Daniel K. H. Tong

Overexpression of transferrin receptor CD71 and its tumorigenic properties in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in endemic Asian regions. In the present study, we investigated the clinical implication and role of transferrin receptor CD71 in ESCC. CD71 has a physiological role in cellular iron intake and is implicated in the carcinogenesis of various types of tumors. In our cohort, more than a 2-fold upregulation of the CD71 transcript was detected in 61.5% of patients using quantitative polymerase chain reaction. Immunohistochemical analysis also showed strong membranous and cytoplasmic localization of CD71 in paraffin-embedded tumors. Staining parallel tumor sections with the proliferative marker Ki-67 revealed that the pattern of Ki-67 staining was associated with CD71 expression. Analysis of clinicopathological data indicated that CD71 overexpression can be used as an indicator for advanced T4 stage (p=0.0307). These data suggested a strong link between CD71 and ESCC. Subsequent in vitro assays using short interfering RNA (siRNA) to suppress CD71 expression confirmed the tumorigenic properties of CD71 in ESCC; cell growth inhibition and cell cycle arrest at S phase were observed in CD71-suppressed cells. The underlying mechanism involved activation of the MEK/ERK pathway. In summary, the present study provides evidence showing the tumorigenic properties of CD71 in ESCC with clinical correlations and suggests targeting CD71 as a strategy for the treatment of ESCC.

Transrectal intraperitoneal assess with transanal endoscopic operation (TEO) device in pig model

Background Gaining peritoneal access with subsequent safe closure is a prerequisite for natural orifice translumenal surgery (NOTES). We explored the possibility of transanal endoscopic operation (TEO) device to perform transrectal peritoneoscopy in a pig model. Objective Performing transrectal peritoneoscopy with TEO device in pig model. Methods Two pigs were used for transrectal peritoneoscopy. A 40-mm rectoscope was inserted via the anus after the induction of general anesthesia. Proctotomy was then created with diathermy and the endoscope was passed through the pararectal space into the peritoneal cavity. Proctotomy was closed with absorbable suture after completion of peritoneoscopy. Results Completion of the procedures was achieved in 2 pigs. Both pigs survived for more than 30 days. Necropsy revealed completely healed rectum with no evidence of leakage or abscess formation. Adhesions around the colostomy site were minimal. Conclusions In conclusion, incorporation of TEO system is safe and useful in animal model for creation and closure of proctotomy for natural orifice translumenal surgery in transrectal access, further experiment should be performed to validate the possibility of application in human. Potential complications need to be addressed and well documented.

Management of oesophageal cancer

Oesophageal cancer is a disease of dismal prognosis. There are variations of epidemiology among different ethnic groups and geographic regions. India is a country with high incidence. This can be attributed to the interplay between environmental, dietary factors and life-style of the population of the country. Optimal therapeutic strategy for patients with oesophageal cancer demands individual consideration.Majority of oesophageal cancer patients present at an advanced stage of disease. Screening programmes or strategies aiming at early diagnosis can improve the prognosis; unfortunately this is not cost-effective except in very high incidence areas. Accurate staging can help select the most appropriate treatments, such as excluding those patients with metastatic disease who are unlikely to benefit from surgery, and treating very early lesions with endoscopic means. When surgery is indicated, treating patient in a high-volume centre can improve the outcome and minimise complications. Although surgical resection remains the main treatment modality, long-term prognosis after surgical resection alone has been suboptimal except in those with early disease. Multidisciplinary approaches including chemotherapy and radiotherapy with or without surgery are increasingly employed for patients with advanced disease. Collaboration among surgeons, clinical oncologists, radiologists and physicians is of utmost importance to achieve the best results. Treatment for patients should be individualised to enhance outcome.

14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules.

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.

Continuous intraoperative vagus nerve stimulation for monitoring of recurrent laryngeal nerve during minimally invasive esophagectomy

For squamous cell carcinoma of the esophagus, extended mediastinal lymphadenectomy especially around the bilateral recurrent laryngeal nerves (RLN) is associated with high risk of nerve injury. This does not only result in hoarseness of voice, increase the chance of pulmonary complications, but would also affect the quality of life of patients in the long term. Methods to improve safety of lymphadenectomy are desirable. Continuous intraoperative nerve monitoring (CIONM) based on a system using vagus nerve stimulation was tested. In thyroidectomy, this system has been shown to be useful. Our patient cohort was unselected, with the intent to perform bilateral RLN dissection undergoing video-assisted thoracoscopic (VATS) esophagectomy. Intermittent nerve stimulation for mapping and CIONM were employed to monitor left RLN nodal dissection, while only intermittent stimulation was used for the right RLN. CIONM has the potential to aid RLN dissection. The learning curves for the placement technique of CIONM, the threshold level and the interpretation of myographic amplitude and latency have been overcome. With the availability of nerve mapping and CIONM, more aggressive and thorough nodal dissection may be possible with less fear of RLN injury.

PET/CT in the evaluation of treatment response to neoadjuvant chemoradiotherapy and prognostication in patients with locally advanced esophageal squamous cell carcinoma

ObjectiveTo investigate the role of fluorine-18-fluorodeoxyglucose PET/computed tomography for the prognostication and evaluation of neoadjuvant chemoradiotherapy response in locally advanced esophageal squamous cell carcinoma. MethodsAll consecutive biopsy-proven esophageal squamous cell carcinoma patients with PET/computed tomography at baseline (PET0) and 1 month after the completion of neoadjuvant chemoradiotherapy (PET1) between January 2008 and December 2013, followed by esophagectomy, were included. Maximum and mean standard uptake values (SUVmax and SUVmean), metabolic tumor volume, and total lesion glycolysis of all lesions at PET0 and PET1 were analyzed. Logistic and Cox regressions were used to identify factors predictive of pathological complete remission (pCR), overall survival, and recurrence-free survival. Cut-offs were identified using leave-one-out cross-validation adjusted receiver operator curve-based methods. A Kaplan–Meier model was adopted to compare survivals between groups using log-rank tests. ResultsOf a total of 52 patients (45 men, age 21–78 years), pCR was achieved in 21 (40.4%). SUVmax of primary tumor at PET1 was independently predictive of pCR [P=0.013, odds ratio=0.736, 95% confidence interval (CI): 0.578–0.937]; using a leave-one-out cross-validation-adjusted cut-off of 2.7, pCR could be predicted with a sensitivity of 71.0%, a specificity of 66.7%, a positive predictive value of 75.9%, and a negative predictive value of 60.9%. In the subset of 40 patients with standardized treatment included in survival analysis, total lesion glycolysis (P=0.002, hazard ratio: 1.029, 95% CI: 1.01–1.048) and SUVmax (P=0.003, hazard ratio: 1.167, 95% CI: 1.055–1.290) of nodal metastasis at PET0 were independently predictive of overall survival and recurrence-free survival, respectively. ConclusionBaseline total lesion glycolysis and SUVmax of nodal metastases are significant independent predictors of survival, whereas post-treatment SUVmax of the primary tumor is predictive of pCR. However, the predictive value of the latter is modest, which may limit its clinical utility.

Alport's syndrome : case of a giant esophageal tumor

Alport’s syndrome–diffuse leiomyomatosis (AS–DL) is a rare clinical entity. The syndrome consists of hematuric nephropathy, ocular lesions, and sensorineural deafness associated with leiomyomas of the gastrointestinal, respiratory and female reproductive tracts. Esophageal leiomyomatosis is characterized by diffuse proliferation of the esophageal wall smooth muscle layer, causing obstruction. The usual presenting symptom is dysphagia. We describe a patient with Alport’s syndrome associated with a large esophageal leiomyoma with dyspnoea as the first presenting symptom. Imaging such as computed tomography (CT) is useful in aiding diagnosis. A high index of suspicion is needed for diagnosis of Alport’s syndrome in a patient presenting with esophageal leiomyomatosis. Surgical resection is currently the treatment of choice in symptomatic individuals.

Gene expression profiling identified high-mobility group AT-hook 2 (HMGA2) as being frequently upregulated in esophageal squamous cell carcinoma.

Background: Esophageal cancer is one of the most deadly malignancies worldwide and esophageal squamous cell carcinoma (ESCC) is the most frequent type. Methods: We identified up-regulated genes from gene expression profiles of HKESC-4 cell line, its parental tumor tissues, non-tumoral esophageal epithelia and lymph nodes with metastatic carcinoma using Human Genome U133 Plus 2.0 microarray. Results: Four genes [High-mobility group AT-hook 2 (HMGA2), paternally expressed 10 (PEG10), SH3 and multiple ankyrin repeat domains 2 (SHANK2) and WNT1 inducible signaling pathway protein 3 (WISP3)] were selected for further validation with real-time quantitative polymerase chain reaction (qPCR) in a panel of ESCC cell lines and clinical specimens. HMGA2 was found to be overexpressed in the panel of ESCC cell lines tested. By using immunohistochemistry, HMGA2 was found to be up-regulated in 70% of ESCC tissues (21 out of 30 cases). Conclusion: This study demonstrates successful use of gene microarray to identify and reveal HMGA2 as a novel and consistently overexpressed gene in ESCC cell lines and clinical samples. - See more at: http://www.sciencedomain.org/abstract.php?iid=177&id=12&aid=963#.UoAhmCdQga8