Publications by authors named "Han-Shui Hsu"

139 Publications

Use of modified-NUTRIC score to assess nutritional risk in surgical intensive care unit.

J Chin Med Assoc 2021 Jun 8. Epub 2021 Jun 8.

Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC Department of Critical Care Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC Division of Cardiovascular Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC Division of Neurosurgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

Background: Modified Nutrition Risk in the Critically Ill (m-NUTRIC) score is used to evaluate the nutritional risk of patients in intensive care units (ICUs). This study aimed to investigate whether m-NUTRIC can be used as a predictive factor related to the outcome of patients in surgical ICU (SICU), and to identify which patients will benefit from aggressive nutritional intervention according to the results of m-NUTRIC score.

Methods: A total of 205 patients who were admitted to surgical ICU (SICU) with ventilator use for more than 24 hours were enrolled. The m-NUTRIC score data was calculated the day when the patients were admitted to SICU. Patients were divided into two groups according to their m-NUTRIC score: the low risk group (<5 points,116 patients) and the high risk group (≥5 points, 89 patients).

Results: In this study, a total of 205 patients were enrolled for analysis, including patients in the low risk group (n = 116) and those in the high risk group (n = 89). The mean duration of ventilator use was 3.6 ± 6.5 days and average SICU stays for all patients was 5.1 ± 7.4 days. The SICU mortality was significantly higher in the high risk group (10.3% vs 1.7%). Comparison between survivals and non-survivals was carried out and the data showed that the AKI, Vasopressors, SOFA, APACHE II, m-NUTRIC score and shock patient, were all significantly associated with higher mortality. The multivariate analysis revealed that acute kidney injury (OR = 13.16; 95% CI = 3.69-46.92; p <0.0001) and m-NUTRIC score were independent factors of ICU mortality in these patients.. A receiver operating characteristic curve was used to calculate the area under the curve, which was 0.801. The data indicated that high m-NUTRIC score were significantly associated with SICU mortality with the cutoff score >4 (sensitivity = 90.5%, specificity = 62.3%, p < 0.001).

Conclusion: We found in this study that the high m-NUTRIC score is an independent factor of ICU mortality and m-NUTRIC score can be used as an initial screening tool for nutritional assessment in patients admitted to surgical ICU. Further investigations to evaluate whether the aggressive nutritional intervention would be beneficial in the SICU patients with higher m-NUTRIC score is mandatory.
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http://dx.doi.org/10.1097/JCMA.0000000000000565DOI Listing
June 2021

Sequence For Surgical Resection of Primary Lung Tumor For Oligometastatic Non-Small Cell Lung Cancer.

Ann Thorac Surg 2021 May 5. Epub 2021 May 5.

Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Differing surgical series for the treatment of primary lung tumor with synchronous oligometastatic stage IV non-small cell lung cancer (NSCLC) have been published; however, outcomes remain ambiguous.

Methods: Patients with synchronous oligometastatic stage IV NSCLC treated from 2005 to 2017 were enrolled to identify the impact of treatment sequence (primary lung resection versus systemic treatment) on progression-free survival (PFS) and overall survival (OS).

Results: Fifty-one patients received tumor resection (84% adenocarcinoma, 55% non-smokers, and 65% driver gene mutation). Resection occurred before or after systemic treatment in 33 (64.7%) and 18 (35.3%) patients, respectively. Patients who received resection first were older (62.1 vs. 54 year) and at a less advanced intrathoracic stage (18% vs. 44%). No significant differences were noted regarding perioperative complication (30% vs. 28%), length of hospital stay (9.0 vs. 10.5 days), percentage of disease progression (91% vs. 94%), overall death (70% vs. 78%), median PFS (14.0 vs. 22.8 months) and OS (44.6 vs. 53.2 months). Patients with single-organ metastasis had significantly longer PFS and OS than those with oligometastases (17.5 vs. 12.8 months, p=0.040 and 55.6 vs. 39.8 months, p=0.035), respectively. Multivariable Cox analysis identified non-solitary metastasis as the only independent predictor of PFS (hazard ratio 2.27; 95% CI, 1.07-4.81, p=0.033).

Conclusions: Primary lung resection before or after induction systemic therapy may benefit patients with oligometastatic NSCLC. Future randomized clinical trials examining the effect of treatment sequence is recommended.
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.057DOI Listing
May 2021

Prognostic histologic subtyping of dominant tumor in resected synchronous multiple adenocarcinomas of lung.

Sci Rep 2021 May 5;11(1):9539. Epub 2021 May 5.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

The prognostic role of histological patterns of dominant tumor (DT) and second dominant tumor (sDT) in synchronous multiple adenocarcinoma (SMADC) of lung remains unclear. SMADC patients diagnosed between 2003 and 2015 were retrospectively reviewed. DT and sDT were defined as two maximum diameters of consolidation among multiple tumors. Histological pattern was determined using IASLC/ATS/ERS classification system. DTs were divided into low- (lepidic), intermediate- (acinar, papillary) and high-grade (micropapillary, solid) subtypes, and sDTs into non-invasive predominant (lepidic) and invasive predominant (acinar, papillary, micropapillary, solid) subtypes. During mean 74-month follow-up among 149 nodal-negative patients having SMADC resected, recurrence was noted in 44 (29.5%), with significantly higher percentage in high-grade DT (p < 0.001). Five-year overall (OS) and disease-free (DFS) survivals in low-, intermediate- and high-grade DT were 96.9%, 94.3%, 63.3% (p < 0.001) and 100%, 87.2%, 30.0%, respectively (p < 0.001). Cox-regression multivariate analysis demonstrated high-grade DT as a significant predictor for DFS (Hazard ratio [HR] 5.324; 95% CI 2.570-11.462, p < 0.001) and OS (HR 3.287; 95% CI 1.323-8.168, p = 0.010). Analyzing DT and sDT together, we found no significant differences in DFS, either in intermediate- or high-grade DT plus invasive or non-invasive sDT. DT was histologically an independent risk factor of DFS and OS in completely resected nodal-negative SMADCs.
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http://dx.doi.org/10.1038/s41598-021-88193-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100294PMC
May 2021

Lung Cancer in Republic of China.

J Thorac Oncol 2021 04;16(4):519-527

Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Republic of China; School of Medicine, National Yang-Ming University, Taipei, Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.10.155DOI Listing
April 2021

Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19.

Part Fibre Toxicol 2021 03 11;18(1):11. Epub 2021 Mar 11.

Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 112, Taiwan.

Background: Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2.

Results: In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2.

Conclusions: These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.
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http://dx.doi.org/10.1186/s12989-021-00404-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948665PMC
March 2021

Preoperative consolidation-to-tumor ratio is effective in the prediction of lymph node metastasis in patients with pulmonary ground-glass component nodules.

Thorac Cancer 2021 04 25;12(8):1203-1209. Epub 2021 Feb 25.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Preoperative positron emission tomography/computed tomography (PET/CT) is recommended as a guideline for staging of lung cancer. However, for patients with pulmonary ground-glass opacity (GGO) nodules who are supposed to have a relatively low risk of incidence of lymphatic metastasis, it remains uncertain whether PET/CT is more effective than consolidation-to-tumor ratio (CTR) in the prediction of regional lymphatic metastasis.

Methods: The data on patients who underwent surgery for lung cancer from 2011 to 2016 were collected retrospectively, which included CTR, results of PET/CT, and pathological characteristics. The patients who had undergone preoperative PET/CT were identified to find the risk factors for lymphatic metastasis. A receiver operating characteristic (ROC) curve and multiple logistic regression was utilized to clarify the predictive value of CTR and main tumor maximal standardized uptake value (SUVmax).

Results: Among 217 patients who had PET/CT before lobectomy, chest computed tomography revealed that 75 patients had CTR greater than 62%. The patients with lymphatic metastasis were shown to have higher CTR and higher main tumor SUVmax. Multiple logistic regression showed that younger age (<60 years), higher main tumor SUVmax on PET/CT, and greater CTR were independent predictive factors for lymphatic metastasis. The area under the ROC curve was comparable, 0.817 for CTR, and 0.816 for main tumor SUVmax.

Conclusions: The present study revealed that CTR was not inferior to main tumor SUVmax considering the predictive power for lymphatic metastasis preoperatively in lung cancer patients with a GGO component. PET/CT might not be necessary preoperatively in selected patients.
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http://dx.doi.org/10.1111/1759-7714.13899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046132PMC
April 2021

A multinational observational study of clinical nutrition practice in patients undergoing major gastrointestinal surgery: The Nutrition Insights Day.

Clin Nutr ESPEN 2021 Feb 22;41:254-260. Epub 2020 Dec 22.

Surin Hospital, Surin, Thailand.

Background And Aims: Patients undergoing major gastrointestinal (GI) surgery, particularly those with malignancies, have a high risk for malnutrition, requiring perioperative nutritional support to reduce complications. During the Nutrition Insights Day (NID), nutritional data of this patient population were documented in seven Asian countries.

Methods: Observational, cross-sectional study with retrospective data collection of nutritional status, calorie/protein targets/intake, and type of clinical nutrition for up to 5 days before NID.

Inclusion Criteria: Adult patients following major GI surgery, pre-existing/at (high) risk for malnutrition, on enteral (EN) and/or parenteral nutrition (PN) and latest surgery within 10 days before the NID.

Exclusion Criteria: Burns, mechanical ventilation on NID, oral nutrition and/or oral nutritional supplements (ONS) on the day before the NID, and emergency procedures.

Results: 536 patients from 83 hospitals, mean age 58.8 ± 15.1 years, 59.1% males, were eligible. Leading diagnosis were GI diseases (48.7%) and GI cancer (45.9%). Malnutrition risk was moderate to high in 54% of patients, low in 46%. Hospital length of stay (LOS) before the NID was 9.3 ± 19.0 days, and time since last surgery 3.7 ± 2.4 days. Lowest caloric/protein deficits were observed in patients receiving EN + PN, followed by PN alone and EN alone. Type of clinical nutrition, Body Mass Index and LOS on surgical intensive care unit (SICU) and/or surgical ward were independent predictors of caloric and of protein deficit.

Conclusion: There is a high prevalence of postoperative nutritional deficits in Asian GI surgery patients, who are either preoperatively malnourished or at risk of malnutrition, indicating a need to improve nutritional support and education.
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http://dx.doi.org/10.1016/j.clnesp.2020.11.029DOI Listing
February 2021

Positive end-expiratory pressure titration with electrical impedance tomography and pressure-volume curve: a randomized trial in moderate to severe ARDS.

Physiol Meas 2021 02 6;42(1):014002. Epub 2021 Feb 6.

Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan.

Objective: The aim of the study was to compare titration of positive end-expiratory pressure (PEEP) with electrical impedance tomography (EIT) and with ventilator-embedded pressure-volume (PV) loop in moderate to severe acute respiratory distress syndrome (ARDS).

Approach: Eighty-seven moderate to severe ARDS patients (arterial oxygen partial pressure to fractional inspired oxygen ratio, PaO/FiO ≤ 200 mmHg) were randomized to either EIT group (n = 42) or PV group (n = 45). All patients received identical medical care using the same general support guidelines and protective mechanical ventilation. In the EIT group, the selected PEEP equaled the airway pressure at the intercept between cumulated collapse and overdistension percentages curves and in the PV group, at the pressure where maximal hysteresis was reached.

Main Results: Baseline characteristics and settings were comparable between the groups. After optimization, PEEP was significantly higher in the PV group (17.4 ± 1.7 versus 16.2 ± 2.6 cmHO, PV versus EIT groups, p = 0.02). After 48 h, driving pressure was significantly higher in the PV group (12.4 ± 3.6 versus 10.9 ± 2.5 cmHO, p = 0.04). Lung mechanics and oxygenation were better in the EIT group but did not statistically differ between the groups. The survival rate was lower in the PV group (44.4% versus 69.0%, p = 0.02; hazard ratio 2.1, confidence interval 1·1-3.9). None of the other pre-specified exploratory clinical endpoints were significantly different.

Significance: In moderate to severe ARDS, PEEP titration guided with EIT, compared with PV curve, might be associated with improved driving pressure and survival rate.

Trial Registration: NCT03112512, 13 April, 2017.
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http://dx.doi.org/10.1088/1361-6579/abd679DOI Listing
February 2021

Significance of preoperative biopsy in radiological solid-dominant clinical stage I non-small-cell lung cancer.

Interact Cardiovasc Thorac Surg 2021 Apr;32(4):537-545

Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Objectives: The present study aimed to clarify the association between preoperative biopsy and surgical outcomes in clinical stage I non-small-cell lung cancer (NSCLC) with different proportions of ground-glass opacity (GGO).

Methods: Data on patients who underwent pulmonary resection for NSCLC from 2006 to 2016 were drawn from a prospective registered database and analysed retrospectively. Patient characteristics collected included tumour size, location and staging, surgical approach, consolidation-tumour ratio, histopathology and the presence or absence of preoperative biopsy to identify the independent prognostic factors of disease-free survival (DFS) and cancer-specific survival. A 1:1 propensity score matching was conducted between the preoperative biopsy and reference groups based on their baseline characteristics measured before the decision for preoperative biopsy.

Results: A total of 1427 patients were collected to achieve an overall 5-year DFS as 84.5% (median follow-up: 67.3 months), stratified to be 99.5% in the GGO-dominant group (n = 430) and 78.2% in the solid-dominant group (n = 997). Only 2 patients (0.5%) in the GGO-dominant group experienced tumour recurrence. For solid-dominant tumours matched with propensity scores (279 in preoperative biopsy vs 279 in reference group), the independent predictors of DFS included preoperative biopsy, sublobar resection, pathological staging and angiolymphatic invasion. Preoperative biopsy was a predictor of cancer-specific survival in univariable analysis but was not in multivariable analysis. Significant differences were also found between matched groups in those with late-delay surgery, but not in patients receiving preoperative biopsy with early-delay surgery (≤21 days).

Conclusion: Preoperative biopsy may worsen surgical outcomes in patients with clinical stage I, solid-dominant NSCLC.
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http://dx.doi.org/10.1093/icvts/ivaa297DOI Listing
April 2021

Clinicopathological Significance of Pathologic Complete Lymph Node Regression After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2021 Apr 20;28(4):2048-2058. Epub 2020 Nov 20.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Pathologic complete lymph node regression (LNR), where the lymph nodes show evidence of neoadjuvant treatment effect but have no viable residual tumor cells, is sometimes observed following neoadjuvant treatments and has been shown to be prognostic; conflicting results exist in the current literature.

Methods: Patients who received neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for squamous carcinoma (ESCC) were retrospectively reviewed and classified according to their LNR score; 0: N(-) with no evidence of tumor involvement or regression; 1: N(-) with evidence of complete regression; 2: N(+) with < 50% viable tumor; and 3: N(+) with > 50% viable tumor.

Results: In total, 136 patients, comprising 73, 25, 16, and 22 patients with LNR scores of 0, 1, 2, or 3, respectively, were included. Pathologic complete LNR (LNR 1) was significantly associated with lower risks of lymphovascular invasion (0%, p < 0.001) and perineural invasion (4%, p = 0.038), and a higher rate of pathologic complete response in the primary tumor (76%, p < 0.001). The 5-year overall survival rates were 42.1%, 52.8%, and 8.0% in patients with an LNR score of 0, 1, and 2/3, respectively (p < 0.001). There was no significant difference between patients with LNR scores of 0 and 1 in overall survival (p = 0.454), disease-free survival (p = 0.501), and cumulative incidence of recurrences (hazard ratio 0.84, 95% confidence interval 0.432-1.623, p = 0.601).

Conclusions: Pathologic complete LNR could be an indicator of nCRT sensitivity and can be regarded as a good prognostic factor in patients with ESCC. In the survival curve analysis that included patients with lymph node regression (LNR) scores of 0 (blue), 1 (red), and 2/3 (green), we found that patients with pathologic complete LNR (LNR 1), which suggests prior positive nodal involvement, had similar outcomes as those without evidence of prior tumor involvement in lymph node (LNR0).
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http://dx.doi.org/10.1245/s10434-020-09363-zDOI Listing
April 2021

Silent Angiomatoid Fibrous Histiocytoma of the Chest Wall.

Ann Thorac Surg 2021 05 4;111(5):e347-e348. Epub 2020 Nov 4.

Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address:

Angiomatoid fibrous histiocytoma is a peculiar borderline neoplasm with indolent behavior, predominantly arising in the superficial area of extremities. We encountered a unique case of asymptomatic angiomatoid fibrous histiocytoma presenting on the chest wall and being adjacent to the parietal pleura, expanding the spectrum of anatomic sites in which angiomatoid fibrous histiocytoma would occur.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.063DOI Listing
May 2021

Multidisciplinary team discussion results in survival benefit for patients with stage III non-small-cell lung cancer.

PLoS One 2020 8;15(10):e0236503. Epub 2020 Oct 8.

Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China (R.O.C).

Background: The treatment for stage III non-small cell lung cancer (NSCLC) often involves multi-modality treatment. This retrospective study aimed to evaluate whether multidisciplinary team (MDT) discussion results in better patient survival.

Materials And Methods: MDT discussion was optional before February 2016 and was actively encouraged by the MDT committee beginning February 2016. We reviewed the medical charts and computer records of patients with stage III NSCLC between January 2013 and December 2018.

Results: A total of 515 patients were included. The median survival of all the patients was 33.9 months (M). The median survival of patients who were treated after MDT discussion was 41.2 M and that of patients treated without MDT discussion was 25.7 M (p = 0.018). The median survival of patients treated before February 2016 was 25.7 M and that of patients treated after February 2016 was 33.9 M (p = 0.003). The median survival of patients with stage IIIA tumors and those with stage IIIB tumors was 39.4 M and 25.7 M, respectively (p = 0.141). Multivariate analysis showed that MDT or not (p<0.001), T staging (p = 0.009), performance status (p<0.001), and surgery (p = 0.016) to be significant prognostic factors.

Conclusion: The results of the study show that MDT discussion results in survival benefit in patients with stage III NSCLC. The MDT discussion, performance status, and if surgery was performed were independent prognostic factors for patients with stage III NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236503PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544080PMC
November 2020

Active surveillance or early resection for ground-glass nodules that need preoperative localization.

J Surg Oncol 2021 Jan 28;123(1):322-331. Epub 2020 Sep 28.

Department of Surgery, Division of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Introduction: Few studies have investigated the impact of active surveillance on pathological outcome ground-glass nodules (GGNs). We focused on GGNs that needed preoperative localization before resection and compared the pathological results between GGNs that underwent early resection or active surveillance.

Methods: We retrospectively reviewed data of resected GGNs between January 2017 and December 2018. GGNs were classified by early resection (Group A) and active surveillance (Group B). Group B was subclassified as no (Group B1) and with (Group B2) growth, and intergroup comparison of pathological results was undertaken.

Results: In total, 509 GGNs (124, 275, and 110 in Groups A, B1, and B2, respectively) were included. Malignancy (primary lung cancer) ratios were 68% and 72% in Groups A and B (p = .312) and 65% and 92% in Groups B1 and B2, respectively (p < .001). The ratios of invasive carcinoma were 21.4%, 9.6%, and 35.6% in Groups A, B1, and B2, respectively. Predictors for invasive carcinoma included history of lung cancer, GGN size ≥ 10 mm, solid size ≥ 6 mm, and GGN growth.

Conclusions: The pathological findings were similar for GGNs in the early resection and active surveillance groups. However, rates of malignancy and invasive carcinoma increased in the group that manifested growth during active surveillance.
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http://dx.doi.org/10.1002/jso.26241DOI Listing
January 2021

Hospital malnutrition in northeast and southeast Asia: A systematic literature review.

Clin Nutr ESPEN 2020 10 19;39:30-45. Epub 2020 Jul 19.

Hasan Sadikin General Hospital, Jl. Pasteur No.38, Pasteur, Kec. Sukajadi, Kota Bandung, Jawa Barat 40161, Indonesia.

Background & Aims: Hospital malnutrition is a prevalent yet frequently under-recognised condition that is associated with adverse clinical and economic consequences. Systematic reviews from various regions of the world have provided regional estimates of the prevalence of malnutrition and the magnitude of the associated health and economic burden; however, a systematic assessment of the prevalence and consequences of hospital malnutrition in northeast and southeast Asia has not been conducted.

Methods: We performed a systematic literature search for articles on hospital malnutrition in 11 Asian countries published in English between January 1, 1997 and January 15, 2018. Studies reporting data on the prevalence, clinical consequences, or economic impact of hospital malnutrition in an adult inpatient population with a sample size ≥30 were eligible for inclusion.

Results: The literature search identified 3207 citations; of these, 92 studies (N = 62,280) met the criteria for inclusion. There was substantial variability in study populations and assessment methods; however, a majority of studies reported a malnutrition prevalence of >40%. Malnutrition was associated with an increase in clinical complications, mortality, length of hospitalisation, hospital readmissions, and healthcare costs.

Conclusions: Hospital malnutrition is a highly prevalent condition among hospitalised patients in northeast and southeast Asia. Additionally, poor nutritional status is associated with increased morbidity and mortality and increased healthcare costs. Further research aimed at improving the identification and proactive management of hospitalised patients at risk for malnutrition is necessary to improve patient outcomes and alleviate the burden on local healthcare budgets.
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http://dx.doi.org/10.1016/j.clnesp.2020.06.001DOI Listing
October 2020

High-Flow Nasal Cannula versus Noninvasive Positive Pressure Ventilation in Patients with Heart Failure after Extubation: An Observational Cohort Study.

Can Respir J 2020 3;2020:6736475. Epub 2020 Jul 3.

Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan.

Noninvasive positive pressure ventilation (NPPV) has been widely applied in patients with high-risk extubation failure, including heart failure. High-flow nasal cannula (HFNC) has been demonstrated to benefit patients with heart failure by reducing cardiac preload. This study aimed to compare the effectiveness of HFNC to NPPV for preventing extubation failure in patients with heart failure. This 3-year retrospective and single-center cohort study included patients with heart failure with left ventricular ejection fraction <50% who received prophylactic HFNC or NPPV after scheduled extubation from January 2015 to January 2018 from a medical center with four adult intensive care units. Demographics, comorbidities, diagnosis, and weaning status were collected. The primary outcome was treatment failure within 72 hours after extubation, which was defined as escalation to NPPV or reintubation in the HFNC group and was defined as requiring reintubation in the NPPV group. Secondary outcomes were reintubation within 72 hours, reintubation, duration of stay, and mortality during the intensive care unit and hospital stay. Of the 104 patients analyzed, characteristics of 58 patients in the HFNC group and 46 patients in the NPPV group were compared. The treatment failure within 72 hours in the two groups was not significantly different (25.9% vs 13%, =0.106). Hypoxemic respiratory failure related treatment failure was significantly higher in the HFNC group. Prophylactic HFNC as first-line therapy had a comparable rate of reintubation within 72 hours to the prophylactic NPPV alone (17.2% vs 13%, =0.556). Other secondary outcomes were similar between the two groups. Among patients with heart failure, HFNC was not inferior to NPPV for preventing extubation failure and reintubation. However, in case of an impending respiratory failure, selective patients may benefit from rescue NPPV.
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http://dx.doi.org/10.1155/2020/6736475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354657PMC
July 2020

Ground glass opacity on chest CT scans from screening to treatment: A literature review.

J Chin Med Assoc 2020 Oct;83(10):887-890

Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.

Lung cancer is the most common cause of cancer death in the world. However, recent studies have found that patients with pulmonary ground-glass opacity (GGO) have a better prognosis. Considering its low invasiveness, sublobar resection may be an appropriate treatment of choice. Low-dose computed tomography (CT) is recommended for the high-risk groups of lung cancer. Patients with nonsolid nodule are suggested to take annual low dose CT following-up. For part-solid or solid nodules, the solid component size less or more than 8 mm is the watershed of surgical treatment. Increasing tumor size is a hint of malignancy. Biopsy can be performed for clinically highly suspected malignant nodules. The endobronchial ultrasound biopsy, CT-guide biopsy, or surgical excision are the mainstream for the diagnosis of lung nodules. But for treatment, the sublobar resection is the mainstream of pulmonary GGO. A precise localization technique makes surgeons get enough resection margin and preserve more pulmonary function of the patients. The different localization technique is suitable for different kind nodular position. For patients with pure pulmonary GGO, annual low dose CT checkup is suitable. If the tumor size or solid part of the tumors increased gradually, adequate sublobar resection after tumor localization technique may provide good prognosis and preserve more pulmonary function of the patients.
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http://dx.doi.org/10.1097/JCMA.0000000000000394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434019PMC
October 2020

Lymphadenectomy is Unnecessary for Pure Ground-Glass Opacity Pulmonary Nodules.

J Clin Med 2020 Mar 2;9(3). Epub 2020 Mar 2.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 100116, Taiwan.

Background: Lobectomy plus lymph node dissection is the standard treatment of early-stage lung cancer, but the low lymph node metastasis rate with ground-glass opacity (GGO) makes surgeons not perform lymphadenectomy. This study aimed to re-evaluate the lymph node metastasis rate of GGO to help make a clinical judgment.

Methods: We performed this retrospective study to enroll patients who received lung cancer surgery from 2011 to 2016. Patient characteristics collected included tumor size, solid part size and lymph node metastasis rate. These patients were categorized into pure GGO and part solid GGO groups to undergo analysis.

Results: Lymph node metastasis rates were 0%, 3.8% and 6.9% in order of the pure GGO group, the GGO predominant group and the solid predominant group. In the lobectomy patients, the solid predominant group still showed to have the highest lymph node metastasis rate and recurrence rate (8.3% and 10.1%).

Conclusion: It is unnecessary to perform lymphadenectomy for patients with pure GGO in view of the 0% lymph node metastasis rate. The higher lymph node metastasis rate in the patients with the solid predominant group, 6.9%, suggested that surgeons should choose a rational lymphadenectomy method according to their GGO property and clinical judgment.
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http://dx.doi.org/10.3390/jcm9030672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141214PMC
March 2020

Electromagnetic navigation-guided versus computed tomography-guided percutaneous localization of small lung nodules before uniportal video-assisted thoracoscopic surgery: a propensity score-matched analysis.

Eur J Cardiothorac Surg 2020 08;58(Suppl_1):i85-i91

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Objectives: An optimal method for preoperative localization of small lung nodules is yet to be established, and there are few comparative studies in the literature. In the present study, we aimed to compare electromagnetic navigation-guided and computed tomography (CT)-guided methods of percutaneous transthoracic localization.

Methods: The clinical, radiographic, surgical and pathological data of patients who underwent electromagnetic navigation-guided localization (EMNGL) and CT-guided localization (CTGL) before uniportal video-assisted thoracic surgery (VATS) were reviewed. Propensity score matching analysis was performed to compare the localization and surgical results.

Results: After matching, 25 EMNGL and 50 CTGL patients were included in the analysis. In the CTGL group, pulmonary haemorrhage and pneumothorax were noted in 56% and 34% of patients, respectively, on postprocedural CT scans. Successful localization was achieved in 96% and 100% of patients in the EMNGL and CTGL groups, respectively (P = 0.333). The median time in the operation room was significantly shorter in the CTGL group {142.5 [interquartile range (IQR) 123.8-175.0] vs 205.0 [IQR 177.5-290.0] min, P < 0.001}. In contrast, EMNGL significantly decreased the total time [205.0 (IQR 177.5-290.0) vs 324.0 (IQR 228.3-374.0) min, P = 0.002]. The median duration of chest drainage was 1 day shorter in the EMNGL group [2.0 (IQR 1.5-2.5) vs 3.0 (IQR 2.0-3.0), P = 0.002]; the surgical complication rates were comparable between the 2 groups.

Conclusions: The localization and surgical results were similar between the EMNGL and CTGL groups. EMNGL is comparable to conventional CTGL with respect to preoperative localization of small lung nodules before uniportal VATS.
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http://dx.doi.org/10.1093/ejcts/ezz338DOI Listing
August 2020

The Prognostic Impact of Extracapsular Lymph Node Involvement in Esophageal Squamous Cell Carcinoma.

Ann Surg Oncol 2020 Aug 20;27(8):3071-3082. Epub 2020 Feb 20.

Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: The role of extracapsular lymph node involvement (ELNI) in esophageal cancer has not been fully investigated. We aim to assess its incidence and prognostic significance in patients with esophageal squamous cell carcinoma (ESCC) treated with and without neoadjuvant treatments.

Methods: Data of patients who underwent esophagectomy for ESCC in a single medical center was retrospectively reviewed. Patients with positive lymph node involvement were classified as either with ELNI or without ELNI (intracapsular lymph node involvement, ILNI). The impact of ELNI on overall survival (OS), disease-free survival (DFS), and disease recurrence was analyzed.

Results: A total of 336 patients, including 179 without (NCRT -) and 157 with (NCRT +) neoadjuvant chemoradiotherapy, were included. Seventy-two of 179 (40.2%) patients in NCRT - group were with positive lymph node, of whom 19 (26.4%) had ELNI, whereas 49 (31.2%) patients in NCRT + group had positive lymph node, of whom 25 (51.0%) had ELNI. In NCRT + group, patients with ELNI had worse outcome compared to those with ILNI in 5-year OS (10.4 vs. 13.8%, p = 0.008), and DFS (5.3 vs. 17.5%, p = 0.008). The presence of ELNI was also associated with more distant recurrence (p = 0.03). In contrast, there was no survival difference between patients with ELNI and ILNI in NCRT - group.

Conclusions: Compared with ILNI, ELNI is a significant poor prognostic factor in patients with ESCC treated with neoadjuvant treatments, but not in those with primary surgery.
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http://dx.doi.org/10.1245/s10434-020-08260-9DOI Listing
August 2020

Surgeons' preference sublobar resection for stage I NSCLC less than 3 cm.

Thorac Cancer 2020 04 9;11(4):907-917. Epub 2020 Feb 9.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: This study aimed to compare survival between standard lobectomy and surgeons' preference sublobar resection among patients with stage I non-small cell lung cancer (NSCLC).

Methods: Medical records of patients undergoing pulmonary resection between 2006 and 2016 were reviewed retrospectively. Differences in disease-free survival (DFS) and DFS-associated factors between patients receiving lobectomy and surgeons' preference sublobar resection were analyzed after 1-1 propensity score-matching (n = 119 per group).

Results: In total, 1064 pathological stage I NSCLC patients were identified, including 816 (76.7%) who underwent lobectomy, 111 (10.4%) who underwent sublobar resection as a compromised procedure (medically unfit), and 137 (12.9%) who underwent surgeons' preference sublobar resection. Rates of five-year DFS for patients undergoing lobectomy, medically unfit, and surgeons' preference sublobar resection were 88.7%, 71.0%, and 93.4%, respectively (P < 0.001). Multivariable Cox regression analysis demonstrated that radiological solid-appearance (adjusted hazard [aHR] = 2.908, P = 0.003), PL2 invasion (aHR = 1.970, P = 0.024), and angiolymphatic invasion (aHR = 2.202, P = 0.005) were significantly associated with lower DFS after adjusting for surgeons' preference sublobar resection (aH = 1.031, P = 0.939). Subgroup analysis of all 403 solid-dominant patients demonstrated equivalent five-year DFS between surgeons' preference sublobar resection and lobectomy (87.7% and 84.1%, respectively, P = 0.721). Propensity-matched analysis showed no differences in five-year DFS in stage I NSCLC patients undergoing lobectomy or surgeons' preference sublobar resection (90.5% vs. 93.4% P = 0.510), and DFS for surgeons' preference sublobar resection remained an insignificant factor (aHR = 0.894, P = 0.834).

Conclusions: Carefully selected patients who have undergone surgeons' preference sublobar resection have comparable outcomes to those receiving lobectomy for stage I NSCLC <3 cm.

Key Points: Significant findings of the study Intended sublobar resection has a good outcome. What this study adds Sublobar resection is applicable for stage I NSCLC <3 cm.
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http://dx.doi.org/10.1111/1759-7714.13336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113050PMC
April 2020

Involvement of collagen XVII in pluripotency gene expression and metabolic reprogramming of lung cancer stem cells.

J Biomed Sci 2020 Jan 13;27(1). Epub 2020 Jan 13.

Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.

Background: Recent advancements in cancer biology field suggest that glucose metabolism is a potential target for cancer treatment. However, little if anything is known about the metabolic profile of cancer stem cells (CSCs) and the related underlying mechanisms.

Methods: The metabolic phenotype in lung CSC was first investigated. The role of collagen XVII, a putative stem cell or CSC candidate marker, in regulating metabolic reprogramming in lung CSC was subsequently studied. Through screening the genes involved in glycolysis, we identified the downstream targets of collagen XVII that were involved in metabolic reprogramming of lung CSCs. Collagen XVII and its downstream targets were then used to predict the prognosis of lung cancer patients.

Results: We showed that an aberrant upregulation of glycolysis and oxidative phosphorylation in lung CSCs is associated with the maintenance of CSC-like features, since blocking glycolysis and oxidative phosphorylation reduces sphere formation, chemoresistance, and tumorigenicity. We also showed that the Oct4-hexokinase 2 (HK2) pathway activated by collagen XVII-laminin-332 through FAK-PI3K/AKT-GSB3β/β-catenin activation induced the upregulation of glycolysis and maintenance of CSC-like features. Finally, we showed that collagen XVII, Oct4, and HK2 could be valuable markers to predict the prognosis of lung cancer patients.

Conculsions: These data suggest the Oct4-HK2 pathway regulated by collagen XVII plays an important role in metabolic reprogramming and maintenance of CSC-like features in lung CSCs, which may aid in the development of new strategies in cancer treatment.
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http://dx.doi.org/10.1186/s12929-019-0593-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956558PMC
January 2020

Particulate Matter Increases the Severity of Bleomycin-Induced Pulmonary Fibrosis through KC-Mediated Neutrophil Chemotaxis.

Int J Mol Sci 2019 Dec 28;21(1). Epub 2019 Dec 28.

Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.

Background: Although particular matter (PM) increases incidence and severity of idiopathic pulmonary fibrosis, the underlying mechanism remains elusive.

Methods: The effects of PM were evaluated in a murine model of bleomycin-induced pulmonary fibrosis. Mice were divided into four groups, receiving: (1) Saline (control), (2) bleomycin, (3) PM, or (4) bleomycin plus PM (Bleo+PM). Additional groups of Bleo+PM mice were treated with sivelestat (an inhibitor of neutrophil elastase) or reparixin (a C-X-C motif chemokine receptor 2 antagonist), or were genetically modified with keratinocyte chemoattractant (KC) deletion.

Results: Pulmonary fibrosis was not observed in the control or PM groups. Bleomycin induced pulmonary fibrosis within 14 days. The Bleo+PM group showed worse pulmonary fibrosis when compared to the bleomycin group. Analyses of immune cell profile and chemokine/cytokine concentrations at day 2-bronchoalveolar lavage fluid (BALF) revealed that the Bleo+PM group had increased neutrophil number and elastase level and KC concentration compared to the bleomycin group. Neutrophil elastase activated the Smad2/Smad3/α-SMA pathway to induce collagen deposition, while sivelestat abrogated the increased severity of pulmonary fibrosis caused by PM. Chemotaxis assay revealed that BALF of the Bleo+PM group recruited neutrophil, which was dependent on KC. Further, genetic KC deletion or pharmaceutical inhibition of KC binding to CXCR2 with reparixin ameliorated the PM-induced increased severity of pulmonary fibrosis.

Conclusions: These data provide evidence that the PM-induced increased severity of pulmonary fibrosis depends on KC-mediated neutrophil chemotaxis and give additional mechanic insight that will aid in the development of therapeutic strategies.
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http://dx.doi.org/10.3390/ijms21010227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981983PMC
December 2019

Complications after Chest Tube Removal and Reinterventions in Patients with Digital Drainage Systems.

J Clin Med 2019 Dec 1;8(12). Epub 2019 Dec 1.

Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University, Taipei 100116, Taiwan.

Introduction: Digital thoracic drainage systems are a new technology in minimally invasive thoracic surgery. However, the criteria for chest tube removal in digital thoracic drainage systems have never been evaluated. We aim to investigate the incidence and predictive factors of complications and reinterventions after drainage tube removal in patients with a digital drainage system.

Method: Patients who received lung resection surgery and had their chest drainage tubes connected with a digital drainage system were retrospectively reviewed.

Results: A total of 497 patients were monitored with digital drainage systems after lung resection surgery. A total of 175 (35.2%) patients had air leak-related complications after drainage tube removals, whereas 25 patients (5.0%) required reintervention. We identified that chest drainage duration of five days was an optimal cut-off value in predicting air leak-related complications and reinterventions. In multiple logistic regression analysis, previous chest surgery history; small size (16 Fr.) drainage tubes; the presence of initial air leaks, defined as air leaks recorded by the digital drainage system immediately after operation; and duration of chest drainage ≥5 days were independent factors of air leak-related complications, whereas the presence of initial air leaks and duration of chest drainage ≥5 days were independent predictive factors of reintervention after drainage tube removal.

Conclusion: Air leak-related complications and reinterventions after drainage tube removals happened in 35.2% and 5.0% of patients with digital thoracic drainage systems. The management of chest drainage tubes in patients with predictive factors, i.e., the presence of initial air leaks and duration of chest drainage of more than five days, should be treated with caution.
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http://dx.doi.org/10.3390/jcm8122092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947439PMC
December 2019

Impact of Intermittent Hypoxia on Sepsis Outcomes in a Murine Model.

Sci Rep 2019 09 9;9(1):12900. Epub 2019 Sep 9.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.

Sleep apnea has been associated with a variety of diseases, but its impact on sepsis outcome remains unclear. This study investigated the effect of intermittent hypoxia [IH]-the principal feature of sleep apnea-on murine sepsis. 5-week-old male C57BL6 mice were assigned to groups receiving severe IH (O2 fluctuating from room air to an O2 nadir of 5.7% with a cycle length of 90 seconds), mild IH (room air to 12%, 4 minutes/cycle), or room air for 3 weeks. Sepsis was induced by cecal ligation and puncture and survival was monitored. Sepsis severity was evaluated by murine sepsis scores, blood bacterial load, plasma tumor necrosis factor-α [TNF-α]/interleukin-6 [IL-6] levels and histopathology of vital organs. Compared with normoxic controls, mice subjected to severe IH had earlier mortality, a lower leukocyte count, higher blood bacterial load, higher plasma TNF-α and IL-6 levels, more severe inflammatory changes in the lung, spleen and small intestine. Mice subjected to mild IH did not differ from normoxic controls, except a higher IL-6 level after sepsis induced. The adverse impact of severe IH was reversed following a 10-day normoxic recovery. In conclusion, severe IH, not mild IH, contributed to poorer outcomes in a murine sepsis model.
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http://dx.doi.org/10.1038/s41598-019-49381-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733849PMC
September 2019

Lymphovascular Invasion as the Major Prognostic Factor in Node-Negative Esophageal Cancer After Primary Esophagectomy.

J Gastrointest Surg 2020 07 3;24(7):1459-1468. Epub 2019 Jul 3.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Studies addressing both lymphovascular invasion (LVI) and perineural invasion (PNI) in patients with esophageal squamous cell carcinoma (ESCC) treated with or without neoadjuvant therapy are limited. We aimed to analyze the incidence and prognostic significance of LVI and PNI in patients with thoracic ESCC.

Methods: This retrospective study included 520 patients with ESCC: 174 patients after neoadjuvant treatment followed by surgery and 346 after primary esophagectomy, from two medical centers. The relationships between LVI, PNI, and other histological factors were evaluated. The Cox regression model was used for survival analysis.

Results: Positive LVI and PNI were noted in 35.6% and 22.4% of patients with residual primary tumor after neoadjuvant treatment and in 39.6% and 24.0% of patients who underwent primary esophagectomy, respectively. In patients with neoadjuvant treatments, the 5-year overall survival rates were 12.7% and 28.3% in patients with positive LVI and negative LVI, respectively (p = 0.001). The 5-year overall survival rates were 6.4% and 29.9% in patients with positive PNI and negative PNI, respectively (p < 0.001). In patients who did not receive neoadjuvant treatment, the 5-year overall survival rates were 28.2% and 61.1% in patients with positive LVI and negative LVI, respectively (p < 0.001). The 5-year overall survival rates were 30.2% and 52.5% in patients with positive PNI and negative PNI (p < 0.001). In subgroup analysis, the presence of PNI was an independent prognostic factor in patients with neoadjuvant treatments, whereas the presence of LVI had more significant prognostic impact in patients with node-negative ESCC after primary esophagectomy.

Conclusions: Both LVI and PNI statuses are significant prognostic factors for patients with ESCC. However, the prognostic impact of LVI was majorly in the subgroup of node-negative patients who received primary esophagectomy.
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http://dx.doi.org/10.1007/s11605-019-04310-0DOI Listing
July 2020

High metabolic rate and stem cell characteristics of esophageal cancer stem-like cells depend on the Hsp27-AKT-HK2 pathway.

Int J Cancer 2019 10 10;145(8):2144-2156. Epub 2019 Apr 10.

Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Tumor progression with chemoresistance and local recurrence is commonly happened during treatment of esophageal squamous cell carcinoma (ESCC). Cancer stem cells (CSC) may respond for tumor progression. However, there are few reports regarding metabolism of esophageal CSCs with clinical correlation. In this work, we demonstrated that ESCC cell lines in spheroid culture display CSC phenotypes, including increased ALDH activity, chemoresistance and tumor initiation, which are dependent on Hsp27 activation. Esophageal CSCs also exhibit reprogrammed metabolic features particularly higher glycolysis and oxidative phosphorylation, which are regulated via the Hsp27-AKT-HK2 pathway. Moreover, HK2 is required for maintenance of CSC phenotypes. Inhibition of CSC metabolism reduces cell growth and tumor formation. Clinically, patients who underwent surgical resection for esophageal cancer, and displayed overexpression of both Hsp27 and HK2, had the worst prognosis of all expression types. In conclusion, stem cells features and aberrant metabolic reprogramming of esophageal CSCs depend on the Hsp27-AKT-HK2 pathway. Targeting Hsp27 and HK2 could be novel therapeutic strategy for treating esophageal cancer and warrants further investigation.
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http://dx.doi.org/10.1002/ijc.32301DOI Listing
October 2019

Impact of perineural invasion as a histopathological prognostic factor in ypStage II/III oesophageal squamous cell carcinoma†.

Eur J Cardiothorac Surg 2019 May;55(5):927-933

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Objectives: The 8th edition American Joint Committee on Cancer Tumour-Nodes-Metastasis (TNM) staging system distinguishes between the clinical (c), pathological (p) and post-neoadjuvant pathological (yp) stage groups. However, the ability to discriminate between ypStage II and ypStage III is poor. We aim to identify prognostic factors in patients with ypStage II/III oesophageal squamous cell carcinoma.

Methods: The data of 150 patients with ypStage II/III oesophageal squamous cell carcinoma from 2 medical centres were retrospectively reviewed. The neoadjuvant treatments included chemotherapy with cisplatin and 5-fluorouracil, administered concurrently with external beam radiation. The determination of perineural invasion (PNI) was based on pathological reports. Survival curves were compared using the log-rank test, and multivariable survival analysis was performed with a Cox regression model.

Results: The 3-year/5-year overall survival rate/median survival in ypStages II, IIIa and IIIb were 35.3%/26.9%/21.9 [95% confidence interval (CI) 14.9-28.8] months, 33.8%/22.5%/22.4 (95% CI 20.1-24.7) months and 21.7%/14.0%/14.4 (95% CI 11.1-17.7) months, respectively (P = 0.07). The 3-year/5-year overall survival rate/median survival was 36.7%/26.4%/22.8 (95% CI 19.2-26.5) months in the absence of PNI and 6.9%/3.4%/9.1 (95% CI 8.9-9.4) months in the presence of PNI (P < 0.001). In the multivariable survival analysis, tumour location in the upper third of the thoracic oesophagus [hazard ratio (HR) 1.692, 95% CI 1.087-2.635; P = 0.020] and positive PNI (HR 3.316, 95% CI 2.005-4.905; P < 0.001) remained as independent prognostic factors.

Conclusions: The existence of PNI after neoadjuvant treatment is closely associated with poor prognosis and could be incorporated into the TNM staging system for better discrimination between patients with ypStage II/III oesophageal squamous cell carcinoma.
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http://dx.doi.org/10.1093/ejcts/ezy380DOI Listing
May 2019

Clinical relevance of PD-L1 and PD-L2 overexpression in patients with esophageal squamous cell carcinoma.

J Thorac Dis 2018 Jul;10(7):4433-4444

Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei.

Background: Even with the advance of diagnosis and the treatment, the 5-year survival rate for esophageal cancer patients is still poor. The checkpoint protein inhibition provides another choice to improve the survival. The expression of the programmed death ligand-1 (PD-L1) was reported but the clinical relevance remained inconsistent in esophageal cancer. Besides, there were few references about the other ligand, programed death ligand-2 (PD-L2). In this study, we evaluated the expressions of PD-L1 and PD-L2 in patients with esophageal squamous cell carcinoma (ESCC) and assessed their clinical relevance.

Methods: From 1996 to 2011, 150 patients undergone complete surgical resection for ESCC were enrolled. Clinical data were recorded. Expression of PD-L1 and PD-L2 on cytoplasm in paraffin embedded tumor samples were analyzed by immunohistochemistry staining and scored with a semi-quantitative method.

Results: Of the patients, 96 (64.0%) patients had PD-L1 overexpression and 63 (42.0%) had PD-L2 overexpression. There was a correlation between the expression of PD-L1 and PD-L2 (P<0.001). Patients without overexpression of PD-L1, pathological T1-2 and N0 status, pathological stage I-II and no post-operative adjuvant treatment had a better disease free survival (DFS). In multivariate analysis, PD-L1 expression and pathological stage were the independent prognostic factors for DFS. The expression of PD-L2 did not influence the DFS. Although not statistically significant, patients without overexpression of PD-L1 and PD-L2 seem to have a better overall survival (OS).

Conclusions: The overexpression of PD-L1 on cytoplasm, not PD-L2, is an independent prognostic factor for DFS in patients with ESCC undergone esophagectomy. However, there is a trend which suggested that patients without overexpression of PD-L1 and PD-L2 had a better OS.
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http://dx.doi.org/10.21037/jtd.2018.06.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106043PMC
July 2018

Adipose-derived stem cell conditioned medium attenuates cisplatin-triggered apoptosis in tongue squamous cell carcinoma.

Oncol Rep 2018 Feb 1;39(2):651-658. Epub 2017 Dec 1.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veteran General Hospital, Taipei, Taiwan, R.O.C.

Autologous fat grafting procedures have noted a markedly increased frequency, not only for cosmetic purposes, but also for deformities after head and neck cancer and breast cancer surgery. Carcinogenesis is always a major concern in cell therapy-related issues. However, there is no literature discussing this issue in head and neck squamous cell carcinoma patients. To evaluate the interaction of tongue cancer cells and adipose-derived stem cells, we performed a series of in vitro experiments. Our results demonstrated that cisplatin significantly reduced the viabilities of SCC‑25 and CAL‑27 cells in a concentration-dependent manner, but it had low cytotoxicity in cisplatin-resistant CAL‑27 (CAR) cells. There was no significant difference in terms of viability among the SCC‑25, CAL‑27, and CAR cells in the adipose-derived stem cell conditioned medium and control groups. There was also no significant difference in terms of cell migration as determined by wound healing assay of SCC‑25, CAL‑27, and CAR cells between the adipose-derived stem cell conditioned medium treatment and control treatment. Importantly, the adipose-derived stem cell conditioned medium attenuated cisplatin-triggered cell death in the SCC‑25 and CAL‑27 cells. Moreover, adipose-derived stem cell conditioned medium markedly inhibited cisplatin-induced apoptotic cell death (sub‑G1 phase) in the CAL‑27 cells. Western blot analyses indicated that cisplatin-induced reductions in pro‑caspase‑3, pro‑caspase‑9, phospho-BAD, phospho-IGF-1R, phospho-AKT, and phospho-ERK in CAL‑27 cells were reversed by adipose-derived stem cell conditioned medium supplement. Taken together, we provide evidence that adipose-derived stem cell conditioned medium protects CAL‑27 cells from cisplatin-induced cell death, possibly through upregulation of the IGF-1R/AKT/ERK signaling pathway.
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http://dx.doi.org/10.3892/or.2017.6126DOI Listing
February 2018

Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis.

Sci Rep 2017 10 27;7(1):14272. Epub 2017 Oct 27.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Pulmonary fibrosis is characterized by fibroblast proliferation and extracellular matrix remodelling, leading to respiratory insufficiency. The mechanisms underlying this progressive and devastating disease remain unclear. Conditions that can impair the function of the endoplasmic reticulum (ER) cause accumulation of unfolded or misfolded proteins, resulting in ER stress and activation of the unfolded protein response (UPR). ER stress has been implicated in many conditions including cancer, diabetes, obesity, and inflammation. It is also involved in lung fibrosis, through myofibroblastic differentiation of fibroblasts; however, the precise role of ER stress in lung fibrosis is unknown. The current study aimed to investigate the underlying mechanisms of ER stress inhibitors in the treatment of bleomycin-induced lung fibrosis. We demonstrated that bleomycin can activate ER stress associated proteins, including GRP78, CHOP, and ATF-4, both in vitro and in vivo. PI3K/AKT acts upstream of ER stress to affect lung fibroblast proliferation, resulting in bleomycin-induced pulmonary fibrosis. Treatment with ER stress inhibitors or a PI3K inhibitor caused a reduction in fibroblast proliferation and improved pulmonary function. The relationship between PI3K/AKT/mTOR and ER stress in pulmonary fibrosis, and the application of PI3K inhibitors and ER stress inhibitors in the treatment of pulmonary fibrosis require further investigation.
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http://dx.doi.org/10.1038/s41598-017-14612-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660192PMC
October 2017