Cholangiocyte Organoids: The New Frontier in Regenerative Medicine for the Study and Treatment of Cholangiopathies.

Cholangiopathies include a group of chronic progressive disorders, affecting the cholangiocytes, the epithelial cells that line the biliary tree, leading to liver parenchymal fibrosis and eventually end-stage liver disease necessitating transplantation. Experimental modeling of these multifactorial cholestatic diseases faces challenges due to the lack of adequate experimental in vitro and in vivo models. A novel approach employs three-dimensional organoid systems that offer several advantages for modeling disease and testing drug response in vitro. Organoids mimic intercellular communication, replicate the architecture of organs, and maintain the cell's original phenotype. Cholangiocyte organoids provide an in vitro model to study the pathogenesis and pharmacotherapeutic treatment of cholangiopathies and show great promise for regenerative therapies. In particular, patient-derived organoids allow personalized medicine approaches and the study of individual disease characteristics. This review highlights the significance of cholangiocyte organoid models in advancing our understanding of cholangiopathies and driving advancements in regenerative medicine strategies.

Artificial Intelligence Tools for the Diagnosis of Eosinophilic Esophagitis in Adults Reporting Dysphagia: Development, External Validation, and Software Creation for Point-of-Care Use.

BACKGROUND: Despite increased awareness of eosinophilic esophagitis (EoE), the diagnostic delay has remained stable over the past 3 decades. There is a need to improve the diagnostic performance and optimize resources allocation in the setting of EoE. OBJECTIVE: We developed and validated 2 point-of-care machine learning (ML) tools to predict a diagnosis of EoE before histology results during office visits. METHODS: We conducted a multicenter study in 3 European tertiary referral centers for EoE. We built predictive ML models using retrospectively extracted clinical and esophagogastroduodenoscopy (EGDS) data collected from 273 EoE and 55 non-EoE dysphagia patients. We validated the models on an independent cohort of 93 consecutive patients with dysphagia undergoing EGDS with biopsies at 2 different centers. Models' performance was assessed by area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values (PPV and NPV). The models were integrated into a point-of-care software package. RESULTS: The model trained on clinical data alone showed an AUC of 0.90 and a sensitivity, specificity, PPV, and NPV of 0.90, 0.75, 0.80, and 0.87, respectively, for the diagnosis of EoE in the external validation cohort. The model trained on a combination of clinical and endoscopic data showed an AUC of 0.94, and a sensitivity, specificity, PPV, and NPV of 0.94, 0.68, 0.77, and 0.91, respectively, in the external validation cohort. CONCLUSION: Our software-integrated models (https://webapplicationing.shinyapps.io/PointOfCare-EoE/) can be used at point-of-care to improve the diagnostic workup of EoE and optimize resources allocation.

Robotic Colonoscopy and Beyond: Insights into Modern Lower Gastrointestinal Endoscopy.

Lower gastrointestinal endoscopy is considered the gold standard for the diagnosis and removal of colonic polyps. Delays in colonoscopy following a positive fecal immunochemical test increase the likelihood of advanced adenomas and colorectal cancer (CRC) occurrence. However, patients may refuse to undergo conventional colonoscopy (CC) due to fear of possible risks and pain or discomfort. In this regard, patients undergoing CC frequently require sedation to better tolerate the procedure, increasing the risk of deep sedation or other complications related to sedation. Accordingly, the use of CC as a first-line screening strategy for CRC is hampered by patients' reluctance due to its invasiveness and anxiety about possible discomfort. To overcome the limitations of CC and improve patients' compliance, several studies have investigated the use of robotic colonoscopy (RC) both in experimental models and in vivo. Self-propelling robotic colonoscopes have proven to be promising thanks to their peculiar dexterity and adaptability to the shape of the lower gastrointestinal tract, allowing a virtually painless examination of the colon. In some instances, when alternatives to CC and RC are required, barium enema (BE), computed tomographic colonography (CTC), and colon capsule endoscopy (CCE) may be options. However, BE and CTC are limited by the need for subsequent investigations whenever suspicious lesions are found. In this narrative review, we discussed the current clinical applications of RC, CTC, and CCE, as well as the advantages and disadvantages of different endoscopic procedures, with a particular focus on RC.

A "tailored" interventional and surgical management for moderate to critical acute pancreatitis in late phase: a cohort study.

PURPOSE: Several interventional procedures are available to treat moderate-to-critical acute pancreatitis (AP) in its late phase. The ongoing debate on these options, together with the scarcity of reported quality of life (QoL) information in the Literature, prompted us to conduct a review of our experience. METHODS: All the patients treated at our referral Center for moderate-to-critical AP according to Determinant-Based Classification (DBC) were retrospectively reviewed. Patients treated conservatively or operated within 4 weeks were excluded. The included patients were managed following a "tailored" interventional-surgical approach, which did not exclude the possibility to skip one or more steps of the classic "step-up" approach, based on the patient's clinical course, and divided into four groups, according to the first procedure performed: percutaneous drainage (PD), endoscopic approach (END), internal derivation (INT), and necrosectomy (NE). In-hospital and mid-term follow-up variables were analyzed. RESULTS: The study sample consisted in 47 patients: 11 patients were treated by PD, 11 by END, 13 by INT, and 12 by NE. A significant distribution of the DBC severity (p = 0.029) was registered among the four groups. Moreover, the NE group had statistically significant reduced SF-36 scores in the domain of social functioning at 3 months (p = 0.011), at 1 year (p = 0.002), and at 2 years (p = 0.001); role limitations due to physical health at 6 months (p = 0.027); and role limitations due to emotional problems at 1 year (p = 0.020). CONCLUSIONS: In the "late phase" of moderate to critical AP requiring an invasive management, PD, END, INT, and NE are all effective options, depending on patents' status and necrosis location. A "tailored" interventional-surgical management could be pursued, but up-front more invasive approaches are at higher risk of worse QoL. TRIAL REGISTRATION: The manuscript was registered at clinicaltrials.gov in 04/2021 and identified with NCT04870268.

Bloodstream infections in patients with rectal colonization by Klebsiella pneumoniae producing different type of carbapenemases: a prospective, cohort study (CHIMERA study).

OBJECTIVE: To investigate the hypothesis that intestinal colonization by different types of carbapenemase-resistant Klebsiella pneumoniae (CR-Kp) leads to different risks for bloodstream infections (BSI) caused by the same colonizing organism. METHODS: Prospective observational study including consecutive CR-Kp rectal carriers admitted to the Pisa University Hospital (December 2018 to December 2019). Patients underwent rectal swabbing with molecular testing for the different carbapenemases at hospital admission and during hospitalization. Rectal carriers were classified as: NDM, KPC, VIM and OXA-48. The primary end point was the rate of BSI by the same colonizing organism in each study group. A multivariate logistic regression analysis was performed to identify factors independently associated with the risk for BSI by the colonizing organism. RESULTS: Of 677 rectal carriers, 382/677 (56.4%) were colonized by NDM, 247/677 (36.5%) by KPC, 39/677 (5.8%) by VIM and 9/677 (1.3%) by OXA-48. Dissemination of NDM-Kp was mostly sustained by ST147, while KPC-Kp belonged to ST512. A higher rate of BSI was documented in NDM rectal carriers compared with KPC rectal carriers (59/382, 15.4% versus 20/247, 8.1%, p 0.004). Incidence rates of BSI per 100 patients/month were significantly higher in the NDM group (22.33, 95% CI 17.26-28.88) than in the KPC group (9.56, 95% CI 6.17-14.82). On multivariate analysis, multi-site extraintestinal colonization, solid organ transplantation, invasive procedures, intravascular device, admission to intensive care unit, cephalosporin, fluoroquinolones and NDM rectal colonization (OR 3.27, 95% CI 1.73-6.18, p < 0.001) were independently associated with BSI. CONCLUSIONS: NDM-Kp was associated with increased risk of BSI compared with KPC-Kp. This finding seems to be strongly related to the high-risk clone ST147.

Improving the Reprocessing Quality of Flexible Thermolabile Endoscopes: How to Learn from Mistakes.

Background: Failure in the reprocessing of thermolabile flexible endoscopes has been reported as one of the most important threats to patient health. Method: A case report and observational study was conducted, from August 2014 to December 2019, in the Digestive Endoscopy Unit of a University Hospital in Italy, where two cases of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae infections in patients undergoing endoscopic retrograde cholangio-pancreatography were observed. Following the risk/safety management practices, an epidemiological investigation was started, duodenoscopes were removed from use and the reprocessing practices reviewed. Moreover, microbiological surveillance of endoscopes was carried out according to the CDC guidelines. Results: In the first phase of sampling, 10/10 (100%) endoscopes were found to be non-compliant, of which 7 showed results for high-concern organisms (HCOs), such as KPC-K. pneumoniae, P. aeruginosa and E. coli. After implementing corrective actions, 12 out of 17 endoscopes were found to be non-compliant (70.5%), of which 8 showed results for HCOs, such as KPC-K. oxytoca and P. aeruginosa. During the last year of regular microbiological surveillance, only 23% of endoscopes (35/152) were found to be non-compliant, of which 7 showed results for HCOs, such as NDM-K. pneumoniae, P. aeruginosa and A. baumannii. The crucial issues were related to samples collected from the internal channels of duodenoscopes. Conclusion: Managing the risk associated with the reprocessing of digestive endoscopes, through risk assessment at every stage of the process, is important for the prevention of infections associated with the use of these device.

Treatment of completely obstructed anastomosis after low rectal resection A trans-anal plus endoscopic trans-colostomy rendez-vous approach and a review of the literature.

AIM: Completely obstructed anastomosis (COA) after low rectal resection (LRR) represents a rare entity difficult to manage. We herein summarize the available evidence from literature on the treatment of this condition and we report our particular experience in the management of a completely obstructed colon-anal anastomosis (CAA) with a trans-anal plus endoscopic trans-colostomy rendez-vous approach. METHODS: The Pub-Med database was inquired from inception to October 2019 about the treatment of COA after LRR reported in English literature. Article selection was carried out according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria. Moreover, clinical, radiological and surgical data of our case presentation were retrieved. RESULTS: Ten articles involving twelve patients and concerning the management of COA were identified. All of them reported the treatment of completely obstructed colon-rectal anastomosis. As we didn't find any article reporting the treatment of completely obstructed CAA, we also described a case of its treatment. The patient was successfully treated at our institution using a rendez-vous approach with a simultaneous trans-colostomy endoscopy, associated to a trans-anal dilatation. This combined approach, thanks to trans-illumination and to the miniature passage of CO2 coming from above, permitted to identify the correct way to surgically establish a trans-anal lumen. The post-procedural course was uneventful. CONCLUSIONS: The treatment of COA after LRR can be very demanding, particularly after CAA. Few data are reported in literature to define the best approach to treat these conditions. Our described rendez-vous technique can represent a valid choice, especially after CAA. KEY WORDS: Colorectal anastomosis, Endoscopic treatment, Low-rectal resection.

Gastrointestinal stromal tumours of stomach: Robot-assisted excision with the da Vinci Surgical System regardless of size and location site.

Aims: The role of minimally invasive surgery of gastrointestinal stromal tumours (GISTs) of the stomach remains uncertain especially for large and/or difficult located tumours. We are hereby presenting a single-centre series of robot-assisted resections using the da Vinci Surgical System (Si or Xi). Subjects and Methods: Data of patients undergoing robot-assisted treatment of gastric GIST were retrieved from the prospectively collected institutional database and a retrospective analysis was performed. Patients were stratified according to size and location of the tumour. Difficult cases (DCs) were considered for size if tumour was >50 mm and/or for location if the tumour was Type II, III or IV sec. Privette/Al-Thani classification. Results: Between May 2010 and February 2017, 12 consecutive patients underwent robot-assisted treatment of GIST at our institution. DCs were 10/12 cases (83.3%), of which 6/10 (50%) for location, 2/10 (25%) for size and 2/10 (25%) for both. The da Vinci Si was used in 8 patients, of which 6 (75%) were DC, and the da Vinci Xi in 4, all of which (100%) were DC. In all patients, excision was by wedge resection. All lesions had microscopically negative resection margins. There was no conversion to open surgery, no tumour ruptures or spillage and no intraoperative complications. Conclusion: Our experience suggests a positive role of the robot da Vinci in getting gastric GIST removal with a conservative approach, regardless of size and location site. Comparative studies with a greater number of patients are necessary for a more robust assessment.

Use of the new da Vinci Xi® during robotic rectal resection for cancer: a pilot matched-case comparison with the da Vinci Si®.

BACKGROUND: The aim of this study was to compare the short-term outcomes of robotic rectal resection with total mesorectal excision (TME) for rectal cancer, with the use of the new da Vinci Xi® (Xi-RobTME group) and the da Vinci Si® (Si-RobTME group). METHODS: Ten patients with histologically confirmed rectal cancer underwent robot-assisted TME with the use of the new da Vinci Xi. The outcomes of Xi-RobTME group were compared with a Si-RobTME group selected using a case-matched methodology. RESULTS: Overall operative times and mean hospital stays were shorter in the Xi-RobTME group. Surgeries were fully robotic with a complete take-down of the splenic flexure in all Xi-RobTME cases, while only four cases of the Si-RobTME group were fully robotic, with two cases of complete take-down of the splenic flexure. CONCLUSIONS: The new da Vinci Xi could offer some advantages with respect to the da Vinci Si in rectal resection for cancer. Copyright © 2016 John Wiley & Sons, Ltd.

Hand-assisted hybrid laparoscopic-robotic total proctocolectomy with ileal pouch--anal anastomosis.

PURPOSE: Few studies have reported minimally invasive total proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). We herein report a novel hand-assisted hybrid laparoscopic-robotic technique for patients with FAP and UC. METHODS: Between February 2010 and March 2014, six patients underwent hand-assisted hybrid laparoscopic-robotic total proctocolectomy with IPAA. The abdominal colectomy was performed laparoscopically with hand assistance through a transverse suprapubic incision, also used to fashion the ileal pouch. The proctectomy was carried out with the da Vinci Surgical System. The IPAA was hand-sewn through a trans-anal approach. The procedure was complemented by a temporary diverting loop ileostomy. RESULTS: The mean hand-assisted laparoscopic surgery (HALS) time was 154.6 (±12.8) min whereas the mean robotic time was 93.6 (±8.1) min. In all cases, a nerve-sparing proctectomy was performed, and no conversion to traditional laparotomy was required. The mean postoperative hospital stay was 13.2 (±7.4) days. No anastomotic leakage was observed. To date, no autonomic neurological disorders have been observed with a mean of 5.8 (±1.3) bowel movements per day. CONCLUSIONS: The hand-assisted hybrid laparoscopic-robotic approach to total proctocolectomy with IPAA has not been previously described. Our report shows the feasibility of this hybrid approach, which surpasses most of the limitations of pure laparoscopic and robotic techniques. Further experience is necessary to refine the technique and fully assess its potential advantages.

Changes in the expression of suppressor of cytokine signalling (SOCS) 2 in the colonic mucosa of acromegalic patients are associated with hyperplastic polyps.

BACKGROUND: Acromegalic patients have increased prevalence of colonic polyps. Development of hyperplastic polyps was related to suppressor of cytokine signalling (SOCS) 2 haploinsufficiency in animal models of acromegaly. OBJECTIVE AND PATIENTS: To evaluate whether variations in SOCS2 expression in the colonic mucosa of acromegalic patients might be associated to hyperplastic polyps, patients with active acromegaly or disease in remission with or without hyperplastic polyps were studied; controls were non-acromegalic subjects age- and sex- matched with or without polyps. MEASUREMENTS: Expression of SOCS1-3 was evaluated by RT-PCR, immunofluorescence and Western blot in the colonic mucosa. Coimmunoprecipatiton was used to evaluate multimeric protein complexes. RESULTS: Acromegalic patients with active disease and hyperplastic polyps had higher levels of SOCS2 transcripts; on the contrary, SOCS1 and SOCS3 transcripts did not differ among the study groups. While the expression of SOCS2 and SOCS3 protein was indistinguishable with that of the corresponding transcripts, SOCS1 protein expression was reduced in active acromegalic patients with polyps. SOCS1 protein was reduced owing to its increased proteasome degradation mediated by SOCS2. The increased SOCS2 and reduced SOCS1 led to increased STAT5b expression, suggesting a higher GH signalling transduction. CONCLUSIONS: Acromegalic patients with active disease and hyperplastic polyps have high levels of SOCS2 and increased SOCS1 degradation, leading to reduced negative feedback on GH signalling, likely favouring a hyperplastic polyps phenotype.

A technique for retroperitoneal pancreas transplantation with portal-enteric drainage.

BACKGROUND: Pancreas transplantation (PTx) with portal-enteric drainage (PED) has been associated with difficulties in respect to arterial anastomosis and graft accessibility for percutaneous biopsy. We describe a new technique that circumvents these difficulties. METHODS: Between April 2001 and April 2004, a total of 113 recipients were scheduled for PTx with PED. The superior mesenteric vein was approached from the right retroperitoneal aspect instead of from the anterior transmesenteric route. The pancreas graft was eventually placed in the right retroperitoneal space, being covered by the ascending colon and its mesentery. RESULTS: One hundred ten (97.3%) PTx were performed as planned. Systemic venous effluent was preferred in three patients because of incidental diagnosis of liver cirrhosis during surgery (n=1) and severe obesity (body mass index>35 kg/m2) (n=2). The Y iliac artery graft was kept as short as possible, and arterial anastomosis was always performed with ease. After a mean follow-up period of 21.2+/-19.9 months, the relaparotomy rate was 13.6%. No patient died after repeat surgery, and none required multiple relaparotomies. Overall, 10 grafts were lost because of acute rejection (n=3), chronic rejection (n=2), venous thrombosis (n=2), recipient death (n=2), and late (6-month) arterial thrombosis (n=1). One-year patient and graft survival were 98.1% and 90.7%, respectively. CONCLUSIONS: Our data confirm that PTx with PED is not associated with an increased risk. The technique described has distinctive technical advantages and should be included in the repertoire of PTx.