POEM (per-oral endoscopic myotomy) is emerging as the new endoscopic standard for treating patients with achalasia. Originating from Japan, POEM is now performed at many tertiary care centers in North America. Hitherto, data from institutions regarding the safety & efficacy of the procedure has shown promising results. To ensure that the procedure is seamless, identifying challenging cases ahead of time would allow for better resource allocation & to plan accordingly. To identify if certain pre-procedural factors are associated with intra-procedural factors or post-procedural complications, to ultimately formulate a POEM difficulty score to allow endoscopists to predict difficult cases ahead of time. 51 POEM procedures performed for achalasia at a tertiary care centre in Japan were analyzed in the study. Most procedures were performed by advanced-therapeutics trainees with close proctoring by experienced endoscopists. Various pre-determined pre-procedural factors (age, sex, achalasia type, duration of symptoms, Eckardt score, morphology & prior treatments); intra-procedural factors (tunnel distention, submucosal fibrosis, abnormal contractions, submucosal oozing, orientation, length of myotomy, procedure time, number of clips used & intra-procedural adverse events) & post-procedural data points were collected & analyzed. A preliminary POEM difficulty score (out of 10) was formulated with each component worth 2 points (tunnel distention, submucosal fibrosis, abnormal contractions, submucosal oozing, orientation). Analyses were performed using chi-square tests for categorical data & T-tests/ANOVAs/Spearmans correlations for continuous data. The mean age was 44.3 ± 15.5 yrs & mean duration of symptoms 8.1 ± 9.9 yrs. Mean Eckardt score was 6.7 ± 2.2. Six patients (11.8%) had an intra-procedural event & 3 (5.9%) had an in-hospital adverse event. In the univariate analyses, the POEM difficulty score did not correlate with the occurrence of an intra-procedural event (p=0.203) or post procedure complications (p=0.80). Factors that correlated with the POEM difficulty score included morphology (S1/S2 vs. NS-D or NS-ND, p=0.006), prior treatments (pneumatic dilation vs. none, p=0.028) & age (p=0.030). A multivariate regression analysis was also conducted with variables removed sequentially, and even though trends were seen with some variables, type of achalasia was the only variable that maintained significance (p=0.048). Based on this study, there are indications that procedures involving older patients; S1/S2 morphology; type of achalasia (Type 1); and those with prior treatments may be more difficult overall. Further validation of these results as well as the POEM difficulty score is needed as our study was limited by smaller numbers, minimal adverse events, more trainee involvement, and less challenging procedures overall. None

Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in-vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD.

POEM is potentially an ideal endoscopic therapy for refractory spastic esophageal disorders (SED) since it not only allows myotomy of the lower esophageal sphincter (LES) but also of the esophageal body, where the hypertensive contractions occur. Limited data exist on the use of POEM for therapy of these difficult-to-treat disorders.

The objective of this study was to identify the mechanism by which mandibular condyle chondrocytes regulate the extracellular matrix. Primary rabbit condylar chondrocytes were isolated, cultured, and treated with transforming growth factor beta 1 (TGF-β1). Cells were then assayed for the following: urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1), collagen types I and II, β1 integrin expression, and proliferative activity. TGF-β1 induced synthesis of collagen type II, αVβ1 integrin, and PAI-1. TGF-β1 induced the growth of chondrocytes and suppressed the synthesis of uPA. Chondrocyte regulation of the extracellular matrix is mediated by TGF-β1. Synthesis of collagen type II, αVβ1 integrin, and PAI-1 is induced, while uPA is suppressed. Also, TGF-β1 induces cellular growth.

Recent advances in endoscopic technology allow us to perform totally endoscopic myotomy for esophageal achalasia. A submucosal tunnel is first created at the anterior wall of the esophagus down to the gastric cardia. Endoscopic myotomy is carried out in the submucosal tunnel and then completed at the end of the submucosal tunnel. After confirmation of smooth passage of the endoscope through esophago-gastric junction, the mucosal incision is closed using regular hemostatic clips.

Esophageal perforation occurring during or after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is a rare, but serious complication. However, reports of its characteristics, including endoscopic imaging and management, have not been fully detailed. To analyze and report the clinical presentation and management of esophageal perforations occurred during or after EMR/ESD. Four hundred seventy-two esophageal neoplasms in 368 patients were treated (171 EMR; ESD 306) at Northern Yokohama Hospital from 2003 to 2012. Esophageal perforation occurred in a total of seven (1.9%) patients, all of whom were male and had undergone ESD. The etiology of perforation was: three (42.9%) intraoperative; three (42.9%) balloon dilatation for stricture prevention; one (14.2%) due to food bolus impaction. All cases were managed non-operatively based on the comprehensive assessment of clinical severity, extent of the injury, and the time interval from perforation to treatment onset. Conservative management included (i) bed rest and continuous monitoring to determine the need for operative intervention; (ii) fasting and intravenous fluid infusion/ tube feeding; and (iii) intravenous antibiotics. All defects closed spontaneously, save one case where closure was achieved by endoscopic clipping. Surgery was not required. Conservative management for esophageal perforation during advanced endoscopic resection is may be possible when there is no delay in diagnosis or treatment. Decision-making should be governed purely by multidisciplinary discussion.

BACKGROUND AND STUDY AIM:Intrapapillary capillary loops (IPCLs) show distinct pattern changes corresponding to tumor progression and depth of invasion, important for in vivo characterization of superficial squamous cell carcinoma (SCC). We examined the relation between invasion depth and histopathologic IPCL diameter.PATIENTS AND METHODS:Prospectively, before lesion resection, magnification endoscopy and narrow band imaging were used to identify IPCL patterns of type V1 (corresponding to tumors limited to the mucosa; 10 patients) and type Vn (submucosally invading tumors; 10 patients). Post-resection, IPCL samples (type I [normal mucosa], n = 103; V1, n = 113; Vn, n = 100) were stained with hematoxylin & eosin, CD34, and desmin, and vessel diameter measured using light microscopy.RESULTS:Mean (standard deviation [SD]) histopathologic calibers of IPCLs of types I, V1, and Vn were significantly different, being 7.7 (2.8) µm, 21.9 (7.4) µm, and 65.2 (22.9) µm; type 1 vs. V1, P < 0.001; V1 vs. Vn, P < 0.001.CONCLUSIONS:Magnification endoscopy observation of IPCLs allows in vivo discrimination between intramucosal and submucosally invasive cancer.

Background and study aims: Resection of submucosal tumors by means of endoscopy has been reported using a variety of techniques, but cannot be performed safely in tumors originating from the muscularis propria. Using the submucosal tunnel created by the technique of peroral endoscopic myotomy (POEM), we report the first series describing the new technique of submucosal endoscopic tumor resection (SET) for tumors of the esophagus and cardia.Patients and methods: SET was attempted in nine consecutive patients with tumors (size > 2cm) of either the esophagus or cardia with clinical indications for lesion removal. Following creation of a submucosal tunnel from 5cm above the tumor, as described previously, the tumor was dissected from the overlying mucosa/submucosa and then carefully removed from the muscular layer using triangle-tip and insulated-tip knives. Following specimen retrieval through the tunnel, the orifice was closed by clips.Results: Of the nine patients, two had tumors that were too large (60mm and 75mm, respectively) to allow safe removal due to loss of endoscopic overview. All remaining tumors (maximal tumor extension 12-30mm) could be resected safely using this method. No complications occurred and follow-up was unremarkable. On histology, all tumors were resected completely (one gastrointestinal stromal tumor, five leiomyomas). The technique had to be modified in one patient with an aberrant pancreas.Conclusions: SET is a promising new technique for selected submucosal tumors in the esophagus and cardia up to a size of 4cm and should be studied further.

Achalasia is a primary motility disorder with an annual incidence of 0.11 cases/100 000 children [1]. In the field of natural orifice transluminal endoscopic surgery (NOTES), the peroral endoscopic myotomy (POEM) [2] [3] is the only treatment to be performed routinely in humans. We report the case of a 3-year old female patient with Down syndrome who presented with severe growth retardation and weight at less than the 3 rd percentile curve. Achalasia was suspected because of vomiting, recurrent cough, aspiration pneumonia, and growth retardation; it was confirmed by barium esophagogram, endoscopy, and esophageal manometry.

Adenovirus-mediated gene therapy shows remarkable promise as a new strategy for advanced pancreatic cancer, but satisfactory clinical results have not yet been obtained. To improve this gene therapy, we investigated the effects of gemcitabine (GEM) on transgene expression by adenoviral vectors and their biological effects. We used Ad-lacZ and adenoviral vector-expressing NK4 (Ad-NK4) as representative adenoviral vectors. These vectors express β-galactosidase (β-gal) and NK4 (which inhibits the invasion of cancer cells), respectively, under the control of the CMV promoter. Cells were infected with the individual adenoviruses and then treated with GEM. GEM increased β-gal mRNA expression and β-gal activity, and increased NK4 expression in both culture media and within infected cells, in dose-dependent manners. The increased expression of NK4 delivered by Ad-NK4 had biological effects by inhibiting the invasion of cancer cells. GEM also enhanced NK4 expression in SUIT-2 cells transfected with an NK4-expressing plasmid, suggesting that GEM enhanced CMV promoter activity. In in vivo experiments, NK4 expression within subcutaneously implanted tumors was increased in GEM-treated mice compared with control mice. These results suggest that adenovirus-mediated gene therapy with GEM may be a promising approach for treating pancreatic cancer, and that this combination therapy may decrease the risks of side effects.

The therapeutic use of angiogenic factors shows promise in the treatment of critical limb ischemia; however, its potential for myonephropathic metabolic syndrome (MNMS), a fatal complication caused by arterial reconstruction, has not been elucidated. The objective of this study was to evaluate the effectiveness of recombinant Sendai virus-mediated gene transfer of fibroblast growth factor-2 (FGF-2) directly compared with that of a radical scavenger, MCI-186, in a rat model of MNMS. MNMS was surgically induced by aortic occlusion below renal arteries for 4 h, followed by 6 h of reperfusion. Administration of MCI-186 (twice; iv 5 min before induced ischemia and ip 5 min before reperfusion; 10 mg/kg, respectively), but not FGF-2 gene transfer (once, 48 h before induced ischemia), dramatically prevented the increase of serum biochemical markers as well as the edema of the gastrocnemius muscle. The effect of MCI-186 was accompanied by the marked suppression of the neutrophilic infiltration into the local (muscle) and remote (lung) organs. Although serum and muscular levels of a neutrophil-chemoattractant (growth-related oncogene/cytokine-induced neutrophil chemoattractant-1) were not affected by any treatment, the serum level of soluble intercellular adhesion molecule-1 was decreased by treatment with MCI-186 but not by treatment with FGF-2. These results suggest the distinct mechanism of MNMS from critical limb ischemia without reperfusion. Therefore, radical scavenging should be paid more attention than therapeutic angiogenesis when arterial circulation is reconstructed.

OBJECTIVE:To assess the expression and distribution of a neurotrophic/antiangiogenic factor, pigment epithelium-derived factor (PEDF), related to angiogenesis that is a possibly key event during atherogenesis in human atherosclerotic plaques.METHODS AND RESULTS:Twenty fresh aortic samples were used for reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry (IHC). In addition, 80 stocked paraffin blocks of coronary arteries from 40 autopsy cases were also used. IHC revealed divergent staining patterns for PEDF in both the aortas and the coronary arteries tested, ie, "cytoplasmic staining" or "extracellular deposition," were observed, respectively. In the areas showing cytoplasmic staining, double PEDF was expressed in a majority of the foamy macrophages and in some smooth muscle cells, and the PEDF-positive cell frequency was positively correlated with that of microvessels in a cell-rich area in the coronary arteries (P<0.0001). Inversely, extracellular deposition of PEDF was seen in acellular areas and was negatively correlated with the number of microvessels (P=0.0003).CONCLUSIONS:These results suggest that PEDF may function as an antiangiogenic factor when it is deposited onto the extracellular matrix. Thus, PEDF may play a significant role in determining the balance of angiogenesis/ antiangiogenesis during atherogenesis.