Therapeutic impact of epidermal growth factor receptor tyrosine kinase inhibitor with various treatment combinations for advanced lung adenocarcinoma.

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.

Prognostic factors associated with 18FDG-PET/CT in esophageal squamous cell carcinoma after trimodality treatment.

PURPOSE: This study aimed to determine the pathological complete response (pCR), overall survival (OS), and disease-free survival (DFS) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) using post-neoadjuvant chemoradiotherapy (nCRT) F-18-fluorodeoxyglucose (18FDG). METHODS: This is a retrospective study of patients with locally advanced ESCC receiving nCRT and then esophagectomy between January 2011 and December 2018 in the Tri-Service General Hospital, Taipei, Taiwan. A total of 50 patients were enrolled in the study. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards model. Univariate and multivariate analysis were used to determine the independent prognostic factors. RESULTS: Fifty patients were enrolled in the study, and 18 had pathological complete response. Post-nCRT SUVmax ≥ 3 is a poor prognostic factor associated with overall survival (HR: 3.665, P = 0.013) and disease-free survival (HR: 3.417, P = 0.011). Poor prognosis was found in the non-pCR plus post-nCRT SUVmax ≥ 3 group compared with pCR plus post-nCRT SUVmax < 3 group. CONCLUSIONS: SUVmax ≥ 3 is a poor prognostic factor in esophageal squamous cell carcinoma after trimodality treatment, even in patients having pathological complete response.

Differentiating focal interstitial fibrosis from adenocarcinoma in persistent pulmonary subsolid nodules (> 5 mm and < 20 mm): the role of coronal thin-section CT images.

OBJECTIVES: To investigate thin-section computed tomography (CT) features of pulmonary subsolid nodules (SSNs) with sizes between 5 and 20 mm to determine predictive factors for differentiating focal interstitial fibrosis (FIF) from adenocarcinoma. METHODS: From January 2017 to December 2018, 169 patients who had persistent SSNs 5-20 mm in size and underwent preoperative nodule localization were enrolled. Patient characteristics and thin-section CT features of the SSNs were reviewed and compared between the FIF and adenocarcinoma groups. Univariable and multivariable analyses were used to identify predictive factors of malignancy. Receiver operating characteristic (ROC) curve analysis was used to quantify the performance of these factors. RESULTS: Among the 169 enrolled SSNs, 103 nodules (60.9%) presented as pure ground-glass opacities (GGOs), and 40 (23.7%) were FIFs. Between the FIF and adenocarcinoma groups, there were significant differences (p< 0.05) in nodule border, shape, thickness, and coronal/axial (C/A) ratio. Multivariable analysis demonstrated that a well-defined border, a nodule thickness >4.2, and a C/A ratio >0.62 were significant independent predictors of malignancy. The performance of a model that incorporated these three predictors in discriminating FIF from adenocarcinoma achieved a high area under the ROC curve (AUC, 0.979) and specificity (97.5%). CONCLUSIONS: For evaluating persistent SSNs 5-20 mm in size, the combination of a well-defined border, a nodule thickness > 4.2, and a C/A ratio > 0.62 is strongly correlated with malignancy. High accuracy and specificity can be achieved by using this predictive model. KEY POINTS: • Thin-section coronal images play an important role in differentiating FIF from adenocarcinoma. • The combination of a well-defined border, nodule thickness>4.2 mm, and C/A ratio >0.62 is associated with malignancy. • This predictive model may be helpful for managing persistent SSNs between 5 and 20 mm in size.

Prognostic value of positron emission tomography in resected stage IA non-small cell lung cancer.

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.

Severity of Pectus Excavatum is a Risk Factor for Primary Spontaneous Pneumothorax.

BACKGROUND AND OBJECTIVE: This study aimed to investigate the relationship between bleb formation, primary spontaneous pneumothorax (PSP) and pectus excavatum (PE). METHODS: From July 2005 to December 2016, the records of 514 patients with PE who underwent the Nuss procedure were obtained from a prospectively collected database and reviewed. Clinical features, images and treatments were analyzed retrospectively. RESULTS: The incidence rate of bleb formation was 26.5% in PE patients. The bleb group had a greater body height (174.4 cm vs. 170.4 cm, p < 0.001), a higher Haller index (HI; 4.2 vs. 3.43, p < 0.001) and a higher risk of developing PSP than the non-bleb group (risk ratio 9.8, p = 0.002). HI values larger than 3.615 had good discriminatory power for predicting bleb formation in patients with PE. With each increase in the HI, PE patients had a 2.2-fold greater odds ratio of bleb formation (odds ratio 2.221, CI 1.481-3.330, p < 0.001). CONCLUSION: We discovered that a high percentage of PE patients have bleb formation and a higher risk of PSP, especially those with an HI >3.615. High-resolution computed tomography of the chest may be useful for evaluating both the HI and the presence of blebs in the lungs before performing a corrective surgical procedure.

Comparing the Prognosis of Patient with Alcohol and Nonalcohol-Associated Cirrhosis with Bacteremia.

AIMS: Patients with liver cirrhosis are more susceptible to bacteremia and more likely to have a poor prognosis in comparison to healthy individuals. Studies on the role of alcohol in cirrhotic patients with bacteremia are limited. Our study aimed to investigate the clinical characteristics and prognostic differences between the patients with alcohol and non-alcohol-associated cirrhosis with bacteremia. METHODS: A single-center, retrospective cohort study was conducted among adult patients who presented to the emergency department from January 2015 to December 2018. All patients diagnosed with liver cirrhosis and bacteremia were enrolled and divided into alcohol-associated and non-alcohol-associated groups according to the etiology of their cirrhosis. We compared their clinical characteristics, laboratory results, microbiological data, and infection source as well as outcome measurements between the two groups. RESULTS: A total of 112 cirrhotic patients with bacteremia (alcohol-associated: 67; non-alcohol-associated: 45) were eligible for this study. In comparison with the non-alcohol-associated group, patients in the alcohol-associated group had a significantly higher rate of intensive care unit transfer (41.8% vs. 22.2%, P = 0.04), septic shock occurrence (56.7% vs. 35.6%, P = 0.04) and 30-day mortality risk (37.3% vs. 15.6%, P = 0.02). Moreover, alcohol-associated cirrhosis and Model for End-Stage Liver Disease score were independent predictors of 30-day mortality in cirrhotic patients with bacteremia. CONCLUSIONS: The etiology of liver cirrhosis influences the outcomes of patients with bacteremia as well as the severity of their cirrhosis.

The application of electrical impedance tomography and surgical outcomes of thoracoscope-assisted surgical stabilization of rib fractures in severe chest trauma.

Serious blunt chest trauma usually induces hemothorax, pneumothorax, and rib fractures. More studies have claimed that early video-assisted thoracoscopic surgery with surgical stabilization of rib fractures (SSRF) results in a good prognosis in patients with major trauma. This study aimed to verify the outcomes in patients with chest trauma whether SSRF was performed. Consecutive patients who were treated in a medical center in Taiwan, for traumatic events between January 2015 and June 2020, were retrospectively reviewed. This study focused on patients with major trauma and thoracic injuries, and they were divided into groups based on whether they received SSRF. We used electrical impedance tomography (EIT) to evaluate the change of ventilation conditions. Different scores used for the evaluation of trauma severity were also compared in this study. Among the 8396 patients who were included, 1529 (18.21%) had major trauma with injury severity score > 16 and were admitted to the intensive care unit initially. A total of 596 patients with chest trauma were admitted, of whom 519 (87%) survived. Younger age and a lower trauma score (including injury severity scale, new injury severity score, trauma and injury severity score, and revised trauma score) account for better survival rates. Moreover, 74 patients received SSRF. They had a shorter intensive care unit (ICU) stay (5.24, p = 0.045) and better performance in electrical impedance tomography (23.46, p < 0.001). In patients with major thoracic injury, older age and higher injury survival scale account for higher mortality rate. Effective surgical stabilization of rib fractures shortened the ICU stay and helped achieve better performance in EIT. Thoracoscope-assisted rib fixation is suggested in severe trauma cases.

Nicotine activates HIF-1α and regulates acid extruders through the nicotinic acetylcholine receptor to promote the Warburg effect in non-small cell lung cancer cells.

Cigarette smoking is the greatest risk factor for lung cancer, accounting for approximately 90% of all lung cancer-related deaths. Moreover, nicotine is associated with lung cancer onset and progression. Hypoxia-inducible factor 1α (HIF-1α) is involved in the metabolic reprogramming of cancer cells and accelerates cancer progression via regulation of pH and acid-base homeostasis. Previous studies have reported that nicotine upregulates HIF-1α expression. Therefore, we hypothesized that nicotine-mediated activation of HIF-1α regulates metabolic reprogramming and pH homeostasis in non-small cell lung cancer A549 cells and could potentially play a role in the progression of lung cancer. We examined the effects of nicotine on metabolic reprogramming and intracellular pH (pHi) homeostasis, which are critical for cancer progression. A549 cells were exposed to nicotine in the absence and presence of the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC). We then analyzed glycolytic stress and the activity and expression of acid-extruder proteins, including the Na+-H+ exchanger 1 (NHE1) and monocarboxylate cotransporters 1 & 4 (MCT1 and MCT4, respectively). Nicotine promoted the Warburg effect, which is associated with accelerated migration of A549 cells through the activation of nicotinic acetylcholine receptors. Furthermore, nicotine upregulated the activities and expression of acid-extruder proteins, namely NHE1 and MCT4, and facilitated glycolysis. To the best of our knowledge, this is the first study to demonstrate that nicotine plays a pivotal regulatory role in metabolic reprogramming as well as regulation of pHi homeostasis in A549 cells via activation of nicotinic acetylcholine receptors and can therefore aggravate lung cancer progression.

Impact of Surgical Intervention on Nonobstructive Dysphagia: A Retrospective Study Based on High-Resolution Impedance Manometry in a Taiwanese Population at a Single Institution.

Esophageal motility disorders account for a large proportion of nonobstructive dysphagia cases, which constitute a heterogeneous group of diagnoses that commonly result in peristaltic derangement and impaired relaxation of the lower esophageal sphincter. We performed a single-institution retrospective study enrolling consecutive patients with chief complaints of dysphagia who underwent HRIM from December 2014 to December 2019, and analyzed demographic, clinical, and manometric data using descriptive statistics. In total, 277 identified patients were included in the final analysis. Ineffective esophageal motility (n = 152, 24.5%) was the most common diagnosis by HRIM, followed by absent contractility, EGJ outflow obstruction, type II achalasia, and type I achalasia. Furthermore, surgery including exploratory, laparoscopic, and robotic myotomy, as well as POEM, is considered the most effective treatment for patients with non-spastic achalasia and EGJOO, due to its effective symptom palliation and prevention of disease progression; surgery also contributes to an obvious improvement of dysphagia compared with slightly less efficacy for other related symptoms. Our study aimed to elaborate the clinical characteristics of patients with nonobstructive dysphagia based on HRIM in a Taiwanese population, and to analyze the therapeutic outcomes of such patients who ultimately underwent surgical interventions.

Benefit of Three-dimensional Image Simulation in Surgical Resection of Early-stage Lung Cancer.

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.

Surgical outcomes of second primary lung cancer after the extrapulmonary malignancy.

OBJECTIVE: To study the surgical outcomes of patients with a second primary lung cancer after the extrapulmonary malignancy. MATERIALS AND METHODS: Patients who underwent surgical resection for lung cancers between January 2005 and December 2014 were reviewed. Clinical data, imaging characteristics of tumors, surgical approaches, and outcomes were analyzed with a mean follow-up of 97 months. RESULTS: Of 1075 patients, 166 (15.4%) had a second primary lung cancer after extrapulmonary malignancy. There were no differences in overall 5-year survival rates (81.8% for the group of lung cancer vs. 72.9% for the second primary lung cancer group, p = 0.069) and 5-year disease-free survival (70.1% for the lung cancer group vs. 70.3% for the second primary lung cancer group, p = 0.863) between the two groups. Gender, performance status, tumor size, and maximum standard uptake value (SUVmax) were significantly different between the two groups. After propensity-score matching analysis, patients in the group with lung cancers had better 5-year overall survival (88.1% vs. 72.1% for the group with second primary lung cancers, p = 0.016) and 5-year disease-free survival (80.6% vs. 70.3% for the group with second primary lung cancers; p = 0.054). In the second primary lung cancer group, the patients with preceding breast or thyroid cancers had better prognoses than did those with other extrapulmonary malignancy. CONCLUSIONS: Second primary lung cancers following extrapulmonary malignancies were not uncommon. Surgical resection is considered for early stage secondary primary lung cancer after meticulous work up and result in fair outcome.

The prognostic factors of recurrence and survival in female patients with lung adenocarcinoma and breast cancer.

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.

Recruitment maneuver leads to increased expression of pro-inflammatory cytokines in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a disease with high morbidity and mortality rates. The recruitment maneuver (RM) is one of the interventions used for ARDS patients suffering from severe hypoxemia. RM works by opening the atelectatic lungs using high transpulmonary pressure. RM has therefore been widely used for many years in patients with ARDS. However, because of the high transpulmonary pressure used in this intervention, there are concerns about both biotrauma and hemodynamic instability. To assess the effects of RM in ARDS, we conducted a study using three groups of pigs (n = 6 in each group): group I (control), group II (ARDS), and group III (ARDS with RM). After measuring the baseline values, ARDS was induced by deactivating the surfactant with 5% Tweens lavage. For pigs of group III, the RM protocol used was positive end-expiratory pressure (PEEP) of 25 cmH2O and peak pressure of 45 cmH2O. Gas exchange, hemodynamics, the expression of cytokines in serum, bronchoalveolar lavage fluid (BALF), and exhaled breath condensates (EBCs) were measured. The baseline measurements taken were similar across the three groups, and no significant difference was noted. After the induction of ARDS, PaO2 substantially decreased, while PaCO2, alveolar-arterial O2 gradient, pulmonary arterial pressure, lung water, level of cytokines in serum, EBCs, and BALF all increased. After RM, gas exchange and lung water level improved, but the level of cytokines in EBCs and BALF increased. Although RM led to an improvement in gas exchange, it may cause release of inflammatory cytokines in the EBCs and BALF.

Adaptive support ventilation attenuates postpneumonectomy acute lung injury in a porcine model.

OBJECTIVES: An optimal ventilation strategy that causes as little mechanical stress and inflammation as possible is critical for patients undergoing pneumonectomy. The aim of this study was to determine whether adaptive support ventilation (ASV) can provide protective ventilation to the remaining lung after pneumonectomy with minimal mechanical stress and less inflammation than volume-control ventilation (VCV). METHODS: In this study, 15 pigs were randomly allocated to 3 groups (n = 5 for each group): the control group, the VCV group and the ASV group. After left pneumonectomy, the VCV group was treated with the volume-control set to 20 ml/kg, and the ASV group with the mode set to achieve 60% of the minute ventilation of 2 lungs. RESULTS: The ASV group had lower alveolar strain than the VCV group. The ASV group exhibited less lung injury and greater alveolar fluid clearance than the VCV group (13.3% vs -17.8%; P ≤ 0.018). Ventilator-induced lung injury was associated with changes in the cytokine levels in the exhaled breath condensate, differential changes in plasma and changes in the cytokines in the bronchoalveolar lavage fluid. Expression of 3 microRNAs (miR449b-3p, P ≤ 0.001; miR451-5p, P = 0.027; and miR144-5p, P = 0.008) was increased in the VCV group compared with the ASV group. CONCLUSIONS: The ASV mode was capable of supporting rapid, shallow breathing patterns to exert lung-protective effects in a porcine postpneumonectomy model. Further investigation of microRNAs as biomarkers of ventilator-induced lung injury is warranted.

Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells.

Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1-300µM) inhibited functional activity of MCT concentration-dependently (up to -42%). Pretreatment with isoorientin (3-100µM) for 24h, MCT activity and cell migration were significantly inhibited (-25% and -40%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.

Feasibility and Clinical Effectiveness of Three-Dimensional Printed Model-Assisted Nuss Procedure.

BACKGROUND: The Nuss procedure is a minimally invasive technique for correcting pectus excavatum. We hypothesized that three-dimensional (3D) simulation may shorten operation time and provide better morphologic outcome. This study aimed to demonstrate the feasibility of the 3D model-assisted Nuss procedure and to compare its potential benefits with those of the traditional Nuss procedure. METHODS: We simulated the targeted curvature, length, and planned intercostal space of a metallic bar, based on the preoperative chest computed tomographic images. After the use of a 3D printing technique, a plastic template bar was produced and sterilized. The metallic bar was bent and placed at the planned intercostal space accordingly. The patients' characteristics, total number of pectus bar placement, total operation time, and improvement percentage of Haller indices were compared with patients who underwent the traditional Nuss procedure. RESULTS: A total of 419 patients underwent the Nuss procedure from January 2010 to July 2017 in our hospital, and 357 patients were eligible and enrolled for the following analysis. Fifteen patients underwent 3D simulation. After performing propensity-score matching analysis, the 3D printing group had a shorter operative time (60.36 versus 74.34 minutes, p < 0.001), fewer metallic bar placements (1.00 versus 1.36 bars, p < 0.001), and better improvement percentages in the Haller indices (20.34% versus 10.06%, p < 0.001) compared with the traditional Nuss procedure. CONCLUSIONS: In this preliminary study, 3D-printed model-assisted Nuss procedure may provide benefits of shorter operative time, fewer metallic bar insertions, and comparable morphologic outcome by preoperative simulation.

Brain metastases in resected non-small cell lung cancer: The impact of different tyrosine kinase inhibitors.

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.

The beneficial application of preoperative 3D printing for surgical stabilization of rib fractures.

OBJECTIVES: The beneficial application of three-dimensional (3D) printing for surgical stabilization of rib fractures (SSRF) has never been proposed in the literature before. The aim of this study was to verify patients' surgical outcomes when utilizing preoperative three-dimensional printing for SSRF. METHODS: We retrospectively reviewed the records of all consecutive patients who were treated at our hospital for SSRF from July 2015 to December 2017. The patients were divided into two groups according to whether or not 3D printing was utilized. RESULTS: Forty-eight patients who underwent SSRF at our hospital were enrolled. Of them, three patients underwent bilateral surgeries. The patients with application of preoperative 3D printing for SSRF had statistically significant associations with shorter operation time per fixed plate (p < 0.001), and a smaller incision length (p < 0.001). CONCLUSIONS: We present an useful technique involving 3D printing for promoting SSRF significantly with shorter operation time and an appropriate incision length.

Functional and molecular mechanism of intracellular pH regulation in human inducible pluripotent stem cells.

AIM: To establish a functional and molecular model of the intracellular pH (pHi) regulatory mechanism in human induced pluripotent stem cells (hiPSCs). METHODS: hiPSCs (HPS0077) were kindly provided by Dr. Dai from the Tri-Service General Hospital (IRB No. B-106-09). Changes in the pHi were detected either by microspectrofluorimetry or by a multimode reader with a pH-sensitive fluorescent probe, BCECF, and the fluorescent ratio was calibrated by the high K+/nigericin method. NH4Cl and Na-acetate prepulse techniques were used to induce rapid intracellular acidosis and alkalization, respectively. The buffering power (ß) was calculated from the ΔpHi induced by perfusing different concentrations of (NH4)2SO4. Western blot techniques and immunocytochemistry staining were used to detect the protein expression of pHi regulators and pluripotency markers. RESULTS: In this study, our results indicated that (1) the steady-state pHi value was found to be 7.5 ± 0.01 (n = 20) and 7.68 ± 0.01 (n =20) in HEPES and 5% CO2/HCO3 --buffered systems, respectively, which were much greater than that in normal adult cells (7.2); (2) in a CO2/HCO3 --buffered system, the values of total intracellular buffering power (ß) can be described by the following equation: ßtot = 107.79 (pHi)2 - 1522.2 (pHi) + 5396.9 (correlation coefficient R 2 = 0.85), in the estimated pHi range of 7.1-8.0; (3) the Na+/H+ exchanger (NHE) and the Na+/HCO3 - cotransporter (NBC) were found to be functionally activated for acid extrusion for pHi values less than 7.5 and 7.68, respectively; (4) V-ATPase and some other unknown Na+-independent acid extruder(s) could only be functionally detected for pHi values less than 7.1; (5) the Cl-/ OH- exchanger (CHE) and the Cl-/HCO3 - anion exchanger (AE) were found to be responsible for the weakening of intracellular proton loading; (6) besides the CHE and the AE, a Cl--independent acid loading mechanism was functionally identified; and (7) in hiPSCs, a strong positive correlation was observed between the loss of pluripotency and the weakening of the intracellular acid extrusion mechanism, which included a decrease in the steady-state pHi value and diminished the functional activity and protein expression of the NHE and the NBC. CONCLUSION: For the first time, we established a functional and molecular model of a pHi regulatory mechanism and demonstrated its strong positive correlation with hiPSC pluripotency.