Efficacy of laparoscopic fundoplication in patients with chronic cough and gastro-oesophageal reflux.

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.

The Impact of Signet Ring Cell Differentiation on Outcome in Patients with Esophageal and Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Little is known about the association between signet ring cell (SRC) differentiation and response to neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal and junctional adenocarcinoma (EAC). We aimed to assess if SRC differentiation is associated with survival and response to nCT or nCRT in patients with EAC. METHODS: Patients who underwent nCT and nCRT followed by surgery for EAC from 2000 until 2016 were identified from two institutional prospectively maintained databases. The pretreatment biopsy report or surgical resection specimen was used to differentiate patients into an SRC or non-SRC group. RESULTS: Overall, 129 (19%) of 689 patients included had SRCs (nCT: n = 64; nCRT: n = 65). The SRC group had a more advanced ypT stage (p = 0.003), a higher number of positive lymph nodes in the resection specimen {median (interquartile range [IQR]) 2 [0-5] vs. 1 [0-3]; p = 0.002} and a higher rate of R1/R2 resections (19.4% vs. 12%; p = 0.026). SRC differentiation was not an independent prognostic factor for overall survival (OS) or disease-free survival (DFS). Following nCT, the SRC group had significantly shorter DFS (median [IQR] 12 [5-50] vs. 23 [8-164]; p = 0.013), but not OS, compared with the non-SRC group. In contrast, no differences according to SRC status for OS or DFS were found in patients who underwent nCRT. CONCLUSIONS: SRC differentiation was not independently associated with worse OS in patients with EAC who underwent neoadjuvant therapy and surgery. However, nCRT was associated with greater tumor downstaging and better DFS.

Neoadjuvant chemotherapy or chemoradiotherapy for adenocarcinoma of the esophagus.

BACKGROUND: The optimal treatment strategy for patients with esophageal adenocarcinoma (EAC) remains undetermined. This study compared outcomes in patients undergoing neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) for EAC. METHODS: Patients who underwent nCT or nCRT followed by surgery for EAC were identified from a prospective database (2000-2017) and included. After propensity score matching, the impact of the treatments on postoperative complications, in-hospital mortality, pathological outcomes, and survival rates were compared. RESULTS: Of the 396 eligible patients, 262 patients were analysed following matching with 131 patients in both groups. There were no significant differences between the nCT and nCRT groups for overall complications (59% vs 57%, P = 0.802) or in-hospital mortality (2% vs 0%, P = 0.156). Patients who had nCRT had more R0 resections (93% vs 83%, P = 0.013), and higher pathological complete response rates (15% vs 5%, P < 0.001). No differences in 5-year overall survival rates (nCT vs nCRT; 44% vs 33%, P = 0.645) were found. CONCLUSION: In this study no differences between nCT and nCRT were seen in postoperative complications and in-hospital mortality in patients treated for EAC. Inspite of improved complete resection and pathological response there was no difference in the overall survival between the treatment modalities.

Neoadjuvant therapy reduces cardiopulmunary function in patients undegoing oesophagectomy.

Neoadjuvant therapy (NAT) for oesophageal cancer may reduce cardiopulmonary function, assessed by cardiopulmonary exercise testing (CPEX). Impaired cardiopulmonary function is associated with mortality following esophagectomy. We sought to assess the impact of NAT on cardiopulmonary function using CPEX and assessing the clinical relevance of any change in particular if changes were associated with post-operative morbidity. This was a prospective, cohort study of 40 patients in whom CPEX was performed before and after NAT. Thirty-eight patients underwent surgery and follow-up with perioperative outcomes measured. The primary variables derived from CPEX were the anaerobic threshold (AT) and peak oxygen uptake (V˙O2peak). There were significant reductions in the AT (pre-NAT: 12.4 ±â€¯3.0 vs. post-NAT 10.6 ±â€¯2.0 mL kg-1.min-1; p = 0.001). This reduction was also evident for V˙O2peak (pre-NAT: 16.6 ±â€¯3.6 vs. post-NAT 14.9 ±â€¯3.7 mL kg-1.min-1; p = 0.004). The relative reduction in V˙O2peak was greater in chemotherapy patients who developed any peri-operative morbidity (p = 0.04). For patients who underwent chemoradiotherapy, there was a significantly greater relative reduction in AT (p = 0.03) for those who encountered a respiratory complication. Cardiopulmonary function significantly declined as a result of NAT prior to oesophagectomy. The reduction in AT and V˙O2peak was similar in both the chemotherapy and chemoradiotherapy groups.

Long-term Health-related Quality of Life Following Esophagectomy: A Nonrandomized Comparison of Thoracoscopically Assisted and Open 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.

Treatment results of curative gastric resection from a specialist Australian unit: low volume with satisfactory outcomes.

BACKGROUND: The incidence of gastric cancer is decreasing in Australia, yet it remains a common cause of cancer-related mortality. Surgical resection remains the cornerstone of curative treatment. High-volume specialized units have reported superior perioperative and oncological outcomes. The role of D2 lymphadenectomy has been controversial as a result of concerns over increased morbidity. Our aim is to report the perioperative and oncological outcomes of curative gastric resection from a specialist Australian upper GI unit. METHODS: Data from a prospectively maintained database were reviewed for all patients undergoing curative resection for gastric adenocarcinoma from a single unit during a 12-year period. Perioperative and long-term outcomes were compiled. RESULTS: There were 255 curative gastric resections during 12 years. An R0 resection was performed in 96 % with a perioperative mortality rate of 1.6 %. A D2 dissection was performed in 85 % of cases in the past 6 years, with no increase in perioperative morbidity or mortality detected. The 5-year overall survival was 53 %. CONCLUSION: Our results demonstrate that both short- and long-term outcomes of surgical resection in gastric cancer patients, comparable to international high-volume centers, can be achieved in an Australian upper GI unit. A D2 lymph node dissection can be performed safely without any increase in perioperative risk in a specialist unit that has the necessary training but also the perioperative support structures to manage these complex patients.

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer.

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.

Whole genome expression array profiling highlights differences in mucosal defense genes in Barrett's esophagus and esophageal adenocarcinoma.

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.

Defining cure for esophageal cancer: analysis of actual 5-year survivors following esophagectomy.

BACKGROUND: Esophagectomy is the mainstay of curative treatment for localized esophageal cancer. However, what constitutes cure is not well defined. This study was undertaken to characterize actual 5-year survivors following esophagectomy and to determine prognostic factors for disease-specific survival (DSS) from 60 months. MATERIALS AND METHODS: Between 1987 and 2004, 398 consecutive patients underwent esophagectomy and had potential for 5 years follow-up. Clinicopathological factors associated with DSS from 5 years onward were analyzed. RESULTS: Median DSS was 25 months. Neoadjuvant therapy was administered to 159 of 398 (40%). There were 114 of 398 (29%) actual 5-year survivors. On multivariate analysis, 5-year survivors were significantly more likely to have lower T classification, N classification, and R0 resections compared with patients who died less than 5 years after surgery. There were 66 of 398 patients (17%) with positive margins, and 6 of these were 5-year survivors. Of the 114 5-year survivors, 17 (15%) subsequently died of esophageal cancer. Prognostic factors for DSS after surviving 5 years were age and T classification for patients treated with neoadjuvant therapy and surgery alone, respectively. Powerful prognostic factors from time of treatment, including nodal status, were no longer prognostic factors after surviving to 5 years. CONCLUSIONS: No single clinicopathological variable negated survival to 5 years. Prognostication once surviving 5 years is difficult. The majority of 5-year survivors can be considered cured of esophageal cancer.

Is concurrent radiation therapy required in patients receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomised phase II trial.

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/m(2)) and infusional 5 fluorouracil (1000 mg/m(2)/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/m(2)/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 enrolled 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.

Factors associated with postoperative pulmonary morbidity after esophagectomy for cancer.

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.

Symptoms, investigations and management of patients with cancer of the oesophagus and gastro-oesophageal junction in Australia.

OBJECTIVE: To document presenting symptoms, investigations and management for Australian patients with oesophageal adenocarcinoma (OAC), gastro-oesophageal junction adenocarcinoma (GOJAC) and oesophageal squamous cell carcinoma (OSCC). DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of a population-based sample of 1100 Australian patients aged 18-79 years with histologically confirmed oesophageal cancer diagnosed in 2002-2005, using data from cancer registries and treatment centres, supplemented with clinical information collected through medical record review in 2006-2007 and mortality information collected in 2008. MAIN OUTCOME MEASURES: Prevalence of primary symptoms, and staging investigations and treatment modalities used. RESULTS: The primary presenting symptom was dysphagia, which was self-reported by 41%, 39% and 48% of patients with OAC, GOJAC and OSCC, respectively. Less common symptoms were reflux, chest pain, bleeding and weight loss. All patients underwent endoscopy, most had a staging computed tomography scan (OAC 93%, GOJAC 95% and OSCC 93%), and about half had positron emission tomography scans (OAC 51%, GOJAC 44% and OSCC 42%). Pretreatment tumour stage was reported in 25% of records, and could be derived from results of investigations in a further 23%, but the remaining half lacked sufficient information to ascribe a pretreatment stage. Curative treatments were attempted for 60% of OAC, 88% of GOJAC and 65% of OSCC patients. Surgery was performed on 52% of OAC, 83% of GOJAC and 41% of OSCC patients. About two-thirds of surgical patients received additional therapies. CONCLUSIONS: With anticipated increases in oesophageal cancer incidence, the resources required to diagnose and manage patients with oesphageal cancer are also likely to rise. Our data provide a baseline from which to plan for the future care of patients with cancers of the oesophagus.

Thoracoscopic-assisted esophagectomy for esophageal cancer: analysis of patterns and prognostic factors for recurrence.

OBJECTIVE: The authors report the recurrence pattern of esophageal cancer after thoracoscopic-assisted esophagectomy (TAE), comparing it to the recurrence pattern after open surgery and identify prognostic factors for recurrence. SUMMARY OF BACKGROUND DATA: To improve long-term survival for esophageal cancer radical surgery has been proposed increasingly, however, recurrent disease remains a problem. Opinion is divided as to the adequacy of resection possible using minimally invasive techniques with concerns that there may be an increased incidence in locoregional recurrence. METHODS: A total of 221 patients who underwent esophagectomy at the Princess Alexandra Hospital without any neoadjuvant or adjuvant therapy were identified from a prospective database. Patients were followed up for the detection of symptomatic recurrence for a median of 59 months. RESULTS: Within this group 165 patients underwent TAE and 56 an open transthoracic esophagectomy (TTE). The 5-year overall recurrence rate was 133/221 (60%). The 5-year rates of symptomatic first recurrence following TAE was 4%, 9%, and 47% for local, regional, and distant recurrence, respectively. The 5-year rates of symptomatic first recurrence following TTE was 5%, 18%, and 55% for local, regional, and distant recurrence, respectively. Operative approach was not a prognostic factor for any type of recurrence. Independent prognostic factors associated with locoregional recurrence were positive margins and number of positive nodes. Distant recurrence was associated with T stage, differentiation, tumor length >6 cm, and number of positive nodes. CONCLUSION: Distant recurrence remains a significant problem in esophageal cancer. TAE achieved adequate locoregional control and compared favorably with open TTE.

Risk stratification for early esophageal adenocarcinoma: analysis of lymphatic spread and prognostic factors.

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.

Laparoscopic upper gut surgery.

Australian surgeons have been prominent in the introduction, development, and consolidation of laparoscopic surgery of the upper gut. In doing this, some of the very best principles of surgical innovation have been in evidence: preliminary animal work in which to test hypotheses and techniques, followed by careful application and documentation in the clinical setting, randomized clinical trials and finally academic reporting and ongoing development. This review documents the introduction of laparoscopic surgery for gastroesophageal reflux, hiatus hernia, achalasia, gastroesophageal malignancy, obesity, and a range of emergency conditions in Australia. Those involved are regarded as world leaders in their field. A vital component of this success has been the close cooperation between surgeons and gastroenterologists within the Gastroenterological Society of Australia.

Similarity of aberrant DNA methylation in Barrett's esophagus and esophageal adenocarcinoma.

BACKGROUND: Barrett's esophagus (BE) is the metaplastic replacement of squamous with columnar epithelium in the esophagus, as a result of reflux. It is the major risk factor for the development of esophageal adenocarcinoma (EAC). Methylation of CpG dinucleotides of normally unmethylated genes is associated with silencing of their expression, and is common in EAC. This study was designed to determine at what stage, in the progression from BE to EAC, methylation of key genes occurs. RESULTS: We examined nine genes (APC, CDKN2A, ID4, MGMT, RBP1, RUNX3, SFRP1, TIMP3, and TMEFF2), frequently methylated in multiple cancer types, in a panel of squamous (19 biopsies from patients without BE or EAC, 16 from patients with BE, 21 from patients with EAC), BE (40 metaplastic, seven high grade dysplastic) and 37 EAC tissues. The methylation frequency, the percentage of samples that had any extent of methylation, for each of the nine genes in the EAC (95%, 59%, 76%, 57%, 70%, 73%, 95%, 74% and 83% respectively) was significantly higher than in any of the squamous groups. The methylation frequency for each of the nine genes in the metaplastic BE (95%, 28%, 78%, 48%, 58%, 48%, 93%, 88% and 75% respectively) was significantly higher than in the squamous samples except for CDKN2A and RBP1. The methylation frequency did not differ between BE and EAC samples, except for CDKN2A and RUNX3 which were significantly higher in EAC. The methylation extent was an estimate of both the number of methylated alleles and the density of methylation on these alleles. This was significantly greater in EAC than in metaplastic BE for all genes except APC, MGMT and TIMP3. There was no significant difference in methylation extent for any gene between high grade dysplastic BE and EAC. CONCLUSION: We found significant methylation in metaplastic BE, which for seven of the nine genes studied did not differ in frequency from that found in EAC. This is also the first report of gene silencing by methylation of ID4 in BE or EAC. This study suggests that metaplastic BE is a highly abnormal tissue, more similar to cancer tissue than to normal epithelium.

Refining esophageal cancer staging after neoadjuvant therapy: importance of treatment response.

OBJECTIVE: Accurate staging is vital for esophageal cancer management. The utility of the American Joint Committee on Cancer (AJCC) staging system 6th edition for esophageal cancer has been questioned for resected patients who receive neoadjuvant chemoradiotherapy (CRT). This study was undertaken to assess the AJCC staging system for patients with esophageal cancer that have received neoadjuvant CRT and to identify clinicopathological variables that predict survival. METHODS: Review of a prospective esophageal cancer database was undertaken for patients that received neoadjuvant CRT and resection. Primary tumor response was defined as major (10% residual tumor cells). Cox regression and concordance analyses were used to determine prognostic factors. Median follow-up was 61 months. RESULTS: Of 131 patients with invasive cancer, there were 40/131 (31%) with squamous cell carcinoma (SCC) and 88/131 (65%) with adenocarcinoma. The procedure-related mortality rate was 3.8%. Median survival was 33 months. A major response was demonstrated by 79/131 (60%) patients. Survival analyses found that the AJCC 6th edition was unable to discriminate between stages 0, I, and IIa or stages IIb and III. Multivariate survival analyses found age, pretreatment tumor length >6 cm, positive lymph nodes, and a major tumor response were independent prognostic factors. These data were used to derive a new staging system that had improved discrimination of stage groups over the current AJCC system. CONCLUSION: The current AJCC staging system for esophageal cancer is inadequate for patients that receive neoadjuvant CRT. Refinement of the AJCC staging system should include primary tumor response for patients receiving neoadjuvant CRT.

Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays.

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.

Comparison of the outcomes between open and minimally invasive esophagectomy.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.