Insights into Therapeutic Response Prediction for Ustekinumab in Ulcerative Colitis Using an Ensemble Bioinformatics Approach.

INTRODUCTION: Optimizing treatment with biological agents is an ideal goal for patients with ulcerative colitis (UC). Recent data suggest that mucosal inflammation patterns and serum cytokine profiles differ between patients who respond and those who do not. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, has shown promise, but predicting treatment response remains a challenge. We aimed to identify prognostic markers of response to ustekinumab in patients with active UC, utilizing information from their mucosal transcriptome. METHODS: We performed a prospective observational study of 36 UC patients initiating treatment with ustekinumab. Colonic mucosal biopsies were obtained before treatment initiation for a gene expression analysis using a microarray panel of 84 inflammatory genes. A differential gene expression analysis (DGEA), correlation analysis, and network centrality analysis on co-expression networks were performed to identify potential biomarkers. Additionally, machine learning (ML) models were employed to predict treatment response based on gene expression data. RESULTS: Seven genes, including BCL6, CXCL5, and FASLG, were significantly upregulated, while IL23A and IL23R were downregulated in non-responders compared to responders. The co-expression analysis revealed distinct patterns between responders and non-responders, with key genes like BCL6 and CRP highlighted in responders and CCL11 and CCL22 in non-responders. The ML algorithms demonstrated a high predictive power, emphasizing the significance of the IL23R, IL23A, and BCL6 genes. CONCLUSIONS: Our study identifies potential biomarkers associated with ustekinumab response in UC patients, shedding light on its underlying mechanisms and variability in treatment outcomes. Integrating transcriptomic approaches, including gene expression analyses and ML, offers valuable insights for personalized treatment strategies and highlights avenues for further research to enhance therapeutic outcomes for patients with UC.

Evaluation of the Quality Changes in Three Commercial Pastourma Samples during Refrigerated Storage Using Physicochemical, Microbiological, and Image Analyses Combined with Chemometrics.

Despite the inherent stability of dried and cured products, such as pastourma, appropriate refrigeration remains essential for preserving their optimal characteristics. This study explored quality and safety characteristics in lamb, beef, and buffalo pastourma during 16-day refrigeration storage after package opening. The comprehensive approach employed Attenuated Total Reflection-Fourier-Transform Infrared (ATR-FTIR) spectroscopy, colorimetry, and image analysis, alongside physicochemical and microbiological analyses, to shed light on these alterations. The findings reveal a reduction in textural uniformity and color vibrancy (fading reds and yellows) across all samples during storage, with lamb pastourma exhibiting the most pronounced effects. Notably, image analysis emerged as a powerful tool, enabling the accurate classification of samples based on storage duration. Additionally, significant variations were observed in moisture content, hue angle, firmness, and TBARS levels, highlighting their influence on pastourma quality. The study documented a gradual decrease in lactic acid bacteria and aerobic plate count populations over time. ATR-FTIR spectra's interpretation revealed the presence of lipids, proteins, carbohydrates, and water. Protein secondary structures, demonstrably influenced by the meat type used, exhibited significant changes during storage, potentially impacting the functional and textural properties of pastourma. Overall, the findings contribute to a deeper understanding of pastourma spoilage during storage, paving the way for the development of improved preservation and storage strategies.

Evaluation of parameters influencing the quality of colon preparation with a split-dose regimen of sulfate salts.

Background: Bowel cleansing is an important factor for the quality of colonoscopy. We aimed to evaluate the efficacy of split-dose oral sulfate salts on bowel preparation and to determine parameters influencing the quality of bowel cleaning. Method: Consecutive adults who completed their preparation for colonoscopy with a regimen of sulfate salts were enrolled. Results: Of the 446 patients, 11 were excluded from the analysis. Among the 435 patients, 257 (59.1%) were female, mean age was 62.0±11.6 years and median body mass index (BMI) 26.1 kg/m2 (interquartile range [IQR] 23.8-29.4). Indications for colonoscopy were screening 155 (35.6%), surveillance 102 (23.5%), or other 178 (40.9%). The median time between the end of second dose of the preparation regimen and colonoscopy initiation was 5:15 h (IQR 4:30-6:00, min: 2:20, max: 12:20). Minor adverse events were reported in 62 (14.3%) patients. BBPS=9 was observed in 279 (64.14%) patients. Segmental BBPS=3 was achieved in 387 (88.97%), 346 (79.54%) and 289 (66.44%) patients (P<0.001) in the descending, transverse and ascending colon, respectively. Multivariate analysis revealed that BMI (odds ratio [OR] 1.05, 95% confidence interval [CI] 1-1.1) and time between the end of the second laxative dose and colonoscopy initiation (OR 1.25, 95%CI 1.08-1.45) were associated with poorer bowel preparation. Conclusions: A split dose of oral sulfate salts is an efficacious and well tolerated regimen. Obesity and a longer time interval between the end of the second dose and colonoscopy initiation negatively influence bowel cleanliness.

Butterfly Wings Effect on High Resolution Manometry in A Patient with Esophageal Achalasia.

A 57-year-old man presented with dysphagia in solids and liquids deteriorating in the last months and weight loss of 3 kg. A thoracic CT revealed a limit dilatation of the lower esophagus with food residue. An upper endoscopy was performed revealing bubble content and a contraction of the Lower Esophageal Sphincter (LES). A barium esophagogram demonstrated deceleration of esophageal emptying and a bird beak sign indicative of esophageal achalasia (Figure A). High resolution esophageal manometry was performed to evaluate the subtype of achalasia. The catheter could not be intubated into the stomach because of LES spasticity, it folded back cephalad at this level, producing a mirror image, the characteristic "butterfly wings" appearance of a folded manometry catheter (Figure B).

Chronic constipation in Parkinson's disease: clinical features and molecular insights on the intestinal epithelial barrier.

Background: Chronic constipation (CC) is a severe symptom in Parkinson's disease (PD), with an unclear pathogenesis. Abnormalities of the enteric nervous system (ENS) and/or intestinal epithelial barrier (IEB) may be pathophysiologically relevant in PD patients with CC. We investigated possible molecular changes of the IEB in PD/CCs compared with CCs and controls. Methods: Twelve PD/CCs (2 female, age range 51-80 years), 20 CCs (15 female, age range 27-78 years), and 23 controls (11 female, age range 32-74 years) were enrolled. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colon biopsies were obtained and assessed for gene and protein expression, and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1), and zonula occludens-1 (ZO-1) by RT-qPCR, immunoblot and immunofluorescence labeling. Results: PD/CCs were clustered in 2 functional categories: patients with delayed TT and altered AM (60%), and a second group showing only modifications in AM pattern (40%). Gene expression of CLDN4, OCCL-1 and ZO-1 was higher in PD/CCs than controls (P<0.05). Conversely, PD/CCs showed a trend to decrease (P>0.05) in CLDN4 and OCCL-1 protein levels than controls, whereas ZO-1 protein was comparable. In PD/CCs compared with controls, decreasing tendency of vasoactive intestinal polypeptide mRNA, protein and immunoreactive fiber density were observed, although the difference was not statistically significant. Conclusion: Transit and anorectal dysfunctions in PD/CCs are associated with difference in ZO-1, OCCL-1 and CLDN4 expression, thus supporting the role of an altered IEB as a contributory mechanism to possible neuronal abnormalities.

Cholangiocarcinoma in the Era of Immunotherapy.

Cholangiocarcinoma (CCA) is a rare malignancy of the gastrointestinal tract, with aggressive behavior, and portends a poor prognosis. Traditionally, it is classified according to its site of involvement as intrahepatic, perihilar, and distal cholangiocarcinoma. A host of genetic and epigenetic factors have been involved in its pathogenesis. Chemotherapy has remained the standard first-line treatment over the last decade, with a disappointing median overall survival of 11 months for locally advanced and metastatic CCA. The advent of immunotherapy has revolutionized the treatment of many pancreaticobiliary malignancies, offering durable responses with a safe therapeutic profile. To date, there have been no significant advances in the management of CCA. Novel immunotherapeutic methods, such as cancer vaccines, adoptive cell therapy, and combinations of immune checkpoint inhibitors with other agents, are currently under investigation and may improve prognosis with overall survival. Efforts to find robust biomarkers for response to treatment along with multiple clinical trials are also ongoing in this regard. In this review, we present an overview of the current advances and the future perspectives of immunotherapy in the management of CCA.

Ureterocystoplasty in Boys with Valve Bladder Syndrome-Is This Method Still up to Date?

Boys with valve bladder syndrome (PUV) require adequate treatment of the lower urinary tract to preserve renal function and improve long-term outcomes. In some patients, further surgery may be necessary to improve bladder capacity and function. Ureterocytoplasty (UCP) is usually carried out with a small segment of intestine or, alternatively, with a dilated ureter. Our aim was to evaluate the long-term outcomes after UCP in boys with PUV. UCP had been performed in 10 boys with PUV at our hospital (2004-2019). Pre- and postoperative data were evaluated in relation to kidney and bladder function, the SWRD score, additional surgery, complications, and long-term follow-up. The mean time between primary valve ablation and UCP was 3.5 years (SD ± 2.0). The median follow-up time was 64.5 months (IQR 36.0-97.25). The mean increase in age-adjusted bladder capacity was 25% (from 77% (SD ± 0.28) to 102% (SD ± 0.46)). Eight boys micturated spontaneously. Ultrasounds showed no severe hydronephrosis (grade 3-4). The SWRD score showed a median decrease from 4.5 (range 2-7) to 3.0 (range 1-5). No conversion of augmentation was required. UCP is a safe and effective approach to improve bladder capacity in boys with PUV. In addition, the possibility of micturating naturally is still maintained.

Endoscopic ultrasound-guided tissue acquisition beyond the pancreas.

Endoscopic ultrasound (EUS) offers the ability to obtain tissue material via a fine needle under direct visualization for cytological or pathological examination. Prior studies have looked at EUS tissue acquisition; however, most reports have been centered around lesions of the pancreas. This paper aims to review the literature on EUS tissue acquisition in other organs (beyond the pancreas) such as the liver, biliary tree, lymph nodes, and upper and lower gastrointestinal tracts. Furthermore, techniques for obtaining tissue samples under EUS guidance continue to evolve. Specifically, some of the techniques that endoscopists employ are suction techniques (i.e., dry heparin, dry suction technique, wet suction technique), the slow pull technique, and the fanning technique. Apart from acquisition techniques, the type and size of the needle utilized play a major role in the quality of samples. This review describes the indications for tissue acquisition for each organ, and also describes and compares the various tissue acquisition techniques, as well as the different needles used according to their shape and size.

Graded pneumatic dilation in subtype I and II achalasia: long-term experience in a single center.

BACKGROUND: The efficacy of pneumatic dilation (PD) in the management of achalasia has yielded variable results. The availability of high-resolution manometry led to the identification of 3 clinically relevant subtypes of achalasia, revealing the poor efficacy of PD in subtype III. Furthermore, PD showed a lower response rate in patients with subtype III compared to laparoscopic Heller myotomy and peroral endoscopic myotomy. This study aimed to investigate the short- and long-term efficacy, safety profile and side effects of PD with a "graded approach" in subtypes I and II achalasia. METHODS: We enrolled 141 patients (male 67, mean age=66±16.26 years) with achalasia (n=27 subtype I, n=74 subtype II and n=40 subtype III) between January 2010 and July 2020 at St. Orsola University Hospital, Bologna, Italy. We analyzed the data of patients with subtypes I and II, who underwent a graded-protocol PD. Short- and long-term clinical efficacy, complications and gastroesophageal reflux disease (GERD) were recorded. RESULTS: One month after graded protocol PD, 100% subtype I and 96.2% subtype II achalasia patients showed clinical remission. The PD procedure was completed without major complications in all patients. In the long-term follow up (median time: 56 months), 95.5% subtype I and 90% subtype II achalasia patients had an Eckardt score ≤3. GERD occurred in 27.7% of all patients. CONCLUSION: A graded-protocol PD applied in the appropriate achalasia subtypes was shown to be a safe and highly effective approach, in both the short- and long-term.

Case Report: Malignant melanoma in a patient with Crohn's disease treated with ustekinumab.

The cornerstone of inflammatory bowel disease (IBD) treatment is immunomodulators. IBD patients are at increased risk of intestinal and extraintestinal malignancy. Ustekinumab is a fully humanized monoclonal anti-IL12/23 antibody with a good safety profile. Malignancies of breast, colon, head and neck, kidney, prostate, thyroid, and non-melanoma skin cancer have been reported among patients who received ustekinumab. We report the case of a 42-year-old Crohn's patient on long-term treatment with ustekinumab, who developed achromatic malignant melanoma. Crohn's was diagnosed at the age of 15, with upper and lower gastrointestinal involvement and was initially treated with azathioprine (2mg/kg for 4 years) and infliximab (5mg/kg for 6 weeks). Due to ileal obstruction, the patient underwent stricturoplasty and received adalimumab (40mg every other week) for two years. He then discontinued therapy and a year later underwent right hemicolectomy. Adalimumab was reinstituted (40mg every other week) and the patient remained in clinical remission for two years. His overall exposure to adalimumab was four years. Ustekinumab was initiated due to a relapse and after 3 years, an incident of scalp itching led to the diagnosis metastatic achromatic malignant melanoma bearing BRAF V600E mutation. He received targeted therapy with an initial good response. We aim to point out the risk of dermatologic malignancy in IBD patients on long-term immunosuppression and the lifelong and meticulous evaluation that is required.

A Modified "Rendezvous" Technique for EUS-guided Recanalization of a Rectal Anastomotic Stricture without Fluoroscopy and Stenting.

Various endoscopic techniques have been described for the treatment of post-operative colonic strictures. Our aim is to report a solely EUS-guided recanalization procedure for a complete rectal stricture, without the use of fluoroscopy or stenting. A 66-year-old male was submitted to low anterior resection and protective ileostomy for rectal adenocarcinoma, complicated with complete anastomotic stricture 6 months later. The patient was treated with a modified EUS-guided rendezvous technique. A colonoscope was advanced through the ileostomy to the sigmoid colon, which was subsequently filled with water. A linear echoendoscope was advanced transanally to the distal part of the rectal anastomosis. The proximal colon was punctured with a 19G needle and a guidewire was advanced through the needle. The rectocolonic fistula tract was first dilated by graduated dilation catheters. Subsequently, progressive pneumatic dilatation was performed. There were no post-procedural complications. At 6-month follow-up the anastomosis was patent, with no significant stricture recurrence. In conclusion, a rendezvous technique for EUS-guided recanalization of complete rectal anastomotic strictures is feasible and safe in a non-radiology assisted setting. In selected cases of distal stenoses balloon dilation could effectively serve as the sole treatment, without the adjunct of stent placement.

Observational Study of Clinical Practice in Patients with Pancreatic Adenocarcinoma in Greece.

BACKGROUND: During the last decade, significant improvement was made in systemic therapy of pancreatic adenocarcinoma (PAC). The impact of this progress in everyday clinical practice has not been fully described yet. The aim of the study was to investigate the pattern followed by Greek Medical Oncologists regarding the treatment of patients with PAC. METHODS: This observational, noninterventional multicenter study recorded clinical data from the files of 200 active patients (alive and under treatment or follow-up) for a two-year period (November 2015 until November 2017) from 20 oncology centers around Greece. RESULTS: In total, 51 (25.5%) patients underwent radical surgical resection of PAC, and 40 (78.4%) of them received adjuvant and 1 (2.0%) neoadjuvant chemotherapy. The median time to recurrence was 7.9 months, and median overall survival (OS), 20.2 months. First-line chemotherapy was administered to 193 (96.5%) patients. The majority of patients were treated with the combination of nab-paclitaxel-gemcitabine (NPG), 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX), or gemcitabine monotherapy. Of them, 39.5% responded to the treatment. Median OS and PFS were 14.1 months and 7.0 months, respectively. Second-line treatment was administered to 112 patients. The majority received NPG, FOLFIRINOX/capecitabine, oxaliplatin, irinotecan (CAPOXIRI), or 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX)/capecitabine, oxaliplatin (CAPOX). Median OS with second-line treatment was 8.6 months, and median PFS, 5.5 months. The most common chemotherapy sequences were NPG as first-line followed by FOLFIRINOX/CAPOXIRI as second-line, NPG followed by FOLFOX/CAPOX, NPG followed by other regimens, and FOLFIRINOX/CAPOXIRI followed by NPG. CONCLUSION: This study described the significant improvement in prognosis of PAC patients receiving palliative chemotherapy and the relatively high rate of receipt of second-line chemotherapy, according to real-world data. However, due to the nonrandomized nature of the study, any comparison between different chemotherapy regimens should be regarded with caution.

Chronic non-allergic rhinitis with neutrophils is associated with higher acid exposure time: A pH-impedance monitoring study.

BACKGROUND & AIM: Chronic rhinitis, a diffuse disease with a prevalence of 40%, can be classified in allergic (AR) and non-allergic rhinitis (NAR). Nasal cytology allows for the identification of different NAR sub-types according to the inflammatory cell infiltrate. NAR etiopathogenesis is not well clarified and, for NARNE (non-allergic rhinitis with neutrophils) subtype, gastroesophageal reflux disease (GERD) has been suggested as one of the etiopathogenetic factors. Aim of this study is to evaluate the role of GERD in patients with NARNE. METHODS: Fifty-one consecutive patients referred to our Ear, Nose and Throat (ENT) unit with nasal symptoms and cytology suggestive for NAR, were enrolled in the study. All the patients performed a gastroenterological evaluation, high resolution esophageal manometry and a 24-h pH-Impedance monitoring. RESULTS: Twenty-five (49%) patients tested positive at nasal cytology for NARNE. A pathologic pH-impedance was identified in seven patients (28%) with NARNE, as opposed to only one (4%) with different NAR subtypes. Statistical analysis showed that higher acid exposure time (AET) and weaker post nasal drainage were more common in NARNE vs. other NAR patients. CONCLUSIONS: NARNE strongly correlates with higher AET and refluxes number; thus, NARNE patients should be tested with pH-impedance monitoring in addition to nasal cytology.

A new mechanism of gastroesophageal reflux in hiatal hernia documented by high-resolution impedance manometry: a case report.

Gastroesophageal reflux disease (GERD) is recognized to be a multifactorial disease and several mechanisms leading to reflux have been described, nevertheless its pathophysiology has not been fully clarified. Hiatus hernia is a known risk factor for GERD since it impairs the esophagogastric junction, leading to: reduction in lower esophageal sphincter pressure; increase in the frequency of the transient lower esophageal sphincter relaxation; and impairment of esophageal clearance. Last generation diagnostic techniques have improved the understanding of these mechanisms. A 72-year-old woman with hiatus hernia and GERD underwent a high resolution impedance manometry (HRIM) after a partial response to treatment with pantoprazole. None of the proposed pathophysiological mechanisms for GERD could explain the presence of reflux: HRIM showed normal lower esophageal sphincter (LES) pressure and contractile integral, complete bolus clearance in all test swallows, and absence of transient LES relaxation. However, after the end of each peristaltic wave, as the LES pressure returned to resting values, a gastroesophageal reflux was detected until the following swallow. We describe an interesting case of a patient with a sliding hiatus hernia, with symptoms suggestive of GERD, in which HRIM revealed a new possible mechanism through which hiatus hernia may lead to GERD.

Treatment of achalasia in the era of high-resolution manometry.

Esophageal achalasia is a primary motility disorder characterized by impaired lower esophageal sphincter relaxation and absence of esophageal peristalsis leading to impaired bolus transit, manifested with symptoms such as dysphagia, regurgitation, retrosternal pain, and weight loss. The standard diagnostic tool is esophageal manometry which demonstrates incomplete relaxation of the lower esophageal sphincter and impaired esophageal peristalsis. Recently, a new advanced technique, high-resolution manometry (HRM) with the addition of pressure topography plotting, using multiple sensors to capture the manometric data as a spatial continuum, allows a detailed pressure recording of the esophageal motility. This technique, currently the gold standard for the diagnosis of achalasia, has led to a subclassification of three manometric types that seem to have different responsiveness to treatment. Because its pathogenesis is as yet unknown, achalasia treatment options are not curative. Type II achalasia patients respond better to treatment compared to those with types I and III. Low-risk patients with type I or II achalasia have good outcome with both graded pneumatic dilatations and laparoscopic Heller myotomy, while type III achalasia patients respond better to laparoscopic Heller myotomy. Although, type III achalasia patients responds less in comparison to types I and II to laparoscopic Heller myotomy. Peroral endoscopic myotomy is a promising new technique but long-term follow-up studies for its safety and efficacy must be performed. This article reviews the current therapeutic options, highlighting the impact of HRM to predict the outcome and the new insights for the treatment of achalasia.