Yi-Dan Lin

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Cisplatin [cis-diaminodichloroplatinum (II) (CDDP)] is the cornerstone of lung cancer chemotherapy. However, its efficacy is limited due to the development of drug resistance in cancer cells. This study was designed to uncover the mechanisms under CDDP resistance in lung cancer cells involving endoplasmic reticulum (ER) stress tolerance-induced and GRP78-dependant Akt activation. In this study we established ER stress-tolerant (ERST) human lung cancer lines H460et and A549et. We found that the ERST Lung cancer cells are resistant to CDDP treatment. We further showed that, compared to the parental cell lines, H460et and A549et show significantly increased GRP78 and phospho(p)-Akt levels. And phosphorylation of Akt, which can be regulated by GRP78, is essential to the ERST-associated CDDP resistance. Our findings identify a new mechanism of regulating Akt activity and a new mechanism through which CDDP resistance is formed in lung cancer cells.

Selective En Masse Ligation of the Thoracic Duct to Prevent Chyle Leak After Esophagectomy

BACKGROUND Postoperative chylothorax remains an important cause of reoperation and prolonged hospital stay after esophagectomy for the treatment of esophageal carcinoma. Chylothorax is potentially life threatening and difficult to manage. The benefit of routine thoracic duct ligation is controversial. A promising alternative is to identify chyle leaks at the time of esophagectomy and perform the ligation selectively. We developed a novel technique to identify chyle leak at the time of esophagectomy and compared it with routine ligation of thoracic duct. METHODS This cohort study involved all of the qualified patients with resectable esophageal carcinoma treated between March 1, 2011, and December 31, 2015, by a single surgical team at West China Hospital. Patients receiving routine en masse ligation of the thoracic duct were assigned to group A, and patients receiving selective en masse ligation of the thoracic duct were assigned to group B. All patients in the selective ligation group received 120 mL olive oil orally before the operation. The end point included frequencies of chyle leak detected at the time of esophagectomy, postoperative chylothorax, and need for chylothorax-related reoperation. RESULTS The study enrolled 296 patients who fulfilled the study requirement: 55 in group A and 241 in group B. Patients in group A experienced significantly higher incidences of postoperative chylothorax and chylothorax-related reoperation than group B (9.1% vs 0% [p < 0.01] and 3.6% vs 0% [p < 0.01]). Incidence of detection of intraoperative chyle leak (chylothorax plus chylous ascites) was significantly higher in group B than in group A (9.5% vs 0%, p < 0.01). No intraoperative or postoperative complications related to preoperative oral olive oil administration or selective en masse ligation of the thoracic duct were observed. CONCLUSIONS Our method of selective en masse ligation of the thoracic duct during esophagectomy was feasible and safe and was associated with reduced rates of postoperative chylothorax.

Novel gene mutations in well-differentiated fetal adenocarcinoma of the lung in the next generation sequencing era

OBJECTIVES Since well-differentiated fetal adenocarcinoma of lung (WDFA) is an extremely rare subtype of invasive lung adenocarcinoma, histologic features, biomarkers and molecular aberrant of it are not fully determined. This article aims to investigate the clinic-pathologic details and potential driver genes of WDFA. MATERIALS AND METHODS Two cases of WDFA were selected from a large cohort of 730 cases of primary adenocarcinoma of the lung resected in West China Hospital of Sichuan University between January 2016 and June 2017, retrospectively. Both of them were conducted to immunohistochemical profile and gene mutation analysis by using 56-parelle-NGS. RESULTS Microscopically, besides conventional histologic characteristics of WDFA, such as well-differentiated glands composed of obvious glycogen-rich cells and squamoid morules formation, remarkable proliferation of benign fibrous tissue, focal necrosis and mitoses were found. Unlike the common adenocarcinomas of the lung, WDFAs showed nuclear/cytoplasmic expression of β-catenin, diffuse expression for TTF-1, and focal for Napsin A. Furthermore, molecular analysis demonstrated two novel missense gene mutations of BRCA2 and TSC2, as well as the classical CTNNB1 gene mutation and silent mutation of DDR2 gene. CONCLUSIONS This report presents the first case with two novel gene mutations of the WDFA, suggesting that in addition to β-catenin, BRCA2 and TSC2 might play some important roles in up-regulation of Wnt signaling pathway. Moreover, use of NGS technique is helpful to understand the biology of this rare neoplasm and provide the potential gene for targeted therapy.

Can lobe-specific lymph node dissection be an alternative to systematic lymph node dissection in treating early-stage non-small cell lung cancer: a comprehensive systematic review and meta-analysis?

Background Whether lobe-specific lymph node dissection (L-SLND) could serve as an alternative to systematic lymph node dissection (SLND) in treating early-stage non-small cell lung cancer (NSCLC) remains unclear. Therefore, we conducted this comprehensive meta-analysis to compare the effect of L-SLND with that of SLND in treating early-stage NSCLC. Methods A systematic literature search in PubMed and Embase was conducted to identify relevant studies up to 30 November 2017. Data including 5-year overall survival (OS) and disease-free survival (DFS) rates, recurrence rates, and morbidity rate were extracted and analysed. Results A total of six studies [one randomized controlled trial (RCT) and five retrospective cohort studies] consisting of 2,037 patients with early-stage NSCLC were included for analysis. Meta-analysis showed that there was no significant difference of 5-year OS [81.7% and 79.5%, respectively; risk ratio (RR) =1.021; 95% confidence interval (CI), 0.977-1.068; P=0.352] and DFS (76.4% and 69.9%, respectively; RR =1.061; 95% CI, 0.999-1.128; P=0.054) between patients treated with L-SLND and those with SLND. Moreover, there was also no significant difference of total recurrence rates (24.3% and 25.8%, respectively; RR =0.892; 95% CI, 0.759-1.048; P=0.166) and loco-regional recurrence rates (7.9% and 9.3%, respectively; RR =0.851; 95% CI, 0.623-1.162; P=0.310) between patients treated with L-SLND and those with SLND. However, patients treated with L-SLND yielded a significant lower morbidity rate than those treated with SLND (10.2% and 13.5%, respectively; RR =0.681; 95% CI, =0.521-0.888; P=0.005). Conclusions L-SLND yielded a significantly lower risk of morbidity compared to SLND without compromising long-term oncologic outcomes based on available studies with relatively poor quality. L-SLND may serve as an alternative to SLND in treating early-stage NSCLC. Further well-conducted RCTs, however, are badly needed to confirm and update our conclusions.

Novel biologic factors correlated to visceral pleural invasion in early-stage non-small cell lung cancer less than 3 cm

Background Visceral pleural invasion (VPI) in early-stage non-small cell lung cancer (NSCLC) is traditionally believed as the result of too much close distance between cancerous lesion and the visceral pleura, but whether there are any other biologic factors correlated to VPI beyond our instinctive thoughts remains unclear. Therefore, we conducted this study to investigate potential factors correlated to VPI comprehensively. Methods Both clinical and pathological characteristics of patients undergoing surgery for NSCLC with a size of ≤3 cm were retrospectively analysed. Results A total of 403 patients were included for analysis. Patients with VPI had older age than those without (61.1 vs. 56.1 years; P<0.001). The mean size of NSCLCs with VPI was larger than those without (2.1 vs. 1.6 cm; P<0.001). Moreover, NSCLCs with VPI were located closer to visceral pleura (0.8 vs. 1.3 cm; P<0.001) and showed larger rates of pleural indentation (86.8% vs. 45.6%; P<0.001) and spiculation (59.7% vs. 34.7%; P<0.001) than those without. Pathologically, NSCLCs with VPI tended more likely to be adenocarcinomas (96.9% vs. 92.7%; P=0.097), and was more likely to be poorly differentiated (38.0% vs. 15.3%; P<0.001), to have cancer embolus (6.2% vs. 0.7%; P=0.001) and lymph node metastasis (29.5% vs. 10.2%; P<0.001) than those without. Besides shorter distance to visceral pleura [odds ratio (OR)=2.169, 95% CI: 1.221-3.855; P=0.008], older age [OR =2.119, 95% confidence interval (CI): 1.255-3.503; P=0.005], pleural indentation (OR =3.679, 95% CI: 1.888-7.169; P<0.001), adenocarcinoma (OR =4.741, 95% CI: 1.383-16.255; P=0.013), and poor tumor differentiation (OR =11.816, 95% CI: 4.470-31.234; P<0.001) were also found to be closely correlated to VPI in early-stage NSCLC. Conclusions Besides shorter distance to visceral pleura and pleural indentation, elderly, adenocarcinoma, and poor tumor differentiation were novel biologic factors correlated to VPI in early-stage NSCLC, which may explain why VPI was an unfavorable prognostic factor for early-stage NSCLC.

The influence of heparin on coagulation function of patients undergoing video-assisted major thoracic surgery

Background Venous thromboembolism (VTE) remains a common complication after major thoracic surgery, especially resection of lung or esophagus cancer. This trial aims to explore the influence of preoperative usage of heparin on coagulation function of patients treated with video-assisted major thoracic surgery. Methods This prospective randomized control trial collected 91 patients who are diagnosed with lung or esophagus cancer intending to accept video-assisted neoplasm resection from June 2016 to May 2017 in West China Hospital, Sichuan University. After admission to hospital, the patients received heparin sodium (unfractionated heparin) 5,000 U twice a day before operation. The change of blood platelet count (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), international normalized ratio (INR) was collected and analyzed at the points of admission to hospital and post-operation. Results The mean value of all coagulation parameters (PLT, PT, APTT, TT, INR, FIB) were in normal range both before and after operation. Postoperative PLT and FIB were not significantly different from preoperative PLT and FIB respectively (P>0.05). Preoperative PT, APTT, and INR increased significantly compared to pre-operation respectively (P<0.05). Postoperative TT significantly decreased when compared to preoperative TT (P<0.05). Preoperative and postoperative abnormal rate of PT or APTT or TT or INR (number of abnormal cases/all cases) was not different significantly respectively (P>0.05). Postoperative mean drainage was 240 mL/d, mean time of hospital stay was 7.50 days, drainage tube was maintained for 4.22 days on average. Conclusions All patients underwent video-assisted major thoracic surgery with preoperative use of heparin, there were significant differences in coagulation function after operation. However, mean values of all coagulation parameters stayed normal range clinically. In a word, the method showed no influence on coagulation function clinically.

Cancerous esophageal stenosis before treatment was significantly correlated to poor prognosis of patients with esophageal cancer: a meta-analysis

Background Cancerous esophageal stenosis encountered during endoscopic ultrasonography before treatment was observed in about 30% of esophageal cancer patients. Since the pT stage in TNM classification measures only the depth of infiltration but not the growth to esophagus, it is interesting to know whether tumor growth into the esophagus (and eventual stenosis) is of added value in prognostic assessment. However, the impact of esophageal stenosis on survival of esophageal cancer patient remains unclear. Therefore, we conducted a meta-analysis focusing on current topic for the first time. Methods A systematic literature search in PubMed and EMBASE was conducted to identify relevant studies up to 14 March 2018. Data of 5-year overall survival (OS) was extracted and analysed. Results A total of five cohort studies consisting of 1,282 patients (278 patients with cancerous esophageal stenosis before treatment and 1,004 patients without) with esophageal cancer treated with surgery, chemoradiotherapy, or palliative therapy were included for analysis. Meta-analysis showed that patients with esophageal stenosis had significantly lower 5-year OS [22.3% and 33.0%, respectively; risk ratio (RR) =1.21; 95% CI, 1.11-1.32; P<0.001; I2=27.1%] than those without. No heterogeneity or publication bias was observed during analysis. Conclusions Patients with cancerous esophageal stenosis identified by endoscopy before treatment had significantly poorer survival than those without. High-quality studies with appropriate adjustments for confounding factor are needed to confirm the findings.

Oesophageal adenocarcinoma has a higher risk of lymph node metastasis than squamous cell carcinoma: a propensity score-matched study

OBJECTIVES The pattern of lymph node metastasis is a predominant element in tumour biology, which is closely related to optimal therapeutic modality. Controversy remains as to which histopathology type of oesophageal cancer-adenocarcinoma or squamous cell carcinoma (SCC)-is more likely to have lymph node metastasis. Therefore, this study aimed to apply propensity score-matched analysis to draw an objective conclusion for providing initial evidence of the potential need for different therapeutic strategies for these 2 cancer types. METHODS A retrospective analysis of patients who underwent radical oesophagectomy with lymphadenectomy, but without preoperative treatment for pathologically and immunohistochemically diagnosed oesophageal adenocarcinoma or SCC, was conducted. Data for analysis included age, gender, body mass index, pathologic findings, procedures of oesophagectomy and rate of lymph node metastasis. Propensity score-matched analysis was conducted to eliminate the bias effects of confounding factors. RESULTS A total of 1204 patients (including 118 with adenocarcinoma and 1086 with SCC) from January 2012 to June 2016 was included for analysis. In the analysis of unmatched patients, those with adenocarcinomas had significantly larger mean numbers of positive lymph nodes (3.8 and 1.5, respectively; P < 0.001) and higher rates of lymph node metastasis (71.2% and 49.0%, respectively; P < 0.001) than those with an SCC. However, other confounding factors such as surgical procedures, tumour location, pT stage and lymphovascular invasion also differed significantly between the adenocarcinoma and SCC cases. In the analysis of 96 matched patients, those confounding factors were well matched, and cases of adenocarcinoma still had a significantly larger mean number of positive lymph node (4.5 and 1.8, respectively; P = 0.003) and higher rate of lymph node metastasis (75.0% and 45.8%, respectively; P = 0.003) than did those with SCC. CONCLUSIONS Cases of oesophageal adenocarcinoma had a higher risk of lymph node metastasis than did those with SCC in this series, which indicates that different therapeutic modalities should be applied for these 2 different malignant entities.