Discriminating association of a common telomerase reverse transcriptase promoter polymorphism with telomere parameters in non-small cell lung cancer with or without epidermal growth factor receptor mutation.

BACKGROUND: The role of epidermal growth factor receptor (EGFR) pathways in regulating telomerase is increasingly being recognised. We analysed the impact of rs2853669 single nucleotide polymorphism (SNP) on telomere parameters and its prognostic value for non-small cell lung cancer (NSCLC) with or without EGFR mutation. METHODS: The association of rs2853669 with telomerase reverse transcriptase (TERT) mRNA level and relative telomere length (RTL) was analysed using resected tumour samples from 250 NSCLC patients. We also investigated the patients' clinical outcomes with a median follow-up of 57 months (2-99 months). RESULTS: The rs2853669 T/C allele was significantly associated with lower TERT mRNA expression (versus C/C and versus T/T; p < 0.001 for both) and shorter RTL (versus C/C and versus T/T; p = 0.039 and 0.023) in patients without EGFR mutation. Such difference was not observed in their counterparts harbouring EGFR mutation. When considering the cohort as a whole, T/C allele was significantly associated with shortest overall survival compared with T/T or C/C allele (mean: 61.8, 80.9 and 88.7 months, plog-rank < 0.001) and disease-free survival (mean: 78.3, 87.9 and 91.5 months, plog-rank = 0.019). Stratification analyses showed that the negative prognostic effect of T/C on OS was constrained in patients without EGFR mutation. CONCLUSION: Our study revealed significant associations of a common SNP within TERT promoter region on telomere parameters and survival in NSCLC patients without EGFR mutation. The result may help providing instruction for therapeutic interventions targeting telomerase and evidence for investigation of TERT-EGFR interacting mechanism in telomere biology.

Sealing of the cystic and appendix arteries with monopolar electrocautery during laparoscopic combined cholecystectomy and appendectomy.

The best method to ligate the arteries during laparoscopic cholecystectomy or appendectomy remains controversy. The aim of this study is to introduce a new approach during laparoscopic combined cholecystectomy and appendectomy using a monopolar electrocautery to seal the cystic and appendix arteries. We retrospectively reviewed data from 57 patients who underwent laparoscopic combined cholecystectomy and appendectomy between December 2006 and June 2016. Each laparoscopic combined cholecystectomy and appendectomy was performed by coagulating and sealing the cystic and appendix arteries. Absorbable clip or coils were then used to ligate the proximal of cystic duct and the stump of appendix. The other side of the cystic duct and appendix which subsequently were to be removed from abdomen were used titanium clips or silk ligature. Of the 57 patients, 3 patients (5.3%) were converted to open surgery due to severe abdominal adhesions or gallbladder perforation. The mean operative time was 56 minutes (range, 40-80 minutes). Mean blood loss was 12 mL (range, 5-120 mL), and the mean postoperative hospital stay was 3.0 days (range, 2-5 days). No postoperative bleeding, biliary leakage, infection, or mortality occurred. Monopolar electrocautery to seal the cystic and appendix arteries is a safe, effective, and economical surgical procedure during laparoscopic combined cholecystectomy and appendectomy. Further randomized controlled clinical trials are required to validate our findings.

LTB4 and montelukast in transplantation-related bronchiolitis obliterans in rats.

BACKGROUND: Lung transplantation is the only effective treatment for end-stage lung diseases. Bronchiolitis obliterans, which is known as non-infectious chronic lung allograft dysfunction (CLAD) in the new classification, is the greatest threat to long-term survival after lung transplantation. This study investigated the role of leukotriene B4 (LTB4) and montelukast in transplantation-related bronchiolitis obliterans and discussed the pathophysiological significance of LTB4 in chronic rejection. METHODS: Rats were randomly divided into an experimental group (montelukast), a positive control group (dexamethasone), and a blank control group (normal saline solution; NS). Each piece of trachea removed from a F344 rat was transplanted into a Lewis rat through a 5-mm incision at the episternum by subcutaneous embedding. The recipients were treated with gastric lavage with 3 mg/kg · d montelukast suspension, 1 mg/kg · d dexamethasone, and 1 mL/kg · d NS, respectively, in each group. On Day 28, peripheral blood was drawn to measure the white blood cell counts and plasma LTB4 levels. The donor specimens were stained by H-E and Masson, and their organizational structure and extent of fibrosis were visually assessed. The measurement data were compared using one-way analysis of variance, and the categorical data were compared using the chi-square test. A P value of less than 0.05 was considered to indicate statistical significance. RESULTS: The white blood cell counts of the montelukast, dexamethasone, and NS groups were (16.0 ± 4.2) × 109/L, (19.5 ± 11.6) × 109/L, and (25.8 ± 3.6) × 109/L; no statistical significance was found (P = 0.101). The concentrations of LTB4 were 2230 ± 592 pg/mL, 1961 ± 922 pg/mL, and 3764 ± 1169 pg/mL, and statistical significance was found between the NS group and each of the others (P = 0.009). The percentages of tracheal occlusion were 73.6% ± 13.8%, 23.4% ± 3.2%, and 89.9% ± 11.3%, and statistical significance was found among the three groups (P = 0.000). CONCLUSIONS: The study established a model to simulate bronchiolitis obliterans after clinical lung transplantation. Oral administration of montelukast reduced plasma LTB4 levels in rats and played a preventive role against tracheal fibrosis after transplantation. This suggests that LTB4 may be involved in bronchiolitis obliterans after pulmonary transplantation. This study indicates a new direction for research into the prevention and treatment of bronchiolitis obliterans after lung transplantation.

A novel facilitated negative-pressure wound therapy for thoracic incision infection after esophagectomy.

BACKGROUND: Negative-pressure wound therapy (NPWT) is the therapeutic management of traumatic soft-tissue wounds and infections. The efficacy of NPWT in the treatment of thoracic incision infection is unclear. We assess the effectiveness and safety of a novel facilitated NPWT for thoracic incision infection after esophagectomy. METHODS: Between Jan. 2013 and Mar. 2016, 380 patients underwent open esophagectomy in our department. Forty-five patients with thoracic incision infection were retrospectively reviewed. Of these patients, 25 were treated with NPWT and 20 patients were treated with open wound dressing. The patients' clinical demographic data, postoperative outcomes and wound treatment cost are reviewed. RESULTS: The thoracic incision infection rate was 11.8%. All of the incision infections were cured in the hospital or on an outpatient basis. No allergic reactions or other side effects occurred with NPWT. Although the patients who were treated with NPWT did not have a significantly shorter postoperative hospital stay than those treated with open wound dressing (P=0.092), the use of NPWT therapy for thoracic incision infection led to a shorter wound healing times (13 vs. 20 days; P=0.004) and a lower wound treatment cost (P=0.020). CONCLUSIONS: Thoracic incision infection is a common complication of esophagectomy. NPWT is a safe and effective therapeutic management for thoracic incision infection that is associated with shortened wound healing times and reduced wound treatment costs than traditional open wound treatment.

Sublobar Resection for Pulmonary Aspergilloma: A Safe Alternative to Lobectomy.

BACKGROUND: This study was performed to evaluate the effectiveness of sublobar resection for the treatment of pulmonary aspergilloma compared with lobectomy. METHODS: Patients with pulmonary aspergilloma who underwent lobectomy or sublobar resection in our department between March 2007 and December 2015 were retrospectively reviewed. Data were collected for patient demographic characteristics, medical history, preoperative investigations, perioperative findings, postoperative conditions, and recurrence status. Propensity-matched comparative analyses were performed to adjust for potential differences of patients' baseline characteristics between the groups. RESULTS: A total of 96 patients underwent lobectomy, 46 patients underwent attempted sublobar resection. The median follow-up time is 53 months. No recurrence was found in either group. Three patients (3.1%) in the lobectomy group required reoperation for bleeding. The patients who underwent sublobar resection had less underlying lung disease (p = 0.031), smaller lesions (p = 0.033), and were more likely to have been treated with video-assisted thoracic surgery (p < 0.001). These differences were eliminated by propensity score matching (46 pairs were successfully matched). Comparative analyses in matched groups demonstrate that there was no marked difference in the volume and duration of chest drainage or the length of postoperative hospital stay. However, the patients with sublobar resection had shorter operation time (p = 0.004), less blood loss (p = 0.042), and less postoperative complication (p = 0.048). CONCLUSIONS: Sublobar resection performed for small simple pulmonary aspergilloma and selected complex pulmonary aspergilloma has a low recurrence rate and confers perioperative advantages compared with lobectomy.

Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma.

Lung cancer, of which non-small cell lung cancer accounts for 80%, remains a leading cause of cancer-related mortality and morbidity worldwide. Our study revealed that the expression of WD repeat containing antisense to P53 (WRAP53) is higher in lung-adenocarcinoma specimens than in specimens from adjacent non-tumor tissues. The prevalence of WRAP53 overexpression was significantly higher in patients with tumor larger than 3.0 cm than in patients with tumor smaller than 3.0 cm. The depletion of WRAP53 inhibits the proliferation of lung-adenocarcinoma A549 and SPC-A-1 cells via G1/S cell-cycle arrest. Several proteins interacting with WRAP53 were identified through co-immunoprecipitation and liquid chromatography/mass spectrometry. These key proteins indicated previously undiscovered functions of WRAP53. These observations strongly suggested that WRAP53 should be considered a promising target in the prevention or treatment of lung adenocarcinoma.

Downregulation of RUVBL1 inhibits proliferation of lung adenocarcinoma cells by G1/S phase cell cycle arrest via multiple mechanisms.

Lung cancer remains a leading cause of cancer-related mortality and morbidity worldwide, of which non-small cell lung cancer (NSCLC) accounts for 80 %. RUVBL1 is a highly conserved eukaryotic AAA+ adenosine 5'-triphosphatase (ATPase) that has many functions highly relevant to cancer. We therefore attempted to determine the potential role of RUVBL1 in the biogenesis of lung adenocarcinoma and obtained some interesting results. Our study revealed that RUVBL1 expression was higher in lung adenocarcinoma specimens than in those of adjacent non-tumor tissues and in lung cancer cell lines than in normal lung cell lines. RUVBL1 knockdown via siRNA reduced proliferation and caused G1/S phase cell cycle arrest in lung adenocarcinoma cell lines. The G1/S phase cell cycle arrest triggered by RUVBL1 downregulation could be attributed, at least in part, to repression of the AKT/GSK-3ß/cyclin D1 pathway and probably to the activation of IRE1α-mediated endoplasmic reticulum (ER) stress. We thus demonstrated for the first time that a knockdown of RUVBL1 could effectively inhibit the proliferation of lung adenocarcinoma A549 and H292 cells through the induction of G1/S phase cell cycle arrest via multiple mechanisms. These observations strongly suggested that RUVBL1 should be considered a promising target for the prevention or therapy of lung adenocarcinoma.

Mediastinal transposition of the omentum reduces infection severity and pharmacy cost for patients undergoing esophagectomy.

BACKGROUND: The greater omentum has been found to be immunologically competent in protecting abdominal organs from inflammation. Anastomotic omentoplasty has been used and proven effective in preventing anastomotic leaks after an esophagectomy. However, pulmonary complications are still a substantial problem after an esophagectomy. This study investigated the benefits of mediastinal transposition of the omentum, a modification of the conventional omental wrapping technique, in controlling overall postoperative intrathoracic complications. METHODS: From January 2010 to March 2015, 208 consecutive patients receiving an open Ivor-Lewis esophagectomy at our institution were retrospectively reviewed. One hundred twenty-one patients with omentum mediastinal transposition were assigned to the transposition group and 87 patients without omental transposition were placed in the non-transposition group. The patients' demographics, postoperative short-term outcomes, and in-hospital cost were documented and analyzed. RESULTS: Mediastinal transposition of the omentum led to a shorter postoperative hospital stay (14 vs. 16 d, P=0.038) and a lower intrathoracic infection rate (30.6% vs. 48.3%, P=0.009). Intrathoracic infection was milder in the transposition group (P=0.005), though a non-significant was found in overall complications (P=0.071). The multivariate logistic regression analyses identified omentum mediastinal transposition (P=0.007, OR=0.415) as an independent protective factor for postoperative intrathoracic infection. The total in-hospital cost was comparable in both groups (P>0.05), whereas the pharmacy cost was lower in the transposition group than in the non-transposition group (¥21,668 vs. ¥27,012, P=0.010). CONCLUSIONS: Mediastinal transposition of the omentum decreases the rate and severity of postoperative intrathoracic infection following an open Ivor-Lewis esophagectomy. This result in decreased pharmacy costs, rather than resulting in an increased economic burden sustained by surgical patients.

Time-to-Progression of NSCLC from Early to Advanced Stages: An Analysis of data from SEER Registry and a Single Institute.

The average time required for cancers to progress through stages can be reflected in the average age of the patients diagnosed at each stage of disease. To estimate the time it takes for non-small-cell lung cancer (NSCLC) to progress through different tumor, node and metastasis (TNM) stages and sizes, we compared the mean adjusted age of 45904 NSCLC patients with different stages and tumor sizes from Surveillance, Epidemiology and End Results (SEER) cancer registry database and our institute. Multiple-linear-regression models for age were generated adjusting for various factors. Caucasian, African-American and Asian patients with stage IA cancers were on average 0.8, 1.0 and 1.38 adjusted years younger, respectively, than those with stage IIIB cancers (p < 0.001). And these with T1a cancers were on average 0.84, 0.92 and 1.21 adjusted years younger, respectively, than patients with T3 cancers (p < 0.001). Patients with tumors measuring larger than 8 cm in diameter were on average 0.85 adjusted years older than these with tumors smaller than 1 cm (p < 0.001), with Caucasian demonstrating the shortest age span (0.79 years, P < 0.001). In conclusion, the time-to-progression of NSCLC from early to advanced stages varied among ethnicities, Caucasian patients demonstrating a more rapid progression nature of tumor than their African-American and Asian counterparts.

Video-assisted thoracic surgery for pulmonary sequestration: a safe alternative procedure.

BACKGROUND: Pulmonary sequestration (PS), a rare congenital anatomic anomaly of the lung, is usually treated through resection by a conventional thoracotomy procedure. The efficacy and safety of video-assisted thoracic surgery (VATS) in PS treatment has seldom been evaluated. To address this research gap, we assessed the efficacy and safety of VATS in the treatment of PS in a large Chinese cohort. METHODS: We retrospectively reviewed 58 patients with PS who had undergone surgical resection in our department between January 2003 and April 2014. Of these patients, 42 (72.4%) underwent thoracotomy, and 16 (27.6%) underwent attempted VATS resection. Clinical and demographic data, including patients' age, sex, complaints, sequestration characteristics, approach and procedures, operative time, resection range, blood loss, drainage volume, chest tube duration, hospital stay, and complications were collected, in addition to short-term follow-up data. RESULTS: Of the 58 participating patients, 55 accepted anatomic lobectomy, 2 accepted wedge resection, and 1 accepted left lower lobectomy combined with lingular segmentectomy. All lesions were located in the lower lobe, with 1-4 aberrant arteries, except one right upper lobe sequestration. Three cases (18.8%) in the VATS group were converted to thoracotomy because of dense adhesion (n=1), hilar fusion (n=1), or bleeding (n=1). No significant differences in operative time, postoperative hospital stay, or perioperative complications were observed between the VATS and thoracotomy groups, although the VATS patients had less blood loss (P=0.032), a greater drainage volume (P=0.001), and a longer chest tube duration (P=0.001) than their thoracotomy counterparts. CONCLUSIONS: VATS is a viable alternative procedure for PS in some patients. Simple sequestration without a thoracic cavity or hilum adhesion is a good indication for VATS resection, particularly for VATS anatomic lobectomy. Thoracic cavity and hilum adhesion remain a challenge for VATS.

Clinical Characteristics and Prognostic Significance of TERT Promoter Mutations in Cancer: A Cohort Study and a Meta-Analysis.

BACKGROUND: The prevalence of telomerase reverse transcriptase (TERT) promoter mutations (pTERTm) in non-small-cell lung cancer (NSCLC) have been investigated, but the results were inconsistent. In addition, several studies have analysed the role of pTERTm in the etiology of various types of cancers, however, the results also remain inconsistent. METHODS: The genomic DNA sequence of 103 NSCLC samples were analysed to investigate the frequency of pTERTm in these patients and to establish whether these mutations are associated with their clinical data. Furthermore, a meta-analysis based on previously published articles and our cohort study was performed to investigate the association of pTERTm with patient gender, age at diagnosis, metastasis status, tumour stage and cancer prognosis (5-year overall survival rate). RESULTS: In the cohort study, 4 patients had C228T and 2 had C250T, with a total mutation frequency up to 5.8%. Significant difference of clinical data between pTERTm carriers and noncarriers was only found in age at diagnosis. In the meta-analysis, We found that pTERTm carriers in cancer patients are older than noncarriers (Mean difference (MD) = 5.24; 95% confidence interval [CI], 2.00 to 8.48), male patients were more likely to harbour pTERTm (odds Ratios (OR) = 1.38; 95% CI, 1.22 to 1.58), and that pTERTm had a significant association with distant metastasis (OR = 3.78; 95% CI, 2.45 to 5.82), a higher tumour grade in patients with glioma (WHO grade III, IV vs. I, II: OR, 2.41; 95% CI, 1.88 to 3.08) and a higher tumour stage in other types of cancer (III, IV vs. I, II: OR, 2.48; 95% CI, 1.48 to 4.15). pTERTm was also significantly associated with a greater risk of death (hazard ratio = 1.71; 95% CI, 1.41 to 2.08). CONCLUSIONS: pTERTm are a moderately prevalent genetic event in NSCLC. The current meta-analysis indicates that pTERTm is associated with patient age, gender and distant metastasis. It may serves as an adverse prognostic factor in individuals with cancers.

RET mutation p.S891A in a Chinese family with familial medullary thyroid carcinoma and associated cutaneous amyloidosis binding OSMR variant p.G513D.

There are no reports on the relationship between familial medullary thyroid carcinoma (FMTC) associated with cutaneous amyloidosis (CA) and RET or OSMR/IL31RA gene mutations. In this study, we investigated a Chinese family with FMTC/CA and found a recurrent RET c.2671T>G (p.S891A) mutation in six of 17 family members. Three of the six p.S891A mutation carriers presented with medullary thyroid carcinoma (MTC). Of them, three (two with and one without MTC) were diagnosed as having combined lichen/macular biphasic CA. We also identified a novel RET variant, c.1573C>T (p.R525W) in five members. Of them, three carriers had no evidence of thyroid/skin or basal serum/stimulated calcitonin abnormalities. In vitro cell proliferation assay indicated that oncogenic activity of RET p.S891A was slightly enhanced by p.R525W, whereas p.R525W alone had no effect on cell proliferation. Meanwhile, we identified a novel OSMR variant, c.1538G>A (p.G513D) in seven members. We noticed that three OSMR p.G513D carriers presenting with CA also had the RET p.S891A mutation. Our investigation indicated that the RET p.S891A mutation combined with OSMR p.G513D may underlie a novel phenotype manifesting as FMTC and CA.

Association between the TERT Genetic Polymorphism rs2853676 and Cancer Risk: Meta-Analysis of 76,108 Cases and 134,215 Controls.

BACKGROUND: Several recent studies have identified that the TERT genetic polymorphism rs2853676 is associated with cancer risk, but presented inconsistent results. We investigated these inconclusive results by performing a meta-analysis to systematically evaluate the association. METHODS: We conducted a search in PubMed, Google Scholar and ISI Web of Science to select studies on the association between TERT rs2853676 and cancer risk. We conducted a stratified analysis using cancer type, ethnicity and source of controls. We calculated the odds ratios (OR) and 95% confidence intervals (CI). Article quality, heterogeneity, sensitivity, publication bias and statistical power were also assessed. RESULTS: 26 articles covering 76,108 cases and 134,215 controls met our inclusion criteria. A significant association between TERT rs2853676 allele A and cancer susceptibility was demonstrated under a per-allele risk analysis (OR = 1.08, 95% CI = 1.04-1.13). Stratification analysis revealed an increased cancer risk in subgroups of glioma, lung cancer and ovarian cancer. No significant increase was found in melanoma, breast cancer, pancreatic cancer and colorectal cancer. In a subgroup analysis of lung cancer, a statistically significant increase was only observed in adenocarcinoma. Moreover, a stratified analysis performed for ethnic groups revealed that the significant increase was only observed in Caucasians, whereas a non-significant increase was found in Asians. CONCLUSIONS: This meta-analysis suggests that the TERT genetic polymorphism rs2853676 is associated with increased risk of glioma, lung adenocarcinoma and ovarian cancer among Caucasians. Further functional studies are warranted to validate this association and investigate further.

The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma.

We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.

Efficacy of electrocoagulation in sealing the cystic artery and cystic duct occluded with only one absorbable clip during laparoscopic cholecystectomy.

BACKGROUND: Even though laparoscopic cholecystectomy (LC) emerged over 20 years ago, controversies persist with regard to the best method to ligate the cystic duct and artery. We proposed to assess the effectiveness and safety of electrocoagulation to seal the cystic artery and cystic duct after their occlusion with only one absorbable clip. MATERIALS AND METHODS: We retrospectively compared the clinical data for 635 patients undergoing LC using electrocoagulation to seal the cystic artery and cystic duct that were occluded with only one absorbable clip (Group 1) and 728 patients undergoing LC using titanium clips (Group 2). In parallel, 30 rabbits randomized into six groups underwent cholecystectomy. After cystic duct ligation with absorbable or titanium clips, the animals were sacrificed 1, 3, or 6 months later, and intraabdominal adhesions were assessed after celiotomy. RESULTS: The mean operative time was significantly shorter (41.6 versus 58.9 minutes, P<.01) in Group 1 than in Group 2. No cystic duct leaks occurred in any patients from Group 1, compared with seven leaks among the 728 (0.96%) patients from Group 2 (P<.05). The morbidity was significantly higher in Group 2 than in Group 1 (3.43% versus 1.58%). Mean intraoperative blood loss and hospitalization length were not significantly different between the two groups, and no deaths occurred in either group. In animal experiments, adhesion was tighter for absorbable than for titanium clips, but fibrous tissue encapsulation was thinner at the site of titanium clips. CONCLUSIONS: Electrocoagulation of the cystic artery and cystic duct that were occluded with only one absorbable clip is safe and effective during LC. This approach is associated with shortened operative times and reduced leakage, compared with the standard method using metal clips.