Endoscopic Gallbladder Drainage: A Comprehensive Review on Indications, Techniques, and Future Perspectives.

In recent years, therapeutic endoscopy has become a fundamental tool in the management of gallbladder diseases in light of its minimal invasiveness, high clinical efficacy, and good safety profile. Both endoscopic transpapillary gallbladder drainage (TGBD) and endoscopic ultrasound (EUS)-guided gallbladder drainage (EUS-GBD) provide effective internal drainage in patients with acute cholecystitis unfit for cholecystectomy, avoiding the drawbacks of external percutaneous gallbladder drainage (PGBD). The availability of dedicated lumen-apposing metal stents (LAMS) for EUS-guided transluminal interventions contributed to the expansion of endoscopic therapies for acute cholecystitis, making endoscopic gallbladder drainage easier, faster, and hence more widely available. Moreover, EUS-GBD with LAMS opened the possibility of several cholecystoscopy-guided interventions, such as gallstone lithotripsy and clearance. Finally, EUS-GBD has also been proposed as a rescue drainage modality in malignant biliary obstruction after failure of standard techniques, with encouraging results. In this review, we will describe the TBGD and EUS-GBD techniques, and we will discuss the available data on clinical efficacy in different settings in comparison with PGBD. Finally, we will comment on the future perspectives of EUS-GBD, discussing the areas of uncertainty in which new data are more strongly awaited.

HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling.

Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.

Feasibility and safety of deep sedation with propofol and remifentanil in spontaneous breathing during endoscopic retrograde cholangiopancreatography: an observational prospective study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an interventional procedure that requires deep sedation or general anaesthesia. The purpose of this prospective observational study was to assess the feasibility and safety of deep sedation in ERCP to maintain spontaneous breathing. METHODS: This is a single-centre observational prospective cohort study conducted in a tertiary referral university hospital. All consecutive patients who needed sedation or general anaesthesia for ERCP were included from January 2021 to June 2021. Deep sedation was achieved and maintained by continuous infusion of an association of propofol and remifentanil. The primary endpoint was to assess the prevalence of major anaesthesia-related complications, such as arrhythmias, hypotension, gas exchange dysfunction, and vomiting (safety endpoint). Secondary endpoints were: (a) to assess the prevalence of signs of an insufficient level of sedation, such as movement, cough, and hiccups (feasibility endpoint): (b) time needed to achieve the target level of sedation and for recovery from anaesthesia. In order to do so we collect the following parameters: peripheral oxygen saturation, fraction of inspired oxygen, noninvasive systemic blood pressure, heart rate, number of breaths per minute, neurological functions with the use of the bispectral index to determine depth of anaesthesia, and partially exhaustive CO2 end pressure to continuously assess the ventilatory status. The collected data were analysed by several tests: Shapiro-Wilk, Student's t, Tuckey post-hoc, Wilcoxon rank-sum and Kruskall-Wallis ran. Statistical analysis was performed using Stata/BE 17.0 (StataCorp LLC). RESULTS: 114 patients were enroled. Eight patients were excluded because they did not meet the inclusion criteria. We found that all patients were hemodynamically stable: intraoperative mean systolic blood pressure was 139,23 mmHg, mean arterial pressure was on average 106,66 mmHg, mean heart rate was 74,471 bpm. The mean time to achieve the target level of sedation was 63 s, while the mean time for the awakening after having stopped drug infusion was 92 s. CONCLUSIONS: During ERCP, deep sedation and analgesia using the association of propofol and remifentanil and maintaining spontaneous breathing are safe and feasible, allowing for a safe and quick recovery from anaesthesia.

Hemostatic Powders in Non-Variceal Upper Gastrointestinal Bleeding: The Open Questions.

Hemostatic powder (HP) is a relatively recent addition to the arsenal of hemostatic endoscopic procedures (HEPs) for gastrointestinal bleeding (GIB) due to benign and malignant lesions. Five types of HP are currently available: TC-325 (Hemospray™), EndoClot™, Ankaferd Blood Stopper®, and, more recently, UI-EWD (NexpowderTM) and CEGP-003 (CGBio™). HP acts as a mechanical barrier and/or promotes platelet activation and coagulation cascade. HP may be used in combination with or as rescue therapy in case of failure of conventional HEPs (CHEPs) and also as monotherapy in large, poorly accessible lesions with multiple bleeding sources. Although the literature on HP is abundant, randomized controlled trials are scant, and some questions remain open. While HP is highly effective in inducing immediate hemostasis in GIB, the rates of rebleeding reported in different studies are very variable, and conditions affecting the stability of hemostasis have not yet been fully elucidated. It is not established whether HP as monotherapy is appropriate in severe GIB, such as spurting peptic ulcers, or should be used only as rescue or adjunctive therapy. Finally, as it can be sprayed on large areas, HP could become the gold standard in malignancy-related GIB, which is often nonresponsive or not amenable to treatment with CHEPs as a result of multiple bleeding points and friable surfaces. This is a narrative review that provides an overview of currently available data and the open questions regarding the use of HP in the management of non-variceal upper GIB due to benign and malignant diseases.

Difficult Biliary Stones: A Comprehensive Review of New and Old Lithotripsy Techniques.

Biliary stones represent the most common indication for therapeutic endoscopic retrograde cholangiopancreatography. Many cases are successfully managed with biliary sphincterotomy and stone extraction with balloon or basket catheters. However, more complex conditions secondary to the specific features of stones, the biliary tract, or patient's needs could make the stone extraction with the standard techniques difficult. Traditionally, mechanical lithotripsy with baskets has been reported as a safe and effective technique to achieve stone clearance. More recently, the increasing use of endoscopic papillary large balloon dilation and the diffusion of single-operator cholangioscopy with laser or electrohydraulic lithotripsy have brought new, safe, and effective therapeutic possibilities to the management of such challenging cases. We here summarize the available evidence about the endoscopic management of difficult common bile duct stones and discuss current indications of different lithotripsy techniques.

Super selective arterial embolization to treat radiation-induced hemorrhagic gastritis: a case report and review of the literature.

Radiation-induced hemorrhagic gastritis (RIHG) is a rare but potentially fatal event following radiotherapy for locally advanced gastric cancer; the treatment of this condition is not standardized. Only few cases of RIHG have been reported, treated with different therapeutic approaches. Here we report the case of a 79-year-old patient who underwent subtotal gastrectomy for gastric cancer, followed by adjuvant chemo-radiotherapy. Approximately 3 months after the end of the treatment, she developed recurrent diffuse bleeding originating from the entire mucosa of the gastric pouch and from a marginal ulcer. As the bleeding was refractory to several endoscopic treatments and surgery was not indicated, the patient underwent two sessions of transcatheter selective arterial embolization, with resolution of bleeding. Arterial embolization has already been reported for the treatment of hemorrhagic cystitis, developing after irradiation of the pelvis for prostate, bladder, rectum, and cervix cancer. However, to our knowledge, it has never been reported as a treatment for hemorrhagic gastritis. Based on this case, we suggest arterial embolization as an option in the management of RIHG, when standard endoscopic treatment fails.

Efficacy of hemostatic powders as monotherapy or rescue therapy in gastrointestinal bleeding related to neoplastic or non-neoplastic lesions.

BACKGROUND: Hemostatic powder (HP) in gastrointestinal bleeding (GIB) is mainly used as rescue therapy after failure of conventional hemostatic procedures (CHP). AIM: To define the best field of application and the efficacy of HP as first choice monotherapy or rescue therapy. METHODS: We compared the efficacy of HP monotherapy, HP rescue therapy, and CHP in the management of active GIB due to neoplastic and non-neoplastic lesions. RESULTS: A total of 108 patients, 43 treated with HP as either first choice or rescue therapy and 65 with CHP, were included in the study. The most frequent sources of bleeding were peptic ulcer and malignancy. Immediate hemostasis rates were: HP monotherapy = 100% in peptic ulcer and 100% in malignancy; HP rescue therapy = 93.2% in peptic ulcer and 85.7% in malignancy; CHP = 77.9% in peptic ulcer and 41.7 in malignancy. Definitive hemostasis rates were: HP monotherapy = 50% in peptic ulcer and 45.5% in malignancy; HP rescue therapy = 73.3% in peptic ulcer and 85.7% in malignancy; CHP = 69.1% in peptic ulcer and 33.3% in malignancy. No difference was found in terms of additional intervention between the three groups. CONCLUSIONS: HP is highly effective as monotherapy and rescue therapy in GIB. GIB related to malignancy may be the best field of application of HP, but confirmatory studies are necessary.

Factors influencing diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in pancreatic and biliary tumors.

BACKGROUND AND AIM: Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is influenced by several factors, primarily operator expertise. Formal training in EUS-FNA, as suggested by the European Society of Gastrointestinal Endoscopy and the American Society for Gastrointestinal Endoscopy guidelines, is not always available and is often expensive and time-consuming. In this study we evaluate factors influencing the diagnostic accuracy of pancreatic EUS-FNA. METHODS: In a retrospective study, 557 consecutive EUS-FNAs were evaluated. Several variables relating to the procedures were considered to calculate the EUS-FNA performance over eight years. RESULTS: A total of 308 out of 557 EUS-FNAs were selected. Overall sensitivity of EUS-FNA was 66% (95% CI: 60.8-71.8), specificity 100%, and diagnostic accuracy 69% (95% CI: 64.0-74.4). An increase in diagnostic accuracy was observed to >90% using a new fine-needle biopsy (FNB) needle and in the case of simultaneous sampling of primary and metastatic lesions. Diagnostic accuracy >80% was observed after 250 procedures, in the absence of rapid on-site cytopathological examination (ROSE). Multivariate logistic regression analysis confirmed that the FNB needle, operator skill, and double EUS-FNA sampling are associated with high diagnostic accuracy. CONCLUSIONS: The learning curve for EUS-FNA may be longer and a considerable number of procedures are needed to achieve high diagnostic accuracy in the absence of ROSE. However, the use of FNB needles and the simultaneous sampling of primary and metastatic lesions can rapidly improve the diagnostic accuracy of the procedure.

The impact of COVID-19 pandemic in the colorectal cancer prevention.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has led to a policy of severe restrictions in almost all countries strongly involved by the pandemic. National Health System is among activities suffering from the COVID-19 and the lockdown. AIM: To evaluate the impact of COVID-19 in colorectal cancer (CRC) prevention. METHODS: We report the change in the hospital organization to meet the growing healthcare needs determined by COVID-19. The limitations of CRC prevention secondary to COVID-19 and their effects on the healthcare are analyzed considering the features of the CRC screening programs in the average-risk population and endoscopic surveillance in patients with inflammatory bowel diseases (IBD). RESULTS: The interruption of CRC prevention may lead to a delayed diagnosis of CRC, possibly in a more advanced stage. The economic burden and the impact on workload for gastroenterologists, surgeons, and oncologists will be greater as long as the CRC prevention remains suspended. To respond to the increased demand for colonoscopy once COVID-19 will be under control, we should optimize the resources. It will be necessary to stratify the CRC risk and reach an order of priority. It should be implemented the number of health workers, equipment, and spaces dedicated to performing colonoscopy for screening purpose and in subjects with alarm symptoms in the shortest time. To this aim, the funds earmarked for healthcare should be increased. CONCLUSION: The economic impact will be dramatic, but COVID-19 is the demonstration that healthcare has to be the primary goal of humans.

Metagenomics Reveals Dysbiosis and a Potentially Pathogenic N. flavescens Strain in Duodenum of Adult Celiac Patients.

OBJECTIVES: Celiac disease (CD)-associated duodenal dysbiosis has not yet been clearly defined, and the mechanisms by which CD-associated dysbiosis could concur to CD development or exacerbation are unknown. In this study, we analyzed the duodenal microbiome of CD patients. METHODS: The microbiome was evaluated in duodenal biopsy samples of 20 adult patients with active CD, 6 CD patients on a gluten-free diet, and 15 controls by DNA sequencing of 16S ribosomal RNA libraries. Bacterial species were cultured, isolated and identified by mass spectrometry. Isolated bacterial species were used to infect CaCo-2 cells, and to stimulate normal duodenal explants and cultured human and murine dendritic cells (DCs). Inflammatory markers and cytokines were evaluated by immunofluorescence and ELISA, respectively. RESULTS: Proteobacteria was the most abundant and Firmicutes and Actinobacteria the least abundant phyla in the microbiome profiles of active CD patients. Members of the Neisseria genus (Betaproteobacteria class) were significantly more abundant in active CD patients than in the other two groups (P=0.03). Neisseria flavescens (CD-Nf) was the most abundant Neisseria species in active CD duodenum. Whole-genome sequencing of CD-Nf and control-Nf showed genetic diversity of the iron acquisition systems and of some hemoglobin-related genes. CD-Nf was able to escape the lysosomal compartment in CaCo-2 cells and to induce an inflammatory response in DCs and in ex-vivo mucosal explants. CONCLUSIONS: Marked dysbiosis and an abundance of a peculiar CD-Nf strain characterize the duodenal microbiome in active CD patients thus suggesting that the CD-associated microbiota could contribute to the many inflammatory signals in this disorder.

Frequency and Cause of Persistent Symptoms in Celiac Disease Patients on a Long-term Gluten-free Diet.

GOALS: To estimate the frequency and cause of nonresponsive celiac disease (CD). BACKGROUND: Treatment of CD is based on life-long adherence to a gluten-free diet (GFD). Some celiac patients experience persistence of symptoms despite a GFD. This condition is defined as nonresponsive CD. STUDY: Celiac patients on a GFD for at least 12 months underwent diet compliance assessment, laboratory tests, breath tests, endoscopic, and histologic evaluations according to the symptoms/signs reported. RESULTS: Seventy of 321 (21.8%) patients had persistent or recurrent symptoms/signs. The cause of symptom persistence was evaluated in 56 of 70 patients. Thirteen of 56 (23%) patients were antiendomysial antibody positive. Among the patients with negative serology, 1 had fibromyalgia, and 3 had evidence that disproved the diagnosis of CD. The remaining 39 patients with negative serology underwent duodenal biopsy sampling, which evidenced histologic alterations in 24 patients. Among the 15 patients with normal histology 3 were lactose intolerant, 9 had irritable bowel syndrome, 2 had gastroesophageal reflux disease, and in 1 patient a cause for the persistent symptom was not identified. In patients with confirmed diagnosis of CD, exposure to dietary gluten was the main cause of persistence of symptoms/signs, and consistently after dietary modification, symptoms resolved in 63% of the patients at later time points during follow-up. CONCLUSION: Nonresponsive CD occurs in nearly one fifth of celiac patients on GFD and its occurrence suggests further investigations to optimize the management of celiac patients.

Analysis of the cytokine profile in the duodenal mucosa of refractory coeliac disease patients.

RCD [refractory CD (coeliac disease)] is characterized by severe symptoms/signs of malabsorption and mucosal damage unresponsive to a GFD (gluten-free diet). The pathogenesis of RCD is not fully understood. In the present paper, we have characterized the mucosal profile of effector cytokines in RCD. Duodenal biopsies were taken from patients with RCD, patients with active CD and normal controls and were analysed for inflammatory cytokines by real-time PCR and ELISA. IFN (interferon)-γ and IL (interleukin)-21 transcripts were increased in active CD patients but not in RCD patients as compared with normal controls, whereas IL-17A RNA was up-regulated in both active CD and RCD. No significant increase in IL-15 transcripts was observed in both active CD and RCD, whereas IL-15 protein was increased in active CD. IL-6 and TNF (tumour necrosis factor)-α were up-regulated only in RCD. As a proof, we present the case of a woman affected by RCD who responded to anti-TNF-α treatment with improvement of malabsorptive symptoms/signs but no healing of mucosal lesions. The findings indicate that the profile of mucosal effector cytokines differs between RCD and active CD and suggest that TNF-α, IL-6 and IL-17A, but not Th1-type cytokines, could drive the detrimental response in this condition.

Indications, Techniques and Future Perspectives of Walled-off Necrosis Management.

Necrotizing pancreatitis is a complex clinical condition burdened with significant morbidity and mortality. In recent years, the huge progress of interventional endoscopic ultrasound (EUS) has allowed a shift in the management of pancreatic necrotic collections from surgical/percutaneous approaches to mini-invasive endoscopic internal drainage and debridement procedures. The development of lumen-apposing metal stents (LAMSs), devices specifically dedicated to transmural EUS interventions, further prompted the diffusion of such techniques. Several studies have reported excellent outcomes of endoscopic interventions, in terms of technical success, clinical efficacy and safety compared to surgical interventions, and thus endoscopic drainage of walled-off necrosis (WON) has become a fundamental tool for the management of such conditions. Despite these advancements, some critical unresolved issues remain. Endoscopic therapeutic approaches to WON are still heterogeneous among different centers and experts. A standardized protocol on indication, timing and technique of endoscopic necrosectomy is still lacking, and experts often adopt a strategy based on personal experience more than robust data from well-conducted studies. In this review, we will summarize the available evidence on endoscopic management of WON and will discuss some unanswered questions in this rapidly evolving field.

Helicobacter pylori infection associates with a mucosal downregulation of ghrelin, negative regulator of Th1-cell responses.

BACKGROUND: Helicobacter pylori (Hp)-related gastritis is characterized by a predominant T helper (Th)1/Th17 cell immunity. Ghrelin (GR) has immunoregulatory properties and inhibits experimental Th cell-dependent pathology. AIMS: To evaluate whether Hp infection associates with changes in GR expression and whether GR negatively regulates Th1/Th17 cytokines during Hp infection. METHODS: GR expression was evaluated by real-time PCR in gastric biopsies taken from Hp-infected and Hp-uninfected patients and in gastric biopsies of Hp-negative subjects cultured with or without H. pylori culture supernatant. To examine whether GR regulates Hp-induced cytokine production, H. pylori-infected gastric biopsies were stimulated with GR, and interleukin (IL)-12, interferon (IFN)-γ and IL-4 transcripts were evaluated by real-time PCR. IL-12 and IFN-γ were also analyzed in lamina propria mononuclear cells (LPMCs) extracted from Hp-infected gastric biopsies and cultured with GR. RESULTS: GR RNA transcripts were reduced in biopsies from Hp-infected patients. Treatment of Hp-negative gastric biopsies with Hp culture supernatant reduced GR RNA expression. GR dose-dependently inhibited RNA expression of IL-12 and IFN-γ but not IL-4 in ex vivo cultures of mucosal explants and in cultures of gastric LPMCs from Hp-positive patients. CONCLUSIONS: GR is downregulated in the gastric mucosa of H. pylori-infected patients. Such a defect could contribute to sustain the ongoing Th1-cell response.

Frequency and Predictors of Dysplasia in Pseudopolyp-like Colorectal Lesions in Patients with Long-Standing Inflammatory Bowel Disease.

Current endoscopic surveillance programs do not consider inflammatory bowel disease (IBD)-associated post-inflammatory polyps (pseudopolyps) per se clinically relevant, even though their presence seems to increase the risk of colorectal cancer (CRC). However, it remains unclear whether the link between pseudopolyps and CRC is indirect or whether some subsets of pseudopolyp-like lesions might eventually undergo neoplastic transformation. This study aimed to assess the frequency and predictors of dysplasia in pseudopolyp-like lesions in a population with long-standing colonic IBD. This was a retrospective, single-center study including patients with a colonic IBD (median disease duration of 192 months) and at least a pseudopolyp-like lesion biopsied or resected in the period from April 2021 to November 2022. One hundred and five pseudopolyps were identified in 105 patients (80 with ulcerative colitis and 25 with Crohn's disease). Twenty-three out of 105 pseudopolyp samples (22%) had dysplastic foci, and half of the dysplastic lesions were hyperplastic. Multivariate analysis showed that the age of the patients (odds ratio (OR) 1.1; p = 0.0012), size (OR 1.39; p = 0.0005), and right colonic location (OR 5.32; p = 0.04) were independent predictors of dysplasia, while previous exposure to immunosuppressors/biologics and left colonic location of the lesions were inversely correlated to dysplasia (OR 0.11; p = 0.005, and OR 0.09; p = 0.0008, respectively). No differences were seen between ulcerative colitis and Crohn's disease patients. Lesions with a size greater than 5 mm had a sensitivity of 87% and a specificity of 63% to be dysplastic. These data show that one-fourth of pseudopolyp-like lesions evident during surveillance colonoscopy in patients with longstanding IBD bear dysplastic foci and suggest treating such lesions properly.

Liver-Specific Contrast-Enhanced Magnetic Resonance Cholangio-Pancreatography (Ce-MRCP) in Non-Invasive Diagnosis of Iatrogenic Biliary Leakage.

Current non-invasive diagnostic modalities of iatrogenic bile leak (BL) are not particularly sensitive and often fail to localise the BL origin. Percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) are considered the gold standard, yet are invasive studies with potential complications. Ce-MRCP has been not comprehensively studied in this setting but may prove particularly helpful given its non-invasive nature and the anatomical dynamic detail. This paper reports a monocentric retrospective study of BL patients referred between January 2018 and November 2022 submitted to Ce-MRCP followed by PTC. The primary outcome was the accuracy of Ce-MRCP in detecting and localising BL compared to PTC and ERCP. Blood tests, coexisting cholangitis features and time for leak resolution were also investigated. Thirty-nine patients were included. Liver-specific contrast-enhanced MRCP detected BL in 69% of cases. The BL localisation was 100% accurate. Total bilirubin above 4 mg/dL was significantly associated with false negative results of Ce-MRCP. Ce-MRCP is highly accurate in detecting and localising BL, but sensitivity is significantly reduced by a high bilirubin level. Ce-MRCP may be very useful in early BL diagnosis and in accurate pre-treatment planning, but can only be reliably used in selected patients with TB < 4 mg/dL. Non-surgical techniques, both radiological and endoscopic, are proven to be effective in terms of leak resolution.

2-Methoxy-5-amino-N-hydroxybenzamide, a derivative of mesalamine, inhibits colon cancer cell growth through cyclo-oxygenase-2-dependent and -independent mechanisms.

COX-2 (cyclo-oxygenase-2) and PGE2 (prostaglandin E2) play a key role in sustaining CRC (colorectal cancer) cell growth and survival. Indeed, the use of agents targeting the COX-2/PGE2 axis has been associated with a reduction in the development of CRC in both humans and murine models of colon carcinogenesis. In the present study, we investigated whether 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a derivative of mesalamine that inhibits CRC cell growth both in vitro and in vivo, negatively regulates COX-2/PGE2 expression in CRC cells and assessed whether the 2-14-mediated anti-neoplastic effect is strictly dependent on the inhibition of this pathway. Our results show that 2-14 blocks the growth and enhances the death of HT-115, a CRC cell line overexpressing COX-2, and that these effects associate with inhibition of COX-2 but not COX-1. 2-14 also down-regulates TNFα (tumour necrosis factor α)-induced COX-2 in HT-29 cells as well as COX-2/PGE2 expression in ex vivo cultures of human CRC explants. Similarly, 2-14 reduces COX-2, but not COX-1, in tumoural areas developing in a mouse model of CAC (colitis-associated colon cancer). Finally, we show that 2-14 exhibits in vitro and in vivo anti-mitogenic effects in DLD-1, a COX-deficient CRC cell line. Taken together, these results suggest that 2-14 inhibits CRC cell growth through COX-2-dependent and -independent mechanisms.