The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing ...the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk.
We report patient outcomes from esophageal resection with respect to morbidity and cancer survival comparing open thoracotomy and laparotomy (Open), with a thoracoscopic/laparotomy approach ...(Thoracoscopic-Assisted) and a total thoracoscopic/laparoscopic approach (Total MIE).
From a prospective database of all patients managed with cancer of the esophagus or esophagogastric junction, patients who had a resection using one of three techniques were analyzed to assess postoperative variables, adequacy of cancer clearance, and survival.
The number of patients for each procedure was as follows: Open, 114; Thoracoscopic-Assisted, 309; and Total MIE, 23. The groups were comparable with respect to preoperative variables. The differences in the postoperative variables were: less median blood loss in the Thoracoscopic-Assisted (400 mL) and Total MIE (300 mL) groups versus Open (600 mL); longer time for Total MIE (330 minutes) versus Thoracoscopic-Assisted (285 minutes) and Open (300 minutes); longer median time in hospital for Open (14 days) versus Thoracoscopic-Assisted (13 days), Total MIE (11 days) and less stricture formation in the Open (6.1%) versus Thoracoscopic-Assisted (21.6%), Total MIE (36%). There were no differences in lymph node retrieval for each of the approaches. Open had more stage III patients (65.8%) versus Thoracoscopic-Assisted (34.4%), Total MIE (52.1%). There was no difference in survival when the groups were compared stage for stage for overall median or 3-year survival.
Minimally invasive techniques to resect the esophagus in patients with cancer were confirmed to be safe and comparable to an open approach with respect to postoperative recovery and cancer survival.
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large ...EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.
Abstract Introduction Preoperative chemotherapy (CT) and preoperative chemoradiation therapy (CRT) for resectable oesophageal cancer have been shown to improve overall survival in meta-analyses. ...There are limited data comparing these preoperative therapies. We report the outcomes of a randomised phase II trial comparing preoperative CT and CRT for resectable adenocarcinoma of the oesophagus and gastro-oesophageal junction. Methods Patients were randomised to receive preoperative CT with cisplatin (80 mg/m2 ) and infusional 5 fluorouracil (1000 mg/m2 /d) on days 1 and 21, or preoperative CRT with the same drugs accompanied by concurrent radiation therapy commencing on day 21 of chemotherapy and the 5 fluorouracil reduced to 800 mg/m2 /d. The radiation dose was 35 Gy in 15 fractions over 3 weeks. The endpoints were toxicity, response rates, resection (R) status, progression-free survival (PFS), overall survival (OS) and quality of life. Results Seventy-five patients were enroled on the study: 36 received preoperative CT and 39 preoperative CRT. Toxicity was similar for CT and CRT. Eight patients (11%) did not proceed to resection. The histopathological response rate (CRT 31% versus CT 8%, p = 0.01) and R1 resection rate (CRT 0% versus CT 11%, p = 0.04) favoured those receiving CRT. The median PFS was 14 and 26 months for CT and CRT respectively ( p = 0.37). The median OS was 29 months for CT compared with 32 months for CRT ( p = 0.83). Conclusions Despite no difference in survival, the improvement from preoperative CRT with respect to margin involvement makes this treatment a reasonable option for bulky, locally advanced resectable adenocarcinoma of the oesophagus.
Esophageal adenocarcinoma (EAC) has become a major concern in Western countries due to rapid rises in incidence coupled with very poor survival rates. One of the key risk factors for the development ...of this cancer is the presence of Barrett's esophagus (BE), which is believed to form in response to repeated gastro-esophageal reflux. In this study we performed comparative, genome-wide expression profiling (using Illumina whole-genome Beadarrays) on total RNA extracted from esophageal biopsy tissues from individuals with EAC, BE (in the absence of EAC) and those with normal squamous epithelium. We combined these data with publically accessible raw data from three similar studies to investigate key gene and ontology differences between these three tissue states. The results support the deduction that BE is a tissue with enhanced glycoprotein synthesis machinery (DPP4, ATP2A3, AGR2) designed to provide strong mucosal defenses aimed at resisting gastro-esophageal reflux. EAC exhibits the enhanced extracellular matrix remodeling (collagens, IGFBP7, PLAU) effects expected in an aggressive form of cancer, as well as evidence of reduced expression of genes associated with mucosal (MUC6, CA2, TFF1) and xenobiotic (AKR1C2, AKR1B10) defenses. When our results are compared to previous whole-genome expression profiling studies keratin, mucin, annexin and trefoil factor gene groups are the most frequently represented differentially expressed gene families. Eleven genes identified here are also represented in at least 3 other profiling studies. We used these genes to discriminate between squamous epithelium, BE and EAC within the two largest cohorts using a support vector machine leave one out cross validation (LOOCV) analysis. While this method was satisfactory for discriminating squamous epithelium and BE, it demonstrates the need for more detailed investigations into profiling changes between BE and EAC.
Background: Barrett's esophagus, a metaplastic precursor to esophageal adenocarcinoma, is becoming increasingly prevalent
in many populations. Clinical studies suggest acid reflux causes Barrett's ...esophagus; however, no population-based estimates
of risk have been reported, and the role of other health factors in modifying risk is unclear.
Methods: We conducted a population-based case-control study in Brisbane, Australia. Cases were 167 patients with histologically
confirmed Barrett's esophagus diagnosed between February and December 2003. Age-matched and sex-matched controls ( n = 261) were randomly selected from a population register. Data on exposure to self-reported symptoms of acid reflux, smoking,
obesity, and other factors were collected through self-completed questionnaires followed by telephone interview. Risks of
Barrett's esophagus and Barrett's esophagus with dysplasia associated with these exposures were estimated by the odds ratio
(OR) and 95% confidence interval (95% CI), both crude and adjusted for other factors.
Results: Self-reported weekly episodes of acid reflux were associated with greatly increased risks of Barrett's esophagus
(adjusted OR, 29.7; 95% CI, 12.2-72.6) and Barrett's esophagus with dysplasia (OR, 59.7; 95% CI, 18.5-193). Smoking was also
associated with risk of Barrett's esophagus. We found evidence of interactions between symptoms of acid reflux and smoking
and obesity. Obese people with self-reported symptoms of acid reflux had markedly higher risks of Barrett's esophagus (OR,
34.4; 95% CI, 6.3-188) than people with reflux alone (OR, 9.3; 95% CI, 1.4-62.2) or obesity alone (OR, 0.7; 95% CI, 0.2-2.4).
Similarly, those reporting both acid reflux symptoms and smoking were at substantially higher risks of Barrett's esophagus
(OR, 51.4; 95% CI, 14.1-188) than those reporting acid reflux or smoking alone.
Conclusions: Although history of symptoms of acid reflux is the principle factor associated with Barrett's esophagus, risks
are substantially increased by obesity and smoking.
Background
Most studies analyzing risk factors for pulmonary morbidity date from the early 1990s. Changes in technology and treatment such as minimally invasive esophagectomy (MIE) and neoadjuvant ...treatment mandate analysis of more contemporary cohorts.
Methods
Predictive factors for overall and specific pulmonary morbidity in 858 patients undergoing esophagectomy between 1998 and 2008 in five Australian university hospitals were analyzed by logistic regression models.
Results
A total of 394 patients underwent open esophagectomy, and 464 patients underwent MIE. A total of 259 patients received neoadjuvant chemoradiotherapy, 139 preoperative chemotherapy alone, and 2 preoperative radiotherapy alone. In-hospital mortality was 3.5%. Smoking and the number of comorbidities were risk factors for overall pulmonary morbidity (odds ratio OR 1.47,
P
= 0.016; OR 1.35,
P
= 0.001) and pneumonia (OR 2.29,
P
= 0.002; 1.56,
P
= 0.005). The risk of respiratory failure was higher in patients with more comorbidities (OR 1.4,
P
= 0.035). Respiratory comorbidities (OR 3.81,
P
= 0.017) were strongly predictive of postoperative acute respiratory distress syndrome (ARDS). ARDS (4.51,
P
= 0.032) or respiratory failure (OR 8.7,
P
< 0.001), but not anastomotic leak (OR 2.22,
P
= 0.074), were independent risk factors for death. MIE (OR 0.11,
P
< 0.001) and thoracic epidural analgesia (OR 0.12,
P
= 0.003) decreased the risk of respiratory failure. Neoadjuvant treatment was not associated with an increased risk of pulmonary complications.
Conclusions
Preoperative comorbidity and smoking were risk factors for respiratory complications, whereas neoadjuvant treatment was not. MIE and the use of thoracic epidural analgesia decreased the risk of respiratory failure. Respiratory failure and ARDS were the only independent factors associated with an increased risk of in-hospital death, whereas anastomotic leakage was not.
Background
The outcome of anti-reflux surgery in patients with suspected gastro-oesophageal reflux-induced cough is frequently uncertain. The aims of this study were to assess the efficacy of ...laparoscopic fundoplication for controlling cough in patients with chronic cough without asthma, who have pathologic gastro-oesophageal reflux, and to identify predictors of response.
Methods
From a prospective database of 1598 patients who have undergone laparoscopic fundoplication, 66 (4%) with proven gastro-oesophageal reflux disease (GORD) and chronic cough without asthma were studied. All patients underwent gastroscopy and 24-h pH monitoring before operation. Heartburn and regurgitation were assessed using a modified DeMeester score. Severity of cough before and after surgery was self-assessed by the patient using a visual analog scale at a minimum of 12 months post-operatively (median 43 mo; range: 14–104 mo). Patients were considered to have responded to fundoplication if they had no cough or the cough had improved by 50% or more after operation.
Results
Cough and heartburn/regurgitation were relieved in 61% (40/66) and 90% (44/49) of the patients, respectively. The presence of typical GORD symptoms or oesophagitis, and pH study variables did not predict the response of the cough to fundoplication.
Conclusion
Refinement in the aetiological diagnosis of chronic cough due to GORD is necessary for improved outcome. Patients diagnosed with GORD-related chronic cough need to be counseled regarding their expectations from anti-reflux surgery.
OBJECTIVE:The aim of this study was to assess long-term health-related quality of life (HRQL) in patients after thoracoscopic and open esophagectomy.
SUMMARY OF BACKGROUND DATA:Trials comparing ...minimally invasive with open transthoracic esophagectomy have shown improved short-term outcomes; however, long-term HRQL data are lacking. This prospective nonrandomized study compared HRQL and survival after thoracoscopically assisted McKeown esophagectomy (TAMK) and open transthoracic Ivor Lewis esophagectomy (TTIL) for esophageal or gastroesophageal junction (GEJ) cancer.
METHODS:Patients with esophageal or GEJ cancer selected for TAMK or TTIL completed baseline and follow-up HRQL assessments for up to 24 months using the EORTC generic and disease-specific measures, QLQ-C30 and QLQ-OES18. Baseline clinical variables were examined between the treatment groups and changes in mean HRQL scores over time estimated and tested using generalised estimating equations with propensity score (generated by boosted regression) adjustment.
RESULTS:Of the 487 patients, 377 underwent TAMK and 110 underwent TTIL. Most clinical variables were similar in the 2 groups; however, there were significantly more patients with AJCC stage 3 disease who underwent TTIL than TAMK (54% vs 32%, P < 0.01) and this was reflected in the survival data.Mean symptom scores for pain were significantly higher in the TTIL group than in TAMK for 2 years postoperatively (P = 0.036). In addition, mean constipation scores were significantly higher for the TTIL group, with a 15-point difference in mean score at 3 months postoperatively (P = 0.037).
CONCLUSIONS:This large comprehensive nonrandomized analysis of longitudinal HRQL shows that TTIL is associated with more pain and constipation than TAMK.
Background
Knowledge of factors related to outcome is vital for the selection of therapeutic alternatives for patients with early (T1) esophageal adenocarcinoma. This study was undertaken to ...determine predictors of lymphatic spread and prognostic factors for T1 esophageal adenocarcinoma following esophagectomy.
Materials and Methods
A prospectively maintained database identified 85 patients with T1 esophageal adenocarcinoma who underwent esophagectomy without neoadjuvant therapy. Depth of tumor invasion (T stage) was subdivided into mucosal (T1a) or submucosal invasion (T1b). Median follow-up was 59 months.
Results
Thoracoscopically assisted 3-phase esophagectomy was performed in 73 of 85 patients (86%). Lymph node metastases (N stage) were identified in 9 of 85 patients (11%). Depth of tumor invasion (T stage), lymphovascular invasion (LVI), and poor differentiation were associated with N stage. The patients could be stratified into 4 risk groups for lymph node metastases: group I—T1a (0 of 35 patients 0% with positive nodes); group II—T1b, well/moderate differentiation and no LVI (1 of 28 patients 4% with positive nodes); group III—T1b, poor differentiation and no LVI (2 of 9 patients 22% with positive nodes); and group IV—T1b any grade with LVI (6 of 13 patients 46% with positive nodes). Survival analyses found T stage, N stage, LVI, and poor differentiation to be significant prognostic factors.
Conclusions
Risk stratification is possible for patents with T1 esophageal adenocarcinoma. Local resection techniques without lymphadenectomy may be alternatives for T1a tumors. Esophagectomy should remain the standard of care for patients with T1b tumors and those with LVI or poor differentiation considered for neoadjuvant therapy.
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