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Objectives: Tyrosine kinase inhibitors (TKIs) are the primary therapeutic option for patients with advanced-stage epidermal growth factor receptor-mutant (EGFR-m) lung adenocarcinoma. However, the role of EGFR-TKIs in advanced-stage lung cancer is uncertain regardless of therapeutic methods. This study investigated the outcome of the impact of epidermal growth factor receptor (EGFR)-TKI in patients with advanced lung adenocarcinoma treated with various therapeutic strategies., Methods: This retrospective analysis used cancer registry data from 1159 patients with lung cancer treated between January 2015 and December 2017 at Tri-Service General Hospital. Only patients with lung adenocarcinoma stages 3B and four were selected for the study. All lung adenocarcinoma patients with ever TKI treatment had an EGFR mutation., Results: Three-hundred sixty-two patients with advanced lung adenocarcinoma with complete medical records were enrolled. According to personalized therapeutic processes, they were divided into nine groups: only TKI treatment, only chemotherapy (CT), TKI with lung cancer salvage surgery, TKI with CT, TKI with radiotherapy (RT), CT with lung cancer salvage surgery, CT with RT, TKI with CT, and lung cancer salvage surgery. A multivariate Cox regression analysis showed TKI with lung cancer salvage surgery (HR: 4.675, p = 0.005) is the only good prognostic treatment. The poor predictors for overall survival were only CT (HR: 0.336, p = 0.048) and TKI with CT (HR: 0.359, p = 0.023). Kaplan-Meier survival analysis showed a statistical significance in an average overall survival (OS) of ever TKI treatment and never TKI treatment (33.24 vs. 17.64 months, p < 0.001). Furthermore, TKI usage duration was statistically increased in TKI with lung cancer salvage surgery (40.4 ± 20.7 vs 14.96 ± 13.13 months, p < 0.001). The survival rate (p = 0.033) and OS (p < 0.001) in lung cancer salvage surgery were statistically better than the group of TKI without surgery., Conclusion: The best therapeutic strategy for advanced lung adenocarcinoma is TKI with lung cancer salvage surgery, according to significantly longer OS and better survival. It also prolonged TKI usage. Mutated EGFR lung adenocarcinoma patients with ever TKI treatment had significantly better survival than with other treatments. Regardless of the combination of other treatments, EGFR mutation with TKI therapy is recommended as a positive prognostic factor for patients with lung adenocarcinoma., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The present study investigated the oncologic outcomes of clinical stage IA2 non-small cell lung cancer (NSCLC) treated using preoperative simulation and surgical resection., Methods: Data of patients who underwent surgical resection for clinical stage IA2 NSCLC between January 2002 and June 2018 were reviewed. Preoperative simulations were indicated for patients with centrally located tumors who could undergo anatomic resection. Clinical features, imaging characteristics of the tumors, surgical approaches, and outcomes were analyzed., Results: Of the 1086 identified patients, 281 patients with clinical stage IA2 NSCLC were enrolled and categorized into 2 groups, with and without preoperative simulation. Tumor location, maximum standard uptake value, histologic grade, disease-free survival, and disease recurrence were significantly different between the 2 groups. For patients with preoperative simulations, 70.7% underwent anatomic resection, whereas for patients without preoperative simulations, 79.7% underwent anatomic resection (P < .001). Patients with preoperative simulations had fewer relapses (2%) than patients without preoperative simulations (11.5%, P < .01)., Conclusions: Preoperative simulation confirmed the relationship between the tumor and surrounding blood vessels and bronchus and ensured an oncologic safety margin. Three-dimensional simulations are a useful and feasible tool for planar operative procedures and satisfy the requirements for early-stage NSCLC. These results are promising but preliminary, and more extended follow-up is needed., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the role of PET in predicting the prognosis of resected stage IA non-small cell lung cancer (NSCLC) and planning individualized therapeutic strategies., Methods: We retrospectively reviewed the data of patients who underwent surgical resection for lung cancer between January 2004 and December 2014. The clinical data, imaging characteristics of nodules, surgical approaches, and outcomes were analyzed., Results: We evaluated 998 cases; 637 patients with pathological stage I disease were categorized as follows: stage IA1 (251 cases), stage IA2 (250 cases), and stage IA3 (136 cases). The mean follow-up period was 109 months. Significant differences were observed in sex, tumor differentiation, epidermal growth factor receptor mutation, smoking habits, lymphovascular space invasion, tumor size, maximum standard uptake value (SUVmax), and carcinoembryonic antigen level among the groups. Multivariable Cox regression revealed that ground-glass opacity ratio (hazard ratio (HR) = 0.001) and tumor SUVmax independently predicted the postoperative risk of relapse for stage IA3 NSCLC. The HR for SUVmax > 4 was 8.986 (p < 0.001). The 5-year overall survival (OS) rates were 87.2%, 92.9%, and 82.7%, and the 5-year disease-free survival (DFS) rates were 93.2%, 84.2%, and 70.51% for stage IA1, IA2, and IA3 NSCLC, respectively (both p < 0.001). OS and DFS rates were poor in stage IA3 NSCLC patients with an SUVmax uptake > 4 (OS, 71.0% and 92.2%; DFS, 50.2% and 87.3%, for SUVmax > 4 and ≤ 4, respectively; both p = 0.001)., Conclusions: SUVmax was a prognostic factor for resected stage IA NSCLC. Postoperative treatment may be considered for IA3 NSCLC with SUVmax > 4., Key Points: • PET helps surgeons to assess patients with early-stage lung cancer. • This retrospective study revealed that PET plays an influential role in predicting the prognosis of resected lung cancer. • Better prognostication aids better planning of therapeutic strategies with diversification., (© 2021. European Society of Radiology.)

Amsacrine, an anticancer drug first synthesised in 1970 by Professor Cain and colleagues, showed excellent preclinical activity and underwent clinical trial in 1978 under the auspices of the US National Cancer Institute, showing activity against acute lymphoblastic leukaemia. In 1984, the enzyme DNA topoisomerase II was identified as a molecular target for amsacrine, acting to poison this enzyme and to induce DNA double-strand breaks. One of the main challenges in the 1980s was to determine whether amsacrine analogues could be developed with activity against solid tumours. A multidisciplinary team was assembled in Auckland, and Professor Denny played a leading role in this approach. Among a large number of drugs developed in the programme, N -[2-(dimethylamino)-ethyl]-acridine-4-carboxamide (DACA), first synthesised by Professor Denny, showed excellent activity against a mouse lung adenocarcinoma. It underwent clinical trial, but dose escalation was prevented by ion channel toxicity. Subsequent work led to the DACA derivative SN 28049, which had increased potency and reduced ion channel toxicity. Mode of action studies suggested that both amsacrine and DACA target the enzyme DNA topoisomerase II but with a different balance of cellular consequences. As primarily a topoisomerase II poison, amsacrine acts to turn the enzyme into a DNA-damaging agent. As primarily topoisomerase II catalytic inhibitors, DACA and SN 28049 act to inhibit the segregation of daughter chromatids during anaphase. The balance between these two actions, one cell cycle phase specific and the other nonspecific, together with pharmacokinetic, cytokinetic and immunogenic considerations, provides links between the actions of acridine derivatives and anthracyclines such as doxorubicin. They also provide insights into the action of cytotoxic DNA-binding drugs.

Sirtuin 6 (SIRT6), a member of the sirtuin family, is a nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase that is involved in various physiological and pathological processes. SIRT6 is generally downregulated and linked to tumorigenesis in non-small cell lung carcinoma (NSCLC), thus regarded as a promising therapeutic target of NSCLC. In this study, we investigated whether MDL-800, an allosteric activator of SIRT6, exerted antiproliferation effect against NSCLC cells in vitro and in vivo. We showed that MDL-800 increased SIRT6 deacetylase activity with an EC 50 value of 11.0 ± 0.3 μM; MDL-800 (10-50 μM) induced dose-dependent deacetylation of histone H3 in 12 NSCLC cell lines. Treatment with MDL-800 dose dependently inhibited the proliferation of 12 NSCLC cell lines with IC 50 values ranging from 21.5 to 34.5 μM. The antiproliferation effect of MDL-800 was significantly diminished by SIRT6 knockout. Treatment with MDL-800 induced remarkable cell cycle arrest at the G 0 /G 1 phase in NSCLC HCC827 and PC9 cells. Furthermore, MDL-800 (25, 50 μM) enhanced the antiproliferation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in osimertinib-resistant HCC827 and PC9 cells as well as in patient-derived primary tumor cells, and suppressed mitogen-activated protein kinase (MAPK) pathway. In HCC827 cell-derived xenograft nude mice, intraperitoneal administration of MDL-800 (80 mg · kg -1  · d -1 , for 14 days) markedly suppressed the tumor growth, accompanied by enhanced SIRT6-dependent histone H3 deacetylation and decreased p-MEK and p-ERK in tumor tissues. Our results provide the pharmacological evidence for future clinical investigation of MDL-800 as a promising lead compound for NSCLC treatment alone or in combination with EGFR-TKIs.

Objective: To evaluate the performance of low-dose computed tomography (LDCT) on lung cancer screening in high-risk populations in Sichuan., Methods: From April 2014 to July 2018, LDCT was performed annually on 3185 subjects aged 50-74 years who had smoked ≥ 20 pack-years (or subjects having quit smoking within 5 years). Information about all deaths and lung cancer diagnoses were obtained by active investigation, or passive matching to disease surveillance system., Results: The screening population had a median age of 60 years. 62.4 % of which were current smokers and had smoked 30 pack-years. After participating in the baseline screening, the compliance rates of subjects consecutively completing one round, two rounds, three rounds, and four rounds of annual screening were 67.22 %, 52.84 %, 43.24 %, and 40.04 %, respectively. The positive rates in baseline and annual screening were 6.53 % and 5.79 %, respectively. During the 5 rounds, a total of 9522 person-times were screened by LDCT with a screening sensitivity of 89.13 % (95 % CI: 76.96-95.27), specificity of 94.36 % (95 % CI: 93.88-94.81), positive predictive value of 7.13 % (95 % CI: 5.30-9.53), and negative predictive value of 99.94 % (95 % CI: 99.87-99.98). There were no statistically significant performance differences between baseline and annual screening. The difference in the proportion of screen-detected stage I lung cancer between baseline screening and annual screening was not statistically significant, neither., Conclusion: The application of LDCT on lung cancer screening in high-risk populations shows favorable compliance and a high screening performance in the project area of Sichuan,China., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to verify the predictors of recurrence and survival in lung adenocarcinoma patients with experiences of breast cancer therapies., Methods: We retrospectively reviewed consecutive patients who were treated at our hospital for lung adenocarcinoma from 2004/01 to 2014/03. The patients were divided into groups of those with lung adenocarcinoma alone and those with lung and breast cancer. Kaplan-Meier plots and log-rank tests were used to estimate outcomes., Results: 54 patients with lung adenocarcinoma and breast cancer were compared with 457 patients with single primary lung adenocarcinomas. After propensity score matching with control of age, operation type, smoking status and pathologic stage, tumor differentiation, recurrence rate and tumor size were significantly different between two groups. The significant predictors for recurrence included undergone chemotherapy (HR = 25, p < 0.001), moderate/poor differentiation (HR = 8.125, p = 0.012), tumor size ≧ 2 cm (HR = 15, p < 0.001), LVSI (HR = 13.67, p = 0.031) and GGO ratio < 50% (HR = 14.667, p = 0.014). The significant prognostic factors for survival were accepted chemotherapy (HR = 6.182, p = 0.021), LVSI (HR = 22, p = 0.012) and GGO ratio < 50% (HR = 9.143, p = 0.045). Kaplan-Meier analysis revealed that patients with lung adenocarcinoma and breast cancer had a better 5-year disease-free survival (p = 0.009), while the Her2-negative patients obtained a better overall survival (p = 0.038)., Conclusions: In patients with breast cancer and lung adenocarcinoma, independent risk factors of recurrence were undergone chemotherapy, moderate/poor differentiation, tumor size ≧ 2 cm, LVSI and GGO ratio < 50%. Only undergone chemotherapy, LVSI and GGO ratio < 50% were significant poor predictors for survival. However, patients with metachronous lung adenocarcinoma and breast cancer had better disease-free survival and less tumor recurrence than patients with lung adenocarcinoma alone.

Objectives: The purpose of this study was to examine the impact of epidermal growth factor receptor (EGFR) mutation status and tyrosine kinase inhibitors (TKIs) on the survival of brain metastases (BM) in patients with surgically resected non-small cell lung cancer (NSCLC)., Methods: We selected the patients who had developed metastatic NSCLC; analyzed the differences between brain metastases and other sites of metastases, including patient characteristics, EGFR status, and survival; and selected the patients who had BM for further investigation. We also compared the treatment effects of first-generation TKIs with those of second-/third-generation TKIs., Results: A total of 785 cases of stage I-IIIa NSCLC were reviewed. Thirty-six (4.6%) patients were identified as having BM. Among them, 14 patients had a mutated EGFR status. No association between EGFR mutation and the incidence of BM was observed (p = 0.199). Patients with mutated EGFRs had significantly longer overall survival and post-recurrence survival than patients with wild-type EGFR mutation (p = 0.001 for both). However, there was no survival difference between patients with exon 19 and exon 21 mutations (p = 0.426). Furthermore, patients who received the second- and/or third-generation EGFR-TKIs had better survival than patients who only received first-generation EGFR-TKIs (p = 0.031). A multivariate analysis indicated that the next-generation TKIs (HR, 0.007; 95% CI, 0.000 to 0.556; p = 0.026) and a longer interval before BM development (HR, 0.848; 95% CI, 0.733 to 0.980; p = 0.025) were significant factors in longer survival., Conclusions: EGFR-TKIs were effective in treating NSCLC patients with BM after curative pulmonary surgery, especially in those patients harboring EGFR mutations. Furthermore, the second-/third-generation EGFR-TKIs showed more promising results than the first-generation EGFR-TKIs in treating those particular patients, though larger studies needed to further prove the results., Competing Interests: The authors have declared that no competing interests exist.

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway., Competing Interests: The authors declare no competing financial interest.

Pipoxolan has been reported to have antitumor activity. However, the effects of pipoxolan on lung cancer cell metastasis remains unclear. This study examined the anti-metastatic effects of pipoxolan on lung adenocarcinoma cancer cells (i.e. CL1-5, CL1-0, and A549) and its underlying molecular mechanisms. Firstly, CL1-5 cell migration was markedly suppressed by pipoxolan when examined by wound scratch assay. Furthermore, transwell and matrigel invasion assays revealed that pipoxolan inhibited lung cancer cells (i.e. CL1-5, CL1-0, and A549) migration/invasion, and showed more sensitive to CL1-5 cell. Therefore, the anti-metastatic effects from pipoxolan have been focused on CL1-5 lung cancer cells. Secondly, these observations have been associated with the reduction in the activities and expressions of matrix metalloproteinase (MMP)-2 and -9 in CL1-5 lung cancer cells. Lastly, pipoxolan administration significantly inhibited phosphorylation c-Jun N-terminal kinase (p-JNK), and p38 MAP Kinase (MAPK) of CL1-5 cells. Based on these results, our results showed that management CL1-5 cells with pipoxolan down-regulated phosphorylation JNK and p38, and then, MMP-2 and -9. These results suggest that pipoxolan might have a new therapeutic potential for anti-metastatic effects in lung cancer cells., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: We investigated factors predicting postoperative recurrence in patients with pathological Stage I nonsmall cell lung cancer (NSCLC)., Methods: All patients with clinical Stage I NSCLC who underwent surgical resection at Tri-Service General Hospital in Taiwan between January 2002 and June 2006 were reviewed retrospectively. All study patients underwent standard staging workups. We reviewed the records of 261 patients with an average follow-up of 93 months; we then included 179 patients with pathological Stage I., Results: Two hundred sixty-one patients with clinical Stage I NSCLC were eligible. There were no significant differences in sex, tumor histopathology, location, and age between the two groups (recurrence and nonrecurrence), except for tumor differentiation (p = 0.002), survival rate (p < 0.001), lymphovascular space invasion (LVSI; p = 0.007), advanced pathology stage (p = 0.022), maximum standard uptake value (SUVmax; p = 0.027), tumor size (p < 0.011), and carcinoembryonic antigen (CEA) levels (p = 0.013). Overall survival was significantly related to postoperative recurrence (p < 0.001) in patients with pathological Stage I, in whom recurrences developed in 11.17%. Only 179 patients with pathological Stage I NSCLC, including 20 patients with postoperative recurrences, were selected. Tumor differentiation (odds ratio 3.581, p = 0.058) and LVSI (odds ratio 5.374, p = 0.020) were independent factors predicting recurrence., Conclusion: Tumor differentiation and LVSI were predictors of postoperative relapse for patients with pathological stage I NSCLC. Risk factors of postoperative recurrence in patients with pathological Stage I NSCLC may enable us to optimize the patient selection for postoperative adjuvant therapies to prevent possibly occult micrometastases., (Copyright © 2014. Published by Elsevier B.V.)

Pulmonary benign metastasizing leiomyoma (PBML) characterized by uterine leiomyoma in the lung is very rare. Here we report the case of a 55-year-old woman with a history of surgically resected multiple uterine leiomyomas who was histopathologically diagnosed with PBML associated with bilateral primary renal cell carcinoma (RCC). Clinicians should be aware of this unusual entity and consider pulmonary leiomyoma as a differential diagnosis in asymptomatic women with primary RCC and a history of hysterectomy for leiomyoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Despite advances in radiation therapy, chemotherapy, and newly developed molecular targeting therapies, long-term survival after resection for patients with NSCLC remains less than 50%. We investigated factors predicting postoperative locoregional recurrences and distant metastases in patients with clinical stage I non-small-cell lung cancer (NSCLC) after surgical resection., Methods: All patients with clinical stage I NSCLC, who underwent surgical resection between January 2002 and June 2006, were reviewed retrospectively. Multiple logistic regression analyses were used to identify independent risk factors for patients with locoregional recurrences and distant metastases., Results: A total of 261 patients were eligible. Overall survival was significant related to locoregional recurrences (P = 0.03) and distant metastases (P <0.001). There were significant differences of locoregional recurrence in tumor differentiation (P = 0.032) and advanced pathological stage (P = 0.002). In the group of distant metastases, there were significant differences in tumor differentiation (P = 0.035), lymphovascular space invasion (P = 0.031). Among the relationship between pattern of distant metastasis and clinicopathologic variables in patients with clinical stage I NSCLC, SUVmax (P = 0.02) and tumor size (P = 0.001) had significant differences. According to multiple logistic regression analysis, tumor differentiation is the only risk factor of postoperative outcome for locoregional recurrence and serum CEA (>3.5 ng/mL) is the predictor of distant metastasis., Conclusions: Tumor differentiation and serum CEA were predictors of postoperative relapse for clinical stage I NSCLC after surgical resection. Risk factors of postoperative recurrence in patients with clinical stage I NSCLC may enable us to optimize the patient selection for postoperative adjuvant therapies or neoadjuvant treatment before surgery.

Cancer metastasis is a primary cause of cancer death. Antrodia cinnamomea (A. cinnamomea), a medicinal mushroom in Taiwan, has been shown antioxidant and anticancer activities. In this study, we first observed that ethanol extract of fruiting bodies of A. cinnamomea (EEAC) exerted a concentration-dependent inhibitory effect on migration and motility of CL1-0 cells in the absence of cytotoxicity. The results of a gelatin zymography assay showed that A. cinnamomea suppressed the activity of matrix metalloproteinase (MMP)-2 and MMP-9 in a concentration-dependent manner. Western blot results demonstrated that treatment with A. cinnamomea decreased the expression of MMP-9 and MMP-2; while the expression of the endogenous inhibitors of these proteins, i.e., tissue inhibitors of MMP (TIMP-1 and TIMP-2) increased. Two major compounds from EEAC codycepin and zhankuic acid A alone and together inhibited MMP-9 and MMP-2 expressions. Further investigation revealed that A. cinnamomea suppressed the phosphorylation of p38, and JNK1/2. A. cinnamomea also suppressed the expressions of PI3K and phosphorylation of AKT. This is the first report confirming the anti-migration activity of this potentially beneficial mushroom against human lung adenocarcinoma CL1-0., (Crown Copyright © 2012. Published by Elsevier GmbH. All rights reserved.)