Dan Falkenback

Heller's esophagomyotomy with or without a 360 degrees floppy Nissen fundoplication for achalasia. Long-term results from a prospective randomized study.

Hellers esophagomyotomy relieves dysphagia but does not restore esophageal peristalsis. The myotomy may induce reflux and the addition of a 360 degrees fundoplication may be hazardous with regard to the remaining aperistaltic esophagus. The aim of this prospectively randomized clinical trial was to compare the outcome for patients with uncomplicated achalasia who underwent an anterior Hellers esophagomyotomy (H group) with or without an additional floppy Nissen fundoplication (H + N group). Between 1984 and 1995, 20 patients were prospectively randomized to one or other of the performed operations, 10 patients per group. Esophagitis including Barretts esophagus (n = 2) was seen under medical treatment, in 6 of 9 in the H group but none in the H + N group. No patient in the H + N group required postoperative continuous acid-reducing drugs. Twenty-four-hour esophageal pH-studies in median 3.4 years after surgery showed pathological reflux expressed as a percentage of time below pH 4 of 13.1% in the H group compared to 0.15% (P < 0.001) in H + N group. One patient with recurrent dysphagia in the H + N group later had an esophagectomy. The remaining patients reported significant improvement of dysphagia without symptoms of reflux at 8.0 years follow-up. Hellers esophagomyotomy eliminates dysphagia, but can induce advanced reflux that requires medical treatment. The addition of a 360 degrees fundoplication eliminates reflux without adding dysphagia in the majority of patients and can be recommended for most patients with uncomplicated achalasia.

Prognostic Impact of Array-based Genomic Profiles in Esophageal Squamous Cell Cancer

BackgroundEsophageal squamous cell carcinoma (ESCC) is a genetically complex tumor type and a major cause of cancer related mortality. Although distinct genetic alterations have been linked to ESCC development and prognosis, the genetic alterations have not gained clinical applicability. We applied array-based comparative genomic hybridization (aCGH) to obtain a whole genome copy number profile relevant for identifying deranged pathways and clinically applicable markers.MethodsA 32 k aCGH platform was used for high resolution mapping of copy number changes in 30 stage I-IV ESCC. Potential interdependent alterations and deranged pathways were identified and copy number changes were correlated to stage, differentiation and survival.ResultsCopy number alterations affected median 19% of the genome and included recurrent gains of chromosome regions 5p, 7p, 7q, 8q, 10q, 11q, 12p, 14q, 16p, 17p, 19p, 19q, and 20q and losses of 3p, 5q, 8p, 9p and 11q. High-level amplifications were observed in 30 regions and recurrently involved 7p11 (EGFR), 11q13 (MYEOV, CCND1, FGF4, FGF3, PPFIA, FAD, TMEM16A, CTTS and SHANK2) and 11q22 (PDFG). Gain of 7p22.3 predicted nodal metastases and gains of 1p36.32 and 19p13.3 independently predicted poor survival in multivariate analysis.ConclusionaCGH profiling verified genetic complexity in ESCC and herein identified imbalances of multiple central tumorigenic pathways. Distinct gains correlate with clinicopathological variables and independently predict survival, suggesting clinical applicability of genomic profiling in ESCC.

Is the course of gastroesophageal reflux disease progressive? A 21-year follow-up.

Abstract Objective. We re-evaluated a cohort of patients referred for reflux symptoms and objectively diagnosed with pathological reflux, with the purpose of clarifying the course of conservatively treated gastroesophageal reflux disease (GERD). Material and methods. All consecutive patients with GERD diagnosed between 1984 and 1988 showing pathologic 24-h pH-metry in the interval 3.8–10% and without any previous surgery in the gastroesophageal tract were assessed for further follow-up. A total of 40 evaluable patients were followed in the years 2007–08 with endoscopy, manometry, 24-h pH-metry, Helicobacter pylori assessment and the self-administered questionnaires the GERD Impact Scale, the Reflux Disease Questionnaire, the Quality of Life in Reflux and Dyspepsia and the Medical Outcome Study Short Form-36 Health Survey. Baseline data from the 1980s were retrieved and compared with the evaluations conducted at follow-up. Results. At follow-up 20.7 years (range 18.8–23.5 years) after referral, the study population showed more use of acid suppressants (p = 0.007) and increasing prevalences of esophagitis (p = 0.001) and Barretts esophagus (p = 0.002). Esophagitis was seen in 16/40 patients (40%) at baseline and in 29/40 (72.5%) at follow-up. No significant deterioration was seen at follow-up in manometry data and in most pH data. Patients with esophagitis (ERD) were less likely to have a positive H. pylori test (hazard ratio 0.054; p = 0.002) than non-erosive (NERD) patients. Symptom evaluations showed significantly lower quality of life in the ERD group. Conclusions. After 20 years a considerable part of the cohort still experienced symptoms of reflux and showed endoscopic progression, although no significant deteriorations were seen in manometry data and in most pH-metry data. H. pylori infection was inversely associated with erosive esophagitis and this supports the hypothesis that H. pylori colonization is a protective factor against GERD.

Prognostic value of cell adhesion in esophageal adenocarcinomas.

Increased understanding of the molecular processes associated with the dysplasia-adenocarcinoma sequence linked to Barretts esophagus may be beneficial for early tumor detection and refined diagnosis as well as for improved prognostication. We applied immunohistochemical staining for the markers Ki-67, p53, beta-catenin and E-cadherin in order to evaluate their prognostic importance in 59 Barretts esophagus-associated adenocarcinomas. Reduced or absent membranous E-cadherin staining was identified in 75% of the tumors and predicted poor prognosis in manova (hazard ratio [HR] 3.3, P = 0.05). The small subset of tumors with low levels (< 10%) of Ki-67 staining showed a worse prognosis (HR 3.2, P < 0.01), whereas immunostaining for p53 and beta-catenin showed no correlation with prognosis. Deranged cell adhesion has been demonstrated to be an early event in tumor development. The down-regulation of E-cadherin and its prognostic importance indicate that cell adhesion may be a prime area for targeted therapies in esophageal adenocarcinoma.

Robot-assisted oesophageal and gastric surgery for benign disease: antireflux operations and Heller's myotomy.

Robot‐assisted general surgery operations are being performed more frequently. This review investigates whether robotic assistance results in significant advantages or disadvantages for the operative treatment of gastro‐oesophageal reflux disease and achalasia.

The prognostic value of TP53 mutations in oesophageal adenocarcinoma: a systematic review and meta-analysis

Objective To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC. Design A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model. Results Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, I2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias (HR 2.11, 95% CI 1.35 to 3.31, I2=0%). Conclusions Patients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage.

MIC-1/GDF15 in Barrett's oesophagus and oesophageal adenocarcinoma.

Background:Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett’s oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC.Methods:One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC.Results:Median tissue expression of MIC-1/GDF15 mRNA was ⩾25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73–0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015).High MIC-1/GDF15 plasma levels (⩾1140 pg ml−1) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01–14.75; P=0.047).Conclusions:Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett’s disease.

Robot-assisted gastrectomy and oesophagectomy for cancer.

Robot‐assisted surgery is a technically feasible alternative to open and laparoscopic surgery, which is being more frequently used in general surgery. We undertook this review to investigate whether robotic assistance provides a significant benefit for oesophagogastric cancer surgery.