From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation.

Microbiota profiling in esophageal diseases: Novel insights into molecular staining and clinical outcomes.

Gut microbiota is recognized nowadays as one of the key players in the development of several gastro-intestinal diseases. The first studies focused mainly on healthy subjects with staining of main bacterial species via culture-based techniques. Subsequently, lots of studies tried to focus on principal esophageal disease enlarged the knowledge on esophageal microbial environment and its role in pathogenesis. Gastro Esophageal Reflux Disease (GERD), the most widespread esophageal condition, seems related to a certain degree of mucosal inflammation, via interleukin (IL) 8 potentially enhanced by bacterial components, lipopolysaccharide (LPS) above all. Gram- bacteria, producing LPS), such as Campylobacter genus, have been found associated with GERD. Barrett esophagus (BE) seems characterized by a Gram- and microaerophils-shaped microbiota. Esophageal cancer (EC) development leads to an overturn in the esophageal environment with the shift from an oral-like microbiome to a prevalently low-abundant and low-diverse Gram--shaped microbiome. Although underinvestigated, also changes in the esophageal microbiome are associated with rare chronic inflammatory or neuropathic disease pathogenesis. The paucity of knowledge about the microbiota-driven mechanisms in esophageal disease pathogenesis is mainly due to the scarce sensitivity of sequencing technology and culture methods applied so far to study commensals in the esophagus. However, the recent advances in molecular techniques, especially with the advent of non-culture-based genomic sequencing tools and the implementation of multi-omics approaches, have revolutionized the microbiome field, with promises of implementing the current knowledge, discovering more mechanisms underneath, and giving insights into the development of novel therapies aimed to re-establish the microbial equilibrium for ameliorating esophageal diseases..

Transoral incisionless fundoplication with Medigus ultrasonic surgical endostapler (MUSE) for the treatment of gastro-esophageal reflux disease: outcomes up to 3 years.

BACKGROUND: Transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) is a new intervention for treatment of gastro-esophageal reflux disease (GERD). We aimed at assessing the clinical, functional, and endoscopic effects of TIF by MUSE. METHODS: Forty-six patients underwent TIF. Proton pump inhibitor (PPI) consumption, GERD-health-related quality of life (HRQL) and reflux symptom index (RSI) questionnaires, upper gastrointestinal (GI) endoscopy, esophageal 24-h pH-impedance recording, and high-resolution manometry (HRM) were done before TIF and scheduled 6 and 12 months later (HRM only at 6-month). PPI consumption and symptoms were then assessed yearly. Data up to 3 years are reported in this study (PP- and ITT-analysis). RESULTS: TIF was successfully performed in 45/46 patients; in one patient esophageal intubation was impossible. Perforation occurred in two cases. One patient required surgery within 6 months. Clinical follow-up was available for 42 patients at 6 months and 1 year, 35 patients at 2 years, and 31 patients at 3 years. At 1, 2, and 3 years, PPI consumption was stopped, respectively, in 64.3%, 62.9%, and 74.2% of cases (ITT-analysis: 58.7%, 56.4%, and 65.7%). GERD-HRQL and RSI scores decreased at least 50%, respectively, in 71.5% and 76.2%, 71.4% and 68.6%, and 67.7% of cases (ITT-analysis: 65.2% and 69.6%, 64.1% and 61.5%, and 60%). A significant improvement of both scores was observed up to 3 years. 6-month and 1-year functional follow-up were possible in 31 and 20 patients. HRM showed significant increase of the median lower esophageal sphincter length and rate of peristaltic waves. Esophageal pH-impedance recording found significantly fewer acid, proximal and total refluxes, and percentage of esophageal pH < 4 total time at 6 months, but not at 1 year. CONCLUSION: TIF by MUSE significantly improved symptoms and PPIs consumption up to 3 years. However, esophagitis still persisted in one-third of cases at 1 year and functional improvement at 6 months was not confirmed at 1 year. Severe complications requiring surgery occurred in two cases. CLINICALTRIALS: GOV: ID: NCT03669874.

Long-term outcomes of transoral incisionless fundoplication for gastro-esophageal reflux disease: systematic-review and meta-analysis.

Background and study aims Few reports exist about long-term outcomes of transoral incisionless fundoplication (TIF) for treating refractory gastro-esophageal reflux disease (GERD). Methods A literature search of four major scientific databases was performed up to May 2020 for studies reporting on more than 3-year outcomes of TIF. Data on atient satisfaction, proton pump inhibitor (PPI) daily consumption, PPI use reduction, GERD health-related quality-of-life (GERD-HRQL) score, and normalization of heartburn and regurgitation scores were pooled and summarized with forest plots. Publication bias and heterogeneity were explored. Results Overall, eight studies (418 patients, 232 men; 55.5 %) with a mean follow-up of 5.3 years (range: 3-10 years) were included. The pooled proportion of patient-reported satisfaction before and after TIF was 12.3 % (95 % CI:12.3-35.1 %, I 2  = 87.4 %) and 70.6 % (95 % CI:51.2-84.6, I 2  = 80 %), respectively, corresponding to an odds ratio of 21.4 (95 % CI:3.27-140.5). Pooled rates of patients completely off PPIs and on occasional PPIs were 53.8 % (95 %CI: 42.0 %-65.1 %) and 75.8 % (95 %CI: 67.6-82.6), respectively. The pooled estimated mean GERD-HRQL scores off PPI before and after TIF werey 26.1 (95 %CI: 21.5-30.7; range: 20.0-35.5) and 5.9, respectively (95 %CI:0.35.1-11.4; range: 5.3-9.8; P  < 0.001). The overall pooled rates of heartburn and regurgitation scores normalization were 73.0 % (95 %CI: 0.62-0.82) and 86 %, respectively (95 %CI: 75.0-91.0 %). Conclusion Our study shows that TIF appears to offer a long-term safe therapeutic option for selected patients with GERD who refuse life-long medical therapy or surgery, are intolerant to PPIs, or are at increased surgical risk.

Transoral incisionless fundoplication with an ultrasonic surgical endostapler for the treatment of gastroesophageal reflux disease: 12-month outcomes.

BACKGROUND: Transoral incisionless fundoplication (TIF) with the Medigus ultrasonic surgical endostapler (MUSE) is a new intervention for the treatment of the gastroesophageal reflux disease (GERD). The aim of this study was to assess the 12-month clinical, functional, and endoscopic effects of TIF by MUSE. METHODS: Patients undergoing MUSE completed the GERD-Health Related Quality of Life (GERD-HRQL) and Reflux Symptom Index (RSI) questionnaires, and underwent endoscopy, esophageal 24-hour pH-impedance recording, and high resolution manometry (HRM) before the TIF procedure and 12 months later, or after 6 months for HRM. RESULTS: Among the 37 patients treated, esophageal intubation was not possible in one and esophageal perforation occurred in another. Clinical and endoscopic follow-up at 12 months was completed in 20 patients, with significant improvements in GERD-HRQL, RSI, heartburn, regurgitation scores, and proton pump inhibitor (PPI) consumption observed. One patient required surgery for persisting symptoms. Functional follow-up was possible in 13 patients and showed no significant improvements in the analyzed parameters. CONCLUSIONS: TIF with MUSE significantly improved symptoms at 1-year follow-up, allowing the consumption of PPIs to be stopped or halved in 90 % of patients.

Transoral incisionless fundoplication with EsophyX for gastroesophageal reflux disease: clinical efficacy is maintained up to 10 years.

Background Transoral incisionless fundoplication with EsophyX is reported to be effective in patients with gastroesophageal reflux disease in short-medium term follow-up. Aim To examine clinical outcomes up to 10 years. Methods In total, 51 procedures were performed in 50 patients. All entered a yearly clinical follow-up schedule including gastroesophageal reflux disease health-related quality-of-life questionnaires, heartburn and regurgitation scores, and daily proton pump inhibitor consumption. Results The procedure was successfully performed in 49/50 patients. Severe complications occurred in 2/51 procedures. The remaining 49 patients were re-evaluated at 2 and 3 years, 41 after 5 years, 30 after 7 years, and 14 after 10 years. Eight patients were lost to follow-up between 3 and 5 years. Seven patients who were unresponsive to endoscopic fundoplication underwent surgical fundoplication. The mean scores at 2 years were significantly lower than before the procedure and did not change substantially during the follow-up. The rates of patients who had stopped or halved antisecretive therapy 2, 3, 5, 7, and 10 years after the procedure were 86.7 %, 84.4 %, 73.5 %, 83.3 %, and 91.7 %, respectively. Conclusions Transoral incisionless fundoplication with EsophyX is an effective therapeutic option for symptomatic gastroesophageal reflux disease patients, with Hill grades I - II or hiatal hernia < 2 cm, who refuse life-long medical therapy or surgery.

Manometric evaluation of anorectal function in patients treated with neoadjuvant chemoradiotherapy and total mesorectal excision for rectal cancer.

BACKGROUND: An altered anorectal function is reported after chemoradiotherapy (CRT) and surgery for rectal cancer. AIM: The aim of this study was to clarify the relative contribution of neoadjuvant chemoradiation and surgical resection on the impairment of anorectal function as evaluated by anorectal manometry. METHODS: Thirty-nine patients with rectal cancer, who underwent neoadjuvant CRT and laparoscopic rectal resection, were evaluated with the Pescatori Faecal Incontinence score, and with anorectal manometry: before neoadjuvant therapy (T0), after neoadjuvant therapy and before surgery (T1), 12 months after stoma closure (T2). RESULTS: Resting and/or maximum squeeze pressure and/or volume thresholds for urgency were below the normal values in 12 (30%) patients at baseline. After CRT the mean resting pressure significantly decreased (p=0.007). Surgery determined a significantly decrease of the resting pressure (p=0.001), of the maximum squeeze pressure (p=0.001) and of the volume threshold for urgency (p=0.001). Impairment of continence was reported by 5, 11 and 18 patients at T0, T1 and T2, with a mean incontinence score of 3, 3.8 and 3.9 respectively. CONCLUSIONS: CRT is detrimental to the function of the internal anal sphincter. Rectal resection significantly affects both internal and external anal sphincter function and the maximum tolerated volume of the neo-rectum, particularly in patients with low rectal cancer, significantly impairing anal continence.

Effect of transoral incisionless fundoplication on symptoms, PPI use, and ph-impedance refluxes of GERD patients.

BACKGROUND: Three previous studies from the same institution have reported that transoral incisionless fundoplication (TIF) with the EsophyX device is effective for creating a continent gastroesophageal valve and for good functional results as measured only by pH-metry in patients with gastroesophageal reflux disease (GERD). The objective of the present study was to evaluate the effect of TIF on symptoms, use of proton pump inhibitors (PPI), esophageal motility, and pH-impedance in patients with symptomatic GERD. METHODS: Twenty consecutive patients were enrolled to complete the GERD-HRQL and GERD-QUAL questionnaires while on and off PPI. They were also examined by upper gastrointestinal (GI) endoscopy to determine Hill grade and Jobe length of the gastroesophageal valve, and to check for hiatal hernia and esophagitis, esophageal manometry, and pH-impedance before and 6 months after TIF. RESULTS: Six months after TIF, the GERD-HRLQ and GERD-QUAL scores off-PPI therapy and the number of total and acid pH-impedance refluxes were significantly reduced (p < 0.05). The PPI had been completely stopped in 55% of the patient and was reduced in 22% of the patients. CONCLUSIONS: At 6-month follow-up, TIF performed using the EsophyX device reduces symptoms and pH-impedance refluxes, allowing interruption or reduction of PPI use in 78% of patients with GERD.

Rectal distensibility and symptoms after stapled and Milligan-Morgan operation for hemorrhoids.

INTRODUCTION: In a previous uncontrolled study, a reduction of rectal distensibility and volume thresholds for sensations have been related to the occurrence of fecal urgency and/or increased stool frequency after stapled hemorrhoidopexy. AIM OF THE STUDY: The aim of this study was to compare rectal symptoms and sensory-motor function after stapled hemorrhoidopexy and Milligan-Morgan hemorrhoidectomy. METHODS: The clinical records of 12 (four women) and ten patients (four women) with third- and fourth-degree hemorrhoids, respectively, who underwent stapled hemorrhoidopexy or Milligan-Morgan's hemorrhoidectomy, were evaluated. One week before and 6 months after surgery, rectal motor and sensory response to distension was assessed by an electronic barostat, and bowel and rectal symptoms were recorded by means of a 7-day diary and Bristol Index scale and psychological symptoms with SCL-90 questionnaire. RESULTS: Rectal distensibility and volume thresholds for sensations were significantly lower after surgery (P < 0.02) in the stapled group. Increased stool frequency and/or fecal urgency arose in 41% of patients in the stapled group and associated with altered rectal distensibility. No difference within and between groups could be demonstrated in SCL-90 score. CONCLUSIONS: Rectal distensibility and volume thresholds for sensations decrease after stapled hemorrhoidopexy. Altered rectal distensibility was associated with rectal urgency and/or increased stool frequency.

Evaluation of rectal sensory and motor function by means of the electronic barostat after stapled hemorrhoidopexy.

PURPOSE: Stapled hemorrhoidopexy is designed to replace the hemorrhoids into the anal canal by excising the redundant rectal mucosa above the anorectal ring, thus resulting in an intrarectal suture. Few studies have evaluated rectal function after this procedure. This prospective study was designed to use the electronic barostat to assess whether rectal motor and sensory functions change after stapled hemorrhoidopexy. METHODS: Ten patients (4 women, mean age, 46 +/- 9 years) with third-degree and fourth-degree hemorrhoids who underwent stapled hemorrhoidopexy were studied. One week before and six months after surgery, they underwent three different rectal distensions (pressure-controlled stepwise, volume-controlled stepwise, and ramp) controlled by an electronic barostat. RESULTS: Rectal distensibility was significantly lower after surgery during pressure stepwise (P = 0.01), during volume stepwise (P = 0.006), and during ramp distension (P = 0.001). Volume thresholds for desire to defecate, urgency, and discomfort were significantly lower after surgery during all three distensions (P < 0.05). Volume threshold for first perception also was significantly lower after surgery during volume ramp distension (P = 0.01). CONCLUSIONS: Rectal distensibility and volume thresholds for sensations decrease after stapled hemorrhoidopexy. These impairments persist for at least six months after surgery.

Artificial neural networks are able to recognize gastro-oesophageal reflux disease patients solely on the basis of clinical data.

BACKGROUND: Artificial neural networks (ANN) are modelling mechanisms that are highly flexible and adaptive to solve the non-linearity inherent in the relationship between symptoms and underlying pathology. OBJECTIVES: To assess the efficacy of ANN in achieving a diagnosis of gastro-oesophageal reflux disease (GORD) using oesophagoscopy or pH-metry as a diagnostic gold standard and discriminant analysis as a statistical comparator technique in a group of patients with typical GORD symptoms and with or without GORD objective findings (e.g. a positive oesophagoscopy or a pathological oesophageal pH-metry). METHODS: The sample of 159 cases (88 men, 71 women) presenting with typical symptoms of GORD, were subdivided on the basis of endoscopy and pH-metry results into two groups: GORD patients with or without oesophagitis, group 1 (N=103), and pH and endoscopy-negative patients in whom both examinations were negative, group 2 (N=56). A total of 101 different independent variables were collected: demographic information, medical history, generic health state and lifestyle, intensity and frequency of typical and atypical symptoms based on the Italian version of the Gastroesophageal Reflux Questionnaire (Mayo Clinic). The diagnosis was used as a dependent variable. Different ANN models were assessed. RESULTS: Specific evolutionary algorithms selected 45 independent variables, concerning clinical and demographic features, as predictors of the diagnosis. The highest predictive performance was achieved by a 'back propagation' ANN, which was consistently 100% accurate in identifying the correct diagnosis compared with 78% obtained by traditional discriminant analysis. CONCLUSION: On the basis of this preliminary work, the use of ANN seems to be a promising approach for predicting diagnosis without the need for invasive diagnostic methods in patients suffering from GORD symptoms.

Electroacupuncture analgesia for colonoscopy. a prospective, randomized, placebo-controlled study.

OBJECTIVE: A study was undertaken to compare the effectiveness of acupuncture in reducing patient's discomfort and anxiety during colonoscopy with a standard sedation protocol. METHODS: Thirty patients scheduled to undergo colonoscopy were randomly assigned to receive acupuncture, sham, or no acupuncture. A verbal rating scale was used to measure patient's pain when the endoscope reached four scheduled positions. Midazolam was administered at baseline and again anytime patients complained of "severe" pain. The amount of midazolam administered was recorded. A verbal rating scale was used to assess patient's satisfaction with the level of sedation achieved. RESULTS: Pain level was lower, although not significantly, in the acupuncture group. Midazolam boluses were required in three patients with acupuncture (30%), eight in the sham group (80%), and nine in the control group (90%) (p = 0.01). Six patients in the acupuncture group (60%) reported optimum acceptance of colonoscopy compared with only one in the sham group (10%) and none in the control group (0%) (p = 0.016). Satisfaction scores, assessed 24-72 h after colonoscopy, were extremely high (median score 90 of 100) in the three groups. CONCLUSIONS: Acupuncture may decrease the demand for sedative drugs during colonoscopy by reducing discomfort and anxiety of the patient and the well-known adverse effects of pharmacologic sedation.