Shang-Jyh Kao

Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for lung cancer: A marker phase I trial

Tumor cells continuously evolve over time in response to host pressures. However, explanations as to how tumor cells are influenced by the inflammatory tumor microenvironment over time are, to date, poorly defined. We hypothesized that prognostic biomarkers could be obtained by exploring the expression of inflammation‐associated genes between early and late stage lung cancer tumor samples.

Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy.

While combined chemotherapy (CT) with an autophagy inducer and an autophagy inhibitor appears paradoxical, it may provide a more effective perturbation of autophagy pathways. We used two dissimilar cell lines to test the hypothesis that autophagy is the common denominator of cell fate after CT. HA22T cells are characterized by CT-induced apoptosis and use autophagy to prevent cell death, while Huh7.5.1 cells exhibit sustained autophagic morphology after CT. Combined CT and rapamycin treatment resulted in a better combination index (CI) in Huh7.5.1 cells than combined CT and chloroquine, while the reverse was true in HA22T cells. The combination of 3 drugs (triplet drug treatment) had the best CI. After triplet drug treatment, HA22T cells switched from protective autophagy to mitochondrial membrane permeabilization and endoplasmic reticulum stress response-induced apoptosis, while Huh7.5.1 cells intensified autophagic lethality. Most importantly, both cell lines showed activation of Akt after CT, while the triplet combination blocked Akt activation through inhibition of phospholipid lipase D activity. This novel finding warrants further investigation as a broad chemosensitization strategy.

Hypofractionated radiotherapy for primary or secondary oligometastatic lung cancer using Tomotherapy

BackgroundTo retrospectively review the outcome of patients with primary or secondary oligometastatic lung cancer, treated with hypofractionated Tomotherapy.MethodsBetween April 2007 and June 2011, a total of 33 patients with oligometastatic intrapulmonary lesions underwent hypofractionated radiotherapy by Tomotherapy along with appropriate systemic therapy. There were 24 primary, and 9 secondary lung cancer cases. The radiation doses ranged from 4.5 to 7.0 Gy per fraction, multiplied by 8–16 fractions. The median dose per fraction was 4.5 Gy (range, 4.5-7.0 Gy), and the median total dose was 49.5 Gy (range, 45–72 Gy). The median estimated biological effective dose at 10 Gy (BED10) was 71.8 Gy (range, 65.3–119.0 Gy), and that at 3 Gy (BED3) was 123.8 Gy (range, 112.5–233.3 Gy). The mean lung dose (MLD) was constrained mainly under 1200 cGy. The median gross tumor volume (GTV) was 27.9 cm3 (range: 2.5–178.1 cm3).ResultsThe median follow-up period was 25.8 months (range, 3.0–60.7 months). The median overall survival (OS) time was 32.1 months for the 24 primary lung cancer patients, and >40 months for the 9 metastatic lung patients. The median survival time of the patients with extra-pulmonary disease (EPD) was 11.2 months versus >50 months (not reached) in the patients without EPD (p < 0.001). Those patients with smaller GTV (≦27.9 cm3) had a better survival than those with larger GTV (>27.9 cm3): >40 months versus 12.85 months (p = 0.047). The patients with ≦2 lesions had a median survival >40 months, whereas those with ≧3 lesions had 26 months (p = 0.065). The 2-year local control (LC) rate was 94.7%. Only 2 patients (6.1%) developed ≧grade 3 radiation pneumonitis.ConclusionUsing Tomotherapy in hypofractionation may be effective for selected primary or secondary lung oligometastatic diseases, without causing significant toxicities. Pulmonary oligometastasis patients without EPD had better survival outcomes than those with EPD. Moreover, GTV is more significant than lesion number in predicting survival.

Improving Radioresponse Through Modification of the Tumor Immunological Microenvironment

Radioresponse is influenced by factors apart from the targeted cancer cells; in fact, endothelial cells and infiltrating immune cells within the tumor microenvironment (TME) are the two main components affecting the outcome of radiotherapy. The benefits of fractionated radiotherapy are attenuated through the upregulation of hypoxia inducible factor-1 α and vascular endothelial growth factor. The therapeutic effect of antiangiogenic agents is counteracted by the mobilization of endogenous proangiogenic cells to the TME. This study highlights the importance of radiation timing within a vascular normalization window and discusses the importance of immune cells that comprise the microenvironment. A balance between favorable tumor-infiltrating immune cells, including cytotoxic T cells, natural killer cells, and dendritic cells, and the unfavorable cells, such as tumor-associated macrophages and regulatory T cells, determines the final tumor-control probability. The reciprocal complementation between combinations of radiotherapy and immunotherapy strategies through modulation of the tumor immunological microenvironment may yield promising results in the future.

Improving Detection Accuracy of Lung Cancer Serum Proteomic Profiling via Two-Stage Training Process

BackgroundSurface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) is a frequently used technique for cancer biomarker research. The specificity of biomarkers detected by SELDI can be influenced by concomitant inflammation. This study aimed to increase detection accuracy using a two-stage analysis process.MethodsSera from 118 lung cancer patients, 72 healthy individuals, and 31 patients with inflammatory disease were randomly divided into training and testing groups by 3:2 ratio. In the training group, the traditional method of using SELDI profile analysis to directly distinguish lung cancer patients from sera was used. The two-stage analysis of distinguishing the healthy people and non-healthy patients (1st-stage) and then differentiating cancer patients from inflammatory disease patients (2nd-stage) to minimize the influence of inflammation was validated in the test group.ResultsIn the test group, the one-stage method had 87.2% sensitivity, 37.5% specificity, and 64.4% accuracy. The two-stage method had lower sensitivity (> 70.1%) but statistically higher specificity (80%) and accuracy (74.7%). The predominantly expressed protein peak at 11480 Da was the primary splitter regardless of one- or two-stage analysis. This peak was suspected to be SAA (Serum Amyloid A) due to the similar m/z countered around this area. This hypothesis was further tested using an SAA ELISA assay.ConclusionsInflammatory disease can severely interfere with the detection accuracy of SELDI profiles for lung cancer. Using a two-stage training process will improve the specificity and accuracy of detecting lung cancer.

Pulmonary Cryptococcosis Mimicking Pulmonary Tuberculosis-A Case Report

Pulmonary tuberculosis, cryptococcosis and Pneumocystis jirovecii pneumonia (in AIDS patients) are the principal causal agents of chronic lung infections in Taiwan. Differentiation between pulmonary tuberculosis and pulmonary cryptococcosis may be difficult if a sputum specimen either not available or tests negative for acid-fast staining. Traditionally, if clinical and radiographic improvements are achieved after an anti-tuberculosis ”therapeutic trial”, the diagnosis of sputum smear-negative pulmonary tuberculosis is strengthened. However, pulmonary cryptococcosis might also resolve spontaneously without anti-fungal therapy, and this improvement might occur during the trial period. Hence, response to an anti-tuberculosis therapeutic trial does not always confirm the diagnosis of pulmonary tuberculosis. We present a case of pulmonary cryptococcosis which was misdiagnosed as sputum smear-negative pulmonary tuberculosis. Pulmonary cryptococcosis must be excluded before the diagnosis of smear-negative pulmonary tuberculosis is made to prevent future confusion. We advocate checking the serum cryptococcal antigen before starting anti-tuberculosis treatment in smear-negative pulmonary tuberculosis, to minimize the possibility of misdiagnosis.

Diffuse Panbronchiolitis Associated with Adult T-cell Leukemia-A Case Report

Diffuse panbronchiolitis (DPB) is a disease characterized by chronic inflammation exclusively located in the respiratory bronchioles. It has been previously reported to occur exclusively in East Asians, primarily in Japanese, Korean, and Chinese populations. The definite causative agent remains unclear; neither environmental factors nor infectious agents have been demonstrated. A significantly high frequency of anti-HTLV-Ⅰ antibody in patients with DPB, higher than in those with other diseases and healthy controls, has been reported. Adult T-cell leukemia/lymphoma (ATL) is a category of lymphoid malignancy characterized histologically by malignant lymphocytes with flower-shaped nuclei, and HTLV-1 has been recognized as a causative agent of ATL. We present a case of DPB complicated by ATL and review the relationship between them.

The Use of Chest Sonography in Diagnosing Pneumothorax in Mechanically Ventilated Patients

Backergound: To evaluate the role of chest sonography in the diagnosis of pneumothorax in mechanically ventilated patients. Methods: The 21 mechanically ventilated patients enrolled in this study presented with a sudden onset of shortness of breath ,an abrupt incrase of peak airway pressure,and arterial desaturation combined with unilateral or bilateral decrease in breath suouds,or had suspicions of pneumothorax based on chest radiographs. Chest sonographic studies were performed in call of these patients. We defined the disappearance of both the “gliding sign ” abd the “comet-tail” artifact as positive ultrasonic findings of pneumothorax. The gold standard we used was one of the following : a gush of air noted after placement of a large-bore needle into the pleural space, continuous air leakage from the chest tube,or obvious pneumothorax on the anteroposterior or lateral decubitus view of the chest radiograph. Results: In the study population, sonographic studies were positive in 10if tge 21 cases. Five of the 10 had hypotension, and emergent large-bore needles were inserted. Eleven of the 21cases showed no sonographic evidence of pneumothorax ,and subsequent chest radiographs also confirmed that. No false positives or false negatives were found. Conclusion: Chest sonography is both highly sensitive and specific for the diagnosis of pneumothorax in mechanically ventilated patients. Therefore, we recommend the use of sonography as an alternative diagnostic tool in mechanically ventilated patients who are suspected of having developed pneumothorax but who can not be definitely diagnosed otherwise.