients with stage I lung adenocarcinoma.

OBJECTIVE: CD10 (neutral endopeptidase) is expressed in various normal and tumor cells, and its biological function can be controlled through enzymatic activity and signaling pathways. We investigated whether CD10 expression predicted disease recurrence and whether it correlated with histologic subtypes of stage I lung adenocarcinoma. MATERIALS AND METHODS: We reviewed tumor slides of resected pathologic stage I lung adenocarcinomas (1995-2009). Tumors were classified according to the IASLC/ATS/ERS classification. CD10 immunohistochemistry was performed using tissue microarrays (n=915). We combined the intensity (0-3) and distribution scores (0-2) for CD10 to create a total score (0-5). Risk of recurrence was estimated using competing risks methods. RESULTS: In the training cohort (n=313), risk of recurrence of patients with high tumoral CD10 (score>1, n=57) was significantly higher (5-year cumulative incidence of recurrence [CIR], 37%) than in those with low CD10 (score≤1; n=256; 5-year CIR, 16%; P<0.001); this finding was confirmed in the validation cohort (n=602, P=0.036). High tumoral CD10 was associated with higher risk of recurrence in acinar (P=0.007) and papillary predominant tumors (P=0.022). High tumoral CD10 was most frequently identified in micropapillary predominant (41%) and solid predominant tumors (34%). On multivariate analysis of intermediate-grade tumors, high tumoral CD10 remained a significant independent risk factor of recurrence (hazard ratio, 1.88; P=0.025). CONCLUSION: In stage I lung adenocarcinoma, tumoral CD10 correlated with high-grade histology and was an independent predictor of recurrence in intermediate-grade tumors.

Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2.

Nrf2 is a key transcription factor for genes coding for antioxidants, detoxification enzymes, and multiple drug resistance and it also confers resistance to anticancer drugs. Here, we hypothesized that mutant p53 could upregulate Nrf2 expression at the transcriptional level, thereby conferring cisplatin resistance in non-small cell lung cancer (NSCLC). Luciferase reporter assays and real-time PCR analysis indicated that the Nrf2 promoter activity and its mRNA levels were markedly suppressed by wild-type p53, but not by mutant p53. Chromatin immunoprecipitation (ChIP) further confirmed that wild-type p53 binds at the p53 putative binding site to block Sp1 binding to the Nrf2 promoter and consequently to suppress the Nrf2 promoter activity. The MTT assay indicated that an increase in Nrf2 expression by mutant p53 is responsible for cisplatin resistance. Among the Nrf2 downstream genes, Bcl-2 and Bcl-xL contribute more strongly to Nrf2-mediated cisplatin resistance when compared with heme oxygenase 1 (HO-1). Cox regression analysis showed that patients with high-Nrf2, high-Bcl-2, high-Bcl-xL mRNA tumors were more commonly occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. The prognostic significance of Nrf2 mRNA levels on OS and RFS was also observed in patients who have received cisplatin-based chemotherapy, particularly in p53-mutant patients. Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC.

Solid Predominant Histologic Subtype in Resected Stage I Lung Adenocarcinoma Is an Independent Predictor of Early, Extrathoracic, Multisite Recurrence and of Poor Postrecurrence Survival.

PURPOSE: To examine the significance of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) histologic subtypes of lung adenocarcinoma for patterns of recurrence and, among patients who recur following resection of stage I lung adenocarcinoma, for postrecurrence survival (PRS). PATIENTS AND METHODS: We reviewed patients with stage I lung adenocarcinoma who had undergone complete surgical resection from 1999 to 2009 (N = 1,120). Tumors were subtyped by using the IASLC/ATS/ERS classification. The effects of the dominant subtype on recurrence and, among patients who recurred, on PRS were investigated. RESULTS: Of 1,120 patients identified, 188 had recurrent disease, 103 of whom died as a result of lung cancer. Among patients who recurred, 2-year PRS was 45%, and median PRS was 26.1 months. Compared with patients with nonsolid tumors, patients with solid predominant tumors had earlier (P = .007), more extrathoracic (P < .001), and more multisite (P = .011) recurrences. Multivariable analysis of primary tumor factors revealed that, among patients who recurred, solid predominant histologic pattern in the primary tumor (hazard ratio [HR], 1.76; P = .016), age older than 65 years (HR, 1.63; P = .01), and sublobar resection (HR, 1.6; P = .01) were significantly associated with worse PRS. Presence of extrathoracic metastasis (HR, 1.76; P = .013) and age older than 65 years at the time of recurrence (HR, 1.7; P = .014) were also significantly associated with worse PRS. CONCLUSION: In patients with stage I primary lung adenocarcinoma, solid predominant subtype is an independent predictor of early recurrence and, among those patients who recur, of worse PRS. Our findings provide a rationale for investigating adjuvant therapy and identify novel therapeutic targets for patients with solid predominant lung adenocarcinoma.

Implementing the new IASLC/ATS/ERS classification of lung adenocarcinomas: results from international and Chinese cohorts.

A new histologic classification of lung adenocarcinoma was proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) in 2011 to provide uniform terminology and diagnostic criteria for multidisciplinary strategic management. This classification proposed a comprehensive histologic subtyping (lepidic, acinar, papillary, micropapillary, and solid pattern) and a semi-quantitative assessment of histologic patterns (in 5% increments) in an effort to choose a single, predominant pattern in invasive adenocarcinomas. The prognostic value of this classification has been validated in large, independent cohorts from multiple countries. In patients who underwent curative-intent surgery, those with either an adenocarcinoma in situ (AIS) or a minimal invasive adenocarcinoma have nearly 100% disease-free survival and are designated "low grade tumors". For invasive adenocarcinomas, the acinar and papillary predominant histologic subtypes were usually designated as "intermediate grade" while the solid and micropapillary predominant histologic subtypes were designated "high grade" tumors; this was based on the statistic difference of overall survival. This classification, coupled with additional prognostic factors [nuclear grade, cribriform pattern, high Ki-67 labeling index, thyroid transcription factor-1 (TTF-1) immunohistochemistry, immune markers, and (18)F-fluorodeoxyglucose uptake on positron emission tomography (PET)] that we have published on, could further stratify patients into prognostic subgroups and may prove helpful for individual patient care. With regard to Chinese oncologists, the implementation of this new classification only requires hematoxylin and eosin (H&E) stained slides and basic pathologic training, both of which require no additional costs. More importantly, this new classification system could provide informative data for better selection and stratification of clinical trials and molecular studies.

Recent advances and clinical implications of the micropapillary histological subtype in lung adenocarcinomas.

Micropapillary (MIP) histologic subtype included in the classification of lung adenocarcinomas (ADCs) is associated with both size- and stage-independent poor prognoses. MIP pattern in lung ADCs, even at small, early stages, correlates with high lymphovascular invasion, visceral pleural invasion and lymph node metastases. Recently, we reported that patients with a MIP component are at a higher risk of locoregional recurrence after limited resection. Identification of a MIP pattern is only possible with permanent pathologic sections; preoperative imaging, cytology or intraoperative frozen section specimens remain unreliable. The intermixed, heterogenous morphology of lung ADC presents a technical challenge in investigating the molecular biology of cells with MIP morphology. A comprehensive understanding of the biology of MIP morphology is vital for therapeutic interventions.