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Competing Interests: CONFLICTS OF INTEREST None to report.

Background: Epstein-Barr virus-positive mucocutaneous ulcer is one of the mature B-cell lymphoproliferative diseases occurring in patients with immune dysfunction including those with immunosuppressive treatment such as methotrexate., Case Presentation: A Japanese elderly man in his 80s with rheumatoid arthritis on methotrexate was admitted to our hospital complaining persistent pharyngeal pain. Laboratory tests revealed severe pancytopenia, elevated C-reactive protein, and increased creatinine levels. An otolaryngological examination showed ulceration of the right tonsil, from which diagnostic biopsy was performed. The diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer was made and bone marrow aspiration revealed hypocellularity and megaloblastic changes. Pancytopenia was improved after discontinuing methotrexate, and repeated bone marrow aspiration test revealed recovery of normal cellularity and disappearance of dysplasia, confirming the diagnosis of methotrexate intoxication. Tonsil ulcer was improved only with discontinuation of methotrexate, which strongly supported the diagnosis of EBV-MCU., Conclusion: Our case suggested that even this best prognosis form of lymphoproliferative disease could lead to fatal complications if not appropriately managed., (© 2024. The Author(s).)

Objectives: Ixekizumab, an interleukin (IL)-17A inhibitor, exerts its therapeutic effects in psoriasis by inhibiting the interleukin (IL)-17 signaling pathway. Common adverse reactions to ixekizumab include injection site reactions and upper respiratory tract infections (URIs), while occurrences of inflammatory bowel disease (IBD) and multiple mucosal ulcers are infrequent. We present a case of a 51-year-old man who developed multiple mucosal ulcers after ixekizumab treatment., Methods: A 51-year-old man presented to our hospital with a 1-month history of pharyngalgia. The flexible laryngoscope displayed mild hyperemia in the pharyngeal mucosa and tonsils, redness and swelling of the epiglottis, as well as multiple ulcers in the oral cavity, uvula, and epiglottis. These ulcers did not improve with conventional treatment., Results: Upon evaluation, the ulcers were an immune-related adverse event induced by ixekizumab. Consequently, a decision was made to discontinue the drug and initiate a therapeutic regimen including corticosteroids and thalidomide. Eventually, the patient's symptoms abated., Conclusions: Biologics are now becoming increasingly popular in psoriasis. It is vital for clinicians to be aware of this potential adverse event and to identify and intervene early to alleviate patients' suffering., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, antipyretic, and analgesic properties and are among the most commonly used drugs. Although the cause of NSAID-induced gastric ulcers is well understood, the mechanism behind small intestinal ulcers remains elusive. In this study, we examined the mechanism through which indomethacin (IM), a prominent NSAID, induces small intestinal ulcers, both in vitro and in vivo. In IEC6 cells, a small intestinal epithelial cell line, IM treatment elevated levels of LC3-II and p62. These expression levels remained unaltered after treatment with chloroquine or bafilomycin, which are vacuolar ATPase (V-ATPase) inhibitors. IM treatment reduced the activity of cathepsin B, a lysosomal protein hydrolytic enzyme, and increased the lysosomal pH. There was a notable increase in subcellular colocalization of LC3 with Lamp2, a lysosome marker, post IM treatment. The increased lysosomal pH and decreased cathepsin B activity were reversed by pretreatment with rapamycin (Rapa) or glucose starvation, both of which stabilize V-ATPase assembly. To validate the in vitro findings in vivo, we established an IM-induced small intestine ulcer mouse model. In this model, we observed multiple ulcerations and heightened inflammation following IM administration. However, pretreatment with Rapa or fasting, which stabilize V-ATPase assembly, mitigated the IM-induced small intestinal ulcers in mice. Coimmunoprecipitation studies demonstrated that IM binds to V-ATPase in vitro and in vivo. These findings suggest that IM induces small intestinal injury through lysosomal dysfunction, likely due to the disassembly of lysosomal V-ATPase caused by direct binding. Moreover, Rapa or starvation can prevent this injury by stabilizing the assembly. SIGNIFICANCE STATEMENT: This study elucidates the largely unknown mechanisms behind small intestinal ulceration induced by indomethacin and reveals the involvement of lysosomal dysfunction via vacuolar ATPase disassembly. The significance lies in identifying potential preventative interventions, such as rapamycin treatment or glucose starvation, offering pivotal insights that extend beyond nonsteroidal anti-inflammatory drugs-induced ulcers to broader gastrointestinal pathologies and treatments, thereby providing a foundation for novel therapeutic strategies aimed at a wide array of gastrointestinal disorders., (Copyright © 2024 by The Author(s).)

31-year-old woman. Diagnosis of ulcerative proctitis in February/2022. Calprotectin 1832 μg/g. Colonoscopy: erythematous, friable and erosive mucosa up to 10 cm from the anal margin. Pathology: compatible with ulcerative colitis with moderate activity. Start of oral mesalazine (3 gr/24 h granules) and topical (1 gr/24 h suppository). After three months, she achieved clinical remission. Calprotectin 57 μg/g. Two months later, she consulted for solid dysphagia, loss of 10 kg, and low-grade fever for a month. Fifteen days before, she went to an emergency room where Prednisone 50 mg/24 h was started. On the day of the assessment, she was receiving 30 mg with no improvement. The next day, gastroscopy showed 6-12 mm esophageal ulcers with non-confluent shallow geographic borders, biopsies were taken. Viral serologies and HLA B51 were requested. Given the severity of the symptoms, empirical treatment was started with Valaciclovir 1 g/12 h. Serologies: IgG for Ebstein Barr virus, cytomegalovirus and herpes virus with negative IgM. Cytomegalovirus viral load: <30 IU/ml. Pathology: acute extensively ulcerated esophagitis, inflammatory infiltrate and some eosinophils with negative histochemical staining for fungi, cytomegalovirus and herpes virus I and II. HLA B51 was negative. Valaciclovir and mesalazine are discontinued after seven days given the known relationship of the latter with low-grade fever and, exceptionally, with esophageal pathology. Three days later, the patient reported clear improvement in dysphagia from the day the mesalazine was discontinued. After eight months, she was still asymptomatic. Upon resolution of the symptoms, control gastroscopy was not performed, and mesalazine has not been reintroduced due to its probable causal association. Mesalazine has an excellent safety profile. Adverse effects include fever, headache, diarrhea and.

The onset of gastroduodenal ulcers is a frequent complication after transplantation, whereas cases of intestinal ulcers are sporadic and poorly described in the literature. A patient on immunosuppressive therapy with tacrolimus and mycophenolate mofetil after kidney transplant for immunoglobulin A-related glomerulonephritis developed symptoms compatible with Crohn disease 7 months after the transplant. The patient was hospitalized for abdominal pain, diarrhea, fever, and weight loss. Imaging and a colonoscopy showed signs of idiopathic inflammatory bowel disease (IBD) affecting the terminal ileum. Behcet's disease, post-transplant lymphoma, cytomegalovirus, Epstein-Barr virus, or mycobacteria infection were excluded. Mycophenolate mofetil was suspended, and steroid therapy was increased without clinical improvement. Eleven units of blood were required for severe anemia. A further colonoscopy revealed ulcerations involving the cecal fundus, ileocecal valve, and distal ileum with bowel stenosis and suspected ischemia. The patient, therefore, underwent an emergency laparoscopic ileocolic resection. The histologic examination did not reveal clear signs of IBD, ischemia, or viral infection of the ileum. The findings seemed indicative of iatrogenic damage from immunosuppressive therapy. The postoperative course was regular, and after 12 months, the patient was asymptomatic, on low-dose tacrolimus and prednisone therapy. During immunosuppressive therapy, the onset of isolated ileal ulcers, which can mimic IBD, may be a sporadic complication., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the efficacy and tolerance after the electrochemotherapy treatment for local therapy of cutaneous and subcutaneous metastases of head-and-neck tumors and malignant melanoma refractory to standard therapies, mainly in neck metastasis of squamous cell carcinoma. And, to evaluate the relation of this response according to the skin reaction (healing with ulcer or dry crust)., Methods: prospective pase II, observational clinical study of 56 patients with metastases of head-and-neck squamous cell carcinoma (n=13), papillary thyroid carcinoma (n=4), adenoid cystic carcinoma of parotid gland (n=1) or malignant melanoma (n=37, 5 in head). Patients were treated by electrochemotherapy (application of electrical pulses into the tumor) after the administration of a single intravenous dose of bleomycin. Kaplan-Meier curves were performed. The statistical significance was evaluated using log-rank test; p-value of less than 0.05 was considered as significant., Results: Overall clinical response was observed in 47 patients (84%). Local side effects were mild in all the patients. Ten patients (76.9%) with neck metastasis of squamous cell carcinoma had some degree of response, but only in one was complete. Patients even with only partial response had a higher overall survival than patients without response (p= 0.02). Most of the patients with squamous cell carcinoma had diminution of pain and anxiety. Response rate and overall survival was higher in MM patients (86.5%) than in squamous cell cancer patients (76.9%) (p= 0.043). The healing process (dry crust/ulcer) was not associated with the overall survival (p= 0.86)., Conclusions: Electrochemotherapy is associated a higher overall survival and diminution of pain and anxiety. Therefore, it is an option as palliative treatment for patients with neck metastasis of squamous cell carcinoma refractory to other therapies or even as a concomitant treatment with newer immunotherapies. The type of healing of the surgical wound could not be associated with a higher rate of response or survival., Level of Evidence: III., (Copyright © 2023 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier España S.L.U. All rights reserved.)

Purpose: The purpose of the study was to evaluate the efficacy and safety of systemic mycophenolate mofetil (MMF) treatment in ocular surface inflammatory diseases., Methods: For this retrospective study, patients who were treated with systemic MMF for ocular surface inflammatory diseases between March 2020 and March 2022 were evaluated. Apart from demographic data, examination notes including MMF treatment indication and systemic side effect interrogation and routine laboratory examinations during drug treatment were extracted from the patient records. Detailed staging scores were performed according to the diagnosis including Foster and Mondino for ocular mucous membrane pemphigoid (MMP) and limbal stem cell deficiency scoring for limbal transplantation. For thorough evaluation, anterior segment pictures were used., Results: Fourteen patients were enrolled to the study, with a mean age of 58 ± 12. MMP (6, 42.8%) and limbal allograft transplantation (6, 42.8%) constituted the main indications for the MMF treatment, followed by keratitis-ichthyosis-deafness (KID) syndrome (1, 7.2%) and Mooren's ulcer (1, 7.2%). Five of six patients with MMP regressed according to both staging systems. Only one remained stable which was evaluated as Stage 3. Furthermore, while all limbal transplant groups (6) stabilized and showed regression according to the individualized limbal stem cell deficiency staging system with no rejection during follow-up. Furthermore, patients with Mooren's ulcer and KID syndrome showed control of the inflammation and stabilization after MMF treatment. No significant systemic side effects apart from constipation and nausea (3) were observed in patients whose routine laboratory tests were stable throughout the follow-up., Conclusion: MMF has the potential to be a valuable and safe systemic agent of first choice in the control of ocular surface inflammatory disorders, especially when topical treatment is not effective. With such studies, it is predicted that MMF may reach wider usage areas with the increase in its effectiveness and safety in its use for ocular surface inflammatory pathologies., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Middle East African Journal of Ophthalmology.)

Introduction: Upper gastrointestinal bleeding (UGIB) is an important complication among critically ill adults, especially those having cardiac surgery as management is complicated by the requirement for antiplatelet/anticoagulant therapy. As a result, stress ulcer prophylaxis (SUP) has become routine practice in many centers, utilizing either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). Recent evidence from the PEPTIC trial indicated an increase in mortality risk among cardiac surgery patients receiving PPIs compared to H2RBs. Considering these findings, alongside practical difficulties surrounding the transition to H2RBs as a prophylactic agent in New Zealand, Wellington Hospital intensive care unit elected to discontinue routine PPI use for SUP in cardiac surgery patients. A retrospective study was conducted to assess patient outcomes following the discontinuation of routine SUP., Method: A retrospective cohort study was conducted of all adult patients who underwent cardiac surgery at Wellington Hospital between February/2018 and January/2022, and divided patients into cohorts before and after the discontinuation of routine use of SUP on the 31st of January 2020. The primary outcomes were the rate of UGIB, oesophagogastroduodenoscopy (OGD) and 180-day postoperative mortality. Secondary outcomes included rates of postoperative Clostridium difficile enteritis, pneumonia, deep sternal wound infection, and length of stay of the index admission., Results: The rate of UGIB statistically significantly increased since the cessation of routine SUP in January 2020 (2.4% vs 5.4%, P -value = .004). This finding was mirrored with the increased rates of OGD (1.9% vs 4.0%, P -value = .005). There were no significant changes in 180-day mortality, hospital length of stay, or any of the postoperative infective complications analyzed, pneumonia, deep sternal wound infection, or C difficile enteritis., Conclusion: This study suggests an association between routine use of SUP and reduced rates of clinically significant UGIB and OGD requirements in cardiac surgery patients without increasing risk of infective complications or postoperative mortality.

Rationale: Tocilizumab, a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody, is used for the treatment of adult-onset Still disease (AOSD). Despite its efficacy in many clinical situations, concerns have been raised regarding intestinal mucosal injury in patients receiving tocilizumab., Patient Concerns: A 64-year-old woman with a history of AOSD was admitted to our hospital with hematochezia. She had AOSD for 15 years and underwent treatment with biweekly tocilizumab 9 months prior to admission. Colonoscopy revealed a large punched-out ulcer in the terminal ileum. On pathological evaluation, nonspecific enteritis with lymphocytes and eosinophils were seen. Based on the location and shape of the lesion, we suspected intestinal Behçet's disease. However, the ulcer reduced in size over time by discontinuation of tocilizumab without additional drug treatment, indicating that it was a drug-induced ulcer., Diagnosis: The patient was diagnosed with tocilizumab-induced small intestinal ulcer., Interventions: The patient treated with the discontinuation of tocilizumab., Outcomes: The discontinuation of tocilizumab resulted in ulcer scarring. There was no recurrence of hematochezia., Lessons: Tocilizumab can cause deep ulcerative lesions in the terminal ileum, which may resemble intestinal Behçet's disease. It is important to continuously monitor abdominal symptoms during tocilizumab therapy and aggressively perform colonoscopy when hematochezia or abdominal pain is observed., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Crohn's disease and coeliac disease are well-known to induce ulcerations in the small-bowel. However, there is a group of very rare chronic ulcerative conditions of the small intestine that has emerged from the intestinal black box nearly 70 years ago, and that has gained interest with the advent of small-bowel capsule endoscopy and device-assisted enteroscopy. These distinct ulcerative enteropathies have come to our attention, and continue to reveal their aetiology and treatment options. Two distinct entities, called cryptogenic multifocal ulcerative stenosing enteritis/enteropathy (CMUSE) and chronic nonspecific multiple ulcers of the small intestine (CNSU) are gaining more clinical attention. CMUSE was first reported in Europe, whereas CNSU was exclusively diagnosed in Japanese patients. With the identification of susceptibility genes impacting prostaglandin metabolism, CMUSE and CNSU have become two distinct pathologies within the group of prostaglandin-associated enteropathies, to be differentiated from medication-induced enteropathies, especially non-steroidal anti-inflammatory drugs (NSAID)-induced enteropathy with similar intestinal ulcerations due to interference with prostaglandin metabolism. The current review provides an historical overview of CMUSE and CNSU publications, in addition to the currently available diagnostic and treatment options, and how to differentiate these rare enteropathies from NSAID-induced enteropathy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest for the current manuscript., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: MTX-LPD is a complication that occurs during MTX treatment. Skin lesions in MTX-LPD are often subcutaneous nodules with occasional necrosis and ulceration. Although MTX-LPD regression is frequently observed upon discontinuation of oral MTX treatment, delayed diagnosis of MTX-LPD with associated ulceration may lead to ulcer enlargement and the need for surgical procedures such as skin grafts., Case Report: A 74-year-old female was diagnosed with RA and administered MTX for 3 years and 8 months. The patient presented with a 2-month-old ulcer on the dorsum of the hand. The ulcer size was 6.5 cm × 5 cm, and it was surrounded by an embankment tumor measuring 7 cm × 6 cm. Although a definitive diagnosis could not be made based on the biopsy specimen, excision of the ulcer-containing mass confirmed MTX-LPD diagnosis. MTX was discontinued, and free-flap reconstruction was performed 3 weeks after the first surgery. The postoperative period was uneventful, and MTX-LPD recurrence was not observed 10 months after the second surgery., Conclusion: Although MTX-LPD with ulceration is rare, it should be considered in cases of refractory ulcers in patients with RA. The discontinuation of MTX based on early MTX-LPD diagnosis is critical to avoid surgical procedures such as skin grafts and flap reconstruction.

Gastric ulcer is the most common gastrointestinal disorder affecting people globally. Although many drugs are available to treat ulcers, the mortality rate is relatively high, and drugs lack selectivity to treat ulcers without causing side effects. In this study, the potential therapeutic effects of phylloquinone were tested against indomethacin-induced gastric ulcer in rats by giving rats a single oral dose of indomethacin (48 mg/kg), followed by phylloquinone (10 mg/kg) orally, once daily for six consecutive days. Phylloquinone significantly attenuated indomethacin-induced oxidative and inflammatory responses through hindering the inflammatory cascade by decreasing the levels of TNF-α, NF-κB, INOS and COX-2 which counteracts indomethacin effects. Also, it increased NAD + which enhanced SIRT-1 level. Furthermore, phylloquinone was effective in increasing mucus secretion, decreasing acid secretion, reversing histological effects caused by indomethacin and minimizing ulcer and lesion indices All these findings indicate that phylloquinone may be used in protection and treatment of indomethacin-induced gastric ulcer., (© 2023 John Wiley & Sons Australia, Ltd.)

Objective: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain and rheumatic conditions. To facilitate patient management, we determined the predictive value of gastrointestinal (GI) symptoms and risk factors for the development of NSAID-associated GI injuries., Methods: Post-hoc analysis of pooled data from naproxen treatment arms of two identical, randomized, double-blind, controlled phase 3 trials in arthritis patients at risk of GI adverse events. Endoscopic incidence of GI ulcers at baseline, and 1, 3, and 6 months was employed as a surrogate parameter for GI injury. For GI symptom analysis, Severity of Dyspepsia Assessment questionnaire was used. For GI risk factor analysis, the high risk factors: previous GI injury, concomitant selective serotonin reuptake inhibitors or corticosteroids, ulcer history, concomitant low-dose aspirin, and age >65 years were employed., Results: Data of 426 naproxen patients were analyzed. Distribution of GI symptoms between patients with and without ulcer was similar; about one third of patients developing an ulcer reported no GI pain symptoms. GI symptoms experienced under naproxen treatment were thus not indicative of GI injury. The proportion of patients developing an ulcer increased with the number of risk factors present, however, about a quarter of patients without any of the analyzed risk factors still developed an ulcer., Conclusion: GI symptoms and the number of risk factors are not reliable predictors of NSAID-induced GI injury to decide which patients need gastroprotection and will lead to a large group of patients with GI injuries. A preventive rather than reactive approach should be taken., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MvdL has served on advisory boards for Grünenthal GmbH. RS has served as speaker and/or on advisory boards of Grünenthal GmbH, Janssen Medtronic, Norgine, Novartis, Pfizer and Takeda. MP and JJ are employees of Grünenthal GmbH., (Copyright: © 2023 van de Laar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A man in his eighties presented with a history of bilateral leg congestive phlebitis, and multiple hepatocellular carcinoma (HCC) treated with sorafenib. When the dose was increased to 400 mg, ulcers appeared under both knees, which worsened, and the drug was discontinued 2 months after administration. However, the ulcers to 30 mm in diameter, requiring debridement and antibiotics. The HCC showed a complete response (CR) based on modified-RECIST criteria; however, after several rounds of locoregional therapy for recurrence, multiple HCCs and metastatic lesions in the Morrison's fossa were detected. Therefore, atezolizumab 1200 mg-bevacizumab 900 mg was started. After the first course, the patient complained of pain below both knees, and when the second course was administered, leg ulcers re-appeared and rapidly worsened. The ulcers were circular and multiple and progressed to deep digging, leading to tendon exposure. Bevacizumab-induced congestive venous ulcer was diagnosed, requiring skin grafts to heal. HCC then showed a CR based on m-RECIST criteria. Initially, the cause of the ulcer was thought to be immune-related adverse effects due to atezolizumab, but experience with sorafenib led us to conclude that the cause was stagnant venous ulcers due to vascular endothelial growth factor receptor inhibitor, which inhibited angiogenesis., (© 2023. Japanese Society of Gastroenterology.)

Background: Overuse of stress ulcer prophylaxis is prevalent globally despite guidelines leading to the added cost, especially the intravenous proton pump inhibitor (IVPPI). This study aims to analyze the prevalence of such overuse and be aware of rational use which may help develop local guidelines., Methods: This study analyzed the prospectively collected data on IVPPI use in adult patients in general wards of medicine and surgery at Patan Hospital, Patan Academy of Health Sciences, Nepal, from April-Jun 2022. Ethical approval was obtained. Variables analyzed were the patient's age, gender, history of peptic ulcer disease, risk for stress ulcer and gastrointestinal bleeding, the status of nil per os (NPO ≥12 hours), appropriate use of IVPPI, and cost., Results: Prevalence of IVPPI use was 36.24% (274/756 admissions), surgery 39.45(189/479), medicine ward 30.68% (85/277). The mean age was 43.1 ±18.6 years, males 113(41.2%), surgery 189 (69%). Inappropriate overuse in 253(92.3%, significantly more in surgery-182 than medicine-7, p=0.001. Appropriate use was in 21 (7.7%, i.e., NPO-15, NPO + gastrointestinal bleed, and NPO + non steroid anti-inflammatory drugs each 3)., Conclusions: Prevalence of IVPPI use was 36.24%. Inappropriate overuse of IVPPI was high (92.2%, 253/274), more in surgery. The nil per os status was the main reason for appropriate use of IVPPI.

Background: The Surviving Sepsis Campaign Guidelines recommend stress ulcer prophylaxis (SUP) for patients with sepsis who have gastrointestinal (GI) bleeding risks; however, the effect of SUP has not been specially studied in these patients., Aims: To determine the effects of SUP versus no prophylaxis on patient-important outcomes in critically ill adult patients with sepsis who have risk factors for GI bleeding., Methods: This retrospective cohort study utilised data from the Medical Information Mart for Intensive Care III database. We compared those who received SUP with proton-pump inhibitors or histamine-2 receptor antagonists for ≥3 days with those who received no prophylaxis. Propensity score matching (PSM) was conducted to make comparisons between groups with similar distributions of study variables. The primary outcome was inhospital mortality., Results: A total of 7744 patients were included in the analysis, with 1088 (14.0%) in the non-SUP group and 6656 (86.0%) in the SUP group. A 1:1 PSM created 866 patients in each cohort. No significant differences were noted between the two groups with regard to inhospital mortality (22.3% vs 20.4%; P = 0.379), GI bleeding (4.7% vs 6.4%; P = 0.172), pneumonia (38.9% vs 36.6%; P = 0.346), Clostridium difficile infection (CDI) (6.4% vs 8.9%; P = 0.0.057) or intensive care unit (ICU) length of stay (LOS) (4.2 days vs 4.6 days; P = 0.394)., Conclusions: Among critically ill, septic, adult patients at risk for GI bleeding, SUP showed no effect on hospital mortality, the rate of GI bleeding, pneumonia, CDI and ICU LOS., (© 2021 Royal Australasian College of Physicians.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause intestinal damage and ulcers and the incidence is increasing. Limonin plays an important role in the regulation of inflammatory diseases, but it has not been reported in the treatment of intestinal injury and ulcers., Methods: Indomethacin (INDO) induced intestinal injury and ulcer model in rats. The indexes related to intestinal injury were detected. Western blot and molecular docking techniques were used to detect the docking between Limonin and Nrf2. Next, ML385, an inhibitor of Nrf2/ARE signaling pathway, was applied to treat intestinal epithelial IEC-6 cells induced by INDO. And CCK8, Western blot, TUNEL, ELISA, DCFH-DA assay, kits, and immunofluorescence were conducted to detect cell activity, apoptosis, inflammatory response, oxidative stress, and tight junction again., Results: INDO can significantly induce intestinal ulcerative lesions in rats. Limonin could improve intestinal ulcerative lesions induced by INDO in rats. Limonin could reduce INDO-induced inflammatory response and oxidative stress in the small intestine of rats, and improve the intestinal barrier dysfunction induced by INDO. Limonin could dock with Nrf2 structure and activate Nrf2/ARE signaling pathway. ML385 could reverse the protective effect of Limonin against INDO-induced cell damage., Conclusion: Limonin ameliorates INDO-induced intestinal damage and ulcers through Nrf2/ARE pathway., (© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Introduction: Endoscopic submucosal dissection for duodenal neoplasms (D-ESD) is considered a technically demanding procedure regarding the high risk of delayed adverse events. Data regarding optimal managements of ulcers after D-ESD are lacking., Methods: A retrospective analysis was performed on consecutive 145 cases of D-ESD for superficial nonampullary duodenal epithelial tumors at a single referral center. Factors related to delayed adverse events and the healing process of ulcers after D-ESD were analyzed., Results: Complete ulcer suture after D-ESD was performed in 128 cases (88%). Two delayed perforation occurred among cases with incomplete suture. Delayed bleeding occurred in 8 cases (6%) within 3 weeks. The ulcer closure rate at second-look endoscopy (SLE) was significantly low among cases with delayed bleeding (12.5% vs. 75%, p = 0.001). The bleeding rate before SLE was significantly high among patients who did not have complete ulcer closure after D-ESD (0.8% vs. 12%, p = 0.036). The ratio of lesions located in the second oral-Vater was significantly low among ulcers re-opened at SLE (38% vs. 14%, p = 0.044). Proton-pump inhibitors (PPIs) were administered for a median of 7 weeks (range 1-8 weeks). At 3 weeks, active ulcer stages were observed in a few cases, and healing or scarring was observed in most cases., Conclusions: Complete ulcer suture was related to decreased risk of delayed adverse events after D-ESD. From the bleeding period and healing process of D-ESD ulcers, the minimum required length of PPI may be 3 weeks after D-ESD., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Monomorphic epitheliotropic intestinal T-cell lymphoma(MEITL)is classified under type Ⅱ enteropathy-associated T-cell lymphoma(EATL). It is a rare disease with a low incidence rate. This study reports a case of a patient with MEITL who developed small intestinal perforation during chemotherapy. The patient was a 55-year-old woman who presented to a previous clinic with epigastric pain. Enteroscopy results showed a map-like ulcer in the jejunum. Examination of the tissue specimen collected from this site suggested T-cell lymphoma. The patient was referred to our hospital for chemotherapy. Seven days following the initiation of chemotherapy, an abdominal computed tomography(CT)revealed free air, leading to a diagnosis of gastrointestinal perforation. Emergency surgery was performed. Intraoperatively, bowel perforation and a degenerative ulcer were observed at 95 cm and 80 to 115 cm from the Treitz' ligament, respectively. In addition, all-layer intestinal necrosis was noted 150 and 90 cm from the terminal ileum. Total resection and anastomosis were performed. Postoperatively, the patient developed sepsis due to chemotherapy-related pancytopenia but recovered. She was discharged on postoperative day 24. Subsequently, positron emission tomography(PET)-CT revealed residual intestinal tumor cells and peritoneal dissemination. Chemotherapy was initiated, but there was no response. The patient died after 6.5 months. A radical treatment for MEITL has not yet been established. More case reports are needed to improve the prognosis of this disease.

Background: Distal ulcerative colitis (UC) is responsible for distressing symptoms and reduces quality of life (QoL). Oral and topical formulations of 5-amino-salicylic acid are the first line therapy for mild to moderate distal UC., Objective: Our aim was to evaluate the impact of mesalazine treatment for mild to moderate ulcerative proctitis and proctosigmoiditis on patient QoL., Methods: Ninety-three patients with mild to moderate ulcerative proctitis and proctosigmoiditis, initiating a treatment with Pentasa, were prospectively included. The primary endpoint was the change from baseline to W8 in patient health-related QoL (HRQoL) as measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) total score., Results: More than 80% of patients were prescribed with a rectal formulation, either alone (47.9%) or with an oral formulation (35.1%), and 17.0% of patients were prescribed oral formulation alone. Mean SIBDQ score was improved at W8 in patients affected with mild and moderate disease ( P  &lt; 0.001 versus baseline in both groups, as well as in patients who achieved clinical remission ( P  &lt; 0.001). Patients who achieved clinical remission at W8 reached a mean change of +6.7 (±7.1), whereas those who did not achieve clinical remission had a mean change of +1.1 (±8.9). Seventy-five per cent of patients had an improvement of their disability index at W8. Fecal incontinence was also improved at W8., Conclusion: HRQoL measuring with the SIBDQ is proportionally related to disease activity in patients with distal UC treated with mesalazine., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Proton pump inhibitor (PPI) indications are limited to gastrointestinal disorders and ulcer prophylaxis. However, PPIs are among the most frequently prescribed drugs., Aim: To evaluate the appropriateness of PPI prescriptions and identify predictive factors for inappropriate PPI use., Design and Setting: Observational study using a Dutch primary care database with all new PPI prescriptions between 2016 and 2018., Method: Individual patient data and details on PPI use were collected. The appropriateness of initiation and continuation of PPI prescriptions was evaluated using the applicable guidelines., Results: In total, 148 926 patients (aged ≥18 years) from 27 general practices were evaluated. A total of 23 601 (16%) patients started PPI therapy (mean age 57 [SD 17] years, 59% female). Valid PPI indications at initiation were seen in 10 466 PPI users (44%). Predictors for inappropriately initiated PPI use were older age (odds ratio [OR] 1.03, 95% confidence interval [CI] = 1.03 to 1.03), and use of non-selective non-steroidal anti-inflammatory drugs (OR 5.15, 95% CI = 4.70 to 5.65), adenosine diphosphate receptor inhibitors (OR 5.07, 95% CI = 3.46 to 7.41), COX-2 inhibitors (also known as coxibs) (OR 3.93, 95% CI = 2.92 to 5.28), and low-dose aspirin (OR 3.83, 95% CI = 3.07 to 4.77). Despite an initial valid indication, PPI use was inaccurately continued in 32% of patients on short-course therapy for dyspepsia and in 11% of patients on ulcer prophylaxis., Conclusion: More than half of PPI users in primary care were found to have an inappropriate indication, with unnecessary ulcer prophylaxis related to drug use being one of the leading causes. Future initiatives to reduce PPI use for unnecessary ulcer prophylaxis and timely deprescription if PPI is no longer indicated, are needed., (© The Authors.)

Background/aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly-used medications, and ailments such as arthritis or heart disease, require long-term use of these drugs, which can induce gastroenteropathy with bleeding and ulcers. This study investigated the associations between efficacy, safety, and gastrointestinal symptoms linked to rebamipide and proton pump inhibitor administration in patients requiring long-term NSAID use., Methods: This study was a multi-center, randomized, open-labeled, pilot design., Results: Thirty-three patients were included. Of these, 15 were included in the study group and 18 were in the control group. NSAID-induced gastric ulcers, which were the primary outcome of this study, did not occur in either the study or control group. Changes in the number of small bowel erosions and ulcers were -0.6 ± 3.06 in the study group and 1.33 ± 4.71 in the control group. The number of subjects with mucosal breaks (defined as multiple erosions and/or ulcers) was three (20%) in the study group and six (40%) in the control group (p = 0.427). No serious adverse events occurred in either group. However, dyspepsia and skin rashes occurred in six patients (31.58%) in the study group and 13 (65%) in the control group (p = 0.036)., Conclusion: Although statistically significant differences were not generated, possibly as a result of the small sample size, mucosal breaks observed via capsule endoscopy revealed that rebamipide was likely to be more effective than lansoprazole in preventing small intestine damage caused by NSAIDs. Furthermore, fewer side-effects emerged with rebamipide.

Background: We previously reported that clumps of a few epithelial cells were scattered in ulcer regions in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC)., Aims: To determine the ectopically localized epithelial clumps might be derived from stem cells or their daughter progenitor cells., Methods: Female BALB/c mice were administered DSS in drinking water for 6 days, followed by withdrawal of DSS for 6 days. Histological and immunohistochemical examinations were conducted in the distal region and proximal region of the colorectum to determine expression of stem cell markers in the epithelial clumps., Results: Similar to the characteristics of UC, the ulcers were more severe in the distal region close to the anus than in the proximal region of the colorectum. Quantitative analyses revealed that the epithelial clumps appeared in relation to the severity of the ulcer, and they expressed the cell adhesion molecules E-cadherin and β-catenin. Among stem cell markers, the epithelial clumps primarily expressed +5 cell marker Dll1 as reserved intestinal stem cells, followed by +4 cell marker Bmi1 and crypt stem cell marker Lgr5 in that order. Nuclear expression of Sox9, but not nuclear β-catenin, was identified in the clumps., Conclusion: The present results suggest that most epithelial clumps comprised crypt-derived, reserved stem cells, which might have potential for mucosal healing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: We compared the efficacy of adalimumab, infliximab, ustekinumab, and vedolizumab on the ability to achieve endoscopic healing (EH) after 1 year of therapy in moderate-severe Crohn's disease (CD)., Methods: This was a pooled analysis of patient-level data from 299 patients with CD from 4 clinical trials. Proportions of patients treated with each biologic were compared for achieving 1-year complete EH (Simple Endoscopic Score for CD [SES-CD] <3) and ileal and colonic EH separately (SES-CD = 0). Multivariate logistic regression was used to model the relationship between biologics and 1-year outcomes and adjusted for disease duration, concomitant corticosteroid use, and prior antitumor necrosis factor failure., Results: Compared with vedolizumab (4/56 [7.1%]), adalimumab (17/61 [27.9%], adjusted odds ratio [OR]: 5.79, 95% confidence interval [CI]: 1.77-18.95, P = 0.004) and infliximab (39/141 [27.7%], aOR: 4.59, 95% CI: 1.48-14.22, P = 0.008) had superior rates of 1-year EH. No significant difference was observed between vedolizumab and ustekinumab. Similar results were observed among biologic-naive patients. Among patients with baseline ileal SES-CD ≥3, no significant differences were observed between biologics for 1-year ileal EH. However, for large (>0.5 cm) ileal ulcers, infliximab (20/49 [40.8%]) had superior rates of no ileal ulcers compared with vedolizumab (2/23 [8.7%], aOR: 5.39, 95% CI: 1.03-28.05, P = 0.045). No other differences were observed. For colonic disease, compared with ustekinumab (9/31 [29.0%]), adalimumab (30/48 [62.5%], aOR: 3.97, 95% CI: 1.45-10.90, P = 0.007) had superior rates of 1-year EH in the colon, with similar trends observed for infliximab (55/105 [52.4%], aOR: 2.08, 95% CI: 0.82-5.27, P = 0.121). No other differences were observed., Discussion: In this post hoc analysis, TNF-α antagonists were overall superior to vedolizumab and ustekinumab for achieving 1-year EH in moderate-severe CD patients., (Copyright © 2022 by The American College of Gastroenterology.)

Chemotherapy extravasation can cause severe harm. There is a lack of evidence-based standardization on the surgical management of such injuries beyond the immediate stage. In an algorithm connecting presentation time post-injury with surgical treatment could help standardize future treatment. This study prospectively validated a preset standardized surgical algorithm based on presentation time in a consecutive series between October 2017 and October 2020. Chemotherapeutic agent, site and extent of injury, type of surgery and outcome at a minimum of 6 months' follow-up were collected. Seven thousand six hundred twelve individuals received chemotherapy during that period; 15 patients suffered extravasation injuries, 2 of whom were referred from outside our hospital. This algorithm distinguished: A) beyond the immediate stage and up to 2 days, treated with saline subcutaneous washout (SCWO) and vacuum-assisted closure (VAC) dressing; B) 2 to 5 days, open surgical decompression and VAC dressing; C) 5 to 10 days, non-operative management with surveillance; and D) more than 10 days, radical necrotic excision with or without VAC dressing and tissue reconstruction. In 2 patients in Group A and 3 patients in Group B, all vesicant symptoms resolved. Five of the 6 patients in Group C (3 vesicant, 3 non-vesicant) did not progress into necrosis or infection, and 1 case of vesicant extravasation progressed to a localized ulcer beyond this period and, as surgery was refused, led to a chronic ulcer with stiffness; 2 cases of non-vesicant extravasation developed a recall phenomenon but resolved after the third cycle. Of the 4 patients in Group D, all vesicant, 2 were treated with no complications, 1 had complex regional pain syndrome (CRPS) due to late presentation, and 1, referred with necrotizing fasciitis, underwent above-elbow amputation but died due to septic shock. This study demonstrated a uniform surgical approach in a series of 15 cases; larger studies are still needed to validate the efficacy of this protocol in reducing morbidity. LEVEL OF EVIDENCE: IV., (Copyright © 2022 SFCM. Published by Elsevier Masson SAS. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 has spread globally. Vaccination for coronavirus disease 2019 (COVID-19) is anticipated to reduce morbidity and mortality. However, the safety of vaccines against COVID-19 is a cause for concern and uncertainty, which leads to vaccine hesitancy. There have been some self-reported questionnaire studies regarding adverse effects after COVID-19 vaccination; however, adverse effects on the oral region are rare. In this report, we present one case of ulcers arising on the bilateral palate mucosa following COVID-19 vaccination, which was suspected to be an adverse effect of vaccination., Competing Interests: Declarations of Competing Interest None, (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Oral bisphosphonates and direct oral anticoagulants are related to upper gastrointestinal ulcers. The present study investigated whether concomitant use of these drugs increase the risk of upper gastrointestinal ulcers and report no increased risk of upper gastrointestinal ulcers compared to the use of either drug alone, when individuals with previous upper gastrointestinal ulcers are excluded., Introduction: This study examines whether concomitant use of oral bisphosphonates (oBP) and direct oral anticoagulants (DOAC) increases the risk of peptic ulcers more than any drug alone., Methods: A population-based cohort study was performed. We sampled a cohort of oBP and DOAC users from a sample of 2,622,742 individuals, consisting of diabetes patients and age- and gender-matched controls, obtained from the Danish National Patient Register. The exposures were concomitant use of oBP and DOAC and single use of DOAC and single use of oBP. The primary endpoint was the first incident peptic ulcer. Information on exposure and outcome were collected from national registries. The period of observation was from 01.01.2008 until 31.12.2018. Unadjusted and adjusted Cox regressions were performed., Results: 8077 individuals received concomitant treatment with DOAC and oBP; 96,451 individuals used DOAC and no oBP; and 118,675 used oBP and no DOAC. The mean duration of follow-up was 1.9 years for concomitant users, 2.5 years for DOAC users, and 4.5 years for oBP users. A total of 4742 individuals with incident peptic ulcers were collected. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to single DOAC treatment in the adjusted analysis (HR = 1.23, 95% CI: 1.03; 1.48). However, the effects were abolished when excluding individuals with a previous ulcer. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to users of oBP in the adjusted model (HR = 1.34, 95% CI: 1.11; 1.63)., Conclusion: Based on our results, concomitant use of oBP and DOAC is associated with a slight increase in the risk of peptic ulcers compared to either drug alone. The prescribing physician should weigh the slight increased risk of ulcer in concomitant users of oBP and DOAC with beneficial reductions in stroke and fractures., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Background: Children hospitalized for critical asthma (CA) in the pediatric ICU (PICU) are commonly prescribed stress ulcer prophylaxis (SUP) to mitigate risk of gastrointestinal (GI) bleeding. We sought to describe trends for SUP prescribing and explore for differences in rates of GI bleeding, gastritis, and SUP-related complications for those with and without SUP exposure., Methods: We performed a retrospective, multicenter cohort study using the Pediatric Hospital Information System registry among 42 children's hospitals from 2010 to 2019 including children 3 to 17 years of age admitted to the PICU for CA. Primary outcomes were chronologic and regional variation in SUP prescribing assessed by Joinpoint regression and Pearson's correlation. Rates of GI bleeding, gastritis, enteric ulceration, and SUP-related complications (C. difficile colitis, necrotizing enterocolitis, and thrombocytopenia) were compared for those with and without SUP exposure., Results: Of 30 177 children studied, 10 387 (34.4%) received SUP. No episodes of GI bleeding were recorded. One subject developed gastric ulceration and 32 (0.1%) gastritis. Linear trends for SUP were observed with rates increasing from 25.5% in 2010 to 42.1% in 2019 (+1.9% annually). Prescribing varied by institution (range: 5.5% to 97.2%) without correlation to admission volumes. Extremely rare rates of SUP-related complications were noted., Conclusions: Although children hospitalized for CA routinely receive SUP, no episodes of GI bleeding were noted over a 10-year period. SUP solely for corticosteroid exposure may be unwarranted. We advocate for a targeted approach to SUP considering alternative risk factors for GI bleeding., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Oral mucosal ulcers are quite common in an otherwise healthy population and can determine a real worsening of the quality of life. Conventional therapy is not appropriate since ulcers often recur and, even if not needed, therapy lasting not less than 2-3 weeks carries a high risk of serious side effects. The use of hyaluronic acid applied as an adhesive gel over the lesions seems to have potential in terms of efficacy and the avoidance of side effects. Of course, hyaluronic acid-based formulations show different effects and tolerability., Methods: In our study, we retrospectively reported the results obtained using a medical device, Bloxaphte® (Bausch & Lomb, Macherio, Monza-Brianza, Italy), applied for 14 days to counteract ulcers in adults., Results: Treatment with the HA-based oral gel determined better results both in terms of the number of oral lesions and in terms of lesion sizes. Regarding the number of lesions, the results are significant even after 6 days of treatment, while 3 days are enough to differentiate the two groups with respect to lesion sizes., Conclusions: Our data clearly demonstrate the healing capability and safety profile of the product in reducing the number and size of the ulcers within the first week of daily application.

Four new series of 1,2,4 triazole derivatives 4a,b 5a-d, 6a-f, and 7a,b possessing methylsulphonylphenyl moiety as COX-2 pharmacophore were designed and synthesized. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compounds 4a, 5b, 6a, and 7a showed the highest selectivity towards the COX-2 enzyme (S.I. = 8.64-14.58) in comparison to celecoxib (S.I. = . 6.44). Interestingly, compounds 4a, 6a, and 7a showed good anti-inflammatory activity with edema inhibition (54.17, 53.03, and 50.29 %, in order) relative to the reference drug celecoxib (49.60%) after 3 h. Additionally, these potent derivatives 4a, 5b, 6a and 7a were significantly less ulcerogenic (U.I. = 2.27-2.97) than both reference drugs celecoxib (U.I. = 2.99) and indomethacin (U.I. = 20.25). Besides, a histopathological study of the stomach was also included. Moreover, docking simulation for the most selective compounds 4a, 5b, 6a, and 7a inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the above findings reveal that newly developed compounds 4a, 6a, and 7a represent a potential selective COX-2 NSAID candidate with minimum gastrointestinal risks., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Gastrointestinal bleeding is the most frequent major complication of antiplatelet therapy. In patients at low bleeding risk, however, clinically overt gastrointestinal bleeding is relatively uncommon., Objectives: The authors sought to assess the effects of different antiplatelet regimens on gastrointestinal mucosal injury by means of a novel magnetically controlled capsule endoscopy system in patients at low bleeding risk., Methods: Patients (n = 505) undergoing percutaneous coronary intervention in whom capsule endoscopy demonstrated no ulcerations or bleeding (although erosions were permitted) after 6 months of dual antiplatelet therapy (DAPT) were randomly assigned to aspirin plus placebo (n = 168), clopidogrel plus placebo (n = 169), or aspirin plus clopidogrel (n = 168) for an additional 6 months. The primary endpoint was the incidence of gastrointestinal mucosal injury (erosions, ulceration, or bleeding) at 6-month or 12-month capsule endoscopy., Results: Gastrointestinal mucosal injury through 12 months was less with single antiplatelet therapy (SAPT) than with DAPT (94.3% vs 99.2%; P = 0.02). Aspirin and clopidogrel monotherapy had similar effects. Among 68 patients without any gastrointestinal injury at randomization (including no erosions), SAPT compared with DAPT caused less gastrointestinal injury (68.1% vs 95.2%; P = 0.006), including fewer new ulcers (8.5% vs 38.1%; P = 0.009). Clinical gastrointestinal bleeding from 6 to 12 months was less with SAPT than with DAPT (0.6% vs 5.4%; P = 0.001)., Conclusions: Despite being at low risk of bleeding, nearly all patients receiving antiplatelet therapy developed gastrointestinal injury, although overt bleeding was infrequent. DAPT for 6 months followed by SAPT with aspirin or clopidogrel from 6 to 12 months resulted in less gastrointestinal mucosal injury and clinical bleeding compared with DAPT through 12 months. (OPT-PEACE [Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by Ankon Magnetically Controlled Capsule Endoscopy]; NCT03198741)., Competing Interests: Funding Support and Author Disclosures The trial was supported by the China National Key R&D Project (contract nos. 2016YFC1301300 and 2016YFC1301303) and an investigator-initiated grant from Ankon Medical Technologies, Shanghai, China. Dr Stone has received speaker honoraria from Cook and Infraredx; has served as a consultant for Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Vectorious, Miracor, Neovasc, Abiomed, Ancora, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Reva, Vascular Dynamics, Shockwave, V-Wave, Cardiomech, and Gore; and has equity/options from Ancora, Cagent, Applied Therapeutics, Biostar funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and MedFocus funds. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. All rights reserved.)

Background: Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson's Disease. However the need for its subcutaneous infusion can lead to skin reactions., Phenomenology Shown: We illustrate necrotic ulcers at infusion sites as a rare event during continuous subcutaneous apomorphine infusion., Educational Value: This case demonstrates the rare adverse event of necrotic ulcers in a patient with long term apomorphine infusion., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Although cases of gastrointestinal toxicity of pembrolizumab have been reported, cases of acute immune-mediated colitis accompanied with metachronous esophageal disorders (esophagitis and ulcer) are rare. We herein report a case of acute colitis and metachronous esophageal ulcers due to an immune-related adverse event following concomitant pembrolizumab chemotherapy for lung adenocarcinoma. To our knowledge, there have so far been no reports of cases in which both acute immune-mediated colitis and metachronous esophageal ulcers developed. We therefore report the details of this case along with a review of the pertinent literature.

Hydroxyurea is a chemotherapeutic agent used for myeloproliferative disorders and sickle cell anemia that is well known to cause painful mucocutaneous ulcers, typically involving the legs or mouth. However, genital ulcerations due to hydroxyurea therapy are a rare, and likely underrecognized, adverse effect with only a few cases reported in the literature to date. Ulcers of the lower legs caused by hydroxyurea are associated with a diagnostic delay, and this is likely exacerbated in cases of genital ulceration due to a lack of awareness. Herein we present two cases of painful genital ulceration in patients on hydroxyurea therapy. In the first Case, an 87 year-old male with polycythemia vera developed an ulcer on the scrotum, which was assessed initially through virtual visits during the COVID-19 pandemic, and was refractory to topical and oral antibiotic treatments. The second case was a 79 year-old male with essential thrombocythemia and a history of persistent leg ulcers who developed erosions of the glans penis. Both patients experienced complete resolution within weeks of discontinuing hydroxyurea therapy. In conclusion, genital ulcers and erosions induced by hydroxyrea may be underrecognized in clinical practice, but if identified, withdrawal of hydroxyurea leads to quick resolution of these lesions and the associated pain., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: To investigate the protective effect and mechanism of rebamipide on NSAIDs associated intestinal injury., Methods: Intestinal injury was induced in Sprague Dawley rats by intragastric administration of diclofenac with rebamipide intervention, and LPS and TAK-242 were given intraperitoneally respectively. The expression of TLR4/NF-κB and the related proteins in the intestinal mucosa were detected. 55 patients taking NSAIDs and diagnosed as NSAIDs associated small intestinal injury were recruited as NSAIDs group. Another 55 patients without NSAIDs and no obvious abnormality in the small bowel served as the control group., Results: The macroscopic and histological scores of the small intestinal mucosa in the rebamipide pretreatment group were significantly lower compared to the diclofenac group (p < 0.01). The expressions of Tollip, ZO-1 and Claudin-1 in the diclofenac group were down-regulated compared with that in the control group, while they increased significantly in the rebamipide pretreatment group (p < 0.01). The expressions of TLR4/NF-κBp65, IL-1β, IL-6, IL-8, and TNF-α significantly increased in the model group while they were down-regulated in the rebamipide pretreatment group (p < 0.05). Administration of LPS 1 h after diclofenac aggravated small intestinal damage, and increased expression of IL-1β, IL-6, IL-8 and TNF-α. Administration of rebamipide did not effectively reverse intestinal injury induced by diclofenac and LPS. In contrast, pretreatment with TAK-242 significantly inhibited damage and prevented the increased expression of the cytokines. The expression of TLR4 and NF-κBp65 in the patients with NSAIDs associated intestinal injury was significantly higher than that in the control group (p < 0.01), while the expression of Tollip was decreased (p < 0.01)., Conclusion: Rebamipide effectively alleviated intestinal mucosa injury by probably suppressing the TLR4/NF-κB signaling pathway and the decreasing of ZO-1 and Claudin-1 induced by diclofenac., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A new series of N'-(substituted phenyl)-2-(1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1 H -inden-3-yl) acetohydrazide derivatives (1 - 25) were prepared in good yields in an efficient manner. All the compounds were fully characterised by the elemental analysis and spectral data. Synthesised compounds were evaluated for antioxidant activity by DPPH method. Compounds 7 (R = 3-methoxyphenyl), 3 (R = 4-dimethylaminophenyl) and 23 (R = 2,4,5-trimethoxy phenyl) substitutions were found to be having highly potent antioxidant activity. Compound 3 , with para dimethylaminophenyl substitution was found to be having highest antioxidant activity. It was further evaluated in vivo for various analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibitory activity in different animal models. Lead compound 3 was found to be significant anti-inflammatory and analgesic agent. It was also evaluated for ulcerogenic activity and demonstrated significant ulcerogenic reduction activity in ethanol and indomethacin model. The LD 50 of compound 3 was found to be 131 mg/kg. The animals treated with compound 3 prior to cisplatin treatment resulted in a significant reduction in COX-2 protein expression when compared to cisplatin-treated group. Sulindac derivative with para dimethylaminophenyl substitution was found to be the most potent antioxidant, anti-inflammatory and analgesic agent as well as with significant gastric sparing activity as compared to standard drug sulindac. Compound 3 significantly downregulated liver tissue COX-2 gene expression.

Competing Interests: Competing interests: None declared.