Severity of GERD and disease progression.

BACKGROUND: Many factors may play a role in the severity and progression of gastroesophageal reflux disease (GERD) since pathophysiology is multifactorial. Data regarding the progression of GERD are controversial: some reports of increased esophageal acid exposure (EAE) and mucosal damage were considered as evidence for a stable disease course, while others interprete these findings as disease progression. The aim of this study is to analyze a large patient-population with persisting symptoms indicative of GERD under protonpumpinhibitor-therapy and identify components characterizing disease severity and progression. METHODS: Patients with symptoms indicative of GERD were included in the study in a tertiary referral center (Frankfurt, Germany). All selected patients were under long-term protonpumpinhibitor-therapy with persistant symptoms. All patients underwent investigations to collect data on their physical status, EAE, severity of esophagitis, anatomical changes, and esophageal functional defects as well as their relation to the duration of the disease. Incidence over time was plotted as survival curves and tested with Log-rank tests for the four main disease markers. Multivariate modeling with COX-regression model was used to estimate the general impact of the four main disease markers on the time course of the disease. In order to elucidate possible causal relationships over time, a path analysis (structural equation model) was calculated. RESULTS: From the database with 1480 data sets, 972 patients were evaluated (542 males, 430 females). The mean age was 50.5 years (range18-89). The mean body mass index was 27.2(19-48). The mean time between the onset of symptoms and the diagnostic investigations was 8.2 years (1-50). A longer disease history for GERD was significantly associated with a higher risk for LES-incompetence. The mean duration from symptom onset to the time of clinical investigation was 9 years for patients with LES-incompetence (n = 563), compared to a mean of 6 years for those with mechanically intact LES (n = 95). A longer period from symptom onset to diagnostics was significantly associated with higher acid exposure. The pathway analysis was significant for the following model: 'history' (P < 0.001➔LES-incompetence & Hiatal Hernia➔(p < 0,001)➔pH-score (P < 0.001).Conclusion: LES-incompetence, the functional deterioration of the LES, and the anatomical alteration at the esophagogastric junction (Hiatal Hernia) as well as an increased EAE were associated with a long history of suffering from GERD. Path modeling suggests a causal sequence overtime of the main disease-parameters, tentatively allowing for a prediction of the course of the disease.

Proceedings from an international conference on ablation therapy for Barrett's mucosa: Brittany, France, 31 August - 2 September 1997.

The increasing incidence of adenocarcinoma of the lower esophagus and cardia arising in Barrett's metaplastic epithelium continues to be of great concern because medical and surgical efforts to reverse the process have been disappointing. A potential answer to the problem is removal of the metaplastic epithelium. Modern technology has introduced physical and chemical modalities which facilitate ablation of the neo-epithelium endoscopically. These techniques have been used in several centers, and preliminary results are encouraging. This report summarizes the proceedings of an international symposium on ablative therapy held in Brittany, France in August 1997.Twenty-eight speakers contributed to the talks on the pathology, pathogenesis, current therapy experimental studies and clinical experience of ablation of Barrett's esophagus.

Safety analysis of first 1000 patients treated with magnetic sphincter augmentation for gastroesophageal reflux disease.

Antireflux surgery with a magnetic sphincter augmentation device (MSAD) restores the competency of the lower esophageal sphincter with a device rather than a tissue fundoplication. As a regulated device, safety information from the published clinical literature can be supplemented by tracking under the Safe Medical Devices Act. The aim of this study was to examine the safety profile of the MSAD in the first 1000 implanted patients. We compiled safety data from all available sources as of July 1, 2013. The analysis included intra/perioperative complications, hospital readmissions, procedure-related interventions, reoperations, and device malfunctions leading to injury or inability to complete the procedure. Over 1000 patients worldwide have been implanted with the MSAD at 82 institutions with median implant duration of 274 days. Event rates were 0.1% intra/perioperative complications, 1.3% hospital readmissions, 5.6% endoscopic dilations, and 3.4% reoperations. All reoperations were performed non-emergently for device removal, with no complications or conversion to laparotomy. The primary reason for device removal was dysphagia. No device migrations or malfunctions were reported. Erosion of the device occurred in one patient (0.1%). The safety analysis of the first 1000 patients treated with MSAD for gastroesophageal reflux disease confirms the safety of this device and the implantation technique. The overall event rates were low based on data from 82 institutions. The MSAD is a safe therapeutic option for patients with chronic, uncomplicated gastroesophageal reflux disease.

Home self-dilatation for esophageal strictures.

Esophageal strictures secondary to caustic ingestion, head and neck radiation and at the anastomosis post-esophagectomy tend to be refractory to one or several dilatations. One option for these strictures is home self-dilatation. The aim of this study was to assess the efficacy and safety of home self-dilatation for a refractory esophageal stricture. A retrospective chart review was performed of all patients from 1997 to 2009 that performed home self-dilatation for an esophageal stricture. Patients with proximal strictures without tortuosity or a shelf proximal to the stricture were selected for self-dilatation. The patients were taught self-dilatation by the surgeon and an experienced nurse, and an appropriate sized Maloney dilator was provided to the patient and returned when no longer needed. There were 16 patients (11 male and 5 female) with a median age of 60 years (range 38-78). The stricture was related to the anastomosis after esophagectomy in 12 patients, caustic injury in 3 patients and cervical chemoradiotherapy in 1 patient. Prior to initiation of self-dilatation patients had a median of four endoscopic dilatations. Self-dilatation was done with a Maloney dilator ranging in size from 45 to 60 French. The median duration of self-dilatation was 16 weeks. No patient had a perforation or complication related to self-dilatation. No patient required stenting or repetitive endoscopic dilatations because of failure of self-dilatation. Strictures recurred in two patients after cessation of self-dilatation and both responded to endoscopic dilatation followed by additional self-dilatation. Self-dilatation effectively resolves refractory esophageal strictures. It was well tolerated, and there were no complications in this series. Home self-dilatation should be considered the treatment of choice in appropriate patients with refractory esophageal strictures in the cervical esophagus.

Circular stapled pyloroplasty: a fast and effective technique for pyloric disruption during esophagectomy with gastric pull-up.

The necessity of pyloroplasty after esophagectomy and gastric pull-up is debated. Disadvantages of a standard pyloroplasty include the potential for leak, shortening of the length of the graft, and complexity when done during a minimally invasive procedure. The aim of this study is to report our experience with a novel internal pyloroplasty technique using a circular stapler (CS pyloroplasty), which is applicable for both laparoscopic and open esophagectomy. The records of all patients who underwent an esophagectomy with gastric pull-up and pyloroplasty between 2002 and 2007 were reviewed. The CS pyloroplasty was performed through a lesser curve gastrotomy with a 21-mm CS, while the standard pyloroplasty entailed a longitudinal full thickness incision through the pylorus with mucosal closure in the same direction and a Graham patch. A CS pyloroplasty was performed in 144 and a standard pyloroplasty in 133 patients. The median patient age was 66years, and the median follow-up was 17months, and was similar for both types of pyloroplasty. Routine postoperative videoesophagram was significantly more likely to show a delay in contrast transit through the pylorus after standard pyloroplasty (16% standard vs. 8% CS pyloroplasty, P= 0.03). Significantly more patients had postoperative endoscopy after standard pyloroplasty (40% standard vs. 24% CS pyloroplasty, P= 0.004), but the frequency of pyloric dilatation was similar. There were no leaks with either technique. A circular stapled pyloroplasty is as efficacious as a standard pyloroplasty after esophagectomy with gastric pull-up. Potential advantages include the ease and simplicity of the procedure along with virtually no risk of a leak and no graft shortening. The technique is amenable to both open and minimally invasive procedures.

The gene expression profile of cardia intestinal metaplasia is similar to that of Barrett's esophagus, not gastric intestinal metaplasia.

The etiology and significance of cardia intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus due to reflux or could reflect generalized gastric intestinal metaplasia due to Helicobacter pylori. The aim of this study was to utilize gene expression data to compare CIM to Barrett's and gastric intestinal metaplasia. Endoscopic biopsies were classified by endoscopic and histologic criteria as CIM (n= 33), Barrett's (n= 25), or gastric intestinal metaplasia of the antrum or body (n= 18). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients and patients with diffuse gastric intestinal metaplasia were excluded. H. pylori was tested for in the biopsies of all patients. After laser-capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of a panel of nine genes that has been shown to differentiate Barrett's from other foregut mucosa. Cluster analysis with linear discriminant analysis of the expression data was used to classify each sample into groups based solely on similarity of gene expression. Cluster analysis was performed for three groups (CIM vs. Barrett's vs. gastric intestinal metaplasia) and two groups (CIM + Barrett's vs. gastric intestinal metaplasia). There was no difference in H. pylori infection among groups (P= 0.66). Clustering into three groups resulted in frequent misclassification between CIM and Barrett's while misclassification of gastric intestinal metaplasia was uncommon. The CIM and Barrett's groups were then combined for two group clustering and linear discriminant analysis correctly predicted 95% of CIM and Barrett's samples and 83% of gastric intestinal metaplasia samples based on gene expression alone. In conclusion, the gene expression profiles of CIM and Barrett's esophagus were similar in 95% of biopsies and differed significantly from that of gastric intestinal metaplasia. The indistinguishable gene expression profile of CIM and BE suggests that they may share a common etiology in the majority of patients with a similar biology, and calls into question the perception that CIM is an innocuous process.

The effect of heterologous anti-lymphocyte seerum on mouse hemopoietic stem cells.

The present study has demonstrated that rabbit anti-mouse lymphocyte serum (RAMLS) has the capability of destroying bone marrow cells and suppressing hemopoietic stem cell function. The in vitro incubation of bone marrow suspensions with RAMLS caused extensive cell lysis with an apparent preferential destruction of lymphoid, erythroid, and blastoid elements. Using the spleen colony assay, the number of functional hemopoietic stem cells was found to be markedly reduced in bone marrow populations exposed to RAMLS in vitro. Further, this loss of stem cell function could be produced by exposing marrow suspensions to small concentrations of antiserum which did not produce detectable cytotoxic effects on the general marrow population. A similar effect of RAMLS upon hemopoietic stem cells was found in vivo. The intravenous injection of RAMLS into lethally irradiated mice immediately after the infusion of isogeneic marrow cells reduced the number of spleen colonies formed, indicating that the antiserum could exhibit a deleterious effect upon stem cells in the bloodstream of the intact animal. Normal animals treated with daily subcutaneous injections of RAMLS for 3 wk had a significantly reduced marrow content of functional hemopoietic stem cells, suggesting that RAMLS can affect stem cells located in situ in the bone marrow. The experiments indicate that RAMLS possesses potential marrow toxicity.

Surgical management of submucosal esophageal cancer: extended or regional lymphadenectomy?

INTRODUCTION: Radical esophagectomy is considered the standard therapy for tumors that infiltrate the submucosa of the esophagus (T1b), as the prevalence of lymph node metastases has been reported in up to 40% of these patients. It remains unclear whether radical esophagectomy with extended lymphadenectomy is needed or whether a surgical procedure with only regional lymphadenectomy suffices. The aim of this study was to compare outcomes of patients who underwent esophagectomy for T1b cancer through a transthoracic approach with extended lymphadenectomy (TTE) with those of patients in whom transhiatal esophagectomy (THE) was performed with a regional lymph node dissection. METHODS: Patients who underwent esophagectomy for T1b cancer between 1990 and 2004 and who did not receive (neo)adjuvant therapy were included. Data were collected from prospective databases of 4 centers. In Leuven, Belgium (n = 101), and Los Angeles, CA (n = 31), patients with T1b tumors had been operated on via TTE with extended lymphadenectomy, whereas in Amsterdam (n = 43) and Rotterdam (n = 47), the Netherlands, THE with regional lymphadenectomy had been performed. RESULTS: The 2 patient groups (TTE, n = 132; THE, n = 90) were comparable with regard to age, body mass index, and ASA classification. Operative time was longer in patients who underwent TTE (390 minutes) versus THE (250 minutes) (P < 0.001). The yield of lymph nodes resected was higher in the TTE group (median: 32) versus THE (median: 10) (P < 0.001). Overall morbidity, in-hospital mortality, and length of hospital stay were comparable between both the groups. In the TTE group, 27.3% of complications were classified as major versus 14.4% in the THE group (P < 0.001); however, the reoperation rate was higher after THE (12.2%) versus TTE (3.8%) (P = 0.01). There was no difference in pathological outcomes (infiltration depth, pN stage, pM stage, positive lymph node ratio) between both groups. Overall, 5-year survival (63.4% TTE vs 69.4% THE; P = 0.55) and disease-free 5-year survival (76.9% TTE vs 78.3% THE; P = 0.65) were comparable between both the groups. In patients with N1 disease, disease-free 5-year survival was 49.8% in the TTE group versus 40.0% in the THE group (P = 0.57). CONCLUSIONS: In patients with submucosal esophageal cancer (T1b), TTE with extended lymphadenectomy and THE with regional lymphadenectomy had similar short-term outcome and long-term survival. In the selected group of T1bN1 patients, TTE may be the preferred operative technique because of a potential disease-free survival benefit; in patients with T1bN0 disease, THE with en bloc dissection of the esophagus and regional lymph nodes offers an oncologically safe and less invasive treatment.

Esophagectomy for cancer in octogenarians.

Because of changes in life expectancy, there is an increasing number of elderly patients with esophageal cancer. The aim of this study was to assess the outcome of esophagectomy for cancer in patients 80 years or older. A retrospective review was performed of the records of all patients who underwent esophagectomy for cancer from 1992 to 2007. A cardiac and pulmonary evaluation was obtained on an individual basis in the younger patients and in all octogenarians. Among 560 patients with esophagectomy for cancer, 47 patients (8%) were octogenarians. The median age of the younger group (n= 513) was 63 years (interquartile range 56-71). Octogenarians had significantly more stage III disease (49% vs 31%, P= 0.02) but received less neoadjuvant therapy than younger patients (2% vs 21%, P= 0.0004). In octogenarians, the transhiatal resection was more common than in the younger group (79% vs 36%, P < 0.0001). Weight loss prior to surgery was similar in both groups, but body mass index was significantly lower in octogenarians (25 vs 28 kg/m(2) , P= 0.0002). Major complications occurred in 26% in octogenarians and 31% in the younger group (P= 0.51). Hospital mortality was similar (9% for octogenarians vs 4% in the younger group, P= 0.13). The median postoperative hospital stay was similar at 16 days (P= 0.69). There was no difference in cancer-related survival (median survival 48.9 vs 59.3 months, P= 0.31 log-rank test). Esophagectomy can be performed safely in carefully selected octogenarians with good cardiac and pulmonary function. Patients should not be denied an esophagectomy based only on their age.

Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case report.

A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology.

Plasma DNA: a molecular marker of surgical insult and postoperative recovery in esophageal cancer.

AIM: To assess plasma DNA changes intraoperatively, to relate plasma DNA to the magnitude of the surgical insult and to monitor the changes during the postoperative recovery period. MATERIAL AND METHOD: Prospective study of 35 patients with esophageal cancer who had esophagectomy of different magnitudes: 19 esophagectomy without thoracotomy and 16 esophagectomy with thoracotomy. The plasma DNA was measured prior to surgery, throughout the course of the operation on four different intervals, and on postoperative days 1, 3, 5, and 7. RESULTS: A significant difference was seen in the median plasma DNA intraoperatively between the two groups: esophagectomy without thoracotomy, 507 ng/ml/min (range 211-2,708), esophagectomy with thoracotomy, median 1,098 ng/ml/min (range 295-22,284; p = 0.014). Postoperative complications were identified in 6 patients who demonstrated a significant elevation in plasma DNA on postoperative days 5 and 7. CONCLUSION: Plasma DNA increases during surgery as a result of cell damage and the rise correlates with the magnitude of surgery. The descent of plasma DNA postoperatively correlates with surgical recovery. Elevation of the plasma DNA during the postoperative period correlates with postoperative complications. Plasma DNA is an objective molecular marker of surgical insult and can be used to monitor postoperative recovery after esophagectomy.

Can clinical and endoscopic findings accurately predict early-stage adenocarcinoma?

BACKGROUND: The presentation and management of esophageal cancer are changing, as more patients are diagnosed at an earlier stage of the disease in which endoscopic treatment methods may be contemplated. Therefore, we conducted a study to determine whether symptomatic and endoscopic findings can accurately identify node-negative early-stage adenocarcinoma. METHODS: A total of 213 consecutive patients (171 men and 42 women) with resectable esophageal adenocarcinoma seen from 1992 to 2002 were evaluated. None of these patients received neoadjuvant chemotherapy or radiation therapy. Using a multivariable model, model-based probabilities of early-stage disease (T1 im/sm N0) were calculated for each combination of the following three features: no dysphagia as main symptom at presentation, tumor length

Predictive factors of coexisting cancer in Barrett's high-grade dysplasia.

BACKGROUND: Identification of high-grade dysplasia (HGD) in Barrett's esophagus has been considered an indication for esophagectomy because of the high risk for coexisting cancer. However, rigorous endoscopic surveillance programs recently have been recommended, reserving esophagectomy for patients whose cancer is identified on biopsy. This approach risks continued surveillance for patients who already have cancer unless reliable markers for the presence of occult cancer are identified. This study aimed to determine the endoscopic, histologic, and demographic features associated with the presence of occult cancer in patients with HGD. METHODS: Endoscopic, histologic, and demographic findings for 31 patients who underwent esophagectomy for HGD were reviewed. The presence of an ulcer, nodule, stricture, or raised area on preoperative endoscopy was noted. The results of endoscopic biopsies taken before resection every 1 to 2 cm along the Barrett's segment were reviewed. The HGD was categorized as unilevel if the dysplasia was limited to one level of biopsy and as multilevel if more than one level was involved. Patients were divided into two groups according to the presence or absence of cancer in the resected specimens, and these variables were compared. RESULTS: The prevalence of coexisting cancer in patients with HGD was 45% (14/31). Of the 31 patients in this study, 9 had a visible lesion. Cancer was found in the resected specimens from 7 (78%) of 9 patients with a visible lesion and 7 (32%) of 22 patients without a visible lesion (p = 0.019). Of 22 patients without a visible lesion, 10 had multilevel and 12 had unilevel HGD. The findings showed that 6 (60%) of 10 patients with multilevel HGD and 1 (8.3%) of 12 patients with unilevel HGD had cancer in the resected esophagus (p = 0.009). CONCLUSION: For patients with HGD, a lesion visible on endoscopy and/or HGD at multiple biopsy levels is associated with an increased risk for coexisting cancer. These patients should be considered for early esophagectomy.

Bravo capsule induction of esophageal hypercontractility and chest pain.

BACKGROUND: The Bravo catheter-free pH monitoring system uses a capsule attached to the esophageal mucosa to detect acid exposure. Placement of the Bravo capsule is associated with intermittent chest pain in 50% of normal volunteers. The authors hypothesized that chest pain in this setting may be attributable to hypertensive esophageal contractions induced by the Bravo capsule. METHODS: The study population consisted of 40 consecutive patients with reflux symptoms who had stationary esophageal manometry within 1 h after Bravo capsule placement. The control group consisted of 40 patients with symptomatic gastroesophageal reflux disease (GERD) from a population of patients with foregut symptoms who were computer matched to the study group for age, sex, lower esophageal sphincter (LES) pressure, LES length, and 24-h pH composite score. The patients in the control group had manometry before Bravo capsule placement. The occurrence of chest pain was assessed before and during the monitoring period by interview and review of the patient's diary. Mean contraction amplitudes in the distal third of the esophagus after 10 wet swallows were averaged. The prevalence of patients with esophageal contraction amplitudes in the distal third that exceeded the 95th percentile of normal (180 mmHg) and the mean amplitude of distal third esophageal contractions in the study and control populations were compared. In the study group, the incidence of chest pain among the patients with hypercontractility of the esophagus was compared with the incidence among those without hypercontractility. RESULTS: The mean contraction amplitude was higher in the study group (144.7 vs 105.5 mmHg; p = 0.002). The number of patients with a mean distal esophageal contraction amplitude exceeding the 95th percentile of normal also was significantly higher in the study group (13/40 vs 5/40; p = 0.03). A total of 10 patients experienced new onset of chest pain with the Bravo capsule in place, and 6 patients experienced hypertensive esophageal contractions. CONCLUSIONS: The intraesophageal Bravo capsule can cause hypertensive esophageal contractions, which may lead to chest pain.

Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma.

BACKGROUND: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker. METHODS: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests. RESULTS: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016). CONCLUSION: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types.

Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma.

Esophageal adenocarcinoma (EAC) is thought to develop through a multistage process in which Barrett's metaplasia progresses through low- and high-grade dysplasia to invasive cancer. Transcriptional silencing of tumor suppressor genes by promoter CpG island hypermethylation has been observed in many types of human cancer. Analysis of CpG island hypermethylation in EAC has thus far been limited to the CDKN2A (p16) gene. In this study, we extend the methylation analysis of EAC to include three other genes, APC, CDH1 (E-cadherin), and ESR1 (ER, estrogen receptor alpha), in addition to CDKN2A. Molecular analysis can provide insight into the complex relationships between tissues with different histologies in Barrett's esophagus and associated adenocarcinoma. Therefore, we have mapped the spatial distribution of methylation patterns in six esophagectomy cases in detail. Hypermethylation of the four CpG islands was analyzed by the MethyLight technique in 107 biopsies derived from these six patients for a total of 428 methylation analyses. Our results show that normal esophageal squamous epithelium is unmethylated at all four CpG islands. CDH1 is unmethylated in most other tissue types as well. Hypermethylation of ESR1 is seen at high frequency in inflammatory reflux esophagitis and at all subsequent stages, whereas APC and CDKN2A hypermethylation is found in Barrett's metaplasia, dysplasia, and EAC. When it occurs, hypermethylation of APC, CDKN2A, and ESR1 is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.

Epigenetic patterns in the progression of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples]. This group could be further subdivided into three classes, according to the absence (CDKN2A, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progression.

Phase I trial of an implanted battery-powered, programmable drug delivery system for continuous doxorubicin administration.

A second generation, implantable drug administration device (DAD, Medtronic, Inc, Minneapolis) which contains a 20-mL drug reservoir, a lithium-thionyl-chloride battery, a peristaltic roller pump, a microprocessor circuit, and an acoustic transducer has entered clinical trials. After surgical placement, drug is entered into and removed from the DAD percutaneously through a Silastic "fill port" using a standard gauge needle and syringe. The pump is noninvasively programmed using a hand-held telemetry wand to administer the drug in a continuous infusion, bolus, or bolus-delay mode. Because of the apparent improved therapeutic index of continuous-infusion doxorubicin (CID), a phase I trial of the Medtronic DAD with CID was begun. Thirteen pumps in 13 patients have functioned for a median of 153 days (range, 11 to 395 days) with one pump still functioning. Four pumps ceased function at 170, 278, 331, and 370 days, respectively; there was a catheter-tip clot on one of the pumps that later malfunctioned. All other pumps functioned until the death of the respective patients. In 84 pump refills, without drug extravasation, the median drug delivery error (actual residual volume--calculated residual volume/calculated residual volume X 100%) was 14%. Doxorubicin was compatible with all components of the drug pathway and did not significantly decompose during two weeks in the drug reservoir. The starting dose of CID was 2.0 mg/m2/d and the maximum tolerated dose was 4.1 mg/m2/d (range, 3.5 to 5.5). A median cumulative doxorubicin dose of 244 mg/m2 per patient (range, 10 to 583 mg/m2) has been infused.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and usefulness of endoscopy for evaluation of the graft and anastomosis early after esophagectomy and reconstruction.

BACKGROUND: Although rare, graft ischemia and necrosis after esophagectomy is a devastating complication. The aim of this study was to review our experience with early endoscopy for evaluation of the graft and anastomosis after esophagectomy and reconstruction. METHODS: From a population of 479 patients who underwent esophagectomy during the years 1996-2003, we identified 102 patients who had endoscopy within 21 days of operation. RESULTS: Endoscopy was performed a median of 9 days after operation. Graft ischemia, anastomotic leak, or both were found in 63 of the 102 patients. Reoperation was necessary in 27% of these patients, including graft removal in nine patients. In 39 patients, endoscopy demonstrated a healthy graft; only one of these patients (2.6%) required reoperation. No patient with ischemia judged insufficient to warrant graft removal on initial endoscopy subsequently lost their graft. There were no complications or anastomotic injuries associated with early endoscopy. CONCLUSION: Endoscopy early after esophagectomy is safe and provides accurate and reliable identification of graft ischemia that can be used to guide the treatment of these patients.