Pei-Ming Huang

High-molecular-weight hyaluronan – a possible new treatment for sepsis-induced lung injury: a preclinical study in mechanically ventilated rats

IntroductionMechanical ventilation with even moderate-sized tidal volumes synergistically increases lung injury in sepsis and has been associated with proinflammatory low-molecular-weight hyaluronan production. High-molecular-weight hyaluronan (HMW HA), in contrast, has been found to be anti-inflammatory. We hypothesized that HMW HA would inhibit lung injury associated with sepsis and mechanical ventilation.MethodsSprague–Dawley rats were randomly divided into four groups: nonventilated control rats; mechanical ventilation plus lipopolysaccharide (LPS) infusion as a model of sepsis; mechanical ventilation plus LPS with HMW HA (1,600 kDa) pretreatment; and mechanical ventilation plus LPS with low-molecular-weight hyaluronan (35 kDa) pretreatment. Rats were mechanically ventilated with low (7 ml/kg) tidal volumes. LPS (1 or 3 mg/kg) or normal saline was infused 1 hour prior to mechanical ventilation. Animals received HMW HA or low-molecular-weight hyaluronan via the intraperitoneal route 18 hours prior to the study or received HMW HA (0.025%, 0.05% or 0.1%) intravenously 1 hour after injection of LPS. After 4 hours of ventilation, animals were sacrificed and the lung neutrophil and monocyte infiltration, the cytokine production, and the lung pathology score were measured.ResultsLPS induced lung neutrophil infiltration, macrophage inflammatory protein-2 and TNFα mRNA and protein, which were decreased in the presence of both 1,600 kDa and 35 kDa hyaluronan pretreatment. Only 1,600 kDa hyaluronan completely blocked both monocyte and neutrophil infiltration and decreased the lung injury. When infused intravenously 1 hour after LPS, 1,600 kDa hyaluronan inhibited lung neutrophil infiltration, macrophage inflammatory protein-2 mRNA expression and lung injury in a dose-dependent manner. The beneficial effects of hyaluronan were partially dependent on the positive charge of the compound.ConclusionsHMW HA may prove to be an effective treatment strategy for sepsis-induced lung injury with mechanical ventilation.

Descending necrotizing mediastinitis: A 10-year surgical experience in a single institution

OBJECTIVE Early diagnosis and aggressive surgical drainage are very important for successful treatment of descending necrotizing mediastinitis. However, the surgical techniques used for this condition remain controversial. We report our 10-year experience of managing this devastating disease, focusing on the multidisciplinary, minimally invasive operative procedures and the unique bacteriologic factors in Taiwan. METHODS Between January 1997 and January 2007, we retrospectively reviewed 18 patients with descending necrotizing mediastinitis who were treated in the National Taiwan University Hospital. Diagnosis and Endo classification were confirmed by computed tomography of the neck and chest. RESULTS Eight women and 10 men were included in this study. The mean age was 57.8 +/- 15.2 years. Cervical drainage was performed in the involved area in all patients. The methods for mediastinal drainage included transcervical (n = 10), video-assisted thoracic surgical drainage (n = 6), subxiphoid drainage (n = 1), and mediastinoscopy-assisted drainage (n = 1). We could not rescue 3 patients because of uncontrolled sepsis before surgery, for a mortality rate of 16.7%. Klebsiella pneumoniae uniquely represents the most common pathogen in diabetic patients (P = .01), leading to more complicated courses in older patients (P =.04) and requiring more surgical interventions (P =.05) than other pathogens. CONCLUSION Transcervical mediastinal drainage is first justified in patients with limited disease in the upper mediastinum. For those with involvement of the lower anterior mediastinum, an additional subxiphoid approach is suggested. Cervicotomy with video-assisted mediastinal drainage is an excellent combination for involvement of the posterior mediastinum and pleural space. Klebsiella pneumoniae uniquely represents the most important and threatening causative pathogen for diabetic patients with descending necrotizing mediastinitis.

Thymectomy for non-thymomatous myasthenia gravis: a comparison of surgical methods and analysis of prognostic factors.

OBJECTIVE While thymectomy is an accepted treatment for myasthenia gravis (MG), video-assisted thoracoscopic surgery (VATS) thymectomy has recently become a popular surgical treatment, especially for non-thymomatous MG (NTMG). This study aims to compare the results of VATS thymectomy and trans-sternal thymectomy, and identify prognostic factors in NTMG patients after thymectomy. METHODS A 10-year retrospective review (January 1995 to December 2004) of 60 consecutive thymectomies (22 trans-sternal thymectomies and 38 VATS thymectomies) of NTMG patients performed in a university teaching hospital was undertaken. RESULTS There were 43 female patients and 17 male patients with a median MG-onset age of 25 years (range: 5-78 years). Median follow-up time was 44 months. VATS thymectomy patients had a shorter hospital stay than the trans-sternal thymectomy patients (5.6 days vs 8.1 days, p=0.008). There was no other statistically significant difference between the two operative methods in NTMG patients, including intensive care unit (ICU) stay, ventilator support time, operative time, postoperative status, complete stable remission (CSR) rate, morbidity and mortality. Three prognostic factors associated with better remission rate were hyperthyroidism (p=0.003), age <40 years (p=0.022) and the presence of thymic hyperplasia (p=0.041). Other factors, including gender, disease duration, preoperative MG severity, acetylcholine receptor antibody, perioperative therapy and operative methods (32% vs 36%, p=0.91, 95% confidence interval (CI)=0.27-3.21) were not statistically relevant to better remission rate. CONCLUSIONS VATS thymectomy is more advantageous for NTMG patients because of shorter hospital stay, less tissue injury, better cosmetic result and equivalent CSR rate. NTMG patients aged <40 years with hyperthyroidism and a histologic diagnosis of lymphofollicular hyperplasia have better chances of remission after thymectomy.

Association of GSTP1 Polymorphism and Survival for Esophageal Cancer

Purpose: Activity of glutathione S-transferase (GST) is associated with detoxification of xenobiotics and the maintenance of cell viability. Genetically variant GSTs produce different enzymatic activities. The clinical significance of this variation is still puzzling. We investigated whether genetic polymorphisms of GST including GSTP1, GSTM1, and GSTT1 affect survival among esophageal cancer patients. Experimental Design: From 1996 to 2002, 233 patients with pathologically proven esophageal cancer were recruited from the Department of Surgery, National Taiwan University Hospital. GST genotypes, including GSTT1, GSTM1, and GSTP1, were determined by PCR or PCR-RFLP. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function and Cox proportional hazards models. Results: The mean survival times (months) of the GSTP1 Ile/Ile, Ile/Val, and Val/Val were 11, 10, and 7, respectively (P < 0.05). The more the patients carried GSTP1 variant Val alleles, the poorer the survival rate (adjusted hazard ratio, 1.36; 95% confidence interval, 1.01-1.84; Ptrend = 0.045). In contrast, no association of GSTT1 or GSTM1 genotypes with survival rate was noted. Conclusion: The presence of the GSTP1 variant allele (Val) is associated with a poorer prognosis of esophageal cancer.

Thoracoscopic pleurodesis for primary spontaneous pneumothorax with high recurrence risk: a prospective randomized trial.

Objective:To compare the efficacy and safety between apical pleurectomy and pleural abrasion with minocycline in primary spontaneous pneumothorax (PSP) with high recurrence risk. Background:The optimal thoracoscopic pleurodesis procedure for PSP with high recurrence risk remains controversial. Methods:Between January 2006 and May 2009, a total of 369 patients with spontaneous pneumothorax were treated by video-assisted thoracoscopic surgery. After stapled bullectomy, 160 patients with no identifiable bleb or multiple blebs (≥3) were randomly chosen to undergo apical pleurectomy (pleurectomy group, 80 patients) or pleural abrasion with minocycline (abrasion/minocycline group, 80 patients). Results:Patients in the pleurectomy group had a longer operation duration (mean, 81.4 minutes vs 55.8 minutes, P < 0.001), a greater amount of operation bleeding (mean, 29.4 mL vs 13.2 mL, P = 0.025), and a greater amount of postoperative chest drainage (mean, 287.4 mL vs 195.8 mL, P = 0.040). Patients in the abrasion/minocycline group had a higher intensity of chest pain and required more frequent meperidine injections. Hemothorax occurred in 3 pleurectomy patients (3.8%). The short-term results showed that the 2 groups had comparable durations of postoperative chest drainage, durations of postoperative hospital stay, and complication rates. After a mean follow-up of 26.1 months, recurrent ipsilateral pneumothorax occurred in 3 patients (3.8%) in the pleurectomy group and 3 patients (3.8%) in the abrasion/minocycline group. Postoperative long-term residual chest pain and pulmonary function were comparable in both groups. Conclusions:Pleural abrasion with minocycline pleurodesis is as effective as apical pleurectomy and either technique is appropriate for treating PSP patients with high recurrence risk. This trial was registered at http://www.clinicaltrials.gov (ID: NCT00270751).

High MW hyaluronan inhibits smoke inhalation-induced lung injury and improves survival

Background and objective:  High MW hyaluronan (HMW HA) as opposed to low MW hyaluronan (LMW HA) has been shown to have anti‐inflammatory and anti‐apoptotic effects. We hypothesized that treatment with HMW HA would block smoke inhalation lung injury by inhibiting smoke‐induced lung inflammation and airway epithelial cell apoptosis.

Retrospective Analysis of Outcome Differences in Preoperative Concurrent Chemoradiation With or Without Elective Nodal Irradiation for Esophageal Squamous Cell Carcinoma

PURPOSE To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. METHODS AND MATERIALS We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. RESULTS The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non-ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. CONCLUSIONS ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome.

Genetic variants in DNA repair predicts the survival of patients with esophageal cancer.

Objective: To investigate the association of the genetic variants in excision repair cross-complementation group 2 (ERCC2) R156R and ERCC4 rs3136038 with survival duration for patients with esophageal cancer. Background: ERCC2 and ERCC4 are important molecules participating nucleotide excision repair system. The clinical relevance of the genetic variants of these genes is largely unknown currently. Patients and Methods: A total of 400 patients with a diagnosis of esophageal cancer were included. The genetic variants in the promoter regions of ERCC2 on R156R and ERCC4 on rs3136038 were analyzed with the TaqMan assay from leukocyte DNA collected before treatment and correlated to survival of the patients. Results: Presence with ERCC2 R156R C/C or ERCC4 rs3136038 C/T genotype of the patients could additively increase risk of death and disease progression. Under multivariate analysis, T, N staging and simultaneous presentation of these unfavorable genotypes were found significant for prognosis (P < 0.05). Accumulation of each unfavorable genotype would associate with adjusted HRs [95% CI] of 1.35 [1.10–1.65] and 1.37 [1.12–1.68] (P ⩽ 0.05) for death and disease progression respectively. The prognostic impact of these genotypes were more evident in the subgroup of patients with early disease status including T staging (II or less), free from lymph node metastasis or being able to undergo surgical resection (P < 0.05 for both overall and disease progression-free survival duration, respectively). Conclusion: Genetic variants in ERCC2 and ERCC4 may provide further survival prediction in addition to TNM staging system of esophageal cancer, which is more evident in the patients with early disease status.

Pediatric empyema: Outcome analysis of thoracoscopic management

OBJECTIVE Thoracoscopy has become a favored modality in treating pediatric empyema. However, the factors affecting the outcome of thoracoscopic management remain unclear. In this study, we report our experience using thoracoscopy to treat empyema in pediatric patients and investigate the factors affecting outcome. METHODS We retrospectively reviewed the demographic data, clinical presentation, radiographic findings, laboratory studies, and hospital course of 101 pediatric patients who underwent thoracoscopy for empyema between 1995 and 2008. RESULTS Empyema was due to pneumococcus infection in 64 patients (63.4%), and 69% of the cultured microorganisms were penicillin nonsusceptible. Chest computed tomography scan was performed in 96 patients, in whom necrotizing pneumonia was noted in 35 (36.5%). Preoperative intensive care unit admission was required for 33 patients (32.7%). Preoperative chest tube drainage was performed in 36 patients (35.6%), and thoracoscopy was used as the primary treatment in the remaining 65 patients. Complications occurred in 10 patients (9.9%); there were no mortalities. The median postoperative hospital stay was 13 days. Multivariate analyses showed that necrotizing pneumonia was significantly associated with the presence of complications, and that necrotizing pneumonia, preoperative intensive care unit admission, and preoperative chest tube drainage were independent risk factors for a longer postoperative hospital stay. CONCLUSION The clinical presentations of empyema in children requiring thoracoscopy are diverse. Patients with necrotizing pneumonia and those requiring preoperative intensive care unit admission and undergoing preoperative chest tube drainage are at high risk for developing complications and requiring longer hospital stay after thoracoscopy.

Prognostic significance of histologic differentiation, carcinoembryonic antigen value, and lymphovascular invasion in stage I non-small cell lung cancer.

OBJECTIVE For stage I non-small cell lung cancer (NSCLC), the only 2 prognostic factors incorporated into the seventh edition of the TNM staging system were tumor size and visceral pleural invasion. However, with this staging system, the prognostic precision of survival has proved elusive, suggesting the need to include additional prognostic factors. To improve prognostic applications and treatment decisions, we investigated clinicopathologic factors affecting progression-free survival in patients with surgically resected stage I NSCLC. METHODS From January 2004 to December 2011, we retrospectively reviewed the clinicopathologic characteristics of 758 consecutive patients with surgically resected stage I NSCLC at the National Taiwan University Hospital. RESULTS The 5-year progression-free survival rate was 82.3% and 64.0% for those with stage IA (n=481) and stage IB (n=277), respectively. Multivariate analysis revealed poor or moderate histologic differentiation and elevated preoperative serum carcinoembryonic antigen were statistically significant risk factors for recurrence in patients with stage IA. Poor or moderate histologic differentiation, elevated preoperative serum carcinoembryonic antigen, lymphovascular invasion, and tumor size>2 cm were statistically significant risk factors for recurrence in patients with stage I NSCLC. The 5-year progression-free survival rate was 93.0%, 73.8%, and 40.6% for stage I patients with no, 1 or 2, and >2 risk factors, respectively (P<.001). CONCLUSIONS In addition to tumor size, we identified 3 other independent risk factors for recurrence in patients with stage I NSCLC. These 3 risk factors warrant consideration as additional predictors in the next version of the TNM staging system.