Introduction

Acute gastrointestinal bleeding (GIB) is a common reason for hospitalization, with a 2%–20% risk of mortality. Identification of patients at high risk of death is essential to make fast and adequate decisions on their management.

Aims & Methods

We developed two machine-learning (ML) models to calculate the risk of in-hospital mortality in patients admitted due to overt GIB.
The prospective, multicenter Hungarian GIB Registry's data were analyzed. We focused on in-hospital mortality and applied statistical binary classification. The predictive performance of XGBoost and Catboost machine-learning algorithms was compared with the Glasgow-Blatchford (GBS) and pre-endoscopic Rockall scores. We evaluated our models using five-fold cross-validation, and performance was measured by area under receiver operating characteristic curve (AUC) analysis with 95% confidence intervals (CI). The individual predictions and the variables' contribution to the outcome were calculated via the SHapley Additive exPlanations (SHAP) method.

Results

Overall, we included 1,021 patients in the analysis; 52% had nonvariceal upper GIB, 30% had lower GIB, and 9% had variceal bleeding. The median age was 70 years; 60% were men. In-hospital death occurred in 108 cases (11%). We selected 19 of 96 input variables in both final ML models. The XGboost and the Catboost model identified patients who died with an AUC of 0.84 (CI: 0.76-0.90; 0.77-0.90; respectively) in the internal validation set, whereas the GBS and pre-endoscopic Rockall clinical scoring system's performance was significantly lower, AUC values of 0.68 (CI: 0.62 - 0.74) and 0.62 (CI: 0.56 - 0.67), respectively. The XGBoost model had a specificity of 0.96 (CI: 0.92-0.98) at a sensitivity of 0.25 (CI: 0.10-0.43) compared with the CatBoost model, which had a specificity of 0.74 (CI: 0.66-0.83) at a sensitivity of 0.78 (CI: 0.57-0.95). In the CatBoost model, the most influential variables contributing to the prediction were CRP level, smoking, melena, minimum systolic blood pressure, previous GIB, Glasgow Coma Scale and hemoglobin level.

Conclusion

The new ML models identified patients with high mortality risk significantly better than GBS and pre-endoscopic Rockall scores. Due to its better sensitivity, we prefer the CatBoost model in determining the in-hospital mortality risk of GIB.

Introduction

Accepted oncological principles advise enbloc, R0, excision of cancer to provide a cure. In Barrett’s neoplasia, this includes T1a and T1b disease, where histology is favorable. While treatment options include endoscopic mucosal resection (EMR) and submucosal endoscopic dissection (ESD), a mechanism for appropriate technique selection has not been described.

Aims & Methods

We conducted a prospective observational study to evaluate the performance of a selective resection algorithm for Barrett’s neoplasia (SRAB). To achieve an enbloc resection, ESD was selected if there was a suspicion for ≥T1a disease and the lesion was >15 mm (January 2017 to April 2023). This was compared with a conventional EMR predominant approach (CEA), where ESD was only performed in cases suspicious for deep submucosal invasion or T1b disease (February 2013 to December 2016). The primary outcome was curative oncologic resection (R0 resection with favorable histologic features).

Results

A total of 298 resections were performed in 298 patients (68 UEA, 230 SRAB). Median lesion size was 20 mm (IQR 15-30). T1a adenocarcinoma was identified in 83 (27.9%) and T1b in 58 (19.5%), of which 31 (10.4%) were SM1. Comparing T1a and T1b disease, the rate of enbloc resection (CEA 12 [46.2%] vs SRAB 103 [90.4%]; P<0.001), R0 excision (CEA 7 [26.9%] vs SRAB 86 [74.8%]; P<0.001) and curative resection (CEA 6 [23.1%] vs SRAB 58 [50.4%]; P=0.011) was higher in the SRAB group. Among all T1a and T1b-SM1 cases with favorable histology, which underwent ESD, 39/46 (84.8%) were R0 excisions and are likely cured. There were no significant differences in adverse events (P>0.788 for all).

Conclusion

A selective resection algorithm optimizes oncologic outcomes for Barrett’s adenocarcinoma and mitigates the risk of piecemeal resection of cancers.

Disclosure

Michael J. Bourke: Research Support: Olympus, Cook Medical, Boston Scientific.

Clinical Case Summary

Introduction: Inflammatory bowel disease (IBD) is linked to cutaneous manifestations in 10% of cases. Neutrophilic dermatoses represent a diagnostic and management challenge, as it requires a dual-targeted treatment approach.
Clinical Case: We present a 67-year-old man with A3L1B1 Crohn’s disease (CD) followed in our IBD consultation. His medical history included previous tobacco abuse, hypertension, type 2 diabetes and ischemic cardiopathy with heart failure. He was medicated for his comorbidities and had been treated with budesonide.
Due to evidence of disease progression, increased fecal calprotectin (FC) at 751ug/g and a history of invasive pulmonary aspergillosis, vedolizumab was initiated.
The patient presented with recurrent erythematous, tender, nodular lesions on the abdomen, limbs and face. Dermatological consultation and cutaneous biopsies led to an initial misdiagnosis of infectious panniculitis, as methicillin sensitive Staphylococcus aureus (MSSA) was isolated and the lesions regressed with antibiotics.
Two months later, cutaneous lesions reappeared and histopathology confirmed IBD-associated erythema nodosum-like neutrophilic dermatosis with MSSA isolation. A 10-week doxycycline course induced their regression. However, recurrence transpired 5 months later, associated with an increased FC (816ug/g).
A swap for ustekinumab (UST) resulted only in transient clinical and biochemical improvement (FC 324ug/g). Despite dose escalation to every 4 weeks, nodular/papular lesions with central postulation recently reappeared, prompting initiation of daptomycin with a potential swap to another drug class.
Conclusions: IBD can be associated with neutrophilic dermatoses and its diagnosis can be challenging. This case reports an CD-associated erythema nodosum-like neutrophilic dermatosis, underscoring its complex approach and management.
Note: We are submitting this case with iconography as it underscores a rare IBD manifestation.

References

Photographs of cutaneous lesions (3-4)

Clinical Case Summary

Introduction: Ustekinumab (UST), a human interleukin-12/23 monoclonal antibody, is approved for the treatment of moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). Some patients may lose response to standard maintenance therapy. Optimization strategies, such as dose escalation and intravenous (IV) re-induction, have been explored in CD, but scarcely studied in UC.
Clinical Case: A 61-year-old woman, with grade III obesity, hypertension, and peripheral venous insufficiency, diagnosed with UC and associated peripheral arthropathy, was initially treated with high-dose corticosteroids (CTS) for a severe exacerbation. She developed CTS dependence and suffered an osteoporotic fracture.
A combined therapy with methotrexate and an accelerated infliximab (IFX) induction regimen was initiated, but a severe exacerbation occurred after the second induction dose. Despite an early third dose, clinical, biochemical and endoscopic (Mayo score 3) activity persisted.
The patient was swapped to UST with maintenance therapy every 4 weeks. After IV infusion, free-CTS clinical and biochemical (fecal calprotectin (FC) <10 ug/g) remission were achieved, but, over time, there was a loss of response, with a FC 4817 ug/g.
Given the initial positive response to IV UST infusion and insights from CD studies, a 520mg IV UST re-induction followed by 4-week maintenance dose was administered. Eight months later, the patient remains in free-CTS clinical remission, with improved arthralgia, biochemical remission (FC 80 ug/g) and endoscopic response.
Conclusions: This case highlights the potential efficacy of IV UST re-induction in recapturing remission in refractory UC. While recognized in CD, UST re-induction may prove beneficial for UC patients with loss of response to standard UST therapy, serving as an alternative before swapping. Further exploration through randomized, multicenter studies is crucial to assess the efficacy and safety of this strategy in UC patients.

Introduction

G-protein coupled receptor-119 (GPR119) agonism is known to modulate non-alcoholic fatty liver disease physiology. However, due to off-target effects, challenges remain for successful GPR119 agonist pharmacotherapy.
Designing a non-systemic drug candidate that locally targets gut-located receptors for incretin secretion is suggested as a safer approach to minimise conventional side effects. This strategy may potentially limit the direct action on pancreatic β-cells; however, chronic use may lead to beneficial outcomes.
We developed a novel small-molecule agent as an oleoyl-lysophosphatidylinositol derivative that stimulates intestinal glucagon-like peptide-1 (GLP-1) secretion by coupling with gut receptors at the orthosteric site.

Aims & Methods

The present study was designed to investigate the chronic impact of novel GPR119 agonist agent ps297 alone and in combination with Sitagliptin on liver health in high-fat diet (HFD)-induced obese mice.
Five-week-old healthy male C57BL6/J mice were fed with HFD for 20 weeks. Normal control mice were maintained on a standard chow diet. A dose-escalation protocol was followed during the treatment phase. Oral administration of the test compound commenced with an initial dose of 10 mg/kg/day for the first week, followed by weekly dose escalations of 10 mg/kg for the subsequent ten weeks until reaching a maximum dose concentration of 90 mg/kg/day. Sitagliptin was gavaged at a fixed dose of 20 mg/kg/day. Vehicle control mice received an equal volume of 0.25% carboxymethyl cellulose in water.
After ten weeks of treatment, blood samples were collected from each 4-hour fasted mice. Biochemical parameters including plasma glucose, triglycerides (TG), cholesterol (CHO), alanine aminotransferase (ALT), and aspartate transaminase (AST) were analysed using an automated analyser. Plasmatic concentrations of metabolic hormones were determined in a multiplex assay platform. Hepatic TG, CHO, and hydroxyproline concentrations were determined in frozen liver tissue samples by colourimetric assay. Liver histology was studied in tissue stored in 10% neutral buffered formalin. Hepatic ballooning was assessed in hematoxylin and eosin-stained sections, imaged using a slide scanner.

Results

Ten-week co-administration of compound ps297 with sitagliptin resulted in higher plasmatic GLP-1 levels compared to the HFD control arm, which led to a significant (p<0.05) reduction in fasting plasma glucose levels in this group. Moreover, combination group exhibited a significant reduction in liver weights (p<0.0001), plasma CHO (p<0.05), ALT (p<0.0001), and AST (p<0.01) levels. Furthermore, combination treatment showed a significant reduction in hepatic TG (p<0.0001) and CHO (p<0.001) concentrations compared to the HFD control group. Elevated hepatic hydroxyproline levels in HFD control mice were attenuated by combination treatment. Additionally, the hepatic ballooning score was found to be significantly reduced in the combination treatment mice.

Conclusion

Sitagliptin combination of ps297, improved glucose homeostasis in HFD-fed obese mice. Additionally, a prominent improvement in liver health status was observed in this group, as evident by reductions in liver weight, plasma liver enzymes, hepatic TG and CHO, and hydroxyproline levels. These findings were further supported by liver histological examination. The overall findings suggest the pharmacological potential of the GPR119 agonist compound ps297 in combination with gliptins to alleviate fatty liver disease, warranting further molecular investigation in disease-specific animal models.

References

Paternoster S, Simpson PV, Kokh E, Kizilkaya HS, Rosenkilde MM, Mancera RL, Keating DJ, Massi M, Falasca M. Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics. Pharmacol. Res. 172 (2021) 105822.

Bahirat UA, Shenoy RR, Talwar R, Goel RJ, Nemmani KVS. Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet. Biochem Biophys Res Commun 495 (2018) 1608-1613

Disclosure

MF and MM are inventors of a patent related to oleoyl-LPI mimetics. Curtin University received funding from Little Green Pharma Pty Ltd. to support MF to conduct the submitted work. LW is a paid employee of Little Green Pharma Pty Ltd. No other relationships or activities that could appear to have influenced the submitted work.

Introduction

​In 2022 the BCLC staging and treatment algorithm for hepatocellular carcinoma (HCC) management has been updated (BCLC_2022), granting for higher flexibility and customized management for HCC patients as compared to the 2018 version.

Aims & Methods

Aim of the study was to evaluate the feasibility of BCLC_2022 in daily clinical practice (BCLC_2018 as benchmark), its impact on response to treatment and on overall survival (OS).
We retrospectively evaluated data of 798 prospectively followed (year 2006 to 2022) patients with de novo HCC: 187 0, 371 A, 132 B, 87 C and 21 D, according to BCLC. First line treatment allocations were discussed by a multidisciplinary team (MTD), following updated recommendations. All patients were followed until death or end of follow-up (12/2022).

Results

Overall, the feasibility if BCLC increased from 51% for the BCLC_2018 to 69% for the BCLC_2022 (p<0.001): 56% to 73% stage 0 (p=0.001), 45% to 72% stage A (p<0.001), 51% to 65% stage B (p=0.02), while no changes were registered for stage C and D. Among BCLC 0 /A patients, 130 (23%) were treated with TACE, which is a “lower priority option” for these stages according to BCLC_2022. The rate of "downward stage migration" was significantly lower with BCLC_2022 (33% to 16%, p<0.001). “Downward stage migration” without curative intent was associated with a lower proportion of complete response to first line treatment in the early stages (0% vs 77%, p=0.003 in BCLC0; 0% vs 57%, p=0.001 in BCLC A) and to a shorter OS [6 months (IQR 2-16) vs 82 months (IQR 42-132), p<0.001 in BCLC 0] as compared to BCLC_2022. Similarly in early stages patients treated with a “lower priority option” had a lower proportion of complete response (82% vs 60%, p=0.01 in BCLC 0 and 74% vs 20%, p<0.001 in BCLC A) and a shorter OS [33 (IQR 23-61) vs 74 months (IQR 42-137) p<0.001 in BCLC A] as compared to those undergoing first choice treatments. In BCLC B and C, an upward stage migration was associated to a higher achievement of complete response (17% vs 52%, p<0.001 in BCLC B and 2% vs 41% p<0.001 in BCLC C), and granted a longer OS [(63 months (IQR 36-72) vs 28 (IQR 18-44), p=0.003 in BCLC B and 21 months (IQR 15-44) vs 11 months (IQR 4-25) in BCLC C] as compared to BCLC 2022. In BCLC 0 and undergoing a “downward stage migration” without curative intent was an independent predictor of mortality [HR 6.94 (95% CI 2.27-21.20) p=0.001], alongside with age [HR 1.08 (95% CI 1.06-1.13), p<0.001] and ALBI grade 3 [HR 9.34 (95% CI 1.21-72.19), p=0.03. Conversely, “upward stage migration” was independently associated to a lower mortarlity risk both in BCLC B” [HR 0.46 (95% CI 0.27-0.80), p=0.006] and C [HR 0.50 (95% CI 0.27-0.92) p=0.03].

Conclusion

The BCLC_2022 updated version of HCC staging and treatment system allowed a greater adherence to the algorithm in clinical practice, without adversely affecting the survival of patients. Choosing a “curative option” for early HCC granted longer survival, as well as the access to treatments with curative intent permits a survival benefit in selected patients in more advanced stages.

Introduction

Research about sarcopenia in primary biliary cholangitis (PBC) patients is limited while sarcopenia commonly occurs in cirrhotic patients. Concomitant sarcopenia in noncirrhotic PBC patients has been rarely explored yet.

Aims & Methods

This study aimed to investigate the prevalence of sarcopenia and the associations between concomitant sarcopenia at baseline and biochemical response to UDCA treatment and clinical outcomes in noncirrhotic primary biliary cholangitis (PBC) patients.
Between January 2009 and July 2022, consecutive PBC patients were retrospectively enrolled. Sarcopenia was assessed via pretreatment CT or MRI scans at the L3 level by the skeletal muscle index. Baseline characteristics, the response rate after 6 and 12 months of ursodeoxycholic acid (UDCA) administration, liver-related adverse events and baseline CRP and IL-6 levels in liver tissue and serum were evaluated.

Results

A total of 142 noncirrhotic PBC patients were included, with sarcopenia identified in 58 (40.8%) patients. The median duration of follow-up was 5.25 (3.23, 6.50) years. The group of PBC patients with sarcopenia demonstrated a lower biochemical response rate (44.9% vs. 64.8%; P=.031) according to the Paris-II criteria after 12 months of UDCA treatment, as well as higher incidence of new-onset ascites (28.1% vs. 13.1%, P=.027) during follow-up. Higher expression levels of baseline CRP and IL-6 in liver tissue and serum were observed in PBC patients with sarcopenia (P<.05).

Conclusion

Sarcopenia was highly prevalent in noncirrhotic PBC patients. Expression levels of baseline CRP and IL-6 in liver tissue and serum were elevated in noncirrhotic PBC patients with sarcopenia. Concomitant sarcopenia at baseline may adversely affect the biochemical response to UDCA treatment and occurrence of liver-related adverse events in PBC patients without cirrhosis.