Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Endoscopic vs. laparoscopic gastrojejunostomy for duodenal obstruction: a randomized study in a porcine model.

BACKGROUND AND STUDY AIMS: Open or laparoscopic gastrojejunostomy is an established treatment for malignant duodenal obstruction but may be associated with significant morbidity and mortality. The purpose of this study was to develop a model for an entirely endoscopic gastrojejunostomy to treat duodenal obstruction, and to compare this with the laparoscopic technique. METHODS: During the first part of the study the endoscopic technique was developed and tested in porcine nonsurvival and survival experiments (n=12). During the second part of the study (n=10), endoscopic gastrojejunostomy for duodenal occlusion was compared with laparoscopic gastrojejunostomy in a survival randomized controlled trial (RCT). For both groups duodenal occlusion was achieved by the laparoscopic approach. RESULTS: In the RCT, the median times for laparoscopic vs. endoscopic gastrojejunostomy were 70 minutes (interquartile range [IQR] 65-75) vs. 210 minutes (IQR 197-220; P=0.01). There was a trend toward increased anastomotic diameter at necropsy in the laparoscopic group (2 cm, IQR 2-3) compared to the endoscopic group (1.8 cm, IQR 1.6-1.8; P=0.06). One animal in the endoscopic group died secondarily to bowel ischemia from volvulus of the jejunal loop. One animal in the laparoscopic group was prematurely sacrificed due to extensive pulmonary congestion and edema. All anastomoses were intact and patent. CONCLUSIONS: Purely endoscopic gastrojejunostomy using the developed technique and devices is feasible and can result in adequate relief of duodenal obstruction. Endoscopic anastomoses tend to be smaller than laparoscopic anastomoses, with the procedures being more time-consuming and associated with higher complication rates.

Quality of life following radiofrequency ablation of dysplastic Barrett's esophagus.

BACKGROUND AND STUDY AIMS: The impact of the diagnosis and treatment of dysplastic Barrett's esophagus on quality of life (QoL) is poorly understood. This study assessed the influence of dysplastic Barrett's esophagus on QoL and evaluated whether endoscopic treatment of dysplastic Barrett's esophagus with radiofrequency ablation (RFA) improves QoL. PATIENTS AND METHODS: We analyzed changes in QoL in the AIM Dysplasia Trial, a multicenter study of patients with dysplastic Barrett's esophagus who were randomly allocated to RFA therapy or a sham intervention. We developed a 10-item questionnaire to assess the influence of dysplastic Barrett's esophagus on QoL. The questionnaire was completed by patients at baseline and 12 months. RESULTS: 127 patients were randomized to RFA (n = 84) or sham (n = 43). At baseline, most patients reported worry about esophageal cancer (71 % RFA, 85 % sham) and esophagectomy (61 % RFA, 68 % sham). Patients also reported depression, impaired QoL, worry, stress, and dissatisfaction with the condition of their esophagus. Of those randomized, 117 patients completed the study to the 12-month end point. Compared with the sham group, patients treated with RFA had significantly less worry about esophageal cancer ( P=0.003) and esophagectomy ( P =0.009). They also had significantly reduced depression ( P=0.02), general worry about the condition of their esophagus ( P≤0.001), impact on daily QoL ( P=0.009), stress ( P=0.03), dissatisfaction with the condition of their esophagus ( P≤0.001), and impact on work and family life ( P=0.02). CONCLUSIONS: Inclusion in the treatment group of this randomized, sham-controlled trial of RFA was associated with improvement in disease-specific health-related quality of life. This improvement appears secondary to a perceived decrease in the risk of cancer.

Endoscopic sutured closure of a gastric natural orifice transluminal endoscopic surgery access gastrotomy compared with open surgical closure in a porcine model. A randomized, multicenter controlled trial.

BACKGROUND AND STUDY AIMS: In natural orifice transluminal endoscopic surgery (NOTES) procedures it is essential to be able to perform secure closure of the access perforation. The aim of this study was to compare endoscopically sutured closure of a gastric access gastrotomy using the tissue apposition system (TAS), with closure via laparotomy in a randomized multicenter study. METHODS: A total of 32 pigs (18 - 42 kg) were used in this study. The gastric NOTES access was created using a needle knife and a 20-mm balloon. Following transgastric pelvic peritoneoscopy, the endoscope was withdrawn into the stomach. The animals were then randomized to endoscopic closure or laparotomy with surgical closure. Procedure time, recovery time, and weight gain were measured. At necropsy, adhesions, abscesses or peritonitis were recorded. RESULTS: Of the 32 pigs, 29 survived 14 days without complications. All endoscopic and all open surgical closures were secure at postmortem. On average two suture pairs were used for endoscopic closure. Surgical closure was quicker (12.5 vs. 20.1 minutes). Recovery time and postoperative weight gain were similar for both groups. Two pigs in the endoscopic group died: one of gastric dilatation, without leakage from the gastrotomy; another was euthanized due to rectal prolapse. In the laparotomy group one pig was euthanized after 7 days due to abdominal wound dehiscence. At necropsy there were significantly more intra-abdominal adhesions in the laparotomized group. CONCLUSION: This randomized controlled study of endoscopic and surgical closure of a gastrotomy made for transperitoneal access for NOTES procedures suggests that both techniques are comparable in technical closure rates, postoperative recovery, and prevention of peritonitis. There were fewer adhesions in the endoscopic group.

Randomized controlled trial comparing endoscopic clips and over-the-scope clips for closure of natural orifice transluminal endoscopic surgery gastrotomies.

BACKGROUND AND STUDY AIM: Secure and reliable endoscopic closure is of paramount importance before clinical introduction of transgastric natural orifice transluminal endoscopic surgery (NOTES). Gastrotomy closure in humans using standard endoclips has been reported. The aim of this study was to assess the safety of standard endoclip closure and to compare it to a new over-the-scope clip (OTSC) specifically designed for gastrotomy closure. MATERIAL AND METHODS: Gastric wall puncture and balloon dilation followed by peritoneoscopy was carried out in 20 female swine. After randomization, closure of the gastric incision was performed using a tissue approximation grasper and either endoclips or OTSCs. RESULTS: Mean (+/- SD) time for gastrotomy closure using endoclips was 31.5 +/- 24.2 minutes (range 8 - 88 minutes) compared with 8.5 +/- 9.1 minutes (range 2 - 31 minutes) using OTSC (P = 0.002). No intraoperative complications occurred. Laparoscopic leak tests with insufflation and saline immersion demonstrated three minor leaks and one major leak in the endoclip closures. No leaks were observed in the OTSC group. At necropsy, complete sealing of the gastrotomy sites was found in all OTSC closures. Small, localized perigastric abscesses were observed in two animals in the OTSC group and in three animals in the endoclip group. One animal in the endoclip group was sacrificed prematurely due to signs of sepsis and was found to have gross peritonitis secondary to a leak. At necropsy, evidence of peritonitis was identified in two other animals in the endoclip group. CONCLUSION: NOTES gastrotomy closure using standard endoclips, even with a tissue approximation grasper, is associated with an increased risk of leakage and intra-abdominal infection compared with OTSC. The significance of perigastric abscesses, which were seen in both groups, warrants further investigation.

Clinical trial: a randomized, study comparing meperidine (pethidine) and fentanyl in adult gastrointestinal endoscopy.

BACKGROUND: There is little evidence to guide choice between meperidine (pethidine) and fentanyl for sedation for gastrointestinal endoscopy. AIM: To compare meperidine with fentanyl in terms of procedure time and analgesia. METHODS: Single centre randomized controlled trial. Patients received narcotic doses and midazolam at the discretion of the attending endoscopist who was unaware of narcotic assignment. Endoscopy and recovery times were then recorded. The main outcome was total procedure time, defined as endoscopy time plus recovery time. Patient discomfort was assessed prior to discharge via visual analogue scale (VAS). RESULTS: In total, 55 patients were randomized to meperidine [44 colonoscopy and 11 esophagogastroduodenoscopy (EGD)] and 56 to fentanyl (45 colonoscopy and 11 EGD). Total procedure time was shorter for those receiving fentanyl (mean = 87.7 min) than for those receiving meperidine (mean = 102.9 min) (P = 0.05). The difference between the groups was explained by a shorter mean recovery time in the fentanyl group (63.0 min) than in the meperidine group (76.2 min) (P = 0.07). Based on post procedure pain scores, examinations with meperidine (mean = 1.99) were less painful when compared with those receiving fentanyl (mean = 2.86, P = 0.03). CONCLUSIONS: Fentanyl shortened total procedure time by reducing recovery time. A simple change in narcotic choice could increase endoscopy unit efficiency.

Modeling stem cell asymmetry in yeast.

For adult stem cells to both self-renew and give rise to differentiating progenitors, they must undergo an inherently asymmetric division. This defining model of asymmetric cell division requires either that stem cells preferentially distribute internal factors, thereby maintaining a stem cell phenotype in one lineage, or that extrinsic signals determine the fate of daughter cells, allowing the maintenance of one stem cell lineage. Although microbial systems are often used to model asymmetry, lineage-specific asymmetry has not been characterized in these organisms. Recently, we identified a stem-cell-like lineage-specific pattern of kinetochore asymmetry in postmeiotic yeast spores. Because the function of the kinetochore is to segregate chromosomes, this asymmetry has the potential to segregate sister chromatids nonrandomly. This may be relevant to stem cells because more than 30 years ago, it was proposed that stem cells selectively segregate one strand of their chromosomes into the self-renewing stem cell lineage (Cairns 1975). Although advanced labeling methods have provided evidence to both support and refute this hypothesis, it remains unclear how nonrandom sister-chromatid segregation might be achieved in a stem cell lineage. We have identified a kinetochore-specific mechanism in yeast that could support lineage-specific nonrandom sister-chromatid segregation and we discuss the implications of this observation.

Endoscopic full-thickness plication for the treatment of GERD: long-term multicenter results.

BACKGROUND: The purpose of the present study was to assess the long-term safety and durability of effect for endoscopic full-thickness plication for the treatment of symptomatic gastroesophageal reflux disease (GERD). The Plicator (NDO Surgical, Inc., Mansfield, MA) used delivers a transmural suture through the gastric cardia to restructure the antireflux barrier. Published reports have shown the Plicator procedure to be effective in reducing GERD symptoms and medication use at 1 year post-plication. METHODS: Twenty-nine patients with chronic heartburn requiring maintenance daily anti-secretory therapy were treated at five sites. Patients received a single full-thickness plication in the gastric cardia 1cm below the gastroesophageal junction (GE) junction. Re-treatments were not permitted. Patients were evaluated at baseline for GERD symptoms and medication use. Intermediate (12 month) and long-term subject follow-up (median follow-up: 36.4 months; range, 31.2-43.9 months) were completed to evaluate procedure safety and durability of effect. RESULTS: Twenty-nine patients completed the 12-month and 36-month follow-up. All procedure-related adverse events occurred acutely, and no new events were observed during extended follow-up. At 36-months post-procedure, 57% (16/28) of baseline proton pump inhibitor (PPI)-dependent patients remained off daily PPI therapy. Treatment effect remained stable from 12- to 36-months, with 21/29 patients off daily PPI at 12 months compared to 17/29 patients at 36-months. Median GERD- Health Related Quality of Life (HRQL) scores remained significantly improved at 36 months versus baseline off-meds scores (8 versus 19, p < 0.001). In addition, the proportion of patients achieving > or = 50% improvement in GERD-HRQL score was consistent from 12 months (59%) to 36 months (55%). CONCLUSIONS: Endoscopic full-thickness plication can reduce GERD symptoms and medication use for at least 3-years post-procedure. Treatment effect is stable from 1 to 3 years, and there are no long-term procedural adverse effects.

Histamine receptor antagonists and incident colorectal adenomas.

BACKGROUND: Prior studies suggest that histamines may modulate the development of colorectal neoplasia. AIM: To assess whether histamine receptor antagonist use was associated with adenoma formation. METHODS: Patients (n = 2366) were drawn from three adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of adenoma(s) and were deemed free of remaining lesions; they were followed with surveillance colonoscopy. Medication use was assessed by questionnaire. Adjusted risk ratios for adenoma formation related to histamine receptor antagonist use (histamine H1 and H2 receptor, H1RA and H2RA) were determined using log linear models. RESULTS: In pooled analyses, H1RA exposure was not associated with subsequent adenoma risk (RR = 1.10; 95% CI 0.97-1.25) or multiple adenoma formation (RR = 0.85; 95% CI 0.67-1.07). H2RA use also was not associated with adenoma (RR = 0.90; 95% CI 0.77-1.06), or multiple adenoma (RR = 0.77; 95% CI 0.57-1.04) in the pooled analyses, but H2RA users in the first trial had a decreased risk of adenoma (RR = 0.70; 95% CI 0.48-1.03) and multiple adenoma (RR = 0.31; 95% CI 0.12-0.79). CONCLUSION: H2RA use was associated with reduced risk for adenoma in one trial, but not in the pooled analyses. Further study would be warranted before undertaking randomized trials of H2RAs for adenoma chemoprevention.

Antineuronal antibodies in idiopathic achalasia and gastro-oesophageal reflux disease.

BACKGROUND AND AIMS: The precise aetiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. We screened sera from patients with achalasia or gastro-oesophageal reflux disease (GORD) to test for circulating antimyenteric neuronal antibodies. METHODS: Serum was obtained from 45 individuals with achalasia, 16 with GORD, and 22 normal controls. Serum was used in immunohistochemistry to label whole mount preparations of ileum and oesophagus of the guinea pig and mouse. Also, sections of superior cervical and dorsal root ganglia, and spinal cord were examined. RESULTS: Positive immunostaining of the myenteric plexus was detected in significantly more achalasia and GORD samples than control samples (achalasia, p<0.001; GORD, p<0.01), and immunoreactivity was significantly more intense with achalasia and GORD serum samples than controls (achalasia, p<0.01; GORD, p<0.05). There was no correlation between intensity of immunoreactivity and duration of achalasia symptoms. In most cases, achalasia and GORD sera stained all ileal submucosal and myenteric neurones, and oesophageal neurones. Immunostaining was not species specific; however, immunostaining was largely specific for enteric neurones. Western blot analysis failed to reveal specific myenteric neuronal proteins that were labelled by antibodies in achalasia or GORD serum. CONCLUSIONS: These data suggest that antineuronal antibodies are generated in response to tissue damage or some other secondary phenomenon in achalasia and GORD. We conclude that antineuronal antibodies found in the serum of patients with achalasia represent an epiphenomenon and not a causative factor.

Perinatal hypoxia-ischemia induces apoptotic and excitotoxic death of periventricular white matter oligodendrocyte progenitors.

Hypoxia-ischemia (HI) is a leading cause of white matter damage, a major contributor to cerebral palsy in premature infants. Preferential white matter damage is believed to result from vulnerability of the immature oligodendrocyte (the pro-OL) to factors elevated during ischemic damage, such as oxygen free radicals and glutamate. In order to determine whether pro-OLs undergo apoptotic death after HI, we analyzed periventricular white matter OLs in P7 rats 4, 12 and 24 h after HI to analyze the time course and mode of cell death. DNA fragmentation was seen at 12 and 24 h of recovery after HI, representing a 17-fold increase over control. In addition, caspase-3 activation was found in NG2+ pro-OLs at 12 h. Electron-microscopic analysis of cell death in the white matter revealed a transition from early necrotic deaths to hybrid cell deaths to classical apoptosis between 4 and 24 h of recovery from HI. The delayed time course of apoptosis in pro-OLs supports the feasibility of interventions to improve clinical outcomes for newborns surviving birth asphyxia.

Hypoxia/ischemia depletes the rat perinatal subventricular zone of oligodendrocyte progenitors and neural stem cells.

Cerebral hypoxia/ischemia of the newborn has a frequency of 4/1,000 births and remains a major cause of cerebral palsy, epilepsy, and mental retardation. Despite progress in understanding the pathogenesis of hypoxic-ischemic injury, the data are incomplete regarding the mechanisms leading to permanent brain injury. Here we tested the hypothesis that cerebral hypoxia/ischemia damages stem/progenitor cells in the subventricular zone (SVZ), resulting in a permanent depletion of oligodendrocytes. We used a widely accepted rat model and examined animals at recovery intervals ranging from 4 h to 3 weeks. Within hours after the hypoxic-ischemic insult 20% of the total cells were deleted from the SVZ. The residual damaged cells appeared necrotic. During 48 h of recovery deaths accumulated; however, these later deaths were predominantly apoptotic. Many apoptotic SVZ cells stained with a marker for immature oligodendrocytes. At 3 weeks survival, the SVZ was smaller and markedly less cellular, and it contained less than 1/4 the normal complement of neural stem cells. The corresponding subcortical white matter was dysmyelinated, relatively devoid of oligodendrocytes and enriched in astrocytes. We conclude that neural stem cells and oligodendrocyte progenitors in the SVZ are vulnerable to hypoxia/ischemia. Consequently, the developmental production of oligodendrocytes is compromised and regeneration of damaged white matter oligodendrocytes does not occur resulting in failed regeneration of CNS myelin in periventricular loci. The resulting dysgenesis of the brain that occurs subsequent to perinatal hypoxic/ischemic injury may contribute to the cognitive and motor dysfunction that results from asphyxia of the newborn.

Anesthetic management of the exit (ex utero intrapartum treatment) procedure.

The EXIT (ex utero intrapartum treatment) procedure is used to maintain fetal-placental circulation during partial delivery of a fetus with a potentially life-threatening upper airway obstruction. We performed the EXIT procedure on a fetus with a large intra-oral cyst. Sevoflurane was used as the anesthetic because of its rapid titratability. Sevoflurane provided excellent maternal and fetal anesthesia. Modifications to previously described monitoring techniques for the EXIT procedure were also used.

The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage.

The evolutionarily conserved protein kinases Mec1 and Rad53 are required for checkpoint response and growth. Here we show that their role in growth is to remove the ribonucleotide reductase inhibitor Sml1 to ensure DNA replication. Sml1 protein levels fluctuate during the cell cycle, being lowest during S phase. The disappearance of Sml1 protein in S phase is due to post-transcriptional regulation and is associated with protein phosphorylation. Both phosphorylation and diminution of Sml1 require MEC1 and RAD53. More over, failure to remove Sml1 in mec1 and rad53 mutants results in incomplete DNA replication, defective mitochondrial DNA propagation, decreased dNTP levels and cell death. Interestingly, similar regulation of Sml1 also occurs after DNA damage. In this case, the regulation requires MEC1 and RAD53, as well as other checkpoint genes. Therefore, Sml1 is a new target of the DNA damage checkpoint and its removal is a conserved function of Mec1 and Rad53 during growth and after damage.

Rad52 forms DNA repair and recombination centers during S phase.

Maintenance of genomic integrity and stable transmission of genetic information depend on a number of DNA repair processes. Failure to faithfully perform these processes can result in genetic alterations and subsequent development of cancer and other genetic diseases. In the eukaryote Saccharomyces cerevisiae, homologous recombination is the major pathway for repairing DNA double-strand breaks. The key role played by Rad52 in this pathway has been attributed to its ability to seek out and mediate annealing of homologous DNA strands. In this study, we find that S. cerevisiae Rad52 fused to green fluorescent protein (GFP) is fully functional in DNA repair and recombination. After induction of DNA double-strand breaks by gamma-irradiation, meiosis, or the HO endonuclease, Rad52-GFP relocalizes from a diffuse nuclear distribution to distinct foci. Interestingly, Rad52 foci are formed almost exclusively during the S phase of mitotic cells, consistent with coordination between recombinational repair and DNA replication. This notion is further strengthened by the dramatic increase in the frequency of Rad52 focus formation observed in a pol12-100 replication mutant and a mec1 DNA damage checkpoint mutant. Furthermore, our data indicate that each Rad52 focus represents a center of recombinational repair capable of processing multiple DNA lesions.

Melatonin replacement therapy in a child with a pineal tumor.

The case report of a child with the diagnosis of a pineal tumor and severe, chronic sleep disorder is reported. Due to treatment of her lesion, the nighttime melatonin secretion was markedly suppressed. For 4(1/2) years, she has been receiving oral melatonin, which has greatly improved her sleep, without any adverse effects. Sleep difficulties should be considered in the management of pineal lesions. Melatonin replacement therapy is beneficial for those patients who have deficient melatonin synthesis.

Transoral, flexible endoscopic suturing for treatment of GERD: a multicenter trial.

BACKGROUND: A totally transoral outpatient procedure for the treatment of GERD would be appealing. METHODS: A multicenter trial was initiated that included 64 patients with GERD treated with an endoscopic suturing device. Inclusion criteria were 3 or more heartburn episodes per week while not taking medication, dependency on antisecretory medicine, and documented acid reflux by pH monitoring. Exclusion criteria were dysphagia, grade 3 or 4 esophagitis, obesity, and hiatus hernia greater than 2 cm in length. Patients underwent manometry, endoscopy, 24-hour pH monitoring, and symptom severity scoring before and after the procedure. Patients were randomized to a linear or circumferential plication configuration. Adverse procedural events were recorded. RESULTS: Mean 6-month symptom score changes demonstrated procedural efficacy. Heartburn severity and frequency as well as regurgitation all improved (p > 0.0001 for each). Twenty-four-hour pH monitoring showed improvement in number of episodes below pH of 4 at 3 and 6 months (p < 0.0007 and 0.0002) and percentage of total time the pH was less than 4 at 6 months (p < 0.011). Plication configuration did not affect symptoms or pH monitoring results. One patient had a self-contained suture perforation that was successfully treated with antibiotics. CONCLUSION: Endoscopic gastroplasty is safe. It is associated with reduced symptoms and medication use at 6 month follow-up in patients with uncomplicated GERD.