Evaluation of an esophageal Doppler probe for the identification of experimental pseudo-electromechanical dissociation: a preliminary study

STUDY OBJECTIVE To determine the effectiveness of an esophageal doppler device to non-invasively detect experimental pseudo-electromechanical dissociation (pseudo-EMD). DESIGN Prospective, controlled, laboratory investigation using an asphyxial canine cardiac arrest model and a newly-developed esophageal flat-flow probe doppler unit. INTERVENTIONS Mongrel dogs (20) were instrumented for hemodynamic monitoring. The esophageal doppler probe was placed in the distal esophagus of each animal. Electromechanical dissociation (EMD) was induced by clamping the endotracheal tube. MEASUREMENTS AND MAIN RESULTS A period of pseudo-EMD was defined as the time where cardiac contractility was present, measured by a micromanometer tipped thoracic aortic catheter, without concurrent femoral pulses by palpation. The pseudo-EMD period could be produced consistently in all 20 animals. The characteristic doppler flow sounds were easily heard using the esophageal device in all animals. The time from endotracheal tube clamping until loss of femoral pulses was 622 +/- 96 s; until loss of radial artery doppler signals was 616 +/- 92 s; until loss of esophageal doppler signals was 728 +/- 88 s; and until loss of aortic fluctuations by thoracic aortic catheter was 728 +/- 82 s. The times to loss of esophageal doppler sounds and loss of aortic fluctuations were not significantly different. However, they were significantly longer than the time to loss of femoral pulses (P < 0.02). CONCLUSIONS The canine asphyxial EMD model can be used for short experimental studies of pseudo-EMD. Pseudo-EMD can be consistently and non-invasively detected with this esophageal doppler device. The device is as reliable as a micromanometer tipped aortic arch catheter in detecting pseudo-EMD. The doppler device could potentially be useful in improving recognition of near cardiac arrest in pre-hospital and emergency department settings. Further research on the utility of this device in other models of low-flow states should be performed.

Tumor budding in upper gastrointestinal carcinomas.

The basis of personalized medicine in oncology is the prediction of an individual's risk of relapse and death from disease. The presence of tumor budding (TB) at the tumor-host interface of gastrointestinal cancers has been recognized as a hallmark of unfavorable disease biology. TB is defined as the presence of dedifferentiated cells or small clusters of up to five cells at the tumor invasive front and can be observed in aggressive carcinomas of the esophagus, stomach, pancreas, ampulla, colon, and rectum. Presence of TB reproducibly correlates with advanced tumor stage, frequent lymphovascular invasion, nodal, and distant metastasis. The UICC has officially recognized TB as additional independent prognostic factor in cancers of the colon and rectum. Recent studies have also characterized TB as a promising prognostic indicator for clinical management of esophageal squamous cell carcinoma, adenocarcinoma of the gastro-esophageal junction, and gastric adenocarcinoma. However, several important issues have to be addressed for application in daily diagnostic practice: (1) validation of prognostic scoring systems for TB in large, multi-center studies, (2) consensus on the optimal assessment method, and (3) inter-observer reproducibility. This review provides a comprehensive analysis of TB in cancers of the upper gastrointestinal tract including critical appraisal of perspectives for further study.

Assessment of tumor regression of esophageal adenocarcinomas after neoadjuvant chemotherapy: comparison of 2 commonly used scoring approaches.

Histopathologic determination of tumor regression provides important prognostic information for locally advanced gastroesophageal carcinomas after neoadjuvant treatment. Regression grading systems mostly refer to the amount of therapy-induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the former tumor site. Although these methods are generally accepted, currently there is no common standard for reporting tumor regression in gastroesophageal cancers. We compared the application of these 2 major principles for assessment of tumor regression: hematoxylin and eosin-stained slides from 89 resection specimens of esophageal adenocarcinomas following neoadjuvant chemotherapy were independently reviewed by 3 pathologists from different institutions. Tumor regression was determined by the 5-tiered Mandard system (fibrosis/tumor relation) and the 4-tiered Becker system (residual tumor in %). Interobserver agreement for the Becker system showed better weighted κ values compared with the Mandard system (0.78 vs. 0.62). Evaluation of the whole embedded tumor site showed improved results (Becker: 0.83; Mandard: 0.73) as compared with only 1 representative slide (Becker: 0.68; Mandard: 0.71). Modification into simplified 3-tiered systems showed comparable interobserver agreement but better prognostic stratification for both systems (log rank Becker: P=0.015; Mandard P=0.03), with independent prognostic impact for overall survival (modified Becker: P=0.011, hazard ratio=3.07; modified Mandard: P=0.023, hazard ratio=2.72). In conclusion, both systems provide substantial to excellent interobserver agreement for estimation of tumor regression after neoadjuvant chemotherapy in esophageal adenocarcinomas. A simple 3-tiered system with the estimation of residual tumor in % (complete regression/1% to 50% residual tumor/>50% residual tumor) maintains the highest reproducibility and prognostic value.

Increased number of non-degranulated mast cells in pancreatic ductal adenocarcinoma but not in acute pancreatitis.

Increasing evidence indicates that tumor microenvironment (TME) is crucial in tumor survival and metastases. Inflammatory cells accumulate around tumors and strangely appear to be permissive to their growth. One key stroma cell is the mast cell (MC), which can secrete numerous pro- and antitumor molecules. We investigated the presence and degranulation state of MC in pancreatic ductal adenocarcinoma (PDAC) as compared to acute ancreatitis (AP). Three different detection methods: (a) toluidine blue staining, as well as immunohistochemistry for (b) tryptase and (c) c-kit, were utilized to assess the number and extent of degranulation of MC in PDAC tissue (n=7), uninvolved pancreatic tissue derived from tumor-free margins (n=7) and tissue form AP (n=4). The number of MC detected with all three methods was significantly increased in PDAC, as compared to normal pancreatic tissue derived from tumor-free margins (p<0.05). The highest number of MC was identified by c-kit, 22.2∓7.5 per high power field (HPF) in PDAC vs 9.7∓5.1 per HPF in normal tissue. Contrary to MC in AP, where most of the detected MC were found degranulated, MC in PDAC appeared intact. In conclusion, MC are increased in number, but not degranulated in PDAC, suggesting that they may contribute to cancer growth by permitting selective release of pro-tumorogenic molecules.

Surgical treatments for esophageal cancers.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of the nurse in preparation of esophageal resection (ER); the management of patients who develop high-grade dysplasia after having undergone Nissen fundoplication; the trajectory of care for the patient with esophageal cancer; the influence of the site of tumor in the choice of treatment; the best location for esophagogastrostomy; management of chylous leak after esophagectomy; the optimal approach to manage thoracic esophageal leak after esophagectomy; the choice for operational approach in surgery of cardioesophageal crossing; the advantages of robot esophagectomy; the place of open esophagectomy; the advantages of esophagectomy compared to definitive chemoradiotherapy; the pathologist report in the resected specimen; the best way to manage patients with unsuspected positive microscopic margin after ER; enhanced recovery after surgery for ER: expedited care protocols; and long-term quality of life in patients following esophagectomy.

Post-therapeutic response evaluation by a combination of endoscopy and CT scan in esophagogastric adenocarcinoma after chemotherapy: better than its reputation.

BACKGROUND Neoadjuvant chemotherapy is an accepted standard of care for locally advanced esophagogastric cancer. As only a subgroup benefits, a response-based tailored treatment would be of interest. The aim of our study was the evaluation of the prognostic and predictive value of clinical response in esophagogastric adenocarcinomas. METHODS Clinical response based on a combination of endoscopy and computed tomography (CT) scan was evaluated retrospectively within a prospective database in center A and then transferred to center B. A total of 686/740 (A) and 184/210 (B) patients, staged cT3/4, cN0/1 underwent neoadjuvant chemotherapy and were then re-staged by endoscopy and CT before undergoing tumor resection. Of 184 patients, 118 (B) additionally had an interim response assessment 4-6 weeks after the start of chemotherapy. RESULTS In A, 479 patients (70 %) were defined as clinical nonresponders, 207 (30 %) as responders. Median survival was 38 months (nonresponders: 27 months, responders: 108 months, log-rank, p < 0.001). Clinical and histopathological response correlated significantly (p < 0.001). In multivariate analysis, clinical response was an independent prognostic factor (HR for death 1.4, 95 %CI 1.0-1.8, p = 0.032). In B, 140 patients (76 %) were nonresponders and 44 (24 %) responded. Median survival was 33 months, (nonresponders: 27 months, responders: not reached, p = 0.003). Interim clinical response evaluation (118 patients) also had prognostic impact (p = 0.008). Interim, preoperative clinical response and histopathological response correlated strongly (p < 0.001). CONCLUSION Preoperative clinical response was an independent prognostic factor in center A, while in center B its prognostic value could only be confirmed in univariate analysis. The accordance with histopathological response was good in both centers, and interim clinical response evaluation showed comparable results to preoperative evaluation.

Coping with esophageal cancer approaches worldwide.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on approaches to the epidemiology, diagnosis, and treatment of esophageal cancer in Europe, South Africa, Kenya, Australia, and China; the molecular classification of esophageal cancers (including cancers at the gastroesophageal junction); the Japanese classification; the scope of the Human Variome Project; and the topographic-anatomic subclassification of adenocarcinomas of the gastroesophageal junction.

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade.

BACKGROUND Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.

Evaluating Esophageal Bolus Transit by Impedance Monitoring

The function of the esophagus is transporting nutrients from the oropharyngeal cavity to the stomach. This is achieved by coordinated contractions and relaxation of the tubular esophagus and the upper and lower esophageal sphincter. Multichannel intraluminal impedance monitoring offers quantification of esophageal bolus transit and/or retention without the use of ionizing radiation. Combined with conventional or high-resolution manometry, impedance measurements complement the quantification of esophageal body contraction and sphincter relaxation, offering a more comprehensive evaluation of esophageal function. Further studies evaluating the utility of quantifying bolus transit will help clarify the role and position of impedance measurements.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma.

Here we explore the role of the interplay between host immune response and epithelial-mesenchymal-transition (EMT)-Type tumor-budding on the outcome of pancreatic adenocarcinoma (PDAC).CD4+, CD8+, and FOXP3+T-cells as well as iNOS+ (M1) and CD163+- macrophages (M2) were assessed on multipunch tissue-microarrays containing 120 well-characterized PDACs, precursor lesions (PanINs) and corresponding normal tissue. Counts were normalized for the percentage of tumor/spot and associated with the clinico-pathological features, including peritumoral (PTB) and intratumoral (ITB) EMT-Type tumor-budding and outcome.Increased FOXP3+T-cell-counts and CD163-macrophages and decreased CD8+T-cell-counts were observed in PDACs compared with normal tissues and PanINs (p < 0.0001). Increased peritumoral FOXP3+T-cell-counts correlated significantly with venous invasion, distant metastasis, R1-status, high-grade ITB, PTB and independently with reduced survival. Increased intratumoral FOXP3+T-cells correlated with lymphatic invasion, N1-stage, PTB and marginally with adverse outcome. High peritumoral CD163-counts correlated with venous invasion, PTB and ITB. High intratumoral CD163-counts correlated with higher T-stage and PTB.PDAC-microenvironment displays a tumor-favoring immune-cell composition especially in the immediate environment of the tumor-buds that promotes further growth and indicates a close interaction of the immune response with the EMT-process. Increased peritumoral FOXP3+T-cell density is identified as an independent adverse prognostic factor in PDAC. Patients with phenotypically aggressive PDACs may profit from targeted immunotherapy against FOXP3.

Epstein-barr virus in gastro-esophageal adenocarcinomas - single center experiences in the context of current literature.

Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) represent a distinct and well-recognized subtype of gastric cancer with a prevalence of around 10% of all GC. In contrast, EBV has not been reported to play a major role in esophageal adenocarcinomas (EAC) and adenocarcinomas of the gastro-esophageal junction (GEJ). We report our experiences on EBV in collections of gastro-esophageal adenocarcinomas from two surgical centers and discuss the current state of research in this field. Tumor samples from 465 primary resected gastro-esophageal adenocarcinomas (118 EAC, 73 GEJ, and 274 GC) were investigated. Presence of EBV was determined by EBV-encoded small RNAs (EBER) in situ hybridization. Results were correlated with pathologic parameters (UICC pTNM category, Her2 status, tumor grading) and survival. EBER positivity was observed in 14 cases. None of the EAC were positive for EBER. In contrast, we observed EBER positivity in 2/73 adenocarcinomas of the GEJ (2.7%) and 12/274 GC (4.4%). These were of intestinal type (seven cases) or unclassifiable (six cases), while only one case was of diffuse type according to the Lauren classification. No association between EBV and pT, pN, or tumor grading was found, neither was there a correlation with clinical outcome. None of the EBER positive cases were Her2 positive. In conclusion, EBV does not seem to play a role in the carcinogenesis of EAC. Moreover, adenocarcinomas of the GEJ show lower rates of EBV positivity compared to GC. Our data only partially correlate with previous reports from the literature. This highlights the need for further research on this distinct entity. Recent reports, however, have identified specific epigenetic and genetic alterations in EBV-associated GC, which might lead to a distinct treatment approach for this specific subtype of GC in the future.

Influence of Different Neoadjuvant Chemotherapy Regimens on Response, Prognosis, and Complication Rate in Patients with Esophagogastric Adenocarcinoma.

BACKGROUND Perioperative chemotherapy improves survival in patients with advanced esophagogastric cancer, but the optimal treatment regimen remains unclear. More intensive chemotherapy may improve outcome, but also increase toxicity and complications. METHODS A total of 843 patients were included in this retrospective study and stratified in 4 groups: doublet therapy with cisplatin or oxaliplatin and 5-fluorouracil (groups A/B) or triplet therapy with additional epirubicin or taxane (groups C/D). The influence of the different neoadjuvant chemotherapy regimens on response, prognosis, and complications was assessed. RESULTS Clinical and pathological response were associated with longer overall survival (OS; p < 0.001). No significant differences regarding response or OS were found, but there was a trend toward better outcome in group D (taxane-containing triplet). In the subgroup of 669 patients with adenocarcinomas of the esophagogastric junction (AEG), patients who had received taxane-containing regimens had a significantly longer OS (p = 0.037), but taxane use was not an independent factor in multivariate analysis. Triple therapy with taxanes did not result in a higher complication rate or postoperative mortality. CONCLUSIONS Although no superior neoadjuvant chemotherapy regimen was identified for patients with esophagogastric adenocarcinoma, taxane-containing regimens should be further investigated in randomized trials, especially in patients with AEG tumors.

Erosive esophageal reflux vs. non erosive esophageal reflux: oral findings in 71 patients.

BACKGROUND The purpose of this clinical study was to assess the prevalence of acidic oral mucosal lesions and periodontal conditions in patients suffering from erosive esophageal reflux disease (ERD) compared with non erosive esophageal reflux disease (NERD) patients, both treated with long term proton pump inhibitors (PPI). METHODS Seventy-one patients with diagnosed GERD were studied: i.e. 29 ERD and 42 NERD patients. Thorough visual examination of the oral mucosa and a periodontal evaluation was performed. The primary outcome was defined as a statistically significant difference, between the two groups, in the presence of acidic lesions of the oral mucosa and specific periodontal parameters. RESULTS This study failed to demonstrate statistically significant differences between ERD and NERD patients with respect to the prevalence of oral mucosal lesions. However, significantly more ERD patients suffered from severe periodontitis (CAL ≥ 5 mm) as compared to NERD patients. Accordingly, it may be assumed that PPI-use had no adverse effects on the prevalence of acidic oral mucosal lesions and on periodontal destruction. CONCLUSIONS Within the limitations of this study it may be concluded that ERD and NERD patients need separate evaluation with respect to periodontal destruction. Moreover, long term PPI medication had no adverse clinical impact on acidic oral mucosal lesions and periodontal destruction. Further studies are necessary to elucidate the role of reflux in the periodontal destruction of ERD individuals.