Multicentric short term and safety study of ineffective esophageal motility patients treated with RefluxStop device.

Gastroesophageal reflux disease (GERD) presents a general health problem with a variety of symptoms and an impairment of life quality. Conservative therapies do not offer sufficient symptom relief in up to 30% of patients. Patients who suffer from ineffective esophageal motility (IEM) and also GERD may exhibit symptoms ranging from mild to severe. In cases where surgical intervention becomes necessary for this diverse group of patients, it is important to consider the potential occurrence of postoperative dysphagia. RefluxStop is a new alternative anti-reflux surgery potentially reducing postoperative dysphagia rates. In this bicentric tertiary hospital observational study consecutive patients diagnosed with PPI refractory GERD and IEM that received RefluxStop implantation were included. A first safety and efficacy evaluation including clinical examination and GERD-HRQL questionnaire was conducted. 40 patients (25 male and 15 female) were included. 31 patients (77.5%) were on PPI at time of surgery, with mean acid exposure time of 8.14% ± 2.53. The median hospital stay was 3 days. Postoperative QoL improved significantly measured by GERD HRQL total score from 32.83 ± 5.08 to 6.6 ± 3.71 (p < 0.001). A 84% reduction of PPI usage (p < 0.001) was noted. 36 patients (90%) showed gone or improved symptoms and were satisfied at first follow-up. Two severe adverse events need mentioning: one postoperative slipping of the RefluxStop with need of immediate revisional operation on the first postoperative day (Clavien-Dindo Score 3b) and one device migration with no necessary further intervention. RefluxStop device implantation is safe and efficient in the short term follow up in patients with GERD and IEM. Further studies and longer follow-up are necessary to prove long-lasting positive effects.

Dietary sugar and Barrett's esophagus.

INTRODUCTION: Barrett's esophagus (BE) represents the premalignant morphology of gastroesophageal reflux disease (GERD). Evidence indicates a positive correlation between GERD vs. obesity and increased sugar consumption. METHODS: Here we analyzed recently published data (2006-2017) on the role of dietary sugar intake for BE development (main focus year 2017). RESULTS: Recent investigations found a positive association between obesity, hip waist ratio and dietary sugar intake and Barrett's esophagus. CONCLUSION: Sugar intake positively associates with BE. A low carbohydrate diet should be recommended for persons with BE and GERD.

Update on the management of Barrett's esophagus in Austria.

BACKGROUND: Barrett's esophagus (BE) is the premalignant manifestation of gastroesophageal reflux disease (GERD). Radiofrequency ablation (RFA) with and without endoscopic resection (ER) is a novel treatment for BE. METHODS: Here we present a single-center update of the recommendations of a recent (June 2015) interdisciplinary expert panel meeting on the management of BE with dysplasia as well as cancer-positive and cancer-negative BE. We conducted a PubMed search of studies published in 2016 and 2017 on the topic of BE and RFA. RESULTS: Our update reconfirms that BE positive for T1a cancer as well as low- and high-grade dysplasia justifies the use of RFA ± ER, offering an 80-100% rate of BE clearance. RFA ± ER of dysplastic BE is tenfold more effective for cancer prevention when compared with surveillance. Risk factors for recurrence and follow-up treatments include baseline histopathology (dysplasia/T1a cancer), esophagitis, hiatal hernia >3 cm, smoking habits, BE segments >3 cm, and >10 years of GERD symptoms. A baseline diagnosis for dysplasia and T1a cancer should include a second expert pathologist opinion. Recent data justify the use of RFA for nondysplastic BE only in controlled clinical trials. Antireflux surgery can be offered to those with function-test-proven, GERD-symptom-positive BE before, during, or after RFA ± ER. Additionally, there is growing evidence that the intake of a sugar-rich diet is positively correlated with the development of GERD, BE, and cancer. CONCLUSION: RFA ± ER should be offered for dysplastic BE and T1a cancer after ER as well as for nondysplastic BE with additional risk factors in controlled trials. Antireflux surgery can be offered to patients with function-test-proven GERD-symptom-positive BE. Diet considerations should be included in the management of GERD and BE.

Endoscopic stent suture fixation for prevention of esophageal stent migration during prolonged dilatation for achalasia treatment.

The aim of this study is to compare endoscopic stent suture fixation with endoscopic clip attachment or the use of partially covered stents (PCS) regarding their capability to prevent stent migration during prolonged dilatation in achalasia. Large-diameter self-expanding metal stents (30 mm × 80 mm) were placed across the gastroesophageal junction in 11 patients with achalasia. Stent removal was scheduled after 4 to 7 days. To prevent stent dislocation, endoscopic clip attachment, endoscopic stent suture fixation, or PCS were used. The Eckardt score was evaluated before and 6 months after prolonged dilatation. After endoscopic stent suture fixation, no (0/4) sutured stent migrated. When endoscopic clips were used, 80% (4/5) clipped stents migrated (p = 0.02). Of two PCS (n = 2), one migrated and one became embedded leading to difficult stent removal. Technical adverse events were not seen in endoscopic stent suture fixation but were significantly correlated with the use of clips or PCS (r = 0.828, p = 0.02). Overall, 72% of patients were in remission regarding their achalasia symptoms 6 months after prolonged dilatation. Endoscopic suture fixation of esophageal stents but not clip attachment appears to be the best method of preventing early migration of esophageal stents placed at difficult locations such as at the naive gastroesophageal junction.

Impact of sarcopenia on outcome in patients with esophageal resection following neoadjuvant chemotherapy for esophageal cancer.

BACKGROUND: Nutritional status and body composition parameters such as sarcopenia are important risk factors for impaired outcome in patients with esophageal cancer. This study was conducted to evaluate the effect of sarcopenia on long-term outcome after esophageal resection following neoadjuvant treatment. METHODS: Skeletal muscle index (SMI) and body composition parameters were measured in patients receiving neoadjuvant treatment for locally advanced esophageal cancer. Endpoints included relapse-free survival (RFS) and overall survival (OS). RESULTS: The study included 130 patients. Sarcopenia was found in 80 patients (61.5%). Patients with squamous-cell cancer (SCC) showed a decreased median SMI of 48 (range 28.4-60.8) cm/m2 compared with that of patients with adenocarcinoma (AC) of 52 (range 34.4-74.2) cm/m2, P < 0.001. The presence of sarcopenia had a significant impact on patient outcome: HR 1.69 (1.04-2.75), P = 0.036. Median OS was 20.5 (7.36-33.64) versus 52.1 (13.55-90.65) months in sarcopenic and non-sarcopenic patients, respectively. Sarcopenia was identified as an independent risk factor: HR 1.72 (1.049-2.83), P = 0.032. CONCLUSION: Our data provide evidence that sarcopenia impacts long-term outcome after esophageal resection in patients who have undergone neoadjuvant therapy. Assessment of the body composition parameter can be a reasonable part of patient selection and may influence treatment methods.

Treatment of Barrett's esophagus: update on new endoscopic surgical modalities.

Barrett's esophagus represents a premalignant condition, which is strongly associated with the incidence of esophageal adenocarcinoma. Currently, there are no validated markers to extract exactly that certain patient that will proceed to neoplastic progression. Therefore, therapeutic options have to include a larger population to provide prophylaxis for affected patients. Recently developed endoscopic therapeutic approaches offer treatment options for prevention or even treatment of limited esophageal adenocarcinoma. At present, high eradication rates of intestinal metaplasia as well as dysplasia are observed, whereas low complication rates offer a convenient safety profile. These striking new methods symbolize a changing paradigm in a field, where minimal-invasive tissue ablating methods and tissue preserving techniques have led to modified regimens. This review will focus on current standards and newly emerging methods to treat Barrett's esophagus and its progression to cancer and will highlight their evolution, potential benefits and their limitations.

Theiler's murine encephalomyelitis virus contrasts with encephalomyocarditis and foot-and-mouth disease viruses in its functional utilization of the StopGo non-standard translation mechanism.

The picornaviruses' genome consists of a positive-sense ssRNA. Like many picornaviruses, cardioviruses synthesize two distinct polyprotein precursors from adjacent but non-overlapping genome segments. Both the [L-1ABCD-2A] and the [2BC-3ABCD] polyproteins are proteolytically processed to yield mature capsid and non-structural proteins, respectively. An unusual translational event, known as 'StopGo' or 'Stop-Carry on', is responsible for the release of the [L-1ABCD-2A] polyprotein from the ribosome and synthesis of the N-terminal amino acid of the [2BC-3ABCD] polyprotein. A common feature of these viruses is the presence of a highly conserved signature sequence for StopGo: -D(V/I)ExNPG(↓)P-, where -D(V/I)ExNPG are the last 7 aa of 2A, and the last P- is the first amino acid of 2B. Here, we report that, in contrast to encephalomyocarditis virus and foot-and-mouth disease virus, a functional StopGo does not appear to be essential for Theiler's murine encephalomyelitis virus viability when tested in vitro and in vivo.

Endoscopic suture fixation of gastrointestinal stents: proof of biomechanical principles and early clinical experience.

BACKGROUND AND STUDY AIMS: Gastrointestinal stents have become an important therapeutic option for several indications. However, migration in up to 40 % of cases represents a significant drawback, especially when covered prostheses are used. We hypothesized that a novel endoscopic suturing device could enable endoluminal stent fixation, which might increase attachment and thereby potentially reduce migration. PATIENTS AND METHODS: In an initial ex vivo porcine model, stents were attached to the esophageal wall with either endoscopic hemoclips or by endoscopic suture stent fixation (ESSF). The distal tension force required to induce dislocation was measured in Newtons (N) by a digital force gauge and was compared with conventional stent placement. ESSF was then performed clinically in five patients, in whom self-expanding metal stents were sutured in place for endoscopic treatment of gastrointestinal fistulas or strictures. RESULTS: Esophageal ESSF was achieved in all experiments and significantly increased the force needed to displace the stent (n = 12; mean force 20.4 N; 95 % confidence interval [CI]: 15.4 - 25.4; P < 0.01) compared with clip fixation (n = 8; mean 6.1 N; 95 %CI 4.7 - 7.6) or stent placement without fixation (n = 16; mean 4.8 N; 95 %CI 4.0 - 5.6). All clinical cases of ESSF were performed successfully (5 /5) and took a median of 15 minutes. Elective stent removal was achieved without complications. One stent migration (1 /5) due to sutures being placed too superficially was observed. More loosely tied sutures remained intact, with the stent attached in place. CONCLUSION: Endoscopic suture fixation of gastrointestinal stents provided significantly enhanced migration resistance in an ex vivo setting. In addition, early clinical experience found ESSF to be technically feasible and easy to accomplish.

Transrectal natural orifice translumenal endoscopic surgery (NOTES) for colorectal resection.

Natural orifice translumenal endoscopic surgery (NOTES) is a new surgical paradigm involving performance of intra-abdominal surgery via a natural orifice and thereafter peritoneal access through an intentionally created hole in a hollow viscus. The vast majority of research in this rapidly evolving field had involved access via an oral or vaginal route. Access via a transanal route, other than the obvious concern over contamination, has many appealing attributes. In addition, transanal surgery has long been a common procedure lending a valuable clinical experience to the foundation of this field of research. Examples of preclinical and clinical research on transanal NOTES colorectal resections are here presented and discussed.

Early failure of the tissue engineered porcine heart valve SYNERGRAFT in pediatric patients.

OBJECTIVES: The first tissue engineered decellularized porcine heart valve, Synergraft (Cryolife Inc., USA) was introduced in Europe as an alternative to conventional biological valves. This is the first report of the rapid failure of these new grafts in a small series. MATERIALS AND METHODS: In 2001, 2 model 500 and 2 model 700 Synergraft valves were implanted in four male children (age 2.5-11 years) in the right ventricular outflow tract as a root. Two patients had a Ross operation and two had a homograft replacement. RESULTS: The cryopreserved Synergraft valves appeared macroscopically unremarkable at implantation. Recovery from surgery was uneventful and good valve function was demonstrated postoperatively. Three children died, two suddenly with severely degenerated Synergraft valves 6 weeks and 1 year after implantation. The third child died on the 7th day due to Synergraft rupture. Subsequently the fourth graft was explanted prophylactically 2 days after implantation. Macroscopically all four grafts showed severe inflammation starting on the outside (day 2 explant) leading to structural failure (day 7 explant) and severe degeneration of the leaflets and wall (6 weeks and 1 year explant). Histology demonstrated severe foreign body type reaction dominated by neutrophil granulocytes and macrophages in the early explants and a lymphocytic reaction at 1 year. In addition significant calcific deposits were demonstrated at all stages. Surprisingly pre-implant samples of the Synergraft revealed incomplete decellularization and calcific deposits. No cell repopulation of the porcine matrix occurred. CONCLUSION: The xenogenic collagen matrix of the Synergraft valve elicits a strong inflammatory response in humans which is non-specific early on and is followed by a lymphocyte response. Structural failure or rapid degeneration of the graft occurred within 1 year. Calcific deposits before implantation and incomplete decellularization may indicate manufacturing problems. The porcine Synergraft treated heart valves should not be implanted at this stage and has been stopped.

Identification of an RNA hairpin in poliovirus RNA that serves as the primary template in the in vitro uridylylation of VPg.

The first step in the replication of the plus-stranded poliovirus RNA is the synthesis of a complementary minus strand. This process is initiated by the covalent attachment of UMP to the terminal protein VPg, yielding VPgpU and VPgpUpU. We have previously shown that these products can be made in vitro in a reaction that requires only synthetic VPg, UTP, poly(A), purified poliovirus RNA polymerase 3D(pol), and Mg(2+) (A. V. Paul, J. H. van Boom, D. Filippov, and E. Wimmer, Nature 393:280-284, 1998). Since such a poly(A)-dependent process cannot confer sufficient specificity to poliovirus RNA replication, we have developed a new assay to search for a viral RNA template in conjunction with viral or cellular factors that could provide this function. We have now discovered a small RNA hairpin in the coding region of protein 2C as the site in PV1(M) RNA that is used as the primary template for the in vitro uridylylation of VPg. This hairpin has recently been described in poliovirus RNA as being an essential structure for the initiation of minus strand RNA synthesis (I. Goodfellow, Y. Chaudhry, A. Richardson, J. Meredith, J. W. Almond, W. Barclay, and D. J. Evans, J. Virol. 74:4590-4600, 2000). The uridylylation reaction either with transcripts of cre(2C) RNA or with full-length PV1(M) RNA as the template is strongly stimulated by the addition of purified viral protein 3CD(pro). Deletion of the cre(2C) RNA sequences from minigenomes eliminates their ability to serve as template in the reaction. A similar signal in the coding region of VP1 in HRV14 RNA (K. L. McKnight and S. M. Lemon, RNA 4:1569-1584, 1998) and the poliovirus cre(2C) can be functionally exchanged in the assay. The mechanism by which the VPgpUpU precursor, made specifically on the cre(2C) template, might be transferred to the site where it serves as primer for poliovirus RNA synthesis, remains to be determined.

Genetic and biochemical studies of poliovirus cis-acting replication element cre in relation to VPg uridylylation.

In addition to highly conserved stem-loop structures located in the 5'- and 3'-nontranslated regions, genome replication of picornaviruses requires cis-acting RNA elements located in the coding region (termed cre) (K. L. McKnight and S. M. Lemon, J. Virol. 70:1941-1952, 1996; P. E. Lobert, N. Escriou, J. Ruelle, and T. Michiels, Proc. Natl. Acad. Sci. USA 96:11560-11565, 1999; I. Goodfellow, Y. Chaudhry, A. Richardson, J. Meredith, J. W. Almond, W. Barclay, and D. J. Evans, J. Virol. 74:4590-4600, 2000). cre elements appear to be essential for minus-strand RNA synthesis by an as-yet-unknown mechanism. We have discovered that the cre element of poliovirus (mapping to the 2C coding region of poliovirus type 1; nucleotides 4444 to 4505 in 2C), which is homologous to the cre element of poliovirus type 3, is preferentially used as a template for the in vitro uridylylation of VPg catalyzed by 3D(pol) in a reaction that is greatly stimulated by 3CD(pro) (A. V. Paul, E. Rieder, D. W. Kim, J. H. van Boom, and E. Wimmer, J. Virol. 74:10359-10370, 2000). Here we report a direct correlation between mutations that eliminate, or severely reduce, the in vitro VPg-uridylylation reaction and produce replication phenotypes in vivo. None of the genetic changes significantly influenced translation or polyprotein processing. A substitution mapping to the first A (A4472C) of a conserved AAACA sequence in the loop of PV-cre(2C) eliminated the ability of the cre RNA to serve as template for VPg uridylylation and abolished RNA infectivity. Mutagenesis of the second A (A4473C; AAACA) severely reduced the yield of VPgpUpU and RNA infectivity was restored only after reversion to the wild-type sequence. The effect of substitution of the third A (A4474G; AAACA) was less severe but reduced both VPg uridylylation and virus yield. Disruption of base pairing within the upper stem region of PV-cre(2C) also affected uridylylation of VPg. Virus derived from transcripts containing mutations in the stem was either viable or quasi-infectious.

Foot-and-mouth disease virus virulent for cattle utilizes the integrin alpha(v)beta3 as its receptor.

Adsorption and plaque formation of foot-and-mouth disease virus (FMDV) serotype A12 are inhibited by antibodies to the integrin alpha(v)beta3 (A. Berinstein et al., J. Virol. 69:2664-2666, 1995). A human cell line, K562, which does not normally express alpha(v)beta3 cannot replicate this serotype unless cells are transfected with cDNAs encoding this integrin (K562-alpha(v)beta3 cells). In contrast, we found that a tissue culture-propagated FMDV, type O1BFS, was able to replicate in nontransfected K562 cells, and replication was not inhibited by antibodies to the endogenously expressed integrin alpha5beta1. A recent report indicating that cell surface heparan sulfate (HS) was required for efficient infection of type O1 (T. Jackson et al., J. Virol. 70:5282-5287, 1996) led us to examine the role of HS and alpha(v)beta3 in FMDV infection. We transfected normal CHO cells, which express HS but not alpha(v)beta3, and two HS-deficient CHO cell lines with cDNAs encoding human alpha(v)beta3, producing a panel of cells that expressed one or both receptors. In these cells, type A12 replication was dependent on expression of alpha(v)beta3, whereas type O1BFS replicated to high titer in normal CHO cells but could not replicate in HS-deficient cells even when they expressed alpha(v)beta3. We have also analyzed two genetically engineered variants of type O1Campos, vCRM4, which has greatly reduced virulence in cattle and can bind to heparin-Sepharose columns, and vCRM8, which is highly virulent in cattle and cannot bind to heparin-Sepharose. vCRM4 replicated in wild-type K562 cells and normal, nontransfected CHO (HS+ alpha(v)beta3-) cells, whereas vCRM8 replicated only in K562 and CHO cells transfected with alpha(v)beta3 cDNAs. A similar result was also obtained in assays using a vCRM4 virus with an engineered RGD-->KGE mutation. These results indicate that virulent FMDV utilizes the alpha(v)beta3 integrin as a primary receptor for infection and that adaptation of type O1 virus to cell culture results in the ability of the virus to utilize HS as a receptor and a concomitant loss of virulence.

The foot-and-mouth disease virus leader proteinase gene is not required for viral replication.

The foot-and-mouth disease virus (FMDV) leader (L) proteinase has only two known functions: (i) autocatalytic removal from the N terminus of the viral polyprotein and (ii) cleavage of the p220 subunit of the eukaryotic initiation factor 4F complex, which helps to shut off host protein synthesis. Cleavage of p220 appears to be important for picornavirus replication, since rhinoviruses and enteroviruses utilize a different proteinase (2A) to cleave p220. To explore the role of L in FMDV replication, we generated synthetic FMDV genomes lacking the L gene and tested their viability in cells. Genomes were constructed with the N-terminal Gly codon of VP4 positioned directly following either the first (Lab) or second (Lb) Met codon of the L protein. Cells transfected with synthetic RNAs lacking L and initiating with the Lab Met codon failed to produce viable virus, but cells transfected with RNAs that utilized the second AUG to drive translation of the viral polyprotein produced viable viruses. These leader-deleted viruses produced plaques on BHK cells that were slightly smaller than those produced by wild-type (WT) virus, grew to slightly lower titers than WT virus in BHK cells, shut off host protein synthesis more slowly than WT virus, and were slightly attenuated in mice. These studies indicate that the L proteinase is not essential for FMDV replication and show that in the cells and animals tested the L gene has a limited effect on virus replication.