Single center experience of endoscopic submucosal dissection (ESD) in early Barrett's adenocarcinoma.

BACKGROUND: Endoscopic mucosal resection (EMR) or radical surgical resection are the standard treatment options for patients with early Barrett's adenocarcinoma (EBAC). Endoscopic submucosal dissection (ESD) is a new endoscopic technique, which allows--in contrast to EMR--endoscopic en-bloc resection of neoplastic lesions greater than 2 cm with complete histological evaluation of the resected specimen. In contrast to Western countries, Barrett's esophagus is less common in Asia indicating the low volume of published data of ESD in EBAC in Japanese series. Therefore, the aim of the present study is to describe the results of ESD in patients with EBAC performed in a German tertiary referral center. METHODS: Between November 2009 and April 2014 ESDs were performed in 22 patients with histologically proven EBAC. Data were given for the en-bloc, the R0, the R0 en-bloc, and the curative resection rate as well as for the complication and the local recurrence rate. RESULTS: ESD was technically possible in all of the 22 patients. 20 of the resected EBAC were mucosal carcinomas, whereas in two patients the tumor showed submucosal invasion. The en-bloc, R0, R0 en-bloc, and curative resection rates were 95.5, 81.8, 81.8 %, and 77.3 %, resp. Complication rate was 27.3 % (perforation n = 1, bleeding n = 2, stenosis n = 3). In case of curative tumor resection, only one local tumor recurrence (5.9 %) occurred after a medium follow-up of 1.6 years. CONCLUSIONS: Despite the small number of patients and a relatively short follow-up, the present data underline the value of ESD, especially in case of curative resections in the definite and less invasive therapy of EBAC. Attention should be drawn toward subsquamous extension of EBAC requiring a sufficient safety margin as an obligate condition for curative R0 resections. Due to the required learning curve and the management of potential complications, ESD should be restricted to greater endoscopic centers.

[Single centre experience of endoscopic submucosal dissection (ESD) in premalignant and malignant gastrointestinal neoplasia]. / Single-Center-Erfahrung mit der Endoskopischen Submukosa-Dissektion (ESD) bei prämalignen und malignen gastrointestinalen Neoplasien.

INTRODUCTION: Worldwide endoscopic submucosal dissection (ESD) of early GI cancers or premalignant neoplasia is becoming increasingly important. In Germany ESD is restricted to larger endoscopic institutions and only a few literature reports are available. The aim of the present study is to describe the results of 46 ESDs conducted in a German endoscopic centre. MATERIAL AND METHODS: Between June 2007 and May 2012 46 ESDs in 45 patients (33 men, 12 women, mean age 66.1 years) were performed in the oesophagus (n = 17), stomach (n = 23) and rectum (n = 6). Data were collected for the en-bloc, R0 and R0 en-bloc resection rates as well as for complications, the curative resection and the local recurrence rates. In order to demonstrate a learning curve, results were evaluated for two periods (June 2007 to November 2010 vs. December 2010 to May 2012). RESULTS: ESD was technically possible in 93.5%. En-bloc, R0, R0 en-bloc and curative resection rates were 90.7%, 74.4%, 67.4% and 65.1%, respectively. The complication rate was 13%. In the second period en-bloc and R0 en-bloc resection rates increased from 81% to 100% and, respectively, from 52.4% to 81.8%. After a medium follow-up of 11.4 months, local tumour recurrence occurred in 10%. In cases of curative R0 en bloc resection of malignant tumours no tumour recurrence occurred. DISCUSSION: Despite the small number of patients, the present data underline the value of ESD, especially in cases of R0 en-bloc resections in the therapy for premalignant and early malignant GI tumours. Due to the required learning curve, ESD should be restricted to larger endoscopic centres in Germany.

Esophageal submucosal dissection under steady pressure automatically controlled endoscopy (SPACE): a randomized preclinical trial.

BACKGROUND AND STUDY AIMS: A new overtube system has been developed for steady pressure automatically controlled endoscopy (SPACE) in the gastrointestinal tract. The objectives of this study were to validate the feasibility and safety of SPACE in the esophagus, and to evaluate its potential advantages over conventional (manually insufflating) endoscopy in endoscopic submucosal dissection (ESD). METHODS: This was a multicenter preclinical trial using acute porcine models (n = 20). In Experiment 1 (feasibility/safety study), SPACE was attempted in the esophagus with continuous monitoring of cardiopulmonary parameters and intraluminal pressures in the downstream bowel. Different insufflation pressures were tested to optimize the insufflation condition. Each session was video-recorded and scored by blinded reviewers. In Experiment 2 (randomized trial), esophageal ESD was attempted using either SPACE or conventional endoscopy, and results were compared. RESULTS: In Experiment 1, SPACE was performed safely without intraluminal pressure elevation in the downstream bowel. According to video review, SPACE provided more stable, reproducible, and rapid visualization than conventional endoscopy. The insufflation pressure was optimized at 14 mmHg for esophageal SPACE. In Experiment 2, ESD was completed in all animals. The ESD time was significantly shorter with SPACE compared with conventional endoscopy (1326 vs. 1616 seconds; P = 0.009). Responses to questionnaires showed that 94 % - 100 % of participants considered SPACE to provide improved exposure and more uniform tissue tension than conventional endoscopy. Other data were comparable. CONCLUSIONS: SPACE is feasible, safe, and potentially effective for complicated endoscopic procedures, such as ESD. SPACE improves and standardizes endoscopic exposure and tissue tension. A clinical study is required to further confirm its safety and clinical effectiveness.

Quantitative analysis of changes in blood concentrations and 'presumed effect-site concentration' of sevoflurane during one-lung ventilation.

During one-lung ventilation, ventilation-perfusion mismatch decreases the arterial concentration of inhaled anaesthetics due to the arterial-to-venous concentration difference. This study tested the hypothesis that in humans, the 'presumed effect-site concentration' (taken as the mid-point between the arterial and superior jugular venous concentrations) of inhaled anaesthetic falls during one-lung (vs two-lung) ventilation. Four patients scheduled for elective prostatectomy (two-lung ventilation) and four patients for elective thoracotomy (one-lung ventilation) were randomly selected and assigned to receive sevoflurane (vaporiser-dial setting, 1.5%). Sevoflurane concentrations were measured periodically from radial artery and superior jugular vein (via a catheter advanced cephalad from the jugular vein). During one-lung ventilation, the end-expiratory sevoflurane concentration was stable at ∼1.3% but the mean (SD) presumed effect-site concentration declined initially from 58 (6.7) to 43 (4.7) µg.ml(-1) (p=0.011) before slowly recovering. A period of insufficient depth of anaesthesia is thus a risk during one-lung ventilation.

Clinical advantage of endoscopic submucosal dissection over endoscopic mucosal resection for early mesopharyngeal and hypopharyngeal cancers.

BACKGROUND AND STUDY AIMS: In previous series, endoscopic mucosal resection (EMR) has been used for the treatment of early-stage mesopharyngeal and hypopharyngeal cancers to preserve patients' quality of life. Endoscopic submucosal dissection (ESD) offers potential advantages in comparison to EMR. So the aim of this retrospective study was to assess the utility of ESD compared with EMR for early-stage cancers of the meso- and hypopharynx. PATIENTS AND METHODS: We studied 56 patients with 69 lesions who underwent either EMR or ESD between April 2001 and December 2008. EMR was performed until January 2007, and ESD was performed from February 2007 onward. We evaluated the en bloc resection rate, R0 resection rate, and treatment-related complications as short-term outcomes. Local recurrence, lymph node metastasis, and disease-related deaths were compared to evaluate long-term outcomes. RESULTS: The en bloc and R0 resection rates were respectively 98 % and 79 % in the ESD group and 37 % and 26 % in the EMR group. There were no cases of treatment-related complications in the EMR group, but postoperative subcutaneous emphysema was observed in two patients in the ESD group. In the EMR group, one patient developed a local recurrence and one developed metastasis to the cervical lymph node and died of primary cancer. CONCLUSIONS: ESD is a useful method of treatment for early mesopharyngeal and hypopharyngeal cancers and may be superior to EMR.

Endoscopic submucosal dissection for treatment of mesopharyngeal and hypopharyngeal carcinomas.

BACKGROUND AND STUDY AIMS: Application of the endoscopic submucosal dissection (ESD) technique, as well as elevation of the larynx in cooperation with an otolaryngologist, under general anesthesia has enabled en-block resection of early mesopharyngeal and hypopharyngeal carcinomas. The aim of this study was to retrospectively evaluate the safety of ESD and the efficacy of the elevation of the larynx for treatment of early mesopharyngeal and hypopharyngeal carcinomas. PATIENTS AND METHODS: The study included 16 lesions in 13 patients who underwent ESD. To provide a sufficient working space, the larynx was elevated under direct laryngoscopy, and a tube was inserted and fixed onto the laryngeal side using the slot on the back of the laryngoscope. RESULTS: The median maximum diameter of the lesions was 12.5 mm (range 2 - 37 mm). The en-block resection rate was 93.8 %. Lateral surgical margins in two patients were difficult to evaluate for technical reasons. The tube could not be removed from four patients on the day of the procedure due to laryngeal edema caused by the local injection. No serious complications were observed. Oral food intake was possible after a mean of 3.3 postoperative days. CONCLUSIONS: With adequate intraoperative and postoperative management, ESD with elevation of the larynx may be very efficient and safe for endoscopic treatment of pharyngeal lesions.

Comparison of standard endoscopic submucosal dissection (ESD) versus an optimized ESD technique for the colon: an animal study.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a promising therapeutic technique for en bloc resection of large gastrointestinal tumors. However, this technique has disadvantages such as a long intervention time, complexity of the procedure, and a higher rate of complications. The primary aims of the study were to show the feasibility of ESD in the pig colon and to evaluate a new ESD technique comprising the use of a newly developed hybrid knife for colon procedures combining RF (radiofrequency) application and a distance-dependent water-jet application. MATERIALS AND METHODS: ESD was conducted at three different locations in the colon according to the computer-generated randomization list, using either the standard technique (injection needle, flex knife, and hook knife as therapeutic instruments and DRY CUT and SWIFT COAG as RF currents), or the new ESD technique (hybrid knife as the therapeutic instrument combined with the new cutting mode ENDO CUT D) in 12 healthy pigs. The perforation and bleeding rates were documented and statistically analyzed. Intervention time, resected specimen size, thermal and mechanical damage of the resection bed, and number of instrument changes required were also recorded. RESULTS: A total of 16 and 18 ESD procedures were performed by the standard and new techniques, respectively. Complete en bloc resection was achieved in all cases. The standard ESD technique showed a perforation rate of 25 % (4/16) whereas the new ESD technique resulted in a 5.5 % perforation rate (1/18) ( P = 0.035); bleeding rates were similar. The new ESD technique was significantly safer compared with the standard ESD technique. CONCLUSIONS: A new ESD technique for the successful en bloc resection in thin-walled regions such as pig colon has been described. This procedure is as effective as the standard procedure but is easier to handle and significantly safer.

Efficacy and safety of endoscopic submucosal dissection for gastric cancer in patients with liver cirrhosis.

Endoscopic submucosal dissection (ESD) has become a widely accepted method for treating gastrointestinal cancer. The aim of this study was to evaluate the efficacy and safety of ESD for gastric cancer in patients with liver cirrhosis. A total of 18 gastric cancers were treated by ESD in 15 patients with cirrhosis. The rate of en bloc resection was 88.9% (16/18). En bloc resection with tumor-free lateral/basal margins (R0 resection) was 77.8% (14/18). Three patients had postoperative bleeding and underwent emergency gastroscopy for hemostasis. No recurrence was observed during the median follow-up of 21.4 months, excluding three patients in whom additional endoscopic resection or surgery was carried out. ESD can be safely performed for gastric cancer in patients with cirrhosis, resulting in a high en bloc resection rate.

Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1.

Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. This study examined the effects of insulin resistance on coronary risk factors in IRS-1 deficient mice, a nonobese animal model of insulin resistance. Blood pressure and plasma triglyceride levels were significantly higher in IRS-1 deficient mice than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in IRS-1 deficient mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, suggesting impaired lipolysis to be involved in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors which may accelerate the progression of atherosclerosis in subjects with insulin resistance.

Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter.

In an attempt to identify transcription factors which activate sterol-regulatory element-binding protein 1c (SREBP-1c) transcription, we screened an expression cDNA library from adipose tissue of SREBP-1 knockout mice using a reporter gene containing the 2.6-kb mouse SREBP-1 gene promoter. We cloned and identified the oxysterol receptors liver X receptor (LXRalpha) and LXRbeta as strong activators of the mouse SREBP-1c promoter. In the transfection studies, expression of either LXRalpha or -beta activated the SREBP-1c promoter-luciferase gene in a dose-dependent manner. Deletion and mutation studies, as well as gel mobility shift assays, located an LXR response element complex consisting of two new LXR-binding motifs which showed high similarity to an LXR response element recently found in the ABC1 gene promoter, a reverse cholesterol transporter. Addition of an LXR ligand, 22(R)-hydroxycholesterol, increased the promoter activity. Coexpression of retinoid X receptor (RXR), a heterodimeric partner, and its ligand 9-cis-retinoic acid also synergistically activated the SREBP-1c promoter. In HepG2 cells, SREBP-1c mRNA and precursor protein levels were induced by treatment with 22(R)-hydroxycholesterol and 9-cis-retinoic acid, confirming that endogenous LXR-RXR activation can induce endogenous SREBP-1c expression. The activation of SREBP-1c by LXR is associated with a slight increase in nuclear SREBP-1c, resulting in activation of the gene for fatty acid synthase, one of its downstream genes, as measured by the luciferase assay. These data demonstrate that LXR-RXR can modify the expression of genes for lipogenic enzymes by regulating SREBP-1c expression, providing a novel link between fatty acid and cholesterol metabolism.

Effect of pre-hospital advanced airway management for out-of-hospital cardiac arrest caused by respiratory disease: a propensity score-matched study.

Optimal pre-hospital care for out-of-hospital cardiac arrest (OHCA) caused by respiratory disease may differ from that for OHCA associated with other aetiologies, especially with respect to respiratory management. We aimed to investigate whether pre-hospital advanced airway management (AAM) was associated with favourable outcomes after OHCA caused by intrinsic respiratory disease. This nationwide, population-based, propensity score-matched study of adult patients in Japan with OHCA due to respiratory disease from 1 January 2005 to 31 December 2012 compared patients with and without pre-hospital AAM. The primary outcome was neurologically favourable survival at one month after the OHCA. Of 49,534 eligible patients, 20,458 received pre-hospital AAM and 29,076 did not. In a propensity score-matched cohort (18,483 versus 18,483 patients), the odds of neurologically favourable survival were significantly lower for patients receiving pre-hospital AAM (0.6% versus 1.5%; odds ratio [OR] 0.42 [95% confidence interval {CI} 0.34 to 0.52]). The results from multivariable logistic regression analysis also showed that pre-hospital AAM was significantly associated with a decreased chance of neurologically favourable survival (adjusted OR 0.43 [95% CI 0.35 to 0.52]). Similar findings were observed for one-month survival and pre-hospital return of spontaneous circulation. In subgroup analyses, pre-hospital AAM was associated with poor neurological outcomes, regardless of the type of airway device used (laryngeal mask airway, adjusted OR 0.35 [95% CI 0.19 to 0.57]; oesophageal obturator airway, adjusted OR 0.44 [95% CI 0.35 to 0.55]; and endotracheal tube, adjusted OR 0.47 [95% CI 0.30 to 0.69]). In conclusion, pre-hospital AAM was associated with poor neurological outcome among patients with OHCA caused by intrinsic respiratory disease.

The useful combination of a higher frequency miniprobe and endoscopic submucosal dissection for the treatment of T1 esophageal cancer.

BACKGROUND: There are few published data on the discrimination ability of endoscopic ultrasonography (EUS) among each subdivision of T1 cancer, and overdiagnosis is an unsolved problem that eventually causes overtreatment. The purpose of this study was to verify whether our treatment strategy incorporating EUS realizes a tailored patient management of T1 esophageal cancer. METHODS: This study comprised 20 esophageal cancer patients undergoing 12- to 20-MHz miniprobes for T staging and a 7.5-MHz dedicated echoendoscope for N staging. Initial therapy constituted endoscopic submucosal dissection (ESD) for endosonographically node-negative, mucosal, or slight submucosal cancers and a primary esophagectomy with three-field lymphadenectomy for deeper cancers. If the ESD specimen revealed no cancer involvement of the muscularis mucosa, the patients entered a follow-up program; otherwise, they were advised to undergo a subsequent esophagectomy and three-field lymphadenectomy. RESULTS: Perfect discrimination accuracy was achieved among T1, T2, and T3 cancers. Whether cancer depth was up to the slight submucosal layer or deeper was correctly differentiated in 12 of 14 T1 cancers (86%). EUS categorized all patients correctly into candidates for either ESD or surgery. The pathological cancer depth of the resected specimens revealed that no patients experienced unnecessary overtreatment. CONCLUSIONS: A higher frequency miniprobe is useful for the detailed evaluation of cancer depth, contributing to decision making for treatment options of T1 esophageal cancer. A miniprobe and echoendoscope in combination with ESD provide an appropriately tailored management plan on an individual basis, avoiding unnecessary treatment or indicating radical surgery.

Correlation of serum pepsinogens and gross appearances combined with histology in early gastric cancer.

The correlation between serum pepsinogen (PG) levels and the gross types was investigated in 128 consecutive patients with early gastric cancer. Although there was no significant difference in age, gender, cancer location, or cancer depth among gross appearances, the distribution of histological type was significantly different between polypoid and depressed cancers: all polypoid cancers except one were intestinal type, whereas nearly a third of depressed cancers were diffuse type. All the patients in whom Helicobacter pylori status was investigated had Helicobacterpylori infection. Combination of gross appearances and histology (polypoid cancer with intestinal type, depressed cancer with intestinal type and depressed cancer with diffuse type) showed a clear difference in distribution of serum PG levels and a ratio between levels of PG I and PG II (I/II ratio). In polypoid cancer with intestinal type, a PG I level and a I/II ratio were significantly lower than those of the others. In depressed cancer with diffuse type, PG I and PG II levels were significantly higher. These findings revealed that backgrounds such as intragastric acidity and extent of gastric atrophy might differ among early gastric cancers with different morphology and histology.

Kinetics of v-src-induced epithelial-mesenchymal transition in developing glandular stomach.

The oncogene function in primary epithelial cells is largely unclear. Recombination organ cultures in combination with the stable and transient gene transfer techniques by retrovirus and electroporation, respectively, enable us to transfer oncogenes specifically into primary epithelial cells of the developing avian glandular stomach (proventriculus). In this system, the epithelium and mesenchyme are mutually dependent on each other for their growth and differentiation. We report here that either stable or transient expression of v-src in the epithelium causes budding and migration of epithelial cells into mesenchyme. In response to the transient expression of v-Src or a constitutive active mutant of MEK, we observed immediate downregulation of the Sonic hedgehog gene and subsequent elimination of E-cadherine expression in migrating cells, suggesting the involvement of MAP kinase signaling pathway in these processes. v-src-expressing cells that were retained in the epithelium underwent apoptosis (anoikis) and detached from the culture. Continuous expression of v-src by, for example, Rous sarcoma virus (RSV) was required for the epithelial cells to acquire the ability to express type I collagen and fibronectin genes (mesenchymal markers), and finally to establish the epithelial-mesenchymal transition. These observations would partly explain why RSV does not apparently cause carcinoma formation, but induces sarcomas exclusively.

Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL.

Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus. Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P<0.05; cross-sectional lesion areas were 191 974+/-102 911 micrometer(2) vs 351 738+/-175 597 micrometer(2), P<0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.

Epidemiological and outcome characteristics of major burns in Tokyo.

The Tokyo Burn Unit Association (TBUA) was established in 1983 funded by the Tokyo Metropolitan Government, and is organized by 13 burn units in Tokyo. TBUA covers more than 90% of severe burn patients occurring in Tokyo, and all of the cases are registered according to the burn injury registration format. The purpose of this study is to analyze the registered data and to elucidate epidemiological and outcome characteristics of major burn injuries in Tokyo. The total of 6988 hospitalized patients had data for epidemiological analysis, and 6401 patients had complete data for outcome analysis as well, and were included in this study. The characteristic profiles for the analysis included age, sex, cause of burns, inhalation injury, %BSA, burn index (BI), length of burn unit stay, and outcome, and were analyzed by age groups. The mean age of the patients was 40.4 years, and 63% of them were male. It was noteworthy that 25% of the total patients were elderly patients over 60 years of age. Flame was the most common cause making up 45.6% followed by scalding (32.0%). The overall mortality rate was 15.4%. Inhalation injury was accompanied in 27.3% of burn patients. The mortality rate was 34.6% with inhalation injury, and 8.2% without inhalation injury. Causes of death showed that multiple organ failure made up 36.9% of total mortality, followed by sepsis 25.2 and shock 19.0%. The burn size (%BSA and BI) and inhalation injury were the factors for high mortality rate in all age groups whereas age was a predictor for high mortality in the patients older than 16 years of age. Gender was not a factor for high mortality in any age group. The mortality rate showed mildly decreasing tendency since 1995 for which implementation of skin bank was thought to be responsible.

Flow cytometric analysis on perforin induction in peripheral blood mononuclear cells with interleukin-2 or OK-432.

Perforin is a protein present in the cytoplasmic granules of killer cells and is considered to be an important effector molecule. We assessed the perforin appearance via flow cytometry in human peripheral blood mononuclear cells stimulated in vitro for 3 days by recombinant interleukin-2 (rIL-2) or OK-432, a biological response modifier. The relationship between the lymphocyte subsets and perforin was investigated via two-color assay. CD4-positive cells had almost no perforin, and most of the CD16-positive cells did. Regarding the relationship with CD8, some of the bright positive cells (which were likely T cells) and most of the dull positive cells (likely NK cells) had perforin. Mean fluorescence was greatest in perforin-positive cells incubated with rIL-2, less in cells incubated with OK-432, and minimal in cells incubated in a medium without additives. Immunohistochemical staining with antiperforin antibody revealed that blast-transformed and enlarge cells were stained positively and that the intensity of staining of each cell alone was enhanced in cells incubated with OK-432 or rIL-2. If the fluorescence intensity of perforin-positive cells correlates with the amount of perforin in those cells, then the appearance of perforin was enhanced with OK-432, more enhanced with rIL-2, and consistent for cytotoxicity against K562 and Daudi cells. IL-2 was induced by OK-432, suggesting that the indirect effect of this IL-2 may play a role in OK-432-perforin induction. The results suggest that perforin may be an effector molecule in killer cells induced by rIL-2 or OK-432.

Functional expression of cloned cDNA encoding sodium channel III.

mRNA synthesized by transcription in vitro of the cloned cDNA encoding rat brain sodium channel III directs the formation of a functional sodium channel in Xenopus oocytes. The tissue distribution of the mRNAs encoding sodium channels I, II and III has been studied by blot hybridization analysis with specific probes.