Jin-Shing Chen

Phosphorylation/Cytoplasmic Localization of p21Cip1/WAF1 Is Associated with HER2/neu Overexpression and Provides a Novel Combination Predictor for Poor Prognosis in Breast Cancer Patients

Purpose: The diversity of biological functions makes p21Cip1/WAF1 (p21) a controversial marker in predicting the prognosis of breast cancer patients. Recent laboratory studies revealed that the regulation of p21 function could be related to different subcellular localizations of p21 by Akt-induced phosphorylation at threonine 145 in HER2/neu-overexpressing breast cancer cells. The purpose of this study was to verify these findings in clinical settings. Experimental Design: The expression status of the key biological markers in the HER2/neu-Akt-p21 pathway in 130 breast cancer specimens was evaluated by immunohistochemical staining and correlated with patients’ clinical parameters and survival. In addition, an antibody against phospho-p21 at threonine 145 [phospho-p21 (T145)] was also used for better validation of these findings. Results: Cytoplasmic localization of p21 is highly correlated with overexpression of phospho-p21 (T145). Both cytoplasmic p21 and overexpression of phospho-p21 (T145) are associated with high expression of HER2/neu and phospho-Akt. Cytoplasmic localization of p21 and overexpression of phospho-p21 (T145), HER2/neu, and phospho-Akt are all associated with worse overall survival. Multivariate analysis of the Cox proportional hazard regression model revealed that cytoplasmic p21 and overexpression of HER2/neu are independently associated with increased risk of death. Combining these two factors stratified patients’ survival into four distinct groups, with a 5-year survival rate of 79% in low HER2/neu and negative/nuclear p21 patients, 60% in high HER2/neu and negative/nuclear p21 patients, 29% in low HER2/neu and cytoplasmic p21 patients, and 16% in high HER2/neu and cytoplasmic p21 patients. Conclusions: The present study, in addition to supporting the mechanisms of p21 regulation derived from laboratory investigation, demonstrates the prognostic importance of phospho-p21 (T145) for the first time and also provides a novel combination of p21 and HER2/neu for better stratification of patients’ survival than any single clinicopathological or biological marker that may play important diagnostic and therapeutic roles for breast cancer patients.

Cancer-specific activation of the survivin promoter and its potential use in gene therapy

Survivin is expressed in many cancers but not in normal adult tissues and is transcriptionally regulated. To test the feasibility of using the survivin promoter to induce cancer-specific transgene expression in lung cancer gene therapy, a vector expressing a luciferase gene driven by the survivin promoter was constructed and evaluated in vitro and in vivo. We found that the survivin promoter was generally more highly activated in cancer cell lines than in normal and immortalized normal cell lines. When delivered intravenously by DNA:liposome complexes, the survivin promoter was more than 200 times more cancer specific than the cytomegalovirus promoter in vivo. To identify lung cancer patients who may benefit from gene therapy with the survivin promoter, we measured survivin protein expression in surgical specimens of 75 non-small-cell lung cancers and 10 normal lung tissues by immunohistochemical staining and found that survivin is expressed in most of the non-small-cell lung cancers tested (81%, 61 of 75) but none of the normal lung tissues. The survivin promoter also induced transgene expression of a mutant Bik in cancer cells, which suppressed the growth of cancer cells in vitro and in vivo. These results indicate that the survivin promoter is a cancer-specific promoter for various cancers and that it may be useful in cancer gene therapy.

miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans

MicroRNAs (miRNAs) influence many biological processes, including cancer. They do so by posttranscriptionally repressing target mRNAs to which they have sequence complementarity. Although it has been postulated that miRNAs can regulate other miRNAs, this has never been shown experimentally to our knowledge. Here, we demonstrate that miR-107 negatively regulates the tumor suppressor miRNA let-7 via a direct interaction. miR-107 was found to be highly expressed in malignant tissue from patients with advanced breast cancer, and its expression was inversely correlated with let-7 expression in tumors and in cancer cell lines. Ectopic expression of miR-107 in human cancer cell lines led to destabilization of mature let-7, increased expression of let-7 targets, and increased malignant phenotypes. In contrast, depletion of endogenous miR-107 dramatically increased the stability of mature let-7 and led to downregulation of let-7 targets. Accordingly, miR-107 expression increased the tumorigenic and metastatic potential of a human breast cancer cell line in mice via inhibition of let-7 and upregulation of let-7 targets. By mutating individual sites within miR-107 and let-7, we found that miR-107 directly interacts with let-7 and that the internal loop of the let-7/miR-107 duplex is critical for repression of let-7 expression. Altogether, we have identified an oncogenic role for miR-107 and provide evidence of a transregulational interaction among miRNAs in human cancer development.

Nonintubated thoracoscopic lobectomy for lung cancer.

Objective:To evaluate the feasibility and safety of thoracoscopic lobectomy without endotracheal intubation. Summary Background Data:General anesthesia with single-lung ventilation is considered mandatory for thoracoscopic lobectomy for non–small cell lung cancer (NSCLC). Nonintubated thoracoscopic lobectomy has not been reported previously. Methods:From August 2009 through June 2010, some 30 consecutive patients with clinical stage I or II NSCLC were treated by nonintubated thoracoscopic lobectomy using epidural anesthesia, intrathoracic vagal blockade, and sedation. To evaluate the feasibility and safety of this novel technique, they were compared with a control group consisting of 30 consecutive patients with clinical stage I or II NSCLC who underwent thoracoscopic lobectomy using intubated general anesthesia from August 2008 through July 2009. Results:Collapse of the operative lung and inhibition of coughing were satisfactory in the nonintubated patients, induced by spontaneous breathing, and vagal blockade. Three patients in the nonintubated group required conversion to intubated-single lung ventilation because of persistent hypoxemia, poor epidural anesthesia pain control, and bleeding. One patient in each group was converted to thoracotomy because of bleeding. The 2 groups had comparable anesthesia durations, surgical durations, blood loss, and numbers of dissected lymph nodes. Patients who underwent nonintubated surgery had lower rates of sore throat (6.7% vs 40.0%, P = 0.002) and earlier resumption of oral intake (mean, 4.7 hours vs 18.8 hours, P < 0.001). Patients undergoing nonintubated surgery also had a trend toward better noncomplication rates (90% vs 66.7%, P = 0.057) and shorter postoperative hospital stays (mean, 5.9 days vs 7.1 days, P = 0.078). Conclusions:Nonintubated thoracoscopic lobectomy is technically feasible and is as safe as lobectomy performed with intubation in highly selected patients. It can be a valid alternative of single-lung-ventilated thoracoscopic surgery in managing early-stage NSCLC.

Strategies to target HER2/neu overexpression for cancer therapy

Amplification or overexpression of the HER2/neu (also known as erbB-2) gene has been noted in various types of human cancers. In addition to malignant transformation, the activation of signaling pathways of HER2/neu enhances various metastasis-associated properties and may render cancer cells resistant to conventional therapies. This, at least partially, contributes to the poor prognosis and lower survival rate of patients. Many studies have demonstrated that repression of HER2/neu overexpression suppresses the malignant phenotypes of cancer cells. Therefore, various novel HER2/neu-blocking agents have been developed, several of which have been tested in clinical trials with satisfactory results, including trastuzumab, a HER2/neu monoclonal antibody that has been approved by the FDA in the treatment of HER2/neu-overexpressing breast cancer patients. In this article, we intend to discuss the biological relevance and significance of HER2/neu overexpression in tumorigenesis, metastasis, and resistance to conventional therapy. We also summarize the currently available strategies and combination therapies targeting HER2/neu-overexpressing cancer cells. Although the optimal treatment for HER2/neu-overexpressing cancer patients remains elusive, the initial success of trastuzumab indicates that HER2/neu is a good target for cancer therapy. Further elucidation of HER2/neu-mediated pathways and downstream molecules is critical to provide alternative therapies, overcome drug resistance, and improve the therapeutic outcome for HER2/neu-overexpressing cancer patients.

Nonintubated thoracoscopic lung resection: a 3-year experience with 285 cases in a single institution.

OBJECTIVE Tracheal intubation with one-lung ventilation is considered mandatory for thoracoscopic surgery. This study reported the experience of thoracoscopic lung resection without endotracheal intubation in a single institution. METHODS From August 2009 through July 2012, 285 consecutive patients were treated by nonintubated thoracoscopic surgery using epidural anesthesia, intrathoracic vagal blockade, and sedation for lobectomy, segmentectomy, or wedge resection in a tertiary medical center. The feasibility and safety of this technique were evaluated. RESULTS The final diagnosis for surgery were primary lung cancer in 159 patients (55.8%), metastatic lung cancer in 17 (6.0%), benign lung tumor in 104 (36.5%), and pneumothorax in 5 (1.8%). The operative methods consisted of conventional (83.2%) and needlescopic (16.8%) thoracoscopic surgery. The operative procedures included lobectomy in 137 patients (48.1%), wedge resection in 132 (46.3%), and segmentectomy in 16 (5.6%). Collapse of the operative lung and inhibition of coughing were satisfactory in most of the patients. Fourteen (4.9%) patients required conversion to tracheal intubation because of significant mediastinal movement [5], persistent hypoxemia [2], dense pleural adhesions [2], ineffective epidural anesthesia [2], bleeding [2], and tachypnea [1]. One patient (0.4%) was converted to thoracotomy because of bleeding. No mortality was noted in our patients. CONCLUSIONS Nonintubated thoracoscopic lung resection is technically feasible and safe in selected patients. It can be a valid alternative in managing patients with pulmonary lesions.

Feasibility and Safety of Nonintubated Thoracoscopic Lobectomy for Geriatric Lung Cancer Patients

BACKGROUND The feasibility and safety of thoracoscopic lobectomy using anesthesia without tracheal intubation for treatment of geriatric non-small cell lung cancer patients is unclear, although it has been used with success in younger populations. METHODS From 2009 through 2011, 84 consecutive patients aged 65 years or older with stage I or II non-small cell lung cancer underwent thoracoscopic lobectomy. Among them, 36 patients were treated without tracheal intubation using epidural anesthesia, intrathoracic vagal blockade, and sedation (nonintubated group). The other 48 patients were treated with single-lung ventilation under general anesthesia intubated with a double-lumen tube (intubated group). The perioperative profiles and short-term outcomes of the two groups were compared. RESULTS The 84 patients were a mean age of 73.0 years (range, 65-87 years). Both groups had comparable preoperative demographic and cancer staging profiles. The anesthetic duration of the nonintubated group was shorter. Both groups had comparable operation duration and blood loss. One patient in the nonintubated group was converted to tracheal intubation due to persistent hypoxemia. Postoperatively, the two groups had comparable hospital stays, complication rates, and dissected lymph nodes. Stridor was noted in 3 patients and delirium in 4 in the intubated group, but none occurred in the nonintubated group. CONCLUSIONS Nonintubated thoracoscopic lobectomy is technically feasible and was as safe as thoracoscopic lobectomy performed with tracheal intubation in the geriatric lung cancer patients. Thoracoscopic lobectomy without tracheal intubation during anesthesia is a valid alternative for managing selected geriatric patients with non-small cell lung cancer.

Needlescopic versus conventional video-assisted thoracic surgery for primary spontaneous pneumothorax: a comparative study

BACKGROUND Management of primary spontaneous pneumothorax by needlescopic video-assisted thoracic surgery (VATS) has rarely been attempted and no comparison study with conventional VATS is available. In this study, we compared the clinical outcomes of needlescopic VATS with conventional VATS in treating primary spontaneous pneumothorax. The technique and our experience with needlescopic VATS are reported. METHODS Between April 2001 and April 2002, a total of 63 patients with recurrent, persistent, or contralateral primary spontaneous pneumothorax were recruited for this study. Operative procedures included needlescopic VATS in 28 patients and conventional VATS in 35 patients. We used a modified operative technique to improve the poor and narrower vision of the needle-videothoracoscope. RESULTS There was no mortality or major complications in either of the two groups. Needlescopic and conventional VATS groups had comparable operation times, postoperative pain, requested doses of meperidine hydrochloride, durations of postoperative chest drainage, and length of hospital stay. After a mean follow-up of 8 months, the needlescopic VATS group had less residual neuralgia (p = 0.021) and better wound satisfaction (p = 0.043) than the conventional VATS group. Ipsilateral recurrence of pneumothorax occurred in 1 patient (3.6%) in the needlescopic VATS group but not in any patients in the conventional VATS group. CONCLUSIONS Our experience showed that needlescopic VATS is technically feasible and can be a satisfactory alternative to conventional VATS in treating primary spontaneous pneumothorax. Limited vision of needlescopic VATS can be improved by the modified technique we used. However, conversion to conventional VATS or minithoracotomy is suggested in selected patients to prevent early recurrence.

Simple aspiration and drainage and intrapleural minocycline pleurodesis versus simple aspiration and drainage for the initial treatment of primary spontaneous pneumothorax: an open-label, parallel-group, prospective, randomised, controlled trial

BACKGROUND Simple aspiration and drainage is a standard initial treatment for primary spontaneous pneumothorax, but the rate of pneumothorax recurrence is substantial. We investigated whether additional minocycline pleurodesis after simple aspiration and drainage reduces the rate of recurrence. METHODS In our open-label, parallel-group, prospective, randomised, controlled trial at two hospitals in Taiwan, patients were aged 15-40 years and had a first episode of primary spontaneous pneumothorax with a rim of air greater than 2 cm on chest radiographs, complete lung expansion without air leakage after pigtail catheter drainage, adequate haematological function, and normal renal and hepatic function. After simple aspiration and drainage via a pigtail catheter, patients were randomly assigned (1:1) to receive 300 mg of minocycline pleurodesis or no further treatment (control group). Randomisation was by computer-generated random numbers in sealed envelopes. Our primary endpoint was rate of pneumothorax recurrence at 1 year. This trial is registered with ClinicalTrials.gov (NCT00418392). FINDINGS Between Dec 31, 2006, and June 30, 2012, 214 patients were randomly assigned-106 to the minocycline group and 108 to the control group (intention-to-treat population). Treatment was unsuccessful within 7 days of randomisation in 14 patients in the minocycline group and 20 patients in the control group. At 1 year, pneumothoraces had recurred in 31 of 106 (29·2%) patients in the minocycline group compared with 53 of 108 (49·1%) in the control group (p=0·003). We noted no procedure-related complications in either group. INTERPRETATION Simple aspiration and drainage followed by minocycline pleurodesis is a safe and more effective treatment for primary spontaneous pneumothorax than is simple aspiration and drainage only. Minocycline pleurodesis should be an adjunct to standard treatment for primary spontaneous pneumothorax. FUNDING Department of Health and National Science Council, Taiwan.

Nonintubated Needlescopic Video-Assisted Thoracic Surgery for Management of Peripheral Lung Nodules

BACKGROUND Video-assisted thoracic operations are usually performed with 5-mm or 10-mm instruments under general anesthesia with single-lung ventilation. Management of peripheral lung nodules by a needlescopic video-assisted thoracoscopic operation, without endotracheal intubation, has rarely been attempted. We evaluated the feasibility and safety of this minimally invasive technique in managing peripheral lung nodules. METHODS From August 2009 through March 2011, 46 patients with peripheral lung nodules were treated using 3-mm needlescopic video-assisted thoracoscopic operations for wedge resection with epidural anesthesia and sedation, without endotracheal intubation. RESULTS A definitive diagnosis was obtained in all 46. Extension of the 3-mm incisions was required in 8 patients because of primary lung cancer requiring a lobectomy in 3, pleural adhesions in 3, and difficulty in identifying or resecting the nodule in 2. Two patients required conversion to intubated single-lung ventilation because of dense adhesions between the lungs and the diaphragm. Operations lasted a mean of 69.2 ± 46.8 minutes. Postoperative side effects occurred in 4 patients, including sore throat, headache, and vomiting requiring medication. Operative complications developed in 1 patient who had air leaks for more than 3 days postoperatively. The mean postoperative chest tube drainage and hospital stay were 1.1 days and 2.7 days, respectively. Postoperative neuralgia was noted in 12 patients (26%). Most patients (74%) were very satisfied or satisfied with the resulting scars. CONCLUSIONS Nonintubated needlescopic video-assisted thoracoscopic operations are technically feasible and safe and may be a less invasive alternative in the management of selected patients with peripheral pulmonary nodules.