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Using the Serial Analysis of Gene Expression (SAGE) database from the Cancer Genome Anatomy Project, we identified heparin co-factor II (HCII), which is over-expressed in non-small cell lung cancer (NSCLC). Here, we investigated the clinical significance of HCII and provided molecular evidence to support the suggestion that HCII could enhance cancer metastasis in NSCLC. We found that high HCII expression in tumour tissue was associated with increased cancer recurrence and shorter overall survival times in 75 clinically operable NSCLC patients. High pretreatment plasma concentration of HCII was associated with reduced overall survival in 57 consecutive NSCLC patients. We over-expressed and knocked down HCII expression in lung cancer cell lines and confirmed that HCII could promote cell motility, invasion ability and filopodium dynamics in NSCLC cells in vitro and increased metastatic colonization in an in vivo mouse model. Exogenous treatment of HCII promoted cancer cell migration, and this promigratory effect of HCII was independent of thrombin. We further showed that HCII could up-regulate cancer cell migration through the activation of PI3K, which acts upstream of Rac1 and Cdc42, and this effect could be blocked by heparin. We suggest that HCII is a novel metastasis enhancer and may be used as a prognostic predictor for heparin treatment in NSCLC. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

Background Early loco-regional failure (LRF) after organ preservation therapy (OPT) varies widely for hypopharyngeal squamous cell carcinoma (HPSCC) patients. We aim to develop and validate a MRI-derived radiomic signature RS for the prediction of 1-year LRF in HPSCC treated with OPT, and investigate its efficacy between OPT and total laryngectomy (TL) cohort. Methods A total of 3912 MRI-based radiomic features (RF) of pretreatment tumors were obtained from 370 HPSCC patients, including OPT cohort1 (OPT1; n = 186), OPT cohort2 (OPT2; n = 88), and TL cohort (TLc; n = 96). Variational autoencoder (VAE), trained with symmetric two encoded and decoded layers of neural network was applied to reduce the dimensionality of original RF to 128 VAE-RF. Least absolute shrinkage and selection operator with 10-fold cross validation performs features selection and constructs RS to predict 1-year LRF events in OPT1, which was validated in OPT2 and TLC. Harrell’s C-index was used to evaluate the discriminative ability of RS. Optimal cut-point for dichotomized RS risk category was determined via Youden index. Pair-wise propensity score matching (caliper 0.2) using pre-treatment variables (age, gender, TNM stage) was applied to compare the impact of OPT and TL under different RS risk categories. Results The RS yielded 1000 times bootstrapping corrected C-index of 0.753, 0.745 and 0.398 in the OPT1, OPT2 and TLC, respectively. Dichotomized risk category using Youden cut-point of RS yielded 1 year LRF predictive accuracy of 71.12%, 70.41%, and 41.74% in OPT1, OPT2 and TLC, respectively. In RS-high risk group, OPT were associated with poor progression-free survival (PFS, HR: 1.752, p = 0.032), while in RS-low risk group, OPT did not deteriorate the PFS (HR: 0.774, p = 0.416). Conclusions The RS-based model provides a novel to predict 1-year LRF and survival in patients with HPSCC who received OPT. The prediction performance discrepancy of MRI-derived RS in TLC also emphasizes the role of TL in RS-high risk group. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Early intracranial progression (ICP) reduce the efficacy of first line radiosurgery (SRS) for brain metastases. We aim to develop and validate a MR imaging-derived radiomic signature (RS) via deep learning approach for the prediction of 1-year disseminated ICP (DICP; more than or equal to 3 lesions and leptomeningeal carcinomatosis) in brain metastases patients treated with SRS. Methods A total of 1304 MRI-based radiomic features of pretreatment tumors were obtained from 208 patients with 451 lesions, who received first line SRS during August 2008 to January 2018. Variational autoencoder (VAE), trained with symmetric two encoded and decoded layers of neural network and 1,649,560 trainable parameters, was applied to reduce the dimensionality of radiomc features to 128 VAE-radiomic features. Penalized regression with 10-fold cross validation using least absolute shrinkage and selection operator performs features selection and construct RS to predict 1-year DICP events in train set of 150 patients, which was validated in test set of 58 patients. Harrell’s C-index was used to evaluate the discriminative ability of RS in both sets. The correlation of VAE-radiomic features and molecular features was analyzed by student t-test. Survival analysis was calculated using the Kaplan-Meier method. Results The RS yielded 1000 times bootstrapping corrected C-index of 0.746 and 0.747 for discrimination of 1-year DICP in the train and test cohorts, respectively. As for the subgroup of patients with lung (n = 175) and breast (n = 23) origin, the RS also showed good predictive performance with C-indices of 0.735 and 0.755, respectively. EGFR-mutation (n = 113) and ER (n = 22) status were associated with selected VAE-radiomic features No. 98 (p = 0.035) and No.127 (p = 0.44), respectively. Dichotomized risk category using RS of -0.769 (Youden index) as cut-off point yielded median overall survival of 57.7 months in low risk compared to 20.5 months in high risk group (p Conclusions The RS model provides a novel approach to predict 1-year DICP and survival in brain metastases receiving SRS, and is warranted to be integrated into GPA for optimal selection of patients treated with first line SRS. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

The effects of Sheng Hua Tang (SHT) on uterine involution and ovarian activity were investigated in postpartum dairy cows. SHT (70 g) was given to dairy cows (n = 10) to evaluate its effects for five days from the first postpartum day. Postpartum cows fed with a basal diet without SHT were used as the control group (n = 10). Ultrasounds and blood tests were recorded for four weeks from postpartum day seven with a 3-d interval. The results showed that the areas and diameters of endometria were significantly (p0.01) reduced in the group that received SHT compared to the control group on the seventh postpartum day. The group that received SHT had an intrauterine fluid volume mean of 1.2±0.6 cm(3), which was significantly lower than that of the control group, 2.3±0.8 cm(3) (p0.01) on the 13th postpartum day. In addition, the uterine tension score was a mean of 1.0±0.0 in the group that received SHT, which was also significantly lower than that of the control group, 1.5±0.5 (p0.01) on the 19th postpartum day. Taken together, the Chinese herbal medicine remedy, SHT, promoted uterine involution and ovarian activity in postpartum dairy cows.

We report a case of giant cell tumor of the left distal femur with simultaneous bilateral pulmonary metastases. Pathologic examination of the left lung nodule showed a metastatic giant cell tumor with a noncontinuous ossified rim, and the right lung nodules were totally hyalinized or ossified without residual giant cell tumor components. Hyalinization was a consistent finding in both the primary bone lesion and the pulmonary metastases. Because the patient did not receive chemotherapy or radiotherapy before her surgical procedure, we believe that these changes represent spontaneous tumor regression.

In order to improve prognostic applications and treatment decisions, we report our experiences of visceral pleural surface invasion (VPSI) in non-small cell lung cancers (NSCLCs) with pleural retraction. A total of 321 NSCLCs with pleural retraction were identified by carefully inspecting surgically resected specimens. The extent of pleural invasion, including the use of elastic stain, was evaluated. Patients with and without VPSI were compared for clinicopathologic parameters and survival. VPSI was identified in 170 (53.0 %) of the stage I–III cases and 98 (43.4 %) of the patients with stage I disease. VPSI was associated with a higher frequency of tumor size greater than 3 cm, moderate/poor differentiation, vascular invasion, mediastinal lymph node metastasis, extranodal involvement, and higher TNM stages. Multivariate analysis revealed VPSI to be a significant independent predictor of unfavorable prognosis. The 5-year survival of patients with and without VPSI was 57.9 and 83.0 %, respectively (P = 0.001), and was 74.3 and 88.5 % (P = 0.005) in stages I–III and stage I disease, respectively. VPSI is an independent factor for poor prognosis in NSCLCs, regardless of lymph node status. Stage IB NSCLCs with PL1 pleural invasion are associated with a survival rate similar to that of stage IA NSCLCs and could be classified as T1 lesions. While surgical treatment is adequate in these patients, stage IB NSCLCs with VPSI have poor prognosis, and these patients should be considered for adjuvant chemotherapy.

Purpose To identify germline polymorphisms to predict concurrent chemoradiation therapy (CCRT) response in esophageal cancer patients. Materials and Methods A total of 139 esophageal cancer patients treated with CCRT (cisplatin-based chemotherapy combined with 40 Gy of irradiation) and subsequent esophagectomy were recruited at the National Taiwan University Hospital between 1997 and 2008. After excluding confounding factors ( i.e ., females and patients aged ≥70 years), 116 patients were enrolled to identify single nucleotide polymorphisms (SNPs) associated with specific CCRT responses. Genotyping arrays and mass spectrometry were used sequentially to determine germline polymorphisms from blood samples. These polymorphisms remain stable throughout disease progression, unlike somatic mutations from tumor tissues. Two-stage design and additive genetic models were adopted in this study. Results From the 26 SNPs identified in the first stage, 2 SNPs were found to be significantly associated with CCRT response in the second stage. Single nucleotide polymorphism rs16863886, located between SGPP2 and FARSB on chromosome 2q36.1, was significantly associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.62–10.30) under additive models. Single nucleotide polymorphism rs4954256, located in ZRANB3 on chromosome 2q21.3, was associated with a 3.93-fold increase in pathologic complete response to CCRT (95% confidence interval 1.57–10.87). The predictive accuracy for CCRT response was 71.59% with these two SNPs combined. Conclusions This is the first study to identify germline polymorphisms with a high accuracy for predicting CCRT response in the treatment of esophageal cancer.

Pleomorphic carcinomas of the lung are uncommon malignant tumors composed of carcinomatous and sarcomatous components and are distinguished from other non-small-cell lung carcinomas by a more aggressive clinical course with early distant metastases and far worse survival. Epidermal growth factor receptor (EGFR) and p53 are common genes involved in the pathogenesis of non-small-cell lung carcinomas, but their roles in pleomorphic carcinomas are unclear. The potential clinical activity of EGFR-targeted therapy is also unknown. A total of 42 pleomorphic carcinomas were identified to investigate somatic mutations of EGFR and p53. Genomic DNA was extracted from microdissected cells of paraffin-embedded tumor tissues. Somatic mutations in EGFR (exons 18–21) and p53 (exons 5–8) were examined. EGFR mutations were detected in 10 of 42 cases. Five of these patients had point mutations in exon 21 majorly with L858R; this mutation was found in both adenocarcinomatous and sarcomatous components in 1 case. The other 5 cases harbored 4 deletions and 1 mutation in exon 19. p53 mutations were found in 12 patients. Notably, identical mutation was observed in carcinomatous and sarcomatous components in 3 patients, and this finding strongly supported the theory of monoclonal histogenesis. The occurrence (23.8%) of EGFR mutations, including the exons 19 and 21 mutations observed frequently in our series, suggests that the patients with inoperable pleomorphic carcinomas are likely to benefit from treatment with EGFR tyrosine kinase inhibitors.

The EGFR gene has been demonstrated to be an important factor influencing treatment response for various cancers, and its expression has been shown to be modified by the polymorphic CA repeat length at the 5′-regulatory sequence in intron 1. We investigated whether this EGFR polymorphism is associated with prognosis in patients with esophageal cancer after concurrent chemoradiotherapy (CCRT) and esophagectomy. A cohort of 148 patients with esophageal cancer received cisplatin-based CCRT (concurrently combined with 40 Gy irradiation) and subsequent esophagectomy. Their EGFR genotypes were determined by polymerase chain reaction from leukocyte DNA, which was obtained before treatment and was correlated with patient survival. Patients with the homozygous short allele (

Mediastinal seminomas are uncommon primary mediastinal neoplasms, and most are solid in appearance. Cystic mediastinal seminoma is an unusual type of extragonadal germ cell tumor that has rarely been reported in the literature. Here we describe a 36-year-old man with a 7.5-cm cystic mediastinal seminoma. The tumor was excised successfully by video-assisted thoracoscopic surgery. No recurrence was noted during 28 months of follow-up.

p53 and epidermal growth factor receptor (EGFR) are common genes involved in the pathogenesis of lung cancer, but their roles in lymphoepithelioma-like carcinomas (LELC) are unclear. In this study, we investigate the roles of p53 and EGFR in LELC carcinogenesis. Forty-six pulmonary LELCs were identified to evaluate p53 and EGFR aberrations. p53 mutations were identified in three patients, which all occurred in exon 8. EGFR mutations were detected in 8 of 46 cases with a majority of exon 21 mutations but without L858R. The other cases harbored mutations in exons 20 and 18. Only one case gained a deletion in exon 19. Notably, EGFR mutation was more commonly observed in patients with tumor size ≤ 3 cm (P = 0.014). In addition, there was a trend of more common EGFR overexpression in female (22/30) than in male patients (7/16, P = 0.061). However, there was no correlation between p53/EGFR mutations and protein expressions, suggesting the presence of complex mechanisms. p53 and EGFR mutations are uncommon in LELCs, indicating that these genes are not the important events in carcinogenesis for this tumor subtype. The EGFR mutation in 35% patients with LELC tumors

Fibroblast growth factor (FGF)-9 belongs to the FGF family which modulate cell proliferation, differentiation, and motility. Benzo(a)pyrene is a polycyclic aromatic hydrocarbon (PAH) and ubiquitous environmental carcinogen present in automobile exhaust, cigarette smoke, and foods. The major purposes of this study were to explore the roles of FGF-9 in the benzo(a)pyrene-induced lung cancer invasion in vitro and the metastatic development of lung adenocarcinoma in human. The data of RT-PCR analysis indicated that treatments of human lung adenocarcinoma CL5 cells with benzo(a)pyrene and a PAH mixture motorcycle exhaust particulate (MEP) extracts increased FGF-9 mRNA expression. The increased expression was blocked by cotreatments with a p38 mitogen-activated protein kinase inhibitor SB202190 and an extracellular signal-regulated kinase inhibitor PD98059. The results of immunoblot analysis and Matrigel assay showed that benzo(a)pyrene and MEP extracts produced a concomitant induction of FGF-9 protein and invasive ability of CL5 cells. The benzo(a)pyrene- and MEP-induced invasion was suppressed by FGF-9 neutralizing antibodies. The results of immunohistochemistry analysis of human lung adenocarcinoma specimens showed that FGF-9 protein was detected in the adenocarcinoma cells but not in normal epithelium. FGF-9 staining intensity was positively correlated with status of disease and degree of lymph node metastasis in these lung adenocarcinomas. These present findings suggest that FGF-9 has potential roles in benzo(a)pyrene-induced CL5 cell invasion and human lung adenocarcinoma metastasis.

Proteus syndrome is a very rare, sporadic and congenital condition that is characterized by postnatal mosaic overgrowth. This disorder is thought to be caused by a somatic gene mutation, but the exact etiology is unknown. Commonly involved tissues include connective tissue, bone, skin and the central nervous system. Another less common symptom involves pulmonary emphysematous changes. This report documents a 25-year-old man with Proteus syndrome who presented with progressive exertional dyspnea and asymmetric overgrowth of his extremities. He underwent left pneumonectomy and his postoperative course was uneventful. Lung tissue showed emphysematous changes with multiple bulla formation and scattered calcification. We also review recent literature related to pulmonary manifestations and management of Proteus syndrome.

Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P=0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P=0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P=0.012, McNemar's test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC.

To investigate the association between clinical/dosimetric factors and postoperative pulmonary complications (PPC) in esophageal cancer patients undergoing neoadjuvant chemotherapy and intensity-modulated radiation therapy (IMRT) followed by thoracic esophagectomy. The data from 52 patients receiving combined modality treatment were analyzed. Chemotherapy was taxane-based in 43 and 5-fluorouracil-based in 9 patients. IMRT (40–45 Gy, median 40 Gy, at 1.8–2 Gy per fraction) was given using a 3–5-beam arrangement. Surgery consisted of open or minimally invasive esophagectomy. The dosimetric parameters were generated from lung dose-volume histogram computed by the treatment planning software. PPC was defined as pneumonia or respiratory insufficiency within 30 days after surgery. Statistical correlations were analyzed between clinical/dosimetric factors and PPC. The incidence of PPC was 34.6%. No patients died of PPC. Two patients (3.8%) became ventilator dependent. In univariate analyses, preoperative forced expiratory volume in 1 s (FEV1) and forced vital capacity before surgery were significantly associated with PPC (P = 0.02 and 0.04, respectively). None of the dosimetric factors predicted development of PPC. For the 51 patients undergoing right transthoracic surgery, higher absolute spared volume of the right lung receiving 15 Gy was significantly associated with PPC (P = 0.03). In multivariate analysis, preoperative FEV1 was the only independent factor associated with PPC (P = 0.002). Preoperative rather than prechemoradiation FEV1 predicts development of PPC. Reducing the absolute volume of the right lung that is irradiated might decrease the risk of PPC for patients receiving right transthoracic surgery.

The evidence concerning open lung biopsy (OLB) for diffuse pulmonary infiltrates in patients with AIDS is limited. This study retrospectively evaluated the diagnostic and therapeutic yields of OLB compared with bronchoscopy for patients with AIDS with diffuse pulmonary infiltrate treated in the National Taiwan University Hospital from 1997 to 2004. There were 15 and 46 patients enrolled in the OLB and bronchoscopic groups in this study, respectively. As compared with the bronchoscopic group, patients from the OLB group had a higher chance of acquiring a specific diagnosis and possible change of therapy (73 vs 32.6% and 60 vs 21.7%, respectively; P < 0.05). There were two (13.3%) patients with prolonged air leak (greater than 7 days) in the OLB group, whereas four patients (8.7%) had procedure-related complications in the bronchoscopic group. There was no procedure-related mortality in the OLB group. This study demonstrated that OLB can be safely performed in select patients and provide a superior diagnostic and therapeutic benefit compared with bronchoscopy for diffuse pulmonary infiltrates in patients with AIDS. This procedure should be performed early in the clinical course to avoid irreversible clinical deterioration of the patients with severe illness.

Claudin (CLDN)-1, a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas.To investigate the clinical significance of CLDN1 expression in patients with lung adenocarcinoma and its role in cancer invasion and metastasis.We examined the CLDN1 mRNA expression in tumor specimens from 64 patients with lung adenocarcinoma and protein expression by immunohistochemistry in an independent cohort of 67 patients with lung adenocarcinoma. CLDN1 functions in cancer cell migration, invasion, and metastatic colonization were studied by overexpression and knockdown of CLDN1. Affymetrix microarrays were performed to identify gene expression changes associated with CLDN1 overexpression.We found that low-CLDN1 mRNA expression had shorter overall survival (P = 0.027, log-rank test) in 64 patients with lung adenocarcinoma, and we confirmed by immunohistochemistry that low CLDN1 expression had shorter overall survival (P = 0.024, log-rank test) in an independent cohort of 67 patients with lung adenocarcinoma. Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, and suppressed cancer cell migration, invasion, and metastasis. Knockdown CLDN1 expression increased cancer cell invasive and metastatic abilities. Affymetrix microarrays identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., connective tissue growth factor [CTGF], thrombospondin 1 [THBS1], deleted in liver cancer 1 [DLC1], occludin [OCLN], zona occludens 1 [ZO-1]) and suppressed expressions of invasion/metastasis enhancers (e.g., secreted phosphoprotein 1 [SPP1], cut-like homeobox 1 [CUTL1], transforming growth factor alpha [TGF-alpha], solute carrier family 2 [faciliated glucose transporter] member 3 [SLC2A3], placental growth factor [PGF]), supporting a role for CLDN1 as an invasion and metastasis suppressor.CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma.

Titanium plate has been widely used in several surgical fields, such as craniofacial reconstruction and orthopedic prosthesis. This prosthesis has been proved not only with good biocompatibility and mechanical strength, but also with light weight and low radiological interference. From October 1991 to May 1995, 6 patients underwent thoracic cage reconstruction with titanium plate in our hospital. They included 5 females and 1 male, with ages ranging from 26 to 62 years. Four of them suffered from primary chest wall tumors (2 desmoid tumors, 1 chondrosarcoma, and 1 hemangioma), one had a recurrent chest wall tumor from breast carcinoma, and one had thoracic hypoplasia. The thoracic cage defect ranged from 5 times 6 cm to 10 times 15 cm, and 1 to 3 titanium plates were used for the reconstruction. No paradoxical movement or other prosthesis-related complications have occurred during the follow-up period. We conclude that titanium plate is a good material for thoracic cage reconstruction.

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-assissted 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.

Background and Objectives To investigate the impact of using paclitaxel in chemoradiation on locally advanced esophageal squamous cell carcinoma (SCC) treated with or without surgery. Methods Of 127 patients with AJCC stages II–III esophageal SCC undergoing definitive chemoradiation (DefCRT, n = 44) or neoadjuvant chemoradiation plus surgery (NeoCRT + S, n = 83), 57 received chemotherapy with paclitaxel and cisplatin (TP), and 70 received 5-fluorouracil and cisplatin (PF). Three-year local progression-free survival (LPFS), distant metastasis-free survival, overall survival, and prognostic factors were retrospectively analyzed. Results The median survival was 30 months. Pathological complete response rate was 41% and 27% with TP and PF, respectively (P = 0.19). NeoCRT + S achieved significantly higher LPFS than DefCRT (71% vs. 39%, P

This study was to compare 18F-FDG positron emission tomography (PET) with thoracic contrast-enhanced CT (CECT) in the ability of lymph node (LN) staging non-small cell lung cancer (NSCLC) in a tuberculosis-prevalent country. The usefulness of dual time point PET imaging (DTPI) in NSCLC nodal staging was also evaluated. We reviewed 96 NSCLC patients (mean age, 65.3 ± 11.7 years) who had received PET studies before their surgery. DTPI were performed on 37 patients (mean age, 64.8 ± 12.2 years) who received an additional scan of thorax 3 h after tracer injection. The accuracies of nodal staging by CECT and PET were evaluated according to final histopathology of hilar and mediastinal LN resected by surgery. The accuracy for nodal staging by CECT was 65.6% and that by PET was 82.3% (p

Objectives According to our previous study, the concurrent detection of p53 and epidermal growth factor receptor mutations significantly improves the clonality assessment and impact management of patients with multiple primary lung cancer. Nevertheless, the treatment, outcome, and safety of patients with this complex disease remain controversial. This series of cases detail our experiences with surgical resections in 92 patients during the past 16 years. Methods A database of 1651 patients was evaluated for unilateral and bilateral synchronous multiple primary lung cancers. The relationships among the location of tumors, number of tumors, tumor size, tumor histology, vascular invasion, regional lymph node metastasis, extranodal extension, type of surgery, mortality, and survival were analyzed. Results The 5-year survival for all synchronous multiple primary lung cancers was 35.3%. The overall surgical mortality was 1.1%. Notably, lymph node metastasis, extranodal extension, vascular invasion, tumors with adenosquamous carcinoma or different histology, and poor survival were observed. Multivariate analysis showed that only the occurrence of lymph node metastasis remained a statistically significant prognostic factor. The 5-year survivals were 52.5% and 15.5% for patients with and without lymph node metastasis, respectively ( P Conclusion An aggressive surgical approach is safe and justified in patients with synchronous multiple primary lung cancers and node-negative diseases. The status of this particular form of non–small cell lung cancers might be considered in the conventional TNM staging system for more accurate prediction of patient prognosis.

The explosion of microarray studies has promised to shed light on the identification of disease markers. To find novel prognostic factors, we used the expression profile of a poor prognostic factor of lung cancer, survivin (BIRC5), as a template to search for and compare transcriptome expression profiles in a lung adenocarcinoma microarray dataset. Trophinin (TRO) was identified as one of the best-correlated genes. The trophinin expression in lung cancer specimens was examined by immunohistochemical staining. The role of trophinin in cancer metastasis was further investigated by approaches of overexpression and knock down with small interfering RNA (siRNA). For stage I lung adenocarcinoma, the patients without trophinin expression had a better overall and disease-free survival. Overexpression of trophinin increases cell invasion ability and knock down with siRNA inhibits cell invasion. Through a combination of data mining and biochemical assays, we identified trophinin, which could enhance cell invasion, as a novel prognostic factor for early stage lung cancer.

Summary The pulmonary hypertension that develops in chronic pulmonary thromboembolic diseases is caused by both mechanical obstruction of the vascular lumen and vascular remodeling, with pathological features similar to those of idiopathic pulmonary arterial hypertension (IPAH). The therapeutic efficacy of pulmonary thromboendarterectomy (PTE) in surgical candidates with chronic thromboembolic pulmonary hypertension (CTEPH) is well-established [Doyle RL, McCrory D, Channick RN, Simonneau G, Conte J. Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126 :63S–71S]. For CTEPH patients who are ineligible for PTE, therapeutic effects of various vasodilators in treatment of IPAH have been demonstrated. Although sildenafil, a phosphodiesterase type-5 inhibitor, has been reported to have short- and long-term benefits in terms of hemodynamics and functional status for inoperable CTEPH patients [Ghofrani HA, Schermuly RT, Rose F, Wiedemann R, Kohstall MG, et al. Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2003; 167 :1139–41; Sheth A, Park JE, Ong YE, Ho TB, Madden BP. Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction. Vascul Pharmacol 2005; 42 :41–5], its role in CTEPH treatment for PTE candidates unwilling to undergo operation has not been explored specifically. We present the case of a 50-year-old female CTEPH patient who was a traditional candidate for PTE with poor clinical response to 3 months of anticoagulant therapy, where dramatic improvements were achieved after adding on 4 months of sildanefil treatment. Her treatment course is detailed, and we discuss the potential therapeutic effects of sildenafil for CTEPH.

Purpose To identify the prognostic factors for pulmonary metastasectomy (PM-ectomy) in hepatocellular carcinoma (HCC). Patients and methods We conducted a retrospective review of patients with pulmonary metastases (PM) from HCC who had undergone curative PM-ectomy at National Taiwan University Hospital between 1990 and 2004. Univariate (log-rank) and multivariate (Cox’s model) analyses of survival were used to identify the significant prognostic factors. Results In total, 34 patients were eligible for curative PM-ectomy. The overall survival rates (Kaplan-Meier) after PM-ectomy were 65.2% and 27.5% at 2 and 5 years, respectively. High alpha-fetoprotein level, positive hepatic resection margin, and short disease-free interval (DFI) were unfavorable factors for overall survival from univariate analysis, however, only DFI (P = 0.028) was identified as an independently prognostic factor by multivariate analysis. Bilateral distribution and more PMs were unfavorable factors for PM-free survival from univariate analysis, with only PM number identified as an independent prognostic factor by multivariate analysis (P = 0.017). Conclusion Patients with longer DFIs and fewer PMs can benefit from PM-ectomy in HCC.

We report two cases of bronchogenic cyst in the diaphragm. Case 1 was a female patient with hepatocellular carcinoma. Computed tomography showed a tumor in the right lower lung and metastasis was suspected initially because of underlying disease and imaging findings. Case 2 was a female patient who presented with prolonged intermittent cough. Computed tomography showed a tumor in the left lower lung. Both tumors were excised by video-assisted thoracoscopic surgery, and the diagnosis was confirmed by histopathology.

Increased telomerase activity has been found in various types of human malignancies, including lung cancer. However, the correlation between the level of telomerase activity and the clinical characteristics of lung cancer patients remains unclear. The levels of telomerase activity in lung cancer specimens and adjacent non-neoplastic tissues obtained from 68 patients who underwent surgery were measured by using a non-radioactive quantitative method. Clinical and pathologic parameters were evaluated with respect to the level of telomerase activity. Prominent telomerase activity was detected in 58 (85.3%) lung cancer tissues and 21 (30.9%) adjacent non-neoplastic tissues. There was a trend of increase in relative telomerase activity in regard to the advanced pathological stage, and lymph node metastasis. Using Cox regression analysis, we found that every 100 unit of increase in relative telomerase activity was associated with an increase in the hazard ratio of death by 13% after controlling for other variables such as age, gender, and stage (Hazard ratio=1.13; 95% CI: 1.03–1.23, P =0.006). For patients with stage I disease, an increase of every 100 unit of relative telomerase activity was associated with an even higher increase of 33% in the hazard ratio of death (Hazard ratio=1.33; 95% CI: 1.07–1.65, P =0.011) and a 16% increase in the hazard of disease recurrence (Hazard ratio=1.16, 95% CI: 1.01–1.33, P =0.032). The level of telomerase activity is positively correlated with the risk of recurrence and mortality of lung cancer. The level of telomerase activity would predict the prognosis of lung cancer patients.

Variations in p53 codon 72 have been identified as significant predisposing factors for various cancers, but molecular mechanisms remain unclear. We investigated associations of p53 overexpression with codon 72 variants and other factors with esophageal cancer. Status of p53 overexpression was determined by immunohistochemical staining. Codon 72 polymorphisms and mutation of p53 was identified by PCR-RFLP and direct sequencing from exons 4 to 9, respectively. We evaluated 126 patients who underwent esophagectomy in the National Taiwan University Hospital, and found that the status of p53 overexpression was significantly influenced by presence of codon 72 polymorphisms. After adjustment for other possible confounders, the incidence of p53 overexpression was significantly decreased in patients with Pro / Pro genotype with an odds ratio (OR) of 0.21 (95% CI: 0.067–0.64) ( p = 0.0065) compared with incidence in patients with Arg / Arg genotype. The incidence of p53 overexpression was additively increased with environmental exposure to cigarette smoke, alcohol, and areca quid. When compared with individuals exposed to only one of these environmental risk factors, patients who had exposure to two or three risk factors had ORs of 6.11 (95% CI: 1.80–20.75) and 6.22 (95% CI: 1.81–21.34) for p53 overexpression, respectively. Elderly patients (age >70 years) were also more likely to have p53 overexpression, with an OR of 5.63 (95% CI: 1.53–20.64) compared with overexpression among patients aged less than 55 years. Forty-one patients received further evaluation of p53 mutation. There was also a higher incidence of, but without reaching a statistical significance, p53 mutation in patients with p53 overexpression (OR[95% CI]: 2.18 [0.52–9.6]) and codon 72 Arg / Arg genotype (OR [95% CI] of 0.8 [0.13–4.2], comparing genotypes of Pro / Pro and Arg / Pro with Arg / Arg ). Our data provide the first observations that the presence of p53 codon 72 variants can be a significant factor influencing p53 overexpression in esophageal cancer, with overexpression also influenced by combined or prolonged environmental exposures.

Background/PurposeConventional training in bronchoscopy may increase patient's discomfort and procedure-related morbidity. Computer-based bronchoscopy simulator (CBBS) permits the acquisition and evaluation of the necessary skills through a realistic bronchoscopic experience. This study was conducted to validate the use of a CBBS system developed in Taiwan as a learning and assessment tool.MethodsTwenty novice bronchoscopists and 10 expert bronchoscopists were enrolled as subjects in this prospective study. The 20 novice bronchoscopists were randomized into two groups, which received conventional bronchoscopic training or CBBS training and then completed a satisfaction survey. Subsequently, the novices who received CBBS training underwent an observational performance trial and the results were compared with those of expert bronchoscopists. All 10 expert bronchoscopists completed a realism survey and observational trial after CBBS performance.ResultsThe satisfaction survey showed that the CBBS training program significantly increased participants' satisfaction (p = 0.002) and interest in learning (p < 0.001). The realism survey by the 10 expert broncho-scopists indicated that CBBS provides a favorable degree of realism with regard to the mechanical and visual parameters examined. Analysis of the performance results showed that the following parameters were capable of differentiating the participants by level of expertise: total procedure time (p = 0.002), percentage of bronchial segments entered (p = 0.012), percentage of bronchial segments identified (p

Objective Estrogen receptor expression in lung cancer has been understudied, particularly in light of its potential biologic importance in the epidemic of lung cancer in women. The expression of estrogen receptors was investigated to better understand the possible role of sex hormones in lung cancer. Methods A total of 301 patients with surgically resected non–small cell lung cancers of stages I to III were explored. Sections of paraffin-embedded tumor samples were stained with estrogen receptor α and estrogen receptor β antibodies. Tumors with moderate-to-strong nuclear staining in at least 50% of the tumor cells were scored as positive for overexpression. Results The overall frequency of overexpression for estrogen receptor β was 45.8% (138/301). It was detected most frequently in female patients (in 54.3% of 127 tumors vs 39.7% of 174 tumors in men, P = .012). However, there was no estrogen receptor α nuclear staining detectable in non–small cell lung cancers. Interestingly, a significant correlation between estrogen receptor β expression, stage of disease, grade of differentiation, smoking status, vascular invasion, and survival in patients with stage II and III disease was found. By using multivariate analysis of survival among patients with stage II and III disease, estrogen receptor β overexpression, stage II tumor, well differentiation, nonsmoking status, and lack of vascular invasion were significantly favorable prognostic factors. Conclusions The results presented here show for the first time that immunohistochemical expression of estrogen receptor β can be used as a prognostic indicator in patients with surgically resected stage II and III non–small cell lung cancers. These observations might offer a possibility for hormonal therapy in patients with lung cancer.

Sclerosing hemangioma (SH) of the lung is an uncommon tumor with a predilection for middle-aged women. This special phenomenon prompted us to examine SH for the expression of ERalpha (human estrogen receptor) and ERbeta (a second isoform of estrogen receptor). To investigate the staining pattern of these tumors, we also stained lung tissues from patients with non-small cell lung carcinomas and nonneoplastic type II pneumocytes for comparison. Thirty-seven pulmonary SHs and 301 non-small cell lung cancers specimens were explored. Expression of ERalpha and ERbeta was immunohistochemically measured. The overall frequency of overexpression for ERbeta was 91.9%. It was detected in both female (in 91.4% of 35 cases) and male (in 100.0% of 2 tumors from men) patients. There was ERbeta overexpression in all 9 tumors of solid pattern, 6 of 7 tumors of papillary pattern, all 4 tumors of sclerotic pattern, 12 of 13 tumors of hemorrhagic pattern, and 3 of 4 tumors of mixed pattern. The staining pattern of the neoplastic cells of the SH was similar to that of type II pneumocytes adjacent to the tumor rather than that of non-small cell lung cancers, in which the frequency of ERbeta overexpression was 45.8%. However, there was no ERalpha detectable in these neoplasms. Estrogen receptor beta overexpression is very frequent in pulmonary SHs, which is similar to that of alveolar cells but quite different from non-small cell carcinoma.

ObjectiveSurgical lung biopsy is considered the final method of diagnostic modality in patients with undiagnosed diffuse pulmonary disease. Nevertheless, the effect of surgical lung biopsy on the diagnosis, treatment, and outcome of the patient still remains controversial. This study reviewed the experiences of surgical lung biopsies in 196 consecutive patients during the past 7 years.MethodsSurgical lung biopsy was performed after achievement of general anesthesia through video-assisted thoracoscopic surgery or a 7-cm minithoracotomy. Biopsy specimens were swabbed for aerobic and anaerobic bacterial, fungal, and mycobacterial cultures. The sections of specimens were routinely stained with hematoxylin and eosin, and acid-fast, Gomori methenamine silver, Gram stain, or other special stains were added if necessary.ResultsThe pathologic diagnosis after surgical lung biopsy included infection (30.6%), interstitial pneumonia or fibrosis (21.9%), diffuse alveolar damage (17.3%), neoplasm (13.3%), autoimmune diseases (8.2%), and others (8.2%). After surgical lung biopsy, 165 (84.2%) patients had changes in their therapy, 124 (63.3%) patients had clinical improvement of their conditions, and 119 (60.7%) patients survived to hospital discharge. Comparison between immunocompromised and immunocompetent patients showed that diagnosis of infection was significantly higher (P < .01) in the former group (41.2% vs 20.2%). In addition, there was no significant difference in the distribution of diagnosis and rate of change in therapy between the respiratory failure and nonrespiratory failure groups. However, the rates of response to therapy and patient survival were significantly lower in the respiratory failure group (51.2% and 41.5%) than in the nonrespiratory failure group (71.9% and 78.1%, P < .05). There was no surgical mortality directly related to the procedure. The surgical morbidity rate was 6.6%.ConclusionSurgical lung biopsy is a safe and accurate diagnostic tool for diffuse pulmonary disease. For a large proportion of the patients, change of therapy and then clinical improvement can be achieved after surgical lung biopsy. Surgical lung biopsy should be considered earlier in patients with undiagnosed diffuse pulmonary disease, especially when the respiratory condition is deteriorating.

Summary The standard treatment for children with idiopathic pulmonary artery hypertension (IPAH) is epoprostenol. Few reports have evaluated oral bosentan therapy in children with severe IPAH. This report details the use of bosentan in a 16-month-old child with severe IPAH who presented as New York Heart Association (NYHA) functional class (FC) IV. His general condition, NYHA FC, serum aminotransferase levels, and arterial blood gases improved after 6 months of treatment. This case provides an example where twofold aminotransferase elevations suspected to result from right heart failure might not be a contraindication for bosentan therapy in children with IPAH.

Epidemiological studies have demonstrated that areca quid chewing can be an independent risk factor for developing esophageal cancer. However, no studies are available to elucidate the mechanisms of how areca induces carcinogenesis in the esophagus. Since the areca nut in Taiwan contains a high concentration of safrole, a well-known carcinogenic agent, we analyzed safrole-DNA adducts by the 32P-postlabelling method in tissue specimens from esophageal cancer patients. In total, we evaluated 47 patients with esophageal cancer (16 areca chewers and 31 non-chewers) who underwent esophagectomy at the National Taiwan University Hospital between 1996 and 2002. Of the individuals with a history of habitual areca chewing (14 cigarette smokers and two non-smokers), one of the tumor tissue samples and five of the normal esophageal mucosa samples were positive for safrole-DNA adducts. All patients positive for safrole-DNA adducts were also cigarette smokers. Such adducts could not be found in patients who did not chew areca, irrespective of their habits of alcohol consumption or cigarette smoking (p

Background Diffuse pulmonary infiltrates is the major complication and cause of mortality after bone marrow transplantation. We analyzed the etiologies and prognostic factors in bone marrow recipients with diffuse pulmonary infiltrates and assessed the role of open lung biopsy in managing this complication. Methods Medical records of patients with diffuse pulmonary infiltrates after bone marrow transplantation were reviewed. Possible prognostic factors were analyzed by multivariate logistic regression. Results Sixty-eight (20%) of 341 bone marrow recipients had diffuse pulmonary infiltrates and 34 died. Thirty-five underwent open lung biopsy, resulting in therapeutic changes in 22 (63%) and clinical improvement in 16 (46%). The leading diagnoses were idiopathic interstitial pneumonitis (40%) and cytomegalovirus pneumonitis (20%). Cytomegalovirus pneumonitis caused radiographically observable interstitial infiltrates exclusively and was frequently associated with hepatitis. Idiopathic interstitial pneumonitis resulted in either diffuse ground-glass opacity or interstitial infiltrates. Three (9%) patients had miliary tuberculosis. Respiratory failure ( p p = 0.016) were the poor prognostic factors. Conclusions Among bone marrow recipients, we found diffuse pulmonary infiltrates in 20% and a mortality rate of 50%. Idiopathic interstitial pneumonitis and cytomegalovirus pneumonitis were the most common causes and should be suspected in patients with diffuse interstitial infiltrates. In endemic areas, miliary tuberculosis should be suspected in bone marrow recipients with diffuse reticulonodular lesions. Respiratory failure and acute graft-versus-host disease were poor prognostic factors. By establishing a correct diagnosis, open lung biopsy led to treatment changes in about two-thirds of these patients.

Objective: The use of a circular stapler in cervical esophagogastric anastomosis remains controversial. This study was to compare the postoperative and long-term results of manual and mechanical techniques for cervical esophagogastric anastomosis after resection for squamous cell carcinoma. Methods: A prospective randomized controlled trial was undertaken in 63 patients with curatively resectable squamous cell cancer of the thoracic esophagus between 1996 and 1999. Patients were randomized to receive either a hand-sewn (32 patients) or circular stapled (31 patients) cervical esophagogastric anastomosis. Results: The mean operating time was longer when the handsewn method was used (524 vs. 447 min, P , 0:001). Anastomotic leakage was noted in seven patients (22%) in the hand-sewn group and eight patients (26%) in the stapler group (P ¼ NS). Hospital mortality occurred in four patients (13%) of the hand-sewn group and in three patients (10%) of the stapler group (P ¼ NS). After the operation, four patients (14%) in the hand-sewn group and five patients (18%) in the stapler group developed a benign esophageal stricture (P ¼ NS). The mean follow-up time was 24 months, and the rates of freedom from benign stricture and survival were comparable in each group. Conclusions: Performing cervical esophagogastric anastomoses using a circular mechanical stapler had a shorter operating time and a comparable outcome to the hand-sewn method. The circular mechanical stapler could be used as an alternative for cervical esophagogastric anastomosis after resection for esophageal squamous cell cancer. q 2004 Elsevier B.V. All rights reserved.

Minimal invasive surgery using a laparoscopic or thoracoscopic approach for cardiomyotomy (Heller myotomy) has become a widely accepted procedure to treat achalasia of the esophagus. In this study, we evaluated the long-term results of Heller myotomy achieved by performing video-assisted thoracic surgery (VATS). We recruited patients with achalasia who had undergone VATS for Heller myotomy from 1991 to 2000 at the National Taiwan University Hospital. The myotomy was performed 6 cm above and 1 cm below the gastroesophageal junction. No fundoplication was performed during the procedure. The symptom score, which included dysphagia, regurgitation, and chest pain, was evaluated before and after surgery. Body weight was also recorded before and after surgery. The cases of 14 patients (4 men, 10 women) were studied. The mean patient age was 41.8 +/- 4.9 years. No postoperative mortality or morbidity was found in these patients. The follow-up duration was 56 +/- 7.17 months. The dysphasia score improved from 3.0 preoperatively to 0.79 +/- 0.30 postoperatively (p=0.001). The reflux score improved from 2.64 +/- 0.17 preoperatively to 0.50 +/- 0.20 postoperatively (p=0.001). All the improvements were still in place at the time of the most recent follow-up examinations. Heller myotomy to treat achalasia using a thoracoscopic approach can provide satisfactory long-term results.