Search

Background: Postoperative survival of esophageal cancer patients has improved with advances in technology and treatment modalities. However, squamous cell carcinoma (SCC) often affects the esophagus together with the head and neck regions, with second primary head and neck cancer (SPHNC) adversely influencing the patients' quality of life. Therefore, patients with esophageal squamous cell carcinoma (ESCC) should be carefully followed up postoperatively. This study evaluated the risk of developing SPHNCs after an esophagectomy for ESCC., Methods: Patients with ESCC who underwent curative esophagectomy from January 2008 to December 2017 from two tertiary medical centers, Taipei Veteran General Hospital and Kaohsiung Veteran General Hospital, were retrospectively reviewed. SPHNC development was documented according to the anatomic region and the cumulative incidence rate and risk factors were analyzed., Results: The median follow-up period of the 435 patients included in our study was 48.5 months [interquartile range (IQR) 16.7-92.4 months]. Among the ESCC patients after curative esophagectomy, younger age <50 [hazard ratio 4.13, 95% CI: 2.53-6.75, p < 0.001) was the only independent factor for developing SPHNCs in the multivariable analysis. The cumulative incidence rate of SPHNCs of patients aged <50 years old was 14.3%, 22.1%, and 34.2% after 3, 5, and 10 years, respectively., Conclusions: There was a high risk of secondary cancer after ESCC in the upper aerodigestive tract, especially the head and neck regions; therefore, active surveillance is strongly recommended, especially in younger patients., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background/purpose: This multi-institutional study was aimed to analyze prognostic factors of completely resected early stage thymoma., Methods: Patients with surgically treated early stage thymoma between 1988 and 2019 were enrolled. Statistical associations were evaluated using the χ 2 test, Fisher's exact test, and Student's t-test. Disease-free survival (DFS) and overall survival (OS) curves were established by the Kaplan-Meier method, and compared using the log-rank test., Results: A total of 229 patients with Masaoka stage I and 131 with Masaoka stage II thymoma were included. The DFS of patients with Masaoka stage I thymoma was associated with neutrophil-to-lymphocyte ratio (NLR, hazard ratio [HR] = 3.18, 95% confidence interval [CI]: 1.34-7.54), and extrathymic malignancies (HR = 4.51, 95% CI: 2.02-10.11), and the OS was associated with NLR (HR = 5.03, 95% CI: 1.61-15.66) and extrathymic malignancies (HR = 7.68, 95% CI: 3.12-18.97). In patients with Masaoka stage II thymoma, DFS was associated with age (HR = 2.50, 95% CI: 1.18-5.27), extent of surgery (HR = 0.41, 95% CI: 0.19-0.87), and NLR (HR = 3.23, 95% CI: 1.11-9.44), and OS was associated with age (HR = 5.77, 95% CI: 1.81-18.34), surgical approach (HR = 8.40, 95% CI: 1.91-37.00), and extrathymic malignancies (HR = 2.96, 95% CI: 1.08-8.12)., Conclusion: In Masaoka stage I thymoma, preoperative NLR and extrathymic malignancies are independently associated with DFS and OS. In Masaoka stage II thymoma, age, extent of surgery, and NLR are independently associated with DFS, and age, surgical approach, and extrathymic malignancies are associated with OS., Competing Interests: Declaration of competing interest All authors declare that there is nothing to be disclosed in this study., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

We present the case of a 60-year-old female patient with no prior history of any systemic disease. She suffered from a prolonged cough that lasted more than 3 months, associated with poor appetite and weight loss of 5 kg. The pathology report of the pre-operative transbronchial needle biopsy was consistent with a neurogenic tumour. Chest computed tomography (CT) revealed a right lower lobe (RLL) mass-like consolidation of 8.67 cm with obstructive pneumonitis and suspicious posterior mediastinal invasion. The tumour was surgically resected with bronchial reconstruction, and the pathological diagnosis was intrabronchial schwannoma located inside the bronchus, a rare tumour that should be included as one of the differential diagnoses of primary bronchial tumours. The possibility of a surgical completed resection should be considered in patients with airway obstruction symptoms., Competing Interests: None declared., (© 2024 The Author(s). Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.)

Backgroud: The standard resection for early-stage thymoma is total thymectomy and complete tumour excision with or without myasthenia gravis but the optimal surgery mode for patients with early-stage non-myasthenic thymoma is debatable. This study analysed the oncological outcomes for non-myasthenic patients with early-stage thymoma treated by thymectomy or limited resection in the long term., Methods: Patients who had resections of thymic neoplasms at Taipei Veteran General Hospital, Taiwan between December 1997 and March 2013 were recruited, exclusive of those combined clinical evidence of myasthenia gravis were reviewed. A total of 113 patients were retrospectively reviewed with pathologic early stage (Masaoka stage I and II) thymoma who underwent limited resection or extended thymectomy to compare their long-term oncologic and surgical outcomes., Results: The median observation time was 134.1 months [interquartile range (IQR) 90.7-176.1 months]. In our cohort, 52 patients underwent extended thymectomy and 61 patients underwent limited resection. Shorter duration of surgery (p < 0.001) and length of stay (p = 0.006) were demonstrated in limited resection group. Six patients experienced thymoma recurrence, two of which had combined myasthenia gravis development after recurrence. There was no significant difference (p = 0.851) in freedom-from-recurrence, with similar 10-year freedom-from-recurrence rates between the limited resection group (96.2 %) and the thymectomy group (93.2 %). Tumour-related survival was also not significantly different between groups (p = 0.726).result CONCLUSION: Patients with early-stage non-myasthenic thymoma who underwent limited resection without complete excision of the thymus achieved similar oncologic outcomes during the long-term follow-up and better peri-operative results compared to those who underwent thymectomy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Prediction of subsolid nodule (SSN) interval growth is crucial for clinical management and decision making in lung cancer screening program. To the best of our knowledge, no study has investigated whether volume doubling time (VDT) is an independent factor for predicting SSN interval growth, or whether its predictive power is better than that of traditional semantic methods, such as nodular diameter or type. This study aimed to investigate whether VDT could provide added value in predicting the long-term natural course of SSNs (<3 cm) regarding stage shift., Methods: This retrospective study enrolled 132 patients with spectrum lesions of lung adenocarcinoma who underwent two consecutive computed tomography (CT) examinations before surgical tissue proofing between 2012 and 2021 in Kaohsiung Veterans General Hospital. The VDTs were manually calculated from the volumetric segmentation using Schwartz's approximation formula. We utilized logistic regression to identify predictors associated with stage shift progression based on the VDT parameter., Results: The average duration of follow-up period was 3.629 years. A VDT-based nomogram model (model 2) based on CT semantic features, clinical characteristics, and the VDT parameter yielded an area under the curve (AUC) of 0.877 [95% confidence interval (CI): 0.807-0.928]. Compared with model 1 (CT semantic features and clinical characteristics), model 2 exhibited the better predictive performance for stage shift (AUC model 1: 0.833 versus AUC model 2: 0.877, P=0.047). In model 2, significant predictors of stage shift growth included initial nodule size [odds ratio (OR) =4.074, 95% CI: 1.368-12.135; P=0.012], SSN classification (OR =0.042; 95% CI: 0.006-0.288; P=0.001), follow-up period (OR =1.692, 95% CI: 1.337-2.140; P<0.001), and VDT classification (OR =2.327, 95% CI: 1.368-3.958; P=0.002). For the stage shift, the mean progression time for the VDT (>400 d) group was 7.595 years, and median progression time was 7.430 years. Additionally, a VDT ≤400 d is an important prognostic factor associated with aggressive growth behavior with a stage shift., Conclusions: VDT is crucial for predicting SSN stage shift growth irrespective of clinical and CT semantic features. This highlights its significance in informing follow-up protocols and surgical planning, emphasizing its prognostic value in predicting SSN growth., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1759/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: This retrospective study aimed to compare the efficacy and safety of one-stage computed tomography (OSCT)- to that of two-stage computed tomography (TSCT)-guided localization for the surgical removal of small lung nodules., Methods: We collected data from patients with ipsilateral pulmonary nodules who underwent localization before surgical removal at Veteran General Hospital Kaohsiung between October 2017 and January 2022. The patients were divided into the OSCT and TSCT groups., Results: We found that OSCT significantly reduced the localization time and risky time compared to TSCT, and the success rate of localization and incidence of pneumothorax were similar in both groups. However, the time spent under general anesthesia was longer in the OSCT group than in the TSCT group., Conclusions: The OSCT-guided approach to localize pulmonary nodules in hybrid operation room is a safe and effective technique for the surgical removal of small lung nodules., (© 2024. The Author(s).)

Rationale and Objectives: This study aimed to assess how different screening methods, specifically self-paid screening versus participation in clinical studies, affect screening efficiency and adherence in a real-world Asian lung cancer screening population., Materials and Methods: This study collected 4166 participants from our hospital imaging database who underwent baseline low-dose computed tomography (LDCT) between January 2014 and August 2021. Adherence status was determined by counting CT scans, with one check indicating non-adherence and two or more checks indicating adherence. The primary objective was to investigate adherence to LDCT follow-up schedules among individuals with baseline pure ground-glass nodules (GGNs) based on different screening settings and to evaluate adherence status and CT follow-up clinical profiles., Results: Of the 4166 participants in the study, 3619 in the self-paid group and 547 in the clinical study group were men, with an average follow-up period of 4.5 years. Significant differences were observed in the proportions of Lung-RADS 4 lesions, subsolid nodules, and pure GGN lesions between the self-paid and clinical trial groups. A significant difference was found in adherence rates between the self-paid screening group (60.5%) and the clinical study group (84.8%) (p < 0.001). Adherence status rates significantly increased with larger GGN sizes across categories (p < 0.001). Multivariate logistic regression revealed that age (odds ratio [OR], 1.025; p = 0.012), smoking habits (OR, 1.744; p = 0.036), and clinical study screening type (OR, 3.097; p < 0.001) significantly influenced the adherence status., Conclusion: The disparities in Asian lung cancer screening emphasize the need for increased efficacy, public awareness, and culturally sensitive approaches to mitigate overdiagnosis and enhance adherence among self-paying groups., Competing Interests: Declaration of Competing Interest All authors completed the ICMJE uniform disclosure form. The authors declare no conflicts of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer., Methods: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ 2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing., Findings: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis., Interpretation: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer., Funding: Ministry of Health and Welfare of Taiwan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Rationales and Objectives: To investigate the prognostic value of the radiomic-based prediction model in predicting the interval growth rate of persistent subsolid nodules (SSNs) with an initial size of ≤ 3 cm manifesting as lung adenocarcinomas., Materials and Methods: A total of 133 patients (mean age, 59.02 years; male, 37.6%) with 133 SSNs who underwent a series of CT examinations at our hospital between 2012 and 2022 were included in this study. Forty-one radiomic features were extracted from each volumetric region of interest. Radiomic features combined with conventional clinical and semantic parameters were then selected for radiomic-based model building. To investigate the model performance in terms of substantial SSN growth and stage shift growth, the model performance was compared by the area under the curve (AUC) obtained by receiver operating characteristic analysis., Results: The mean follow-up period was 3.62 years. For substantial SSN growth, a radiomic-based model (Model 2) based on clinical characteristics, CT semantic features, and radiomic features yielded an AUCs of 0.869 (95% CI: 0.799-0.922). In comparison with Model 1 (clinical characteristics and CT semantic features), Model 2 performed better than Model 1 for substantial SSN growth (AUC model 1:0.793 versus AUC model 2:0.869, p = 0.028). A radiomic-based nomogram combining sex, follow-up period, and three radiomic features was built for substantial SSN growth prediction. For the stage shift growth, a radiomic-based model (Model 4) based on clinical characteristics, CT semantic features, and radiomic features yielded an AUCs of 0.883 (95% CI: 0.815-0.933). Compared with Model 3 (clinical characteristics and CT semantic features), Model 4 performed better than the model 3 for stage shift growth (AUC model 1: 0.769 versus AUC model 2: 0.883, p = 0.006). A radiomic-based nomogram combining the initial nodule size, SSN classification, follow-up period, and three radiomic features was built to predict the stage shift growth., Conclusion: Radiomic-based models have superior utility in estimating the prognostic interval growth of patients with early lung adenocarcinomas (≤ 3 cm) than conventional clinical-semantic models in terms of substantial interval growth and stage shift growth, potentially guiding clinical decision-making with follow-up strategies of SSNs in personalized precision medicine., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

With the popularization of lung cancer screening, many persistent subsolid nodules (SSNs) have been identified clinically, especially in Asian non-smokers. However, many studies have found that SSNs exhibit heterogeneous growth trends during long-term follow ups. This article adopted a narrative approach to extensively review the available literature on the topic to explore the definitions, rationale, and clinical application of different interval growths of subsolid pulmonary nodule management and follow-up strategies. The development of SSN growth thresholds with different growth patterns could support clinical decision making with follow-up guidelines to reduce over- and delayed diagnoses. In conclusion, using different SSN growth thresholds could optimize the follow-up management and clinical decision making of SSNs in lung cancer screening programs. This could further reduce the lung cancer mortality rate and potential harm from overdiagnosis and over management.

Purpose: To compare the diagnostic performance of radiomic analysis with machine learning (ML) model with a convolutional neural network (CNN) in differentiating thymic epithelial tumors (TETs) from other prevascular mediastinal tumors (PMTs)., Methods: A retrospective study was performed in patients with PMTs and undergoing surgical resection or biopsy in National Cheng Kung University Hospital, Tainan, Taiwan, E-Da Hospital, Kaohsiung, Taiwan, and Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan between January 2010 and December 2019. Clinical data including age, sex, myasthenia gravis (MG) symptoms and pathologic diagnosis were collected. The datasets were divided into UECT (unenhanced computed tomography) and CECT (enhanced computed tomography) for analysis and modelling. Radiomics model and 3D CNN model were used to differentiate TETs from non-TET PMTs (including cyst, malignant germ cell tumor, lymphoma and teratoma). The macro F1-score and receiver operating characteristic (ROC) analysis were performed to evaluate the prediction models., Result: In the UECT dataset, there were 297 patients with TETs and 79 patients with other PMTs. The performance of radiomic analysis with machine learning model using LightGBM with Extra Tree (macro F1-Score = 83.95%, ROC-AUC = 0.9117) had better performance than the 3D CNN model (macro F1-score = 75.54%, ROC-AUC = 0.9015). In the CECT dataset, there were 296 patients with TETs and 77 patients with other PMTs. The performance of radiomic analysis with machine learning model using LightGBM with Extra Tree (macro F1-Score = 85.65%, ROC-AUC = 0.9464) had better performance than the 3D CNN model (macro F1-score = 81.01%, ROC-AUC = 0.9275)., Conclusion: Our study revealed that the individualized prediction model integrating clinical information and radiomic features using machine learning demonstrated better predictive performance in the differentiation of TETs from other PMTs at chest CT scan than 3D CNN model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chang, Tang, Wei, Lin, Wu, Wu, Liu, Yen, Ma and Tseng.)

Background: This study compares the surgical and long-term outcomes, including disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS), between lobe-specific lymph node dissection (L-SND) and systematic lymph node dissection (SND) among patients with stage I non-small cell lung cancer (NSCLC)., Methods: In this retrospective study, 107 patients diagnosed with clinical stage I NSCLC undergoing video-assisted thoracic surgery lobectomy (exclusion of the right middle lobe) from January 2011 to December 2018 were enrolled. The patients were assigned to the L-SND ( n = 28) and SND ( n = 79) groups according to the procedure performed on them. Demographics, perioperative data, and surgical and long-term oncological outcomes were collected and compared between the L-SND and SND groups., Results: The mean follow-duration was 60.6 months. The demographic data and surgical outcomes and long-term oncological outcomes were not significantly different between the two groups. The 5-year OS of the L-SND and SND groups was 82% and 84%, respectively. The 5-year DFS of the L-SND and SND groups was 70% and 65%, respectively. The 5-year CSS of the L-SND and SND groups was 80% and 86%, respectively. All the surgical and long-term outcomes were not statistically different between the two groups., Conclusion: L-SND showed comparable surgical and oncologic outcomes with SND for clinical stage I NSCLC. L-SND could be a treatment choice for stage I NSCLC.

Background: Patients with persistent pulmonary subsolid nodules have a relatively high incidence of lung adenocarcinoma. Preoperative early diagnosis of invasive pulmonary adenocarcinoma spectrum lesions could help avoid extensive advanced cancer management and overdiagnosis in lung cancer screening programs., Methods: In total, 260 consecutive patients with persistent subsolid nodules ≤30 mm (n=260) confirmed by surgical pathology were retrospectively investigated from February 2016 to August 2020 at the Kaohsiung Veterans General Hospital. All patients underwent surgical resection within 3 months of the chest CT exam. The study subjects were divided into a training cohort (N=195) and a validation cohort (N=65) at a ratio of 3:1. The purpose of our study was to develop and validate a least absolute shrinkage and selection operator-derived nomogram integrating semantic-radiomic features in differentiating preinvasive and invasive pulmonary adenocarcinoma lesions, and compare its predictive value with clinical-semantic, semantic, and radiologist's performance., Results: In the training cohort of 195 subsolid nodules, 106 invasive lesions and 89 preinvasive lesions were identified. We developed a least absolute shrinkage and selection operator-derived combined nomogram prediction model based on six predictors (nodular size, CTR, roundness, GLCM&#95;Entropy&#95;log10, HISTO&#95;Entropy&#95;log10, and CONVENTIONAL&#95;Humean) to predict the invasive pulmonary adenocarcinoma lesions. Compared with other predictive models, the least absolute shrinkage and selection operator-derived model showed better diagnostic performance with an area under the curve of 0.957 (95% CI: 0.918 to 0.981) for detecting invasive pulmonary adenocarcinoma lesions with balanced sensitivity (92.45%) and specificity (88.64%). The results of Hosmer-Lemeshow test showed P values of 0.394 and 0.787 in the training and validation cohorts, respectively, indicating good calibration power., Conclusions: We developed a least absolute shrinkage and selection operator-derived model integrating semantic-radiomic features with good calibration. This nomogram may help physicians to identify invasive pulmonary adenocarcinoma lesions for guidance in personalized medicine and make more informed decisions on managing subsolid nodules., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-308/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

The pregnant uterus is an immunologically rich organ, with dynamic changes in the inflammatory milieu and immune cell function underlying key stages of pregnancy. Recent studies have implicated dysregulated expression of the interleukin-1 (IL-1) family cytokine, IL-33, and its receptor, ST2, in poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. How IL-33 supports pregnancy progression in vivo is not well understood. Here, we demonstrate that maternal IL-33 signaling critically regulates uterine tissue remodeling and immune cell function during early pregnancy in mice. IL-33-deficient dams exhibit defects in implantation chamber formation and decidualization, and abnormal vascular remodeling during early pregnancy. These defects coincide with delays in early embryogenesis, increased resorptions, and impaired fetal and placental growth by late pregnancy. At a cellular level, myometrial fibroblasts, and decidual endothelial and stromal cells, are the main IL-33 + cell types in the uterus during decidualization and early placentation, whereas ST2 is expressed by uterine immune populations associated with type 2 immune responses, including ILC2s, Tregs, CD4 + T cells, M2- and cDC2-like myeloid cells, and mast cells. Early pregnancy defects in IL-33-deficient dams are associated with impaired type 2 cytokine responses by uterine lymphocytes and fewer Arginase-1 + macrophages in the uterine microenvironment. Collectively, our data highlight a regulatory network, involving crosstalk between IL-33-producing nonimmune cells and ST2 + immune cells at the maternal-fetal interface, that critically supports pregnancy progression in mice. This work has the potential to advance our understanding of how IL-33 signaling may support optimal pregnancy outcomes in women.

Objectives: Patients with lung cancer pose a high risk of morbidity and mortality after lung resection. Those who receive perioperative cardiopulmonary rehabilitation (PRCR) have better prognosis. Peak oxygen consumption (peak VO 2 ), VO 2 at the ventilatory threshold (VO 2 at VT), and slope of minute ventilation to carbon dioxide production (V E /V CO2 slope) measured during pre-surgical cardiopulmonary exercise testing (CPET) have prognostic values after lung resection. We aimed to investigate the influence of individualized PRCR on postoperative complications in patients undergoing video-assisted thoracic surgery (VATS) for lung cancer with different pre-surgical risks., Methods: This was a retrospective study. We recruited 125 patients who underwent VATS for lung cancer between 2017 and 2021. CPET was administered before surgery to evaluate the risk level and PRCR was performed based on the individual risk level defined by peak VO2, VO2 at VT, and VE/VCO2 slope, respectively. The primary outcomes were intensive care unit (ICU) and hospital lengths of stay, endotracheal intubation time (ETT), and chest tube insertion time (CTT). The secondary outcomes were postoperative complications (PPCs), including subcutaneous emphysema, pneumothorax, pleural effusion, atelectasis, infection, and empyema., Results: Three intergroup comparisons based on the risk level by peak VO2 (3 groups), VO2 at VT (2 groups), and VE/VCO2 slope (3 groups) were done. All of the comparisons showed no significant differences in both the primary and secondary outcomes ( p = 0.061-0.910)., Conclusion: Patients with different risk levels showed comparable prognosis and PPCs after undergoing CPET-guided PRCR. PRCR should be encouraged in patients undergoing VATS for lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chao, Tuan, Tang, Tsai, Chung, Chen and Lin.)

Lung cancer is the most frequent cause of cancer-related death around the world. With the recent introduction of low-dose lung computed tomography for lung cancer screening, there has been an increasing number of smoking- and non-smoking-related lung cancer cases worldwide that are manifesting with subsolid nodules, especially in Asian populations. However, the pros and cons of lung cancer screening also follow the implementation of lung cancer screening programs. Here, we review the literature related to radiomics for early lung cancer diagnosis. There are four main radiomics applications: the classification of lung nodules as being malignant/benign; determining the degree of invasiveness of the lung adenocarcinoma; histopathologic subtyping; and prognostication in lung cancer prediction models. In conclusion, radiomics offers great potential to improve diagnosis and personalized risk stratification in early lung cancer diagnosis through patient-doctor cooperation and shared decision making.

Abstract: This study aimed to investigate the time trend variation in the surgical volume and prognostic outcome of patients with lung cancer after the gradual prolonged implementation of a low-dose computed tomography (LDCT) lung cancer screening program.Using the hospital-based cancer registry data on number of patients with lung cancer and deaths from 2008 to 2017, we conducted a retrospective study using a hospital-based cohort to investigate the relationship between changes in lung cancer surgical volume, the proportion of lung-sparing surgery, and prolonged prognostic outcomes after the gradual implementation of the LDCT lung cancer screening program in recent years.From 2008 to 2017, 3251 patients were diagnosed with lung cancer according to the hospital-based cancer registry. The 5-year mortality rate decreased gradually from 83.54% to 69.44% between 2008 and 2017. The volume of total lung cancer surgical procedures and proportion of lung-sparing surgery performed gradually increased significantly from 2008 to 2017, especially from 2014 to 2017 after implementation of a large volume of LDCT lung cancer screening examinations. In conclusion, our real-world data suggest that there will be an increase in cases of operable early-stage lung cancers, which in turn will increase the surgical volume and proportion of lung-sparing surgery, after the gradual implementation of the LDCT lung cancer screening program in recent years. These findings suggest the importance of a successful national policy regarding LDCT screening programs, regulation of shortage of thoracic surgeons, thoracic radiologist workforce training positions, and education programs., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A multiinstitutional study was conducted to analyze prognosticators of completely resected and pathologic T3 N0 M0 (pT3 N0 M0) stage thymic epithelial tumors., Methods: A total of 607 patients with surgically treated thymic epithelial tumors between June 1988 and December 2017 were enrolled. A Cox proportional hazards model and an inverse probability of treatment weighting-adjusted analysis using the propensity score were performed., Results: A total of 394 patients with thymoma and 130 patients with thymic carcinoma underwent complete tumor resections. Forty-one thymomas and 49 thymic carcinomas were confirmed as pT3 N0 M0 stage tumors. Postoperative adjuvant radiotherapy was associated with improved disease-free and overall survival in patients with thymoma (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23 to 0.69; and HR, 0.24; 95% CI, 0.11 to 0.52, respectively) and in patients with thymic carcinoma (HR, 0.15; 95% CI, 0.07 to 0.33; and HR, 0.12; 95% CI, 0.05 to 0.31, respectively). Although lung invasion was associated with poor disease-free survival (HR, 3.28; 95% CI, 1.90 to 5.89) and overall survival (HR, 2.60; 95% CI, 1.21 to 6.07), male sex (HR, 1.88; 95% CI, 1.10 to 3.18), older age (HR, 2.77; 95% CI, 1.29 to 5.70), and advanced histologic features (HR, 3.84; 95% CI, 1.42 to 14.51) were associated with poor overall survival in patients with pT3 N0 M0 thymoma. Adjuvant chemotherapy was associated with improved disease-free survival (HR, 0.11; 95% CI, 0.03 to 0.41) and overall survival (HR, 0.11; 95% CI, 0.06 to 0.20) in patients with pT3 N0 M0 thymic carcinoma with superior vena cava or innominate vein invasion., Conclusions: Postoperative radiotherapy was associated with improved survival in patients with pT3 N0 M0 thymic epithelial tumors. Lung invasion was associated with poor survival in patients with pT3 N0 M0 thymoma. Adjuvant chemotherapy was associated with improved survival in patients with pT3 N0 M0 thymic carcinoma with superior vena cava or innominate vein invasion., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This study aims to predict the histological invasiveness of pulmonary adenocarcinoma spectrum manifesting with subsolid nodules ≦ 3 cm using the preoperative CT-based radiomic approach. A total of 186 patients with 203 SSNs confirmed with surgically pathologic proof were retrospectively reviewed from February 2016 to March 2020 for training cohort modeling. The validation cohort included 50 subjects with 57 SSNs confirmed with surgically pathologic proof from April 2020 to August 2020. CT-based radiomic features were extracted using an open-source software with 3D nodular volume segmentation manually. The association between CT-based conventional features/selected radiomic features and histological invasiveness of pulmonary adenocarcinoma status were analyzed. Diagnostic models were built using conventional CT features, selected radiomic CT features and experienced radiologists. In addition, we compared diagnostic performance between radiomic CT feature, conventional CT features and experienced radiologists. In the training cohort of 203 SSNs, there were 106 invasive lesions and 97 pre-invasive lesions. Logistic analysis identified that a selected radiomic feature named GLCM&#95;Entropy&#95;log10 was the predictor for histological invasiveness of pulmonary adenocarcinoma spectrum (OR: 38.081, 95% CI 2.735-530.309, p = 0.007). The sensitivity and specificity for predicting histological invasiveness of pulmonary adenocarcinoma spectrum using the cutoff value of CT-based radiomic parameter (GLCM&#95;Entropy&#95;log10) were 84.8% and 79.2% respectively (area under curve, 0.878). The diagnostic model of CT-based radiomic feature was compared to those of conventional CT feature (morphologic and quantitative) and three experienced radiologists. The diagnostic performance of radiomic feature was similar to those of the quantitative CT feature (nodular size and solid component, both lung and mediastinal window) in prediction invasive pulmonary adenocarcinoma (IPA). The AUC value of CT radiomic feature was higher than those of conventional CT morphologic feature and three experienced radiologists. The c-statistic of the training cohort model was 0.878 (95% CI 0.831-0.925) and 0.923 (0.854-0.991) in the validation cohort. Calibration was good in both cohorts. The diagnostic performance of CT-based radiomic feature is not inferior to solid component (lung and mediastinal window) and nodular size for predicting invasiveness. CT-based radiomic feature and nomogram could help to differentiate IPA lesions from preinvasive lesions in the both independent training and validation cohorts. The nomogram may help clinicians with decision making in the management of subsolid nodules.

Low-dose computed tomography lung cancer screening aims to detect early-stage lung cancers in order to decrease the incidence of advanced-stage lung cancers and to reduce lung cancer mortality. We analyzed the time trends of lung cancer stage distribution and mortality rates after the gradual implementation of the low-dose computed tomography lung cancer screening in a hospital-based cohort. Using the hospital-based cancer registry data on lung cancer number and death from 2007 to 2014, we aim to evaluate the trends in stage distribution and mortality rate after the gradual implementation of low-dose computed tomography lung cancer screening program over recent years. From 2007 to 2014, overall 2542 cases of lung cancers were diagnosed according to hospital-based cancer registry. For the 1-year mortality rate, the mortality rate decreased gradually from 48.16 to 37.04% between 2007 and 2014. For the 5-year mortality rate, the mortality rate decreased gradually from 88.49 to 69.44% between 2007 and 2014. There was a gradual decrease in stage IV lung cancer with the corresponding sharp increase in stage I early lung cancer after following the implementation of the large volume of the low-dose computed tomography examination between the years 2011 and 2014. In conclusion, these results suggest that the gradual implementation of low-dose computed tomography lung screening program could lead to a remarkable decrease in lung cancer mortality and a remarkable stage shift in the trend over time in this hospital-based cohort.

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Screening programs for lung cancer aim to allow diagnosis at the early stage, and therefore the decline in mortality rates. Thus, the aim of this retrospective cohort study was to the comparison of screened and non-screened lung cancer in terms of lung cancer characteristics, overdiagnosis and survival rate. A retrospective study in which 2883 patients with 2883 lung cancer diagnosed according to the hospital-based lung cancer register database between 2007 and 2017. A comparison was performed in term of clinical characteristics and outcomes of lung cancer between the screened and non-screening patient groups. 2883 subjects were identified (93 screened and 2790 non-screened). Screened group patients were younger (59.91 ± 8.14 versus 67.58 ± 12.95; p < 0.0001), and were more likely to be female than non-screened group (61.3% versus 36.8%; p < 0.0001). The screened group showed significantly better outcomes in overall mortality than the non-screened group (10.75% versus 79.06%; <0.0001). In a Cox proportional hazard model, lung cancer in the screened group proved to be an independent prognostic factor in lung cancer subjects. Our findings point to the improved survival outcome in the screened group and might underline the benefit of low-dose computed tomography (LDCT) screening program in Asian populations with the high prevalence of non-smoking-related lung cancer. Further study aimed at the LDCT mass screening program targeting at light smokers and non-smoker outside of existing screening criteria is warranted.

Background: The long-term natural course and outcomes of subsolid nodules (SSNs) in terms of true growth, substantial growth, and stage shift need to be clarified., Methods: Between 2002 and 2016, 128 subjects with persistent SSNs of 3cm or smaller were enrolled. The baseline and interval changes in the series computed tomography (CT) findings during the follow-up period were subsequently reviewed., Results: The mean follow-up period was 3.57±2.93years. The cumulative percentage of growth nodules of the part-solid nodule (PSN) group was significantly higher than that of the ground-glass nodule (GGN) group by Kaplan-Meier estimation (all p<0.0001). For true SSN growth, GGNs usually take a median follow-up of 7 years to grow; PSNs usually take a median follow-up of 3 years to grow. For substantial SSN growth, GGNs usually take a median follow-up of 9 years to grow; PSNs usually take a median follow-up of 3 years to grow. For stage shift, GGNs usually take a median follow-up of 12 years to grow; PSNs usually take a median follow-up of 9 years to grow., Conclusions: The natural course in terms of true growth, substantial growth, and stage shift differed significantly according to their nodule type, which could contribute to the development of follow-up guidelines and management strategy of pulmonary SSNs., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Rationale: Bronchoscopic cryotherapy has been considered as one of the optional interventions for unresectable malignant central airway obstruction (CAO). And it provides high safety and effectiveness in airway patency re-establishment. This report describes the interventional bronchoscopic cryotherapy for a patient with CAO caused by squamous cell carcinoma of the esophagus. We display a series of dramatic change of chest radiographs before and after the intervention., Patient Concerns: A 70-year-old man with squamous cell carcinoma of the middle third of the esophagus (initial staging, pT2N0M0; stage IIB; in January 2017) underwent Video-assisted esophagectomy and reconstruction with a gastric conduit via a substernal route. Following Chest computed tomography and positron emission tomography revealed disease progression with paratracheal metastases. Progressive dyspnea and chest pain lasted for a month, and he was admitted to the ER., Diagnoses: Blood gas analysis revealed type I respiratory failure (pH, 7.445; PaO2, 69.4 mmHg; PaCO2, 40.6 mmHg). Other laboratory data were grossly normal. Chest radiography revealed a total left lung collapse. Chest CT identified a tumor blocking the left mainstem bronchus with the consolidation of the left lung., Interventions: Dexamethasone and epinephrine inhalation were administered for initial symptom relief. Bronchoscopy performed 4 days after admission revealed a huge tumor completely occluding the left mainstem bronchus orifice. The occlusion was completely resolved following cryotherapy. Then, the first course of palliative chemotherapy with cisplatin plus fluorouracil, followed by the second course a month later, was administered., Outcomes: The latest chest radiograph showed a patent airway. The patient's condition remained stable for at least the following 2 months., Lessons: Malignant CAO is a rare but potentially life-threatening condition. Several acceptable bronchoscopy techniques exist for treatment. Cryotherapy has high safety and effectiveness in airway patency re-establishment.

Pleomorphic carcinoma (PC) of lung, a rare malignant lung tumor, is predominated in male smokers with over 65 years of age. The clinical presentations of PC are various including chest pain, cough, and dyspnea and so on. Asymptomatic patients have been also reported. In our case, a female non-smoker with middle age, who initially developed symptoms like empyema was diagnosed advanced PC. Poor progression occurred in this patient within one month from diagnosis to expiration. The lesson from this case is that malignancy of lung such as PC could not be excluded if a patient develops unmanageable empyema., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Rationale and Objectives: The main aim of this study was to evaluate the clinical validity and correlation with pathologic invasiveness in the pulmonary adenocarcinoma spectrum based on the novel qualitative computed tomography criterion for subsolid nodule (SSN) classification, which classified SSN into pure ground-glass nodule, heterogeneous ground-glass nodule, and part-solid nodule. In addition, we compared the performance of the conventional and novel classifications., Materials and Methods: The computed tomography images of 41 SSN nodules were interpreted by six observers independently, and the SSN characteristics were classified according to both the conventional and the novel classification systems. Each observer assessed 41 nodules in two different classifications separated by a minimum of 8 weeks. The kappa (κ) coefficient test was used to determine the reliability. The correlation between pulmonary adenocarcinoma spectrum and the SSN classification was analyzed with Spearman correlation coefficients., Results: Interobserver agreement (κ) was 0.702 (range 0.42-0.89) and 0.707 (range 0.58-0.88) for the conventional and the novel classifications for SSN, respectively, and intraobserver agreement (κ) was 0.92 and 0.88 for the conventional and the novel classifications for SSN, respectively. The novel SSN classification (correlation coefficient range 0.622-0.732) is more strongly correlated with the pathologic invasiveness degree of lesions in adenocarcinoma spectrum than the conventional SSN classification (correlation coefficient range 0.458-0.644)., Conclusions: The agreement between observers on the novel SSN classification system was good and had better correlation with pathologic invasiveness than the conventional SSN classification. Further studies are needed to confirm these results on interobserver agreement., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objectives: We proposed a modification of the ACR Lung Imaging Reporting and Data System (Lung-RADS) to clarify the characteristics of subsolid nodules with categories 1-11, and to compare the diagnostic accuracy with Lung-RADS and National Lung Screening Trial criteria in an Asian population with high prevalence of adenocarcinoma., Methods: We analyzed a retrospective cohort of 1978 consecutive healthy subjects (72.8% nonsmoker) who underwent low-dose computed tomography from August 2013 to October 2014 (1084 men, 894 women). Lung-RADS categories 2 and 3 were modified to include subcategories of 2A/2B/2C and 3A/3B/3C, respectively. Clinical information and nodule characteristics were recorded. Receiver operating characteristic curves were used to compare diagnostic accuracy at different cutoffs., Results: Thirty-two subjects (30 nonsmokers) had pathology-proven adenocarcinoma spectrum lesions in the follow-up period (1.6 ± 0.5 years). Modified Lung-RADS, using modified Lung-RADS category 2C as cutoff, had an area under the curve (AUC) of 0.973 in predicting adenocarcinoma spectrum lesions (sensitivity of 100%, specificity of 89.3%), which was significantly higher than that of Lung-RADS (AUC = 0.815, P < .001) and National Lung Screening Trial (AUC = 0.906, P < .001). Furthermore, modified Lung-RADS showed an AUC of 0.992 in predicting invasive adenocarcinoma (sensitivity of 95%, specificity of 97.8%) when category 3B was used as cutoff., Conclusions: Modified Lung-RADS may substantially improve sensitivity while maintaining specificity for detection of adenocarcinoma spectrum lesions in an Asian population. Compared to Lung-RADS, it has enhanced ability to differentiate invasive from indolent adenocarcinoma by more refined subclassification of subsolid nodules using two cutoff values of category 2C and 3B. The effect of using modified Lung-RADS in clinical practice must be carefully studied in prospective large cohort studies., (Copyright © 2018 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Thymomas are enigmatic tumors for which surgical resection is the mainstay of treatment. However, there are still many debates about resected thymomas with pleural recurrence. Repetitive operations for thymomas involving pleural recurrence are still the treatment of choice. Herein, we present a case with a suitable performance status for re-operation with a new application for argon beam coagulation. Both our experience and the currently available evidence suggest that surgical resection could be considered for patients with advanced thymomas, even for patients with locally advanced or Masaoka-Koga stage IV thymomas. Multimodality or multimodal, treatments resulted in better oncological outcomes for these patients. In this case, we proved that the new application of argon beam coagulation for a thymoma patient with pleural recurrence is safe and feasible. Additional evidence should be collected, and patients should be followed to assess long-term benefits., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

We aimed to analyze CT features of persistent subsolid nodules (SSN) ≦3 cm diagnosed pathologically as adenocarcinoma spectrum to investigate whether parameters enable distinction between invasive pulmonary adenocarcinomas (IPAs) and pre-invasive lesions. A total of 129 patients with 141 SSNs confirmed with surgically pathologic proof were retrospectively reviewed. Of 141 SSNs, there were 57 pure ground-glass nodules (GGNs), 22 heterogeneous GGNs, and 62 part-solid nodules. SSN subclassification showed a significant linear trend with invasive degree of the adenocarcinoma spectrum (pure GGNs 7%; heterogeneous GGNs 36.4%; part-solid nodules 85.5%, P for trend <0.0001). For IPA detection in 141 SSNs, a solid part of ≧3 mm was the most specificity (sensitivity, 76.9%; specificity, 94.7%), followed by air-bronchogram sign (sensitivity, 53.8%; specificity, 89.5%), SSN subclassification (sensitivity, 81.5%; specificity, 88.2%), and a lesion size ≧12 mm (sensitivity, 84.6%; specificity, 76.3%). For IPA detection in 79 pure or heterogeneous GGNs, the heterogeneous GGN sign was the most useful finding, with most specificity (sensitivity, 66.7%; specificity, 79.1%), followed by CT attenuation (HU) of ≧-493 (sensitivity, 75%; specificity, 74.6%) and a lesion size ≧10 mm (sensitivity, 83.3%; specificity, 70.1%). In conclusion, this simple combined visual and semiquantitative analysis of CT features helps distinguish IPAs from pre-invasive lesions.

Angiomatosis is a nonneoplastic proliferative vascular lesion, which occurs mostly in diverse soft tissues. We observed a rare case of mediastinal angiomatosis with intraspinal invasion that mimicked a dumbbell tumor in a 63-year-old man with a history of prostate adenocarcinoma. A roentgenogram of the chest showed that the patient had left pleural effusion and a left paraspinal mass, computed tomography disclosed a low-density fusiform lesion over the left paraspinal region, and magnetic resonance imaging confirmed a large posterior mediastinal tumor with T4 intraspinal invasion. The tumor was completely excised through a laminectomy of the T3-5 spine, followed by thoracoscopic removal of the mediastinal part. The definitive diagnosis was angiomatosis. Surgical removal of such a dumbbell-mimicked tumor is mandatory because it may progress to spinal cord compression., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The National Lung Screening Trial (NLST) showed low-dose screening chest computed tomography (CT) reduced the lung cancer mortality rate up to 20% in high-risk patients in the United States. We aimed to investigate the impact of applying the NLST eligibility criteria to the population in Taiwan, and to identify additional risk factors to select subjects at risk for lung cancer., Patients and Methods: We retrospectively reviewed the medical records of 1763 asymptomatic healthy subjects (age range, 40-80 years) who voluntarily underwent low-dose chest CT (1029 male, 734 female) from August 2013 to August 2014. Clinical information and nodule characteristics were recorded. The results of subsequent follow-up and outcome were also recorded., Results: A total of 8.4% (148/1763) of subjects would have been eligible for lung cancer screening based on the NLST criteria. However, only 1 of these eligible subjects would have a lung cancer detected at baseline. Among the 1615 subjects who did not meet the NLST criteria, the detection rates of lung cancer were 2.6% in women and 0.56% in men. Logistic regression showed that female gender and a family history of lung cancer were the 2 most important predictors of lung cancer in Taiwan (odds ratio, 6.367; P = .003; odds ratio, 3.017; P = .016, respectively)., Conclusions: In conclusion, NLST eligibility criteria may not be effective in screening for lung cancer in Taiwan. A risk-based prediction model based on the family history of lung cancer and female gender can potentially improve the efficiency of lung cancer screening programs in Taiwan., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We have previously demonstrated that peptide fragments of human serum albumin can be developed into potential renal targeting drug carriers. However, the interactions of these peptide fragments with red blood cells and plasma components are not evaluated well and there is yet no report on the evaluation of the hemocompatibility of peptide fragments. In this study, three kinds of peptide fragments were prepared and identified by amino acid analysis, and the blood compatibility of the peptide fragments was investigated by measuring blood coagulation, platelet and complement activation and hemolysis activity. Results indicated that all the peptide fragments prepared were highly hemocompatible without causing any clot formation, red blood cell aggregation or immune response. In addition, data from the cytotoxicity assay using HeLa cells and Madin-Darby canine kidney cells suggested that these peptide fragments do not induce toxicity towards either cell lines at concentrations up to 5 mg/ml. Therefore, it can be concluded that peptide fragments exhibit good hemocompatibility with no unwanted effect on the viability of renal cells, preliminarily demonstrating that it is safe to use peptide fragments as renal targeting drug carriers., (© The Author(s) 2015.)

The discovery of cancer cell-selective tumour necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis generated broad excitement and development of TRAIL receptor agonists (TRA) as potential cancer therapy. Studies demonstrating the synergistic combination effect of SMAC mimetics and TRA further suggested potentially effective treatment in multiple tumour settings. However, predictive biomarkers allowing identification of patients that could respond to treatment are lacking. Here, we described a high throughput combination screen conducted across a panel of 31 breast cancer cell lines in which we observed highly synergistic activity between TRAIL and the inhibitors of apoptosis proteins (IAP) inhibitor (IAPi) AZD5582 in ~30% of cell lines. We detected no difference in the expression levels of the IAPi or TRAIL-targeted proteins or common modulators of the apoptotic pathway between the sensitive and resistant cell lines. Synergistic combination effect of AZD5582 and TRAIL correlated with sensitivity to TRAIL, but not to AZD5582 as a single agent. TRAIL treatment led to significantly greater activity of Caspase-8 in sensitive than in resistant cell lines (P=0.002). The majority (12/14) of AZD5582+TRAIL-resistant cell lines retained a functional cell death pathway, as they were sensitive to AZD5582+TNFα combination treatment. This suggested that failure of the TRAIL receptor complex to transduce the death signal to Caspase-8 underlies AZD5582+TRAIL resistance. We developed a 3D spheroid assay and demonstrated its suitability for the ex vivo analysis of the Caspase-8 activity as a predictive biomarker. Altogether, our study demonstrated a link between the functionality of the TRAIL receptor pathway and the synergistic activity of the IAPi+TRA combination treatment. It also provided a rationale for development of the Caspase-8 activity assay as a functional predictive biomarker that could allow better prediction of the response to IAPi+TRA-based therapies than the analysis of expression levels of protein biomarkers.

CYP24A1 is the multicatalytic cytochrome P450 responsible for the catabolism of vitamin D via the C23- and C24-oxidation pathways. We successfully expressed the labile human enzyme in Escherichia coli and partially purified it in an active state that permitted detailed characterization of its metabolism of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] and the intermediates of the C24-oxidation pathway in a phospholipid-vesicle reconstituted system. The C24-oxidation pathway intermediates, 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, 24-oxo-1,23,25-trihydroxyvitamin D3 and tetranor-1,23-dihydroxyvitamin D3, were enzymatically produced from 1,25(OH)2 D3 using rat CYP24A1. Both 1,25(OH)2 D3 and 1,23-dihydroxy-24,25,26,27-tetranorvitamin D3 were found to partition strongly into the phospholipid bilayer when in aqueous medium. Changes to the phospholipid concentration did not affect the kinetic parameters for the metabolism of 1,25(OH)2 D3 by CYP24A1, indicating that it is the concentration of substrates in the membrane phase (mol substrate·mol phospholipid(-1) ) that determines their rate of metabolism. CYP24A1 exhibited Km values for the different C24-intermediates ranging from 0.34 to 15 mmol·mol phospholipid(-1) , with 24-oxo-1,23,25-trihydroxyvitamin D3 [24-oxo-1,23,25(OH)3 D3] displaying the lowest and 1,24,25-trihydroxyvitamin D3 [1,24,25(OH)3 D3] displaying the highest. The kcat values varied by up to 3.8-fold, with 1,24,25(OH)3 D3 displaying the highest kcat (34 min(-1) ) and 24-oxo-1,23,25(OH)3 D3 the lowest. The data show that the cleavage of the side chain of 24-oxo-1,23,25(OH)3 D3 occurs with the highest catalytic efficiency (kcat /Km ) and produces 1-hydroxy-23-oxo-24,25,26,27-tetranorvitamin D3 and not 1,23-dihydroxy-24,25,26,27-tetranorvitamin D3, as the primary product. These kinetic analyses also show that intermediates of the C24-oxidation pathway effectively compete with precursor substrates for binding to the active site of the enzyme, which manifests as an accumulation of intermediates, indicating that they dissociate after each catalytic step., (© 2014 FEBS.)

Aim: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics., Materials and Methods: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism., Results: 20S- and 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 μg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes., Conclusion: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.

We investigated the metabolism of vitamin D2 to hydroxyvitamin D2 metabolites ((OH)D2) by human placentas ex-utero, adrenal glands ex-vivo and cultured human epidermal keratinocytes and colonic Caco-2 cells, and identified 20(OH)D2, 17,20(OH)₂D2, 1,20(OH)₂D2, 25(OH)D2 and 1,25(OH)₂D2 as products. Inhibition of product formation by 22R-hydroxycholesterol indicated involvement of CYP11A1 in 20- and 17-hydroxylation of vitamin D2, while use of ketoconazole indicated involvement of CYP27B1 in 1α-hydroxylation of products. Studies with purified human CYP11A1 confirmed the ability of this enzyme to convert vitamin D2 to 20(OH)D2 and 17,20(OH)₂D2. In placentas and Caco-2 cells, production of 20(OH)D2 was higher than 25(OH)D2 while in human keratinocytes the production of 20(OH)D2 and 25(OH)D2 were comparable. HaCaT keratinocytes showed high accumulation of 1,20(OH)₂D2 relative to 20(OH)D2 indicating substantial CYP27B1 activity. This is the first in vivo evidence for a novel pathway of vitamin D2 metabolism initiated by CYP11A1 and modified by CYP27B1, with the product profile showing tissue- and cell-type specificity., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

CYP11A1 can hydroxylate vitamin D3 at carbons 17, 20, 22, and 23, producing a range of secosteroids which are biologically active with respect to their ability to inhibit proliferation and stimulate differentiation of various cell types, including cancer cells. As 1α-hydroxylation of the primary metabolite of CYP11A1 action, 20S-hydroxyvitamin D3 [20(OH)D3], greatly influences its properties, we examined the ability of both human and mouse CYP27B1 to 1α-hydroxylate six secosteroids generated by CYP11A1. Based on their kcat/Km values, all CYP11A1-derived metabolites are poor substrates for CYP27B1 from both species compared with 25-hydroxyvitamin D3. No hydroxylation of metabolites with a 17α-hydroxyl group was observed. 17α,20-Dihydroxyvitamin D3 acted as an inhibitor on human CYP27B1 but not the mouse enzyme. We also tested CYP27B1 activity on 20,24-, 20,25-, and 20,26-dihydroxyvitamin D3, which are products of CYP24A1 or CYP27A1 activity on 20(OH)D3. All three compounds were metabolized with higher catalytic efficiency (kcat/Km) by both mouse and human CYP27B1 than 25-hydroxyvitamin D3. CYP27B1 action on these new dihydroxy derivatives was confirmed to be 1α-hydroxylation by mass spectrometry and nuclear magnetic resonance analyses. Both 1,20,25- and 1,20,26- trihydroxyvitamin D3 were tested for their ability to inhibit melanoma (SKMEL-188) colony formation, and were significantly more active than 20(OH)D3. This study shows that CYP11A1-derived secosteroids are 1α-hydroxylated by both human and mouse CYP27B1 with low catalytic efficiency, and that the presence of a 17α-hydroxyl group completely blocks 1α-hydroxylation. In contrast, the secondary metabolites produced by subsequent hydroxylation of 20(OH)D3 at C24, C25, or C26 are very good substrates for CYP27B1.

20-Hydroxyvitamin D(3) (20(OH)D(3)), the major product of CYP11A1 action on vitamin D(3), is biologically active and is produced in vivo. As well as potentially having important physiological actions, it is of interest as a therapeutic agent due to its lack of calcemic activity. In the current study we have examined the ability of CYP24A1, the enzyme that inactivates 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), to metabolize 20(OH)D(3). Rat CYP24A1 was expressed in Escherichia coli, purified by Ni-affinity chromatography and assayed with substrates incorporated into phospholipid vesicles which served as a model of the inner mitochondrial membrane. In this system CYP24A1 metabolized 1,25(OH)(2)D(3) with a catalytic efficiency 1.4-fold higher than that seen for 25-hydroxyvitamin D(3) (25(OH)D(3)). CYP24A1 hydroxylated 20(OH)D(3) to several dihydroxy-derivatives with the major two identified by NMR as 20,24-dihydroxyvitamin D(3) (20,24(OH)(2)D(3)) and 20,25-dihydroxyvitamin D(3) (20,25(OH)(2)D(3)). The catalytic efficiency of CYP24A1 for 20(OH)D(3) metabolism was more than 10-fold lower than for either 25(OH)D(3) or 1,25(OH)(2)D(3) and no secondary metabolites were produced. The two major products, 20,24(OH)(2)D(3) and 20,25(OH)(2)D(3), caused significantly greater inhibition of colony formation by SKMEL-188 melanoma cells than either 1,25(OH)(2)D(3) or the parent 20(OH)D(3), showing that CYP24A1 plays an activating, rather than an inactivating role on 20(OH)D(3)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To define the interaction of novel secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D(3) with a full length (D(3)) side chain and hydroxy-secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D(3) were more potent than pD analogues. Molecular modeling of the binding of the secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel secosteroids., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We define previously unrecognized in vivo pathways of vitamin D(3) (D3) metabolism generating novel D3-hydroxyderivatives different from 25-hydroxyvitamin D(3) [25(OH)D3] and 1,25(OH)(2)D3. Their novel products include 20-hydroxyvitamin D(3) [20(OH)D3], 22(OH)D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, 1,20(OH)(2)D3, 1,20,23(OH)(3)D3, and 17,20,23(OH)(3)D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ∼20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α-hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH)(2)D3 → 17,20,23(OH)(3)D3 with further 1α-hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH)(2)D3 and D3 → 22(OH)D3 → 20,22(OH)(2)D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH)(2)D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH)(2)D3, 20,22(OH)(2)D3, and 17,20,23(OH)(3)D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH)(2)D3.

The non-naturally occurring 20R epimer of 20-hydroxyvitamin D3 is synthesized based on chemical design and hypothesis. The 20R isomer is separated by semipreparative HPLC, and its structure is characterized. A comparison of 20R isomer to its 20S counterpart in biological evaluation demonstrates that they have different behaviors in antiproliferative and metabolic studies., (© 2012 American Chemical Society)

20-hydroxyvitamin D(2) [20(OH)D(2)] inhibits DNA synthesis in epidermal keratinocytes, melanocytes, and melanoma cells in a dose- and time-dependent manner. This inhibition is dependent on cell type, with keratinocytes and melanoma cells being more sensitive than normal melanocytes. The antiproliferative activity of 20(OH)D(2) is similar to that of 1,25(OH)(2)D(3) and of newly synthesized 1,20(OH)(2)D(2) but significantly higher than that of 25(OH)D(3). 20(OH)D(2) also displays tumorostatic effects. In keratinocytes 20(OH)D(2) inhibits expression of cyclins and stimulates involucrin expression. It also stimulates CYP24 expression, however, to a significantly lower degree than that by 1,25(OH)(2)D(3) or 25(OH)D(3). 20(OH)D(2) is a poor substrate for CYP27B1 with overall catalytic efficiency being 24- and 41-fold lower than for 25(OH)D(3) with the mouse and human enzymes, respectively. No conversion of 20(OH)D(2) to 1,20(OH)(2)D(2) was detected in intact HaCaT keratinocytes. 20(OH)D(2) also demonstrates anti-leukemic activity but with lower potency than 1,25(OH)(2)D(3). The phenotypic effects of 20(OH)D(2) are mediated through interaction with the vitamin D receptor (VDR) as documented by attenuation of cell proliferation after silencing of VDR, by enhancement of the inhibitory effect through stable overexpression of VDR and by the demonstration that 20(OH)D(2) induces time-dependent translocation of VDR from the cytoplasm to the nucleus at a comparable rate to that for 1,25(OH)(2)D(3). In vivo tests show that while 1,25(OH)(2)D(3) at doses as low as 0.8 μg/kg induces calcium deposits in the kidney and heart, 20(OH)D(2) is devoid of such activity even at doses as high as 4 μg/kg. Silencing of CY27B1 in human keratinocytes showed that 20(OH)D(2) does not require its transformation to 1,20(OH)(2)D(2) for its biological activity. Thus 20(OH)D(2) shows cell-type dependent antiproliferative and prodifferentiation activities through activation of VDR, while having no detectable toxic calcemic activity, and is a poor substrate for CYP27B1.

20,23-Dihydroxyvitamin D(3) [20,23(OH)(2)D(3)] is a biologically active metabolite produced by the action of cytochrome P450scc (CYP11A1) on vitamin D(3). It inhibits keratinocyte proliferation, stimulates differentiation, and inhibits nuclear factor-kappaB activity, working as a vitamin D receptor agonist. We have tested the ability of purified mouse 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1) to add a 1alpha-hydroxyl group to this vitamin D analog and determined whether this altered its biological activity. 20,23(OH)(2)D(3) incorporated into phospholipid vesicles was converted to a single product by CYP27B1, confirmed to be 1alpha,20,23-trihydroxyvitamin D(3) [1,20,23(OH)(3)D(3)] by mass spectrometry and NMR. The 20,23(OH)(2)D(3) was a relatively poor substrate for CYP27B1 compared with the normal substrate, 25-hydroxyvitamin D(3), displaying a 5-fold higher K(m) and 8-fold lower k(cat) value. Both 20,23(OH)(2)D(3) and 1,20,23(OH)(3)D(3) decreased neonatal human epidermal keratinocyte proliferation, showing significant effects at a lower concentration (0.1 nM) than that seen for 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] at 24 h of treatment. Both compounds also decreased cell biomass relative to that of control cells, measured by staining with sulforhodamine B. They caused little stimulation of the expression of the vitamin D receptor at the mRNA level compared with the 30-fold induction observed with the same concentration (100 nM) of 1,25(OH)(2)D(3) at 24 h. Addition of a 1alpha-hydroxyl group to 20,23(OH)(2)D(3) greatly enhanced its ability to stimulate the expression of the CYP24 gene but not to the extent seen with 1,25(OH)(2)D(3). This study shows that purified CYP27B1 can add a 1alpha-hydroxyl group to 20,23(OH)(2)D(3) with the product showing altered biological activity, especially for the stimulation of CYP24 gene expression.

CYP27B1 catalyzes the 1alpha-hydroxylation of 25-hydroxyvitamin D3 to 1alpha,25-dihydroxyvitamin D3, the hormonally active form of vitamin D3. To further characterize mouse CYP27B1, it was expressed in Escherichia coli, purified and its activity measured on substrates incorporated into phospholipid vesicles, which served as a model of the inner mitochondrial membrane. 25-Hydroxyvitamin D3 and 25-hydroxyvitamin D2 in vesicles underwent 1alpha-hydroxylation with similar kinetics, the catalytic rate constants (k(cat)) were 41 and 48mol/min/mol P450, respectively, while K(m) values were 5.9 and 4.6mmol/mol phospholipid, respectively. CYP27B1 showed inhibition when substrate concentrations in the membrane were greater than 4 times K(m), more pronounced with 25-hydroxyvitamin D3 than 25-hydroxyvitamin D2. Higher catalytic efficiency was seen in vesicles prepared from dioleoyl phosphatidylcholine and cardiolipin than for dimyristoyl phosphatidylcholine vesicles. CYP27B1 also catalyzed 1alpha-hydroxylation of vesicle-associated 24R,25-dihydroxyvitamin D3 and 20-hydroxyvitamin D3, and 25-hydroxylation of 1alpha-hydroxyvitamin D3 and 1alpha-hydroxyvitamin D2, but with much lower efficiency than for 25(OH)D3. This study shows that CYP27B1 can hydroxylate 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 associated with phospholipid membranes with the highest activity yet reported for the enzyme. The expressed enzyme has low activity at higher concentrations of 25-hydroxyvitamin D in membranes, revealing that substrate inhibition may contribute to the regulation of the activity of this enzyme., (2010 Elsevier Ltd. All rights reserved.)

Background: In discriminant analysis of microarray data, usually a small number of samples are expressed by a large number of genes. It is not only difficult but also unnecessary to conduct the discriminant analysis with all the genes. Hence, gene selection is usually performed to select important genes., Results: A gene selection method searches for an optimal or near optimal subset of genes with respect to a given evaluation criterion. In this paper, we propose a new evaluation criterion, named the leave-one-out calculation (LOOC, A list of abbreviations appears just above the list of references) measure. A gene selection method, named leave-one-out calculation sequential forward selection (LOOCSFS) algorithm, is then presented by combining the LOOC measure with the sequential forward selection scheme. Further, a novel gene selection algorithm, the gradient-based leave-one-out gene selection (GLGS) algorithm, is also proposed. Both of the gene selection algorithms originate from an efficient and exact calculation of the leave-one-out cross-validation error of the least squares support vector machine (LS-SVM). The proposed approaches are applied to two microarray datasets and compared to other well-known gene selection methods using codes available from the second author., Conclusion: The proposed gene selection approaches can provide gene subsets leading to more accurate classification results, while their computational complexity is comparable to the existing methods. The GLGS algorithm can also better scale to datasets with a very large number of genes.

The main aim of this study was to validate the use of the Caucasian-based knee height equations for predicting stature of Chinese elderly subjects and to compare the predicted height to those estimated by equations derived from elderly subjects of Chinese origin. The study was performed by a survey by measurement of convenience samples. Twenty-one women and 26 men were recruited to validate the use of the Caucasian-based equations. The Chinese-based predictive equations were derived from 164 women and 89 men. The sample included ambulatory elderly subjects of Chinese origin, 60 years of age or older. These subjects were without spinal curvature and able to stand erect. Measurements were taken for height by a standard hospital scale. Calipers was used to measure knee height while the subject was in the sitting position. The measured stature and that predicted by the Caucasian-based equations were significantly different in Chinese elderly women but not in men. New regression models are being developed for the elderly Chinese population in Hong Kong. The relationship between stature, knee height and age appears to be ethnicity- and gender-dependent. While stature of elderly Chinese men can be estimated by either the Caucasian-based or Chinese-based equation, the regression model developed in the present study will better estimate the stature in elderly Chinese women.