Hung Jen Chen

Increased Lung Cancer Risk among Patients with Pulmonary Tuberculosis: A Population Cohort Study

Introduction: Given one third of the human population have been infected with tuberculosis, it is important to delineate the relationship between tuberculosis and lung cancer. This study explored whether contracting pulmonary tuberculosis is associated with an increased risk of developing lung cancers. Methods: In a cohort of 716,872 insured subjects, free from cancers, aged 20 years and older, 4480 patients with newly diagnosed tuberculosis were identified from the universal insurance claims in 1998–2000 and tracked until 2007 with the remaining insured without tuberculosis. We compared the incidence of lung cancers between the two cohorts and measured the associated hazard of developing lung cancer. Results: The incidence of lung cancers was approximately 11-fold higher in the cohort of patients with tuberculosis than nontuberculosis subjects (26.3 versus 2.41 per 10,000 person-years). Cox proportional hazard regression analysis showed a hazard ratio of 4.37 (95% confidence interval [CI]: 3.56–5.36) for the tuberculosis cohort after adjustment for the sociodemographic variables or 3.32 (95% CI: 2.70–4.09) after further adjustment for chronic obstructive pulmonary disease (COPD), smoking-related cancers (other than lung cancer), etc. The hazard ratio increased to 6.22 (95% CI: 4.87–7.94) with the combined effect with COPD or to 15.5 (95% CI: 2.17–110) with the combined effect with other smoking-related cancers. Conclusions: This study provides a compelling evidence of increased lung cancer risk among individuals with tuberculosis. The risk may increase further with coexisting COPD or other smoking-related cancers.

Anti-IFN-γ autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16: 02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection

Adult patients with disseminated nontuberculous mycobacterial (dNTM) infections usually have severe immune system defects. Recently, several studies have shown that anti-IFN-γ autoantibodies may play an important role in the pathogenicity of dNTM infections. A considerable proportion of reported cases of anti-IFN-γ autoantibodies show either clinical or laboratory evidence of autoimmune disease. In the present study, we identified 19 formerly healthy adults who later developed dNTM infections, of whom 17 were further investigated immunologically. High-titer anti-IFN-γ autoantibodies capable of inhibiting IL-12 production in vitro were found in the plasma of all of these patients. In addition to dNTM infection, 35% and 71% of our patients also suffered from salmonellosis and herpes zoster, respectively. This observation suggests that IFN-γ may be crucial in controlling salmonella infection and reactivating latent varicella-zoster virus infection in humans. 2 HLA alleles, DRB1*16:02 DQB1*05:02 (odds ratio 8.68; 95% confidence interval, 3.47-21.90; P = 1.1 × 10(-6); Pc = 3.08 × 10(-5) and odds ratio 7.16; 95% confidence interval, 3.02-17.05; P = 1 × 10(-7); Pc = 1.4 × 10(-6), respectively), were found in 82% (14 of 17) of our patients. In conclusion, our data suggest that anti-IFN-γ autoantibodies may play a critical role in the pathogenesis of dNTM infections and reactivation of latent varicella-zoster virus infection and are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02.

Pleural Effusions in Febrile Medical ICU Patients: Chest Ultrasound Study

STUDY OBJECTIVES To assess the necessity of thoracentesis in febrile medical ICU (MICU) patients, and to evaluate the efficiency and reliability of sonographic effusion patterns for diagnosing empyema. DESIGN AND SETTING A prospective, 1-year, tertiary-care hospital study of febrile MICU patients with physical, radiographic, and ultrasonographic evidence of pleural effusion. PATIENTS During this study period, we screened 1,640 patients who had been admitted to the MICU; of these, 94 patients had a temperature > 38 degrees C for > 8 h with evidence of pleural effusion proven by chest radiography and ultrasound. INTERVENTION Routine thoracentesis and pleural effusion cultures were performed in 94 febrile patients under portable chest ultrasound guidance. Three days later, if the first pleural effusion culture was inconclusive and the patient still had persistent fever of > 38 degrees C, we repeated the diagnostic thoracentesis and pleural effusion culture. In total, 118 procedures were performed in those 94 febrile patients. MEASUREMENTS AND RESULTS In all, 58 patients (62%) had infectious exudates (parapneumonic, n = 36; empyema, n = 15; urosepsis, n = 3; liver abscess, n = 2; deep neck infection, n = 1; and wound infection, n = 1), 28 patients (30%) had transudates, and 8 patients (8%) had noninfectious exudates. The prevalence of empyema in febrile patients admitted to the MICU was 16% (15 of 94 patients). Analyses of the sonographic patterns of the 15 patients with empyema out of the 118 thoracenteses performed showed the following: anechoic pattern, 0% (0 of 47 procedures); complex nonseptated and relatively nonhyperechoic pattern, 0% (0 of 36 procedures); complex nonseptated and relatively hyperechoic pattern, 100% (2 of 2 procedures); complex septated pattern, 35% (11 of 31 procedures); and homogeneously echogenic pattern, 100% (2 of 2 procedures). Hemothorax was the only complication, and it occurred in two patients (2%). Both patients had a favorable outcome after drainage. CONCLUSION Portable chest ultrasound examination and ultrasound-guided thoracentesis in febrile MICU patients are safe, feasible, and useful methods for diagnosing thoracic empyema. Our results suggest that only some sonographic patterns of pleural effusion (homogeneously echogenic, complex nonseptated and relatively hyperechoic, and complex septated) deserve aggressive assessment and rapid management.

Clinical Investigations in Critical CarePleural Effusions in Febrile Medical ICU Patients: Chest Ultrasound Study

STUDY OBJECTIVES To assess the necessity of thoracentesis in febrile medical ICU (MICU) patients, and to evaluate the efficiency and reliability of sonographic effusion patterns for diagnosing empyema. DESIGN AND SETTING A prospective, 1-year, tertiary-care hospital study of febrile MICU patients with physical, radiographic, and ultrasonographic evidence of pleural effusion. PATIENTS During this study period, we screened 1,640 patients who had been admitted to the MICU; of these, 94 patients had a temperature > 38 degrees C for > 8 h with evidence of pleural effusion proven by chest radiography and ultrasound. INTERVENTION Routine thoracentesis and pleural effusion cultures were performed in 94 febrile patients under portable chest ultrasound guidance. Three days later, if the first pleural effusion culture was inconclusive and the patient still had persistent fever of > 38 degrees C, we repeated the diagnostic thoracentesis and pleural effusion culture. In total, 118 procedures were performed in those 94 febrile patients. MEASUREMENTS AND RESULTS In all, 58 patients (62%) had infectious exudates (parapneumonic, n = 36; empyema, n = 15; urosepsis, n = 3; liver abscess, n = 2; deep neck infection, n = 1; and wound infection, n = 1), 28 patients (30%) had transudates, and 8 patients (8%) had noninfectious exudates. The prevalence of empyema in febrile patients admitted to the MICU was 16% (15 of 94 patients). Analyses of the sonographic patterns of the 15 patients with empyema out of the 118 thoracenteses performed showed the following: anechoic pattern, 0% (0 of 47 procedures); complex nonseptated and relatively nonhyperechoic pattern, 0% (0 of 36 procedures); complex nonseptated and relatively hyperechoic pattern, 100% (2 of 2 procedures); complex septated pattern, 35% (11 of 31 procedures); and homogeneously echogenic pattern, 100% (2 of 2 procedures). Hemothorax was the only complication, and it occurred in two patients (2%). Both patients had a favorable outcome after drainage. CONCLUSION Portable chest ultrasound examination and ultrasound-guided thoracentesis in febrile MICU patients are safe, feasible, and useful methods for diagnosing thoracic empyema. Our results suggest that only some sonographic patterns of pleural effusion (homogeneously echogenic, complex nonseptated and relatively hyperechoic, and complex septated) deserve aggressive assessment and rapid management.

Transthoracic Ultrasonography in Predicting the Outcome of Small-Bore Catheter Drainage in Empyemas or Complicated Parapneumonic Effusions

Thoracic sonography has been advocated as being complementary to small-bore catheter drainage in pleural effusions. However, it is not known whether the initial sonographic appearances of empyemas or complicated parapneumonic effusions (CPPEs) can predict the outcomes of small-bore catheter drainage for these pleural insults. This retrospective study investigated the outcomes of patients who had been diagnosed with empyema and CPPE and had received ultrasound-guided small-bore catheter (size from 12F to 16F) drainage in a tertiary university hospital from September 2005 to August 2007. Patients were excluded when empyemas or CPPEs were traumatic, they were less than 18 years old or their charts were incomplete. We evaluated 141 small-bore catheters in 70 patients with empyemas and 71 patients with CPPEs over a two-year period. The mean age was 58+/-15 y and the male gender was more frequent (112 men, 79%). The overall successful rate of small-bore catheter drainage in empyemas or CPPEs was 63% (89/141). The sonographic appearances of these empyemas or CPPEs exhibited a complex septated pattern in 57% (81/141) of patients and a complex nonseptated pattern in 43% (60/141) of patients. The success rate in a complex nonseptated sonographic pattern was significantly higher than in a complex septated sonographic pattern (48/60, 80% vs. 41/81, 51%, respectively; p=0.001). Moreover, patients with complex septated sonographic patterns also had higher intensive care unit admission rates compared with nonseptated sonographic patterns (22/81, 27%, vs. 8/60, 13%, respectively; p=0.0047), as well as infection-related mortality rates (17/81, 21% vs. 4/60, 7%, respectively; p=0.018). The appearance of sonographic septation is a useful sign to help predict the outcome of small-bore catheter drainage in cases of empyemas or CPPEs. Patients with a complex septated sonographic pattern have a poorer prognosis for a successful outcome, higher ICU admission rate and a higher mortality rate.

ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway.

The transmembrane cell adhesion protein ADAM9 has been implicated in cancer cell migration and lung cancer metastasis to the brain, but the underpinning mechanisms are unclear and clinical support has been lacking. Here, we demonstrate that ADAM9 enhances the ability of tissue plasminogen activator (tPA) to cleave and stimulate the function of the promigratory protein CDCP1 to promote lung metastasis. Blocking this mechanism of cancer cell migration prolonged survival in tumor-bearing mice and cooperated with dexamethasone and dasatinib (a dual Src/Abl kinase inhibitor) treatment to enhance cytotoxic treatment. In clinical specimens, high levels of ADAM9 and CDCP1 correlated with poor prognosis and high risk of mortality in patients with lung cancer. Moreover, ADAM9 levels in brain metastases derived from lung tumors were relatively higher than the levels observed in primary lung tumors. Our results show how ADAM9 regulates lung cancer metastasis to the brain by facilitating the tPA-mediated cleavage of CDCP1, with potential implications to target this network as a strategy to prevent or treat brain metastatic disease.

Ultrasound in Peripheral Pulmonary Air-Fluid Lesions: Color Doppler Imaging as an Aid in Differentiating Empyema and Abscess

BACKGROUND The aim of this study was to reevaluate the clinical significance of sonographic appearances, in particular the application of color Doppler ultrasound imaging, in discriminating peripheral air-fluid lung abscess from empyema. METHODS We retrospectively studied patients who had had peripheral air-fluid lesions due to empyema or lung abscess and who had undergone color Doppler ultrasound and grayscale ultrasound examinations between January 2003 and October 2007. A total of 34 patients with confirmed lung abscess and 30 patients with empyema were identified. The four sonographic characteristics observed and analyzed were the wall characteristics of the lesions (wall width, luminal margin, outer margin, and chest wall angle), split pleura sign, internal echogenicity (suspended microbubble sign, complex-septated effusions, and passive atelectasis), and identification of color Doppler ultrasound vessel signals in pericavitary lesions (consolidation or atelectasis). RESULTS Among the sonographic characteristics, complex-septated effusions and passive atelectasis were specific for empyema, but the sensitivity was only 40% (n = 12 of 30) and 47% (n = 14 of 30), respectively. The identification of color Doppler ultrasound vessel signals in pericavitary consolidation was the most useful and specific for identifying lung abscesses. In our series, if we define the identification of color Doppler ultrasound vessel signals in a pericavitary consolidation as a predictor for peripheral lung abscess, we can achieve sensitivity, specificity, positive predictive value, and negative predictive value of 94%, 100%, 100%, and 94%, respectively. CONCLUSIONS Color Doppler ultrasound is a powerful tool for differentiating the peripheral air-fluid abscess from empyema, with high specificity and without any risk.

Aberrant alternative splicing events in Parkinson's disease.

Alternative splicing (AS) using a sole gene to express multiple transcripts with diverse protein coding sequences and/or RNA regulatory elements raises genomic complexities. In the nervous system, several thousand AS events play important roles in ion transportation, receptor recognition, neurotransmission, memory, and learning. Not surprisingly, AS influences human physiology, development, and disease. Many research studies have focused on aberrant AS in nervous system diseases, including Parkinsons disease (PD), the second most common progressive neurodegenerative disorder of the central nervous system. PD affects the lives of several million people globally. It is caused by protein aggregation, such as in Lewy bodies, and the loss of dopamine-containing neurons in the substantia nigra of the midbrain. To our knowledge, six genes, including PARK2, SNCAIP, LRRK2, SNCA, SRRM2, and MAPT, are involved in aberrant AS events in PD patients. In this review, we highlight the relevance of aberrant AS in PD and discuss the use of an aberrant AS profile as a potential diagnostic or prognostic marker for PD and as a possible means of applying therapy.

Pigtail catheter for the management of pneumothorax in mechanically ventilated patients.

PURPOSE There has been a paucity of data regarding the efficacy and safety of small-bore chest tubes (pigtail catheter) for the management of pneumothorax in mechanically ventilated patients. METHODS We conducted a retrospective review of mechanically ventilated patients who underwent pigtail catheter drainage as their initial therapy for pneumothorax in the emergency department and intensive care unit from January 2004 through January 2007 in a university hospital. RESULTS Among the 62 enrolled patients, there were 41 men (66%) and 21 women (34%), with a mean age of 63.8 +/- 20.3 years. A total of 70 episodes of pneumothoraces occurred in the intensive care unit, and 48 episodes of pneumothoraces (68.6%) were successfully treated with pigtail catheters. The average duration of pigtail drainage was 5.9 days (1-27 days). No major complications occurred through use of this procedure, except for pleural infections (n = 3, 4.2%) and clogged tube (n = 1, 1.4%). Comparing the variables between the success and failure of pigtail treatment, the failure group had a significantly higher proportion of Fio(2) >60% requirement (45.5% vs. 14.6%, P = .005) and higher positive end-expiratory pressure levels (8.7 +/- 3.0 vs. 6.2+/- 2.3 mm Hg, P = .001) at the time of pneumothorax onset than the success group. Further comparing the efficacy of pigtail drainage between barotraumas and iatrogenic pneumothorax, pigtail catheters for management of iatrogenic pneumothorax had a significantly higher success rate than barotraumas (87.5% vs. 43.3%, P < .0001). CONCLUSION Pigtail catheter drainage is relatively effective in treating iatrogenic but less promising for barotraumatic pneumothoraces.

Identification of Five Driver Gene Mutations in Patients with Treatment-Naïve Lung Adenocarcinoma in Taiwan

Background It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. Methods This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). Results From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. Conclusion This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.