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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.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.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.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.

Background: Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan. Methods: Using Taiwanese multiple data sources, we formed an age-matched case–control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011–2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem. Results: The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%). Conclusions: The adapted PLCOT models had high predictive performance. Impact: The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Background:Methods synthesizing multiple data sources without prospective datasets have been proposed for absolute risk model development. This study proposed methods for adapting risk models for another population without prospective cohorts, which would help alleviate the health disparities caused by advances in absolute risk models. To exemplify, we adapted the lung cancer risk model PLCOM2012, well studied in the west, for Taiwan.Methods:Using Taiwanese multiple data sources, we formed an age-matched case–control study of ever-smokers (AMCCSE), estimated the number of ever-smoking lung cancer patients in 2011–2016 (NESLP2011), and synthesized a dataset resembling the population of cancer-free ever-smokers in 2010 regarding the PLCOM2012 risk factors (SPES2010). The AMCCSE was used to estimate the overall calibration slope, and the requirement that NESLP2011 equals the estimated total risk of individuals in SPES2010 was used to handle the calibration-in-the-large problem.Results:The adapted model PLCOT-1 (PLCOT-2) had an AUC of 0.78 (0.75). They had high performance in calibration and clinical usefulness on subgroups of SPES2010 defined by age and smoking experience. Selecting the same number of individuals for low-dose computed tomography screening using PLCOT-1 (PLCOT-2) would have identified approximately 6% (8%) more lung cancers than the US Preventive Services Task Forces 2021 criteria. Smokers having 40+ pack-years had an average PLCOT-1 (PLCOT-2) risk of 3.8% (2.6%).Conclusions:The adapted PLCOT models had high predictive performance.Impact:The PLCOT models could be used to design lung cancer screening programs in Taiwan. The methods could be applicable to other cancer models.

Supplementary Data from Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan

Supplementary Figure from Recalibrating Risk Prediction Models by Synthesizing Data Sources: Adapting the Lung Cancer PLCO Model for Taiwan

The standard treatment for early-stage lung cancer is complete tumor excision by limited resection of the lung. Pre-operative 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 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 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 localization accuracies 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. 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.

Supplementary Figure 2 PDF file - 132K, (A) The expression levels of MnSOD evaluated by Western blotting were not changed by FoxM1-knockdown in A549 and H1355 cells. (B) The expression levels of MMP1 and MMP2 evaluated by Western blotting decreased in a dose-dependent manner; however, the change of MMP7 and MMP9 expression was not observed in MnSOD-knockdown A549 cells

Supplementary Figure 1 PDF file - 101K, The expression level of E2F1 evaluated by Western blotting was not changed by MnSOD-knockdown in H1355 cells compared with non-specific shRNA control cells

Supplementary Table 1 PDF file - 142K, Relationship of MnSOD IHC, FoxM1, MMP2 and MnSOD mRNA expression with clinical parameters in lung adenocarcinoma patients

Supplementary Table 2 PDF file - 144K, List of primer sequences (5'�|��3') and their reaction conditions used in the present study

Supplementary Data PDF file - 268K,Supplementary Figure 1. The expression level of E2F1 evaluated by Western blotting was not changed by MnSOD-knockdown in H1355 cells compared with non-specific shRNA control cells. Supplementary figure 2. (A) The expression levels of MnSOD evaluated by Western blotting were not changed by FoxM1-knockdown in A549 and H1355 cells. (B) The expression levels of MMP1 and MMP2 evaluated by Western blotting decreased in a dose-dependent manner; however, the change of MMP7 and MMP9 expression was not observed in MnSOD-knockdown A549 cells. Supplementary Table 1. Relationship of MnSOD IHC, FoxM1, MMP2 and MnSOD mRNA expression with clinical parameters in lung adenocarcinoma patients. Supplementary Table 2. List of primer sequences (5'�|��3') and their reaction conditions used in the present study

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme responsible for the elimination of superoxide radical. The role of MnSOD in tumor progression in different human cancers is still controversial. In the present study, MnSOD expression in lung cancer cells was explored by knockdown or overexpression using transfection of a short hairpin RNA (shRNA) or an expression vector, respectively, to determine whether MnSOD expression mediates lung cancer cell migration, invasion, and oncogenic potential by increasing FoxM1 and MMP2 expression. Western blotting showed that FoxM1 and MMP2 expression was dependent on MnSOD expression, suggesting that FoxM1 could be upregulated by MnSOD. Three FoxM1 promoters were constructed to verify this activation of FoxM1 by MnSOD and to determine the transcription factors responsible. Luciferase reporter and chromatin immunoprecipitation assays indicated that MnSOD overexpression in lung cancer cells promoted binding of E2F1 and Sp1 to their putative FoxM1 promoter-binding sites and activated FoxM1 reporter activity. MnSOD also enhanced the potential for cell migration, invasion, and anchorage-independent colony growth on soft-agar plates, again via upregulation of FoxM1 and MMP2 expression. In patients with lung cancer, evaluation of MnSOD expression in lung tumors by immunohistochemistry indicated a positive correlation between FoxM1 and MMP2 mRNA expressions. Kaplan–Meier and Cox regression analysis revealed a poorer overall survival (OS) and relapse-free survival (RFS) in patients with MnSOD-positive tumors than with MnSOD-negative tumors. We conclude that MnSOD may promote tumor aggressiveness via upregulation of the FoxM1–MMP2 axis, and that MnSOD expression can independently predict survival and relapse in patients with resected lung adenocarcinoma. Mol Cancer Res; 11(3); 261–71. ©2012 AACR.

Supplementary Tables 1-2 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Purpose: Although existence of humoral immunity has been previously shown in malignant pleural effusions, only a limited number of immunogenic tumor-associated antigens (TAA) have been identified and associated with lung cancer. In this study, we intended to identify more TAAs in pleural effusion–derived tumor cells.Experimental Design: Using morphologically normal lung tissues as a control lysate in Western blotting analyses, 54 tumor samples were screened with autologous effusion antibodies. Biochemical purification and mass spectrometric identification of TAAs were done using established effusion tumor cell lines as antigen sources. We identified a p48 antigen as α-enolase (ENO1). Semiquantitative immunohistochemistry was used to evaluate expression status of ENO1 in the tissue samples of 80 patients with non–small cell lung cancer (NSCLC) and then correlated with clinical variables.Results: Using ENO1-specifc antiserum, up-regulation of ENO1 expression in effusion tumor cells from 11 of 17 patients was clearly observed compared with human normal lung primary epithelial and non-cancer-associated effusion cells. Immunohistochemical studies consistently showed high level of ENO1 expression in all the tumors we have examined thus far. Log-rank and Cox's analyses of ENO1 expression status revealed that its expression level in primary tumors was a key factor contributing to overall- and progression-free survivals of patients (P < 0.05). The same result was also obtained in the early stage of NSCLC patients, showing that tumors expressing relatively higher ENO1 level were tightly correlated with poorer survival outcomes.Conclusions: Our data strongly support a prognostic role of ENO1 in determining tumor malignancy of patients with NSCLC.

Supplementary Figure Legends - PDF file 57K, Supplementary Figure Legends

Supplementary Figure 1 - PDF file 36K, Doubling time of IL-10-knockdown TL1 cells and IL-10-overexpressing TL4 cells and the error bars represent the S.D. of triplicate results

Supplementary Figure 4 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Supplementary Fig. 1. PAK1 confers erlotinib resistance in lung adenocarcinoma cells regardless of EGFR mutation Supplementary Fig. 2. The optimal concentration of gefitinib was obtained from the dose-dependent experiments Supplementary Fig. 3. PAK1 transcription is regulated by the PI3K/AKT/C/EBP-β /miR-145 cascades and PAK1 targeted by miR-145 may confer PAK1-mediated TKI resistance in EGFR-wild-type cells Supplementary Fig. 4. PAK1 modulates Mcl-1 protein stability via phosphorylation of Mcl-1 at Ser-159. Supplementary Fig. 5. The association of PAK1 and E-cadherin mRNA expression with overall survival (OS) and relapse free survival (RFS) in lung adenocarcinoma patients. Supplementary Table 1. Relationships of PAK1 and E-cadherin mRNA levels with clinico-pathological parameters, and the association between PAK1 and E-caherin mRNA levels in lung adenocarcinoma patients. Supplementary Table 2. The association of PAK1 and E-cadherin mRNA level with the response to TKI therapy in lung adenocarcinoma patients. Supplementary Table 3. Cox regression analysis for the prognostic value of PAK1 and E-cadherin mRNA levels on OS and RFS in lung adenocarcinoma patients.

Supplementary Figure 2 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Supplementary Figure 2 - PDF file 65K, Kaplan-Meier analysis was used to assess the influence of IL-10 and CIP2A on overall survival in (A) all study population, (B) patients with HPV 16/18 E6 positive tumor, and (C) patients with HPV 16/18 E6 negative tumor

PDF file - 430K

Supplementary Figures S1-S4; Supplementary Tables S1-S3.

Purpose: To assess whether polymorphisms of genes related to estrogen biosynthesis and metabolism are associated with EGFR mutations.Experimental Design: We studied 617 patients with lung adenocarcinoma, including 302 never-smoking women. On the basis of multiple candidate genes approach, the effects of polymorphisms of CYP17, CYP19A1, ERα, and COMT in association with the occurrence of EGFR mutations were evaluated using logistic regression analysis.Results: In female never-smokers, significant associations with EGFR L858R mutation were found for the tetranucleotide (TTTA)n repeats in CYP19A1 (odds ratio, 2.6; 95%CI, 1.2–5.7 for 1 or 2 alleles with (TTTA)n repeats >7 compared with both alleles with (TTTA)n repeats ≤7), and the rs2234693 in ERα (OR, 2.1; 95% CI, 1.1–4.0 for C/T and C/C genotypes compared with T/T genotype). The C/C genotype (vs. T/T genotype) of ERα was significantly associated with EGFR L858R mutation (OR, 3.0; 95% CI, 1.1–8.1), in-frame deletion (OR, 2.9; 95% CI, 1.1–7.6) and other mutations (OR, 4.3; 95% CI, 1.3–14.0). The genotype of COMT rs4680 was significantly associated with EGFR L858R mutation in female and male never-smokers showing OR's (95% CI) of 1.8 (1.0–3.2) and 3.6 (1.1–11.3), respectively, for genotypes G/A and G/G compared with genotype A/A. The number of risk alleles of CYP17, CYP19A1, ERα, and COMT was associated with an increasing OR of EGFR L858R mutation in female never-smokers (P = 0.0002 for trend).Conclusions: The L858R mutation of EGFR is associated with polymorphisms of genes related to estrogen biosynthesis and metabolism in never-smoking female lung adenocarcinoma patients. Clin Cancer Res; 17(8); 2149–58. ©2011 AACR.

Supplementary Figures 3 and 4 - PDF file 262K, S3: Exogenous IL-10 regulates tumor migration capability of lung cancer cells; S4: The migration and invasion ability of TL1 cells was decreased in IL-10R knock down stable clone

Supplementary Figure Legends 1-4 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Supplementary Methods; Supplementary Table S1.

Purpose: Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial.Experimental Design: To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10–mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model.Results: Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element-binding protein (CREB) and C/enhancer-binding protein β (C/EBPβ) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10–mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors.Conclusion: IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients’ outcome and life quality. Clin Cancer Res; 19(15); 4092–103. ©2013 AACR.

Purpose: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance.Experimental Design: Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-β/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated.Results: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR–wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-β/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low–E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low–E-cadherin tumors.Conclusions: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA–expressing tumors. Clin Cancer Res; 22(21); 5370–82. ©2016 AACR.

Purpose:Fas ligand (FasL) −844T/C polymorphism (rs763110) has a demonstrated association with lung cancer risk. FasL −844CC with higher FasL expression has been suggested to contribute to tumor progression via immune escape. However, the impact of FasL −844T/C polymorphism on the clinical outcome of non–small cell lung cancer (NSCLC) remains to be identified.Experimental Design: A total of 385 adjacent normal lung tissues from patients with NSCLC were collected to determine FasL −844T/C polymorphism by PCR-based restriction fragment length polymorphism. FasL mRNA and protein expression in lung tumors were evaluated by real-time PCR and immunohistochemistry. The prognostic value of FasL −844T/C polymorphism on survival and relapse was determined by Kaplan–Meier analysis and Cox proportional hazards models.Results: The FasL −844CC genotype had higher prevalence in those with advanced tumors than in those with early tumors (P = 0.008). In addition, patients with the FasL −844CC genotype were more prone to tumor relapse than those with the FasL −844TT+TC genotype (62.1% vs. 37.9%, P = 0.001). Multivariate Cox regression analysis showed that patients with the FasL −844CC genotype had poorer survival in terms of overall survival (OS) and relapse-free survival (RFS) than those with the FasL −844TT+TC genotype (24.1 vs. 42.8 months for OS, HR = 1.455, P = 0.004; 15.4 vs. 31.4 months for RFS, HR = 1.710, P < 0.001).Conclusions:FasL −844T/C polymorphism may predict survival and relapse in NSCLC. We suggest that FasL may be a molecular target for immunotherapeutic interventions to improve the clinical outcome of patients with NSCLC. This finding should be validated by another investigative group. Clin Cancer Res; 17(18); 5991–9. ©2011 AACR.

Supplementary Figure 1 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Supplementary Figure 3 from Identification of α-Enolase as an Autoantigen in Lung Cancer: Its Overexpression Is Associated with Clinical Outcomes

Supplementary Figures 1-2 from Human Papillomavirus 16/18 E6 Oncoprotein Is Expressed in Lung Cancer and Related with p53 Inactivation

Supplementary Methods, Figure 1, Tables 1-9 from Paxillin Predicts Survival and Relapse in Non–Small Cell Lung Cancer by MicroRNA-218 Targeting

Supplementary Figures 1-4 from p53 Dysfunction by Xeroderma Pigmentosum Group C Defects Enhance Lung Adenocarcinoma Metastasis via Increased Mmp1 Expression

Inactivation of p53 by human papillomavirus 16/18 E6 plays a crucial role in cervical tumorigenesis. To investigate the involvement of HPV16/18 in lung tumorigenesis, the association between HPV16 or HPV18 E6 and p53 protein expression in 122 lung tumors was evaluated by immunohistochemistry, and data showed that HPV16/18 E6 expression correlated inversely with p53 expression, which was further confirmed by tissue in situ immunostaining. Real-time reverse transcription-PCR analysis indicated that E6-positive tumors had lower p21WAF1/CIP1 and mdm2 mRNA levels than E6-negative tumors. To elucidate the role of E6 in p53 inactivation, we successfully established lung adenocarcinoma cell lines with or without HPV16 infection from patients' pleural effusions. Western blotting showed that E6 protein was indeed expressed in HPV16-infected cells and a lower level of p53 protein was observed in E6-positive cells compared with E6-negative cells. Moreover, the levels of p21WAF1/CIP1 and mdm2 mRNA in E6-positive cells were lower than in E6-negative cells. The interaction of E6 with p53 protein was revealed by immunoprecipitation assay showing that p53 could be inactivated by E6 protein. Conversely, p53 proteins and p21WAF1/CIP1 and mdm2 mRNA expressions were restored in E6-knockdown cells by RNA interference compared with control cells. These results reveal that HPV16/18 E6 may be partially involved in p53 inactivation to down-regulate p21WAF1/CIP1 and mdm2 transcription. In conclusion, HPV16/18 E6 is indeed expressed in HPV DNA–positive lung tumors and is involved in p53 inactivation to contributing to HPV-mediated lung tumorigenesis. [Cancer Res 2007;67(22):10686–93]

Supplementary Methods, Figure Legends 1-4 from p53 Dysfunction by Xeroderma Pigmentosum Group C Defects Enhance Lung Adenocarcinoma Metastasis via Increased Mmp1 Expression

IntroductionAnaplastic 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.MethodsThis 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.ResultsAmong 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 relevanceFor 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.

Background The optimal radiotherapy dose for locally advanced esophageal squamous cell carcinoma in endemic areas treated with neoadjuvant concurrent chemoradiotherapy is unclear. Methods Eligible patients diagnosed between 2010 and 2019 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders. The hazard ratio (HR) of death was compared between high dose (50–50.4 Gy) and low dose (40–41.4 Gy) radiotherapy. We also evaluated other outcomes and performed supplementary analyses via an alternative approach. Results Our study population consisted of 644 patients. The PS weight-adjusted HR of death was 0.92 (95% confidence interval: 0.7–1.19, p = 0.51). There were no statistically significant differences for other outcomes or supplementary analyses. Conclusions In this population-based study from an endemic area, we found no significant difference in overall survival between high vs. low radiotherapy doses.

The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

Total thyroidectomy is the treatment of choice for multinodular goiter (MNG). In some of these cases, incidental thyroid cancer (ITC) is detected postoperatively. Papillary thyroid microcarcinoma (PTMC), the most common type of ITC, has clinical factors and pathologic similarities with ITC that have not been well clarified previously. We investigated the incidence and characteristics of ITC and PTMC in euthyroid patients undergoing total thyroidectomy for MNG.We retrospectively investigated the data of 151 euthyroid patients who underwent total thyroidectomy for MNG between January 2016 and December 2020. Patients with PTMC were then selected from among those with ITC for further data analysis.The incidence rates of ITC and PTMC were 31.1% (47/151) and 21.1% (32/151), respectively. The mean age of patients with ITC was 52.8 ± 11.7 years, which was younger than that of patients with benign MNG (57.2 ± 12.5 years, p0.05). Bilateral cancer was observed in 17 patients with ITC (17/47, 36.2%) and nine with PTMC (9/32, 28.1%). The numbers of patients in the ITC and PTMC groups whose cancer was not on the side comprising the dominant tumor were 15 (15/47, 31.9%) and 13 (13/32, 40.6%), respectively. The multivariate analysis demonstrated that younger age was a clinical factor associated with ITC and PTMC.Younger age is a clinical factor for ITC and PTMC. We recommend taking considering clinical factors and pathologic characteristics of ITC and PTC when considering total thyroidectomy in euthyroid patients with MNG.

Different approaches to endoscopic thyroidectomy utilize incisions that result in inevitable physical trauma to patients since postoperative tissue fibrosis and scars will influence their quality of life for a lifetime. Over the past few years, most studies have discussed the safety concerns of different kinds of endoscopic thyroidectomy; conversely, there has been less discussion on postoperative quality of life. Because most patients undergoing thyroidectomy for cancer or benign diseases are likely to have long-term survival, it is essential to study the cosmetic outcome of patients' scars from minimally invasive video-assisted thyroidectomy (MIVAT) and bilateral axillo-breast approach (BABA) robotic thyroidectomy on quality of life. From July 2015 to December 2017, 95 patients-60 who underwent MIVAT and 35 who underwent BABA robotic thyroidectomy-were retrospectively studied. Patient demographics, operative indications, pathologic findings, pain scores after surgery, complications, perception of scars, and overall satisfaction were compared between the two groups. The cosmetic outcome and overall satisfaction were evaluated at least 2 years after the operation using the patient scar assessment questionnaire and the 36-item short form health survey (SF-36). There was no statistically significant difference in scar perception between the two groups. However, in the SF-36, the MIVAT group had better satisfaction than the BABA robotic group regarding general health, vitality, mental health, and health change. MIVAT and BABA robotic thyroidectomy can be safely performed in selected patients, and patients who underwent MIVAT had better postoperative qualities of life than those who underwent the BABA robotic approach.

Synthetic bone graft has gained considerable attention because of an increase in the aged population. In the present study, a biphasic bone graft composed of hydroxyapatite (HAp) and calcium sulfate (CS) is prepared using a gel-foaming technique. The gel is prepared at a temperature as low as 35 °C; many pores are introduced into the gel through an agitation process. The foamed gel can be cut into any shape and size. After sintering, the porosity of the biphasic bone graft is approximately 70%. Depending on the HAp/CS ratio, the amount of macropores and micropores can be tailored. The macropores of approximately 130 μm diameter are interconnected with each other through openings of 40 μm size. The biphasic bone graft exhibits no cytotoxicity; preosteoblast cells can adhere and proliferate on the surface of the fabricated bone graft. However, migration of these cells into the bone graft is considerably limited in the in vitro study. When the biphasic bone graft is implanted into the distal femur of rats, with the combined effect of osteoblast and osteoclast cells, more than 90% of the bone graft is degraded after 3 months. New trabeculae bone and bone marrow are observed within the bone defect. The HAp/CS composite can thus be used as degradable bone grafts.

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.

Background The human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene encodes a DNA glycosylase that removes 8-hydroxy-2-deoxyguanine (8-OH-dG) DNA damage to protect against gene mutations. The association of hOGG1 Ser326Cys polymorphism with lung cancer risk has predicted that hOGG1-Cys variants are less effective at removing 8-OH-dG damage from DNA; therefore, these variants might show an increased occurrence of tumor suppressor gene and oncogene mutations. However, no evidence has yet supported this hypothesis. Methods Direct sequencing was performed to examine the mutations of p53 and EGFR genes in lung tumors from patients with non-small cell lung cancer (NSCLC). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine hOGG1 Ser326Cys polymorphism in this study population. Results A total of 99 p53-mutated and 99 EGFR-mutated patients with NSCLC were selected to explore the possible associations of these mutations with hOGG1 Ser326Cys polymorphism. The p53-mutated and EGFR-mutated patients were divided into nondeletion and deletion subgroups. P53 deletion mutations were more commonly observed in male than in female patients (P = 0.030). However, EGFR exon 19 deletion mutations were more prevalent in female and adenocarcinoma patients than in male and squamous cell carcinoma patients (P = 0.028 for genders, P = 0.017 for tumor histology). Interestingly, p53 and EGFR exon 19 deletion mutations were more frequent in patients with hOGG1 Ser/Cys + Cys/Cys hOGG1-Cys variants than with the hOGG1 Ser/Ser genotype (P = 0.010 for p53, P = 0.032 for EGFR). Conclusions We suggest that the association of hOGG1 Ser326Cys polymorphism with lung cancer risk could be partially explained by increases in p53 and EGFR deletion mutations. Key points SIGNIFICANT FINDINGS OF THE STUDY: NSCLC patients with hOGG1-Cys variants may have a higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. What this study adds NSCLC patients with hOGG1-Cys variants might be helpful to predict patients having higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib or erlotinib could be a higher risk to occur EGFR T790M mutation.

Objective To compare the effects of computerized cognitive training (CCT) and tai chi (TC) with usual care (UC) on cognitive functions and secondary outcomes in older adults with traumatic brain injury. Participants and settings Ninety-six patients aged 55 years and older who had a diagnosis of traumatic brain injury requiring hospital admission. Design Randomized controlled trial. Main measures The Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination, modified Telephone Interview of Cognitive Status, and Trail Making Tests A and B. Results Compared with UC, CCT increased scores on the MDRS's total, attention, and memory and those on the Mini-Mental State Examination and Telephone Interview of Cognitive Status over the 6-month intervention; TC increased scores on the MDRS's total and conceptualization and those on the Mini-Mental State Examination over the 6-month intervention, while it also increased scores on the MDRS's total and initiation/preservation and those on the Telephone Interview of Cognitive Status and reduced the time to complete the Trail Making Test B over the 12-month study. Furthermore, compared with UC, CCT increased handgrip strength and TC reduced the time to complete 5 sit-to-stands over the 6-month intervention. Conclusion Both CCT and TC may improve global cognition and different specific cognitive domains in older traumatic brain injury patients; the TC's effect may last for at least an additional 6 months.