Medicine and Pharmacology

Abstract: Primary biliary cholangitis (PBC) is a systemic disease in which musculoskeletal complications may impair function despite satisfactory biochemical control. This narrative review integrates PBC-specific evidence on sarcopenia, osteoporosis and osteosarcopenia with mechanistic studies of cholestasis, muscle-bone interactions and peroxisome proliferator-activated receptor (PPAR) signalling. Muscle depletion occurs before cirrhosis, but heterogeneous definitions and retrospective designs limit prevalence estimates and prognostic interpretation. Population-based studies link PBC to fractures and increased post-fracture mortality, whereas dedicated osteosarcopenia studies remain limited. Nutritional compromise, inflammation, endocrine abnormalities, symptom-related inactivity and advanced liver disease converge on the muscle-bone unit. General densitometric and fracture-risk frameworks remain necessary because PBC-specific integrated thresholds are unvalidated. PPAR agonists improve biochemical activity and, for some agents, symptoms, but their musculoskeletal effects must be considered separately by receptor isoform. Experimental oxidative adaptation and exploratory bone-density findings do not establish sarcopenia reversal or fracture protection; fracture signals and potential muscle toxicity require independent assessment. Ileal bile acid transporter inhibition offers pruritus relief but also requires attention to fat-soluble vitamins and skeletal safety. Integrated evaluation of symptoms, strength, body composition, physical performance and fracture risk may identify actionable limitations. Prospective cohorts and controlled interventions with predefined musculoskeletal endpoints are needed to establish clinically meaningful benefit.

Abstract: For half a century, digestive endoscopy has advanced under a single dominant paradigm — morphological endoscopy — whose object is the morphological lesion, whose epistemic path is look–classify–confirm by pathology, and whose endpoint is resection of what is seen. That paradigm has delivered enormous value, but the clinical problems now dominating gastroenterology — antimicrobial resistance beyond the reach of empirical therapy and checkpoint-resistant, immunologically “cold” tumors — are problems of interfacial state rather than of form, and they mark the object boundary of a paradigm built on morphology. Meanwhile, the elements of a successor paradigm are already in the endoscopy suite — confocal microscopy, molecular imaging, artificial intelligence, in vivo pathology, same-access resection — yet none has simultaneously changed the object, the epistemic path, and the practical endpoint. We therefore propose interfacial endoscopy as a paradigm of equal standing: within a single endoscopic access, pathogen and immune phenotypes at the mucosal interface are read out in a one-stop manner, and the same access performs targeted in situ intervention — read the interface, classify the phenotype, intervene at once. The paradigm's three-layer structure (ontological, epistemological, praxical) is grounded in two published precursors from our program — the HP-REVISE closed loop for H. pylori pathogen phenotyping and ROSE-mIF immune phenotyping linked to same-access oncolytic intervention — and it stands before a defined five-item validation agenda. If validated, interfacial endoscopy would reposition gastroenterology as an interface-based discipline of in situ precision diagnosis and therapy, elevating the endoscope from the “eyes” of the field to its “eyes, readout, and hand”.

Abstract: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder closely associated with obesity, type 2 diabetes, dyslipidemia, and cardiovascular complications. Excessive fructose consumption may contribute to MASLD development and progression by promoting hepatic de novo lipogenesis, advanced glycation end product (AGE) formation, oxidative stress, and chronic inflammation. This review aims to critically examine the molecular pathways linking fructose metabolism and AGE–RAGE signaling to hepatic injury and cardiovascular dysfunction, highlighting their interconnected roles within the liver–heart axis. Fructose metabolism increases the availability of lipogenic substrates and reactive carbonyl intermediates, favoring lipid accumulation and AGE generation. Subsequent activation of the receptor for AGEs (RAGE) stimulates oxidative and inflammatory signaling, including reactive oxygen species production and NF-κB activation. These processes may impair antioxidant defenses, promote mitochondrial dysfunction, activate hepatic stellate cells, and contribute to steatohepatitis and fibrosis. Beyond the liver, AGE–RAGE signaling is implicated in endothelial dysfunction, vascular inflammation, atherosclerosis, and adverse cardiac remodeling. Intestinal barrier disruption and inflammatory mediator release may further amplify these interconnected metabolic disturbances. We also discuss experimental and clinical evidence concerning fructose intake, hepatic and cardiovascular outcomes, and emerging therapeutic approaches targeting glycation, oxidative stress, and inflammation. However, heterogeneity in dietary exposures, study designs, and clinical endpoints limits causal interpretation. By integrating metabolic, inflammatory, and vascular mechanisms, this review identifies potential therapeutic targets and research priorities for understanding and mitigating fructose-associated cardiometabolic injury in MASLD. Particular attention is given to the distinction between mechanistic findings and human evidence, as well as the need for larger studies.

Abstract: Fecal incontinence (FI) is the recurrent and uncontrolled passage of fecal material, in-cluding episodes of soiling or underwear staining. Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction characterized by recurrent abdominal pain or dis-comfort associated with altered bowel habits, including diarrhea, constipation, or a mixed pattern. Although these conditions have traditionally been considered sepa-rately, increasing evidence suggests that they frequently overlap, especially in patients with diarrhea-predominant IBS. In this setting, FI should not be regarded as a simple consequence of anal sphincter weakness. Loose stools, urgency, altered colonic transit, rectal hypersensitivity, anorectal sensorimotor dysfunction, pelvic floor impairment, and reduced continence reserve may interact and promote leakage. Additional struc-tural, iatrogenic, and patient-related factors may further increase susceptibility. The overlap is often underrecognized because many patients do not spontaneously report fecal leakage, despite its relevant impact on quality of life and daily functioning. A careful history, direct but non-stigmatizing questioning, physical examination, symp-tom assessment, and selective investigations are therefore essential to identify the dominant clinical phenotype and exclude secondary causes. Treatment should be indi-vidualized and progressive, combining optimization of bowel habits and IBS-directed strategies with anorectal rehabilitation and, when needed, more advanced FI-directed treatments. Recognizing FI as part of the clinical spectrum of IBS may improve diag-nostic accuracy, promote earlier treatment, and support a more integrated and pa-tient-centered approach to care.

Abstract: Neurofibromas are rare benign tumors of the peripheral nerve sheath, predominantly associated with neurofibromatosis type 1 (NF1). Isolated colorectal neurofibromas that arise in patients without clinical manifestations of NF1 are extremely rare and are frequently identified inadvertently during endoscopic examinations. The rarity of these conditions complicates diagnosis, necessitating histopathologic and immunohistochemical validation. We report a case of an incidental rectal submucosal neurofibroma found during a colonoscopy performed to evaluate chronic constipation in a patient with no previous diagnosis of neurofibromatosis.

Abstract: Background and aims: Lifestyle factors could influence the development of metabolic dysfunction–associated steatotic liver disease (MASLD). However, there is a lack of data including the consumption of ultra-processed foods (UPF) within the broad field of steatotic liver disease. Methods: Dietary intake and physical activity were assessed using standardized questionnaires in patients with MASLD, ALD and healthy controls. Liver disease severity was quantified by transient elastography and liver histology. Results: One hundred and fifty-two patients with MASLD were recruited and compared with 95 patients with ALD and 31 controls. Patients with MASLD consume significantly less total calories than patients with ALD (1620 vs. 2290 kcal/day, p < 0.0001), primarily due to lower alcohol intake, despite a higher body mass index. ALD patients consume lower proportions of proteins, lipids, carbohydrates, and dietary fibres than MASLD and control groups. Fibre intake is higher in the control group compared with the MASLD and ALD groups. In the biopsied MASLD subgroup, significant fibrosis is associated with a lower fibre intake (15 vs. 19 g/day, p = 0.03). No differences in NOVA category distribution are observed between MASLD and control groups, and UPF intake is not associated with liver histological severity. Controls devote a greater proportion of leisure-time physical activity (54% vs. 11% in MASLD and 17% in ALD, p < 0.0001). Conclusions: Patients with MASLD and ALD exhibit lower dietary fibre intake and reduced leisure-time physical activity compared with controls. Fibre intake, but not UPF consumption, is associated with fibrosis severity in MASLD.

Abstract: Inflammatory bowel disease (IBD) is increasingly recognized as a disorder in which extracellular matrix (ECM) remodeling is not merely a downstream consequence of mucosal inflammation but a potential significant contributor in pathogenesis. The intestinal ECM regulates epithelial barrier integrity, immune cell trafficking and the resolution of inflammation. Evidence derived predominantly from murine models demonstrates that structural, compositional and mechanical alterations may emerge before clinical symptoms. This pre-symptomatic state is characterized by subclinical immune infiltration and elevated matrix remodeling enzyme activity within the intestinal epithelium. During active disease, remodeling intensifies, with increased matrix metalloproteinase activity generating ECM fragments that reflect endoscopic severity and may discriminate flares from remission. This review synthesizes the evidence on ECM remodeling during the pre-symptomatic and flare phases, emphasizing the ECM as an active driver of early inflammation. Recognizing this early window opens opportunities for diagnostic and therapeutic strategies beyond the current focus on established mucosal inflammation.

Abstract: Gut health is recognized as an important contributor to overall health, yet there is no widely accepted definition or standardized approach to its measurement. This work aimed to characterize how gut health is measured and described across academic research and patient-facing materials, and to evaluate available evidence on reliability and validity of commonly used measures. A systematic review of the literature since 2011 was conducted to identify measures of gut health used in human studies; a review of selected medical association materials was also completed to assess how gut health is communicated to in potential patient-facing materials. Measures were categorized across domains of symptoms, function, integrity, and immunity, and a targeted review of reliability and validity of the different tools and measurements identified from the systematic literature review was performed. Substantial heterogeneity in how gut health is conceptualized and measured was observed and gut health was rarely defined. While a broad range of tools and measurements are available and there is good evidence for their overall reliability and validity, there is a lack of evidence supporting their reliability and validity specific to gut health. This review provides a foundation for identifying candidate measures and gaps in validation for defining gut health.

Abstract: Background: Successful generation of patient-derived organoids (PDOs) from pancreatic ductal adenocarcinoma (PDAC) depends on an adequate amount of viable tissue. After routine endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) yields tissue for pathological diagnosis, additional needle passes are typically required to obtain organoid-culture material. This study examined whether air-flush tissue recovery (ATR) of residual needle-tract tissue can derive pancreatic cancer organoids without extra passes. Methods: We enrolled 10 PDAC patients who underwent EUS-FNA at two centers (The Ninth Medical Center of Chinese PLA General Hospital and the Second Hospital of Hebei Medical University) between February and June 2026. Using a self-controlled design, conventional FNA tissue strips (FNA group) and air-flush-recovered needle-tract residuals (ATR group) were collected from each patient and used to establish organoids. The two groups were compared for P3-generation passage rate, histological features, and molecular characteristics. Results: The ≥P3 success rate was 60.0% (6/10) in both the FNA and ATR groups. The overall organoid establishment rate (at least one method) was 80.0% (8/10). Hematoxylin and eosin (HE) staining and immunohistochemistry showed that organoids from both sources retained the histological morphology and key molecular features of the primary tumor, with consistent expression patterns. Conclusions: Harvesting residual tissue from the EUS-FNA needle tract by air flushing enables successful establishment of pancreatic cancer PDOs. The establishment success rate is comparable to that of organoids derived from conventional FNA specimens. In high-risk patients who cannot tolerate additional passes, a single ATR sample can still provide material for organoid generation; simultaneously culturing FNA tissue strips together with ATR residuals improved the overall organoid establishment rate from one puncture. This minimally invasive protocol is straightforward to perform and merits validation in larger cohorts.

Abstract: Thrombocytopenia is one of the most common hematological complications of chronic liver disease (CLD) and becomes clinically relevant mainly when invasive diagnostic or therapeutic procedures are required. Its pathogenesis is multifactorial and includes splenic sequestration secondary to portal hypertension, reduced hepatic thrombopoietin (TPO) synthesis, bone marrow suppression, immune-mediated platelet destruction, and increased platelet consumption. In line with the concept of rebalanced hemostasis, platelet count alone is a poor predictor of procedural bleeding in CLD, and contemporary guidelines increasingly emphasize procedure-specific bleeding risk and patient-related factors rather than correction of an isolated laboratory value. Prophylactic platelet concentrate (PC) transfusion provides only a transient and often unpredictable platelet increment in this population and carries the risk of transfusion reactions, alloimmunization, and platelet transfusion refractoriness. This review summarizes the pathophysiology and clinical significance of thrombocytopenia in CLD, critically evaluates the indications for and efficacy of PC transfusion, and discusses alternative strategies, including recombinant human TPO, TPO receptor agonists (TPO-RAs), splenic interventions, and portal decompression. PC transfusion remains essential when rapid correction is required, particularly in active bleeding or urgent procedures, whereas the TPO-Ras, avatrombopag and lusutrombopag, offer an effective oral alternative in selected patients undergoing elective procedures. A management algorithm integrating these considerations is proposed.

Abstract: Background and Objectives: Inflammatory bowel disease (IBD) is associated with chronic inflammation and an increased risk of impaired bone metabolism. Wnt-pathway regula-tors -including sclerostin (sclerostin), dickkopf-1 (DKK-1), and periostin (periostin)- are key mediators of osteoblast and osteocyte function, yet data on their role in IBD-related bone alterations remain limited. This study aimed to evaluate serum levels of DKK-1, scle-rostin, and periostin in IBD patients. Materials and Methods: In this observational case–control study, 89 adults with IBD (58 CD, 31 UC) and 73 age- and sex-matched healthy controls were evaluated. Fasting serum levels of sclerostin, DKK-1, periostin, calcium, phosphorus, magnesium, and 25(OH)D were measured. BMD at the lumbar spine and femoral regions was assessed by DXA. Results: Patients with IBD showed elevated in-flammation, reflected by higher CRP and ESR compared with controls. Sclerostin levels were significantly lower in IBD and independently associated with disease status, age, corticosteroid use, vitamin D supplementation, and disease activity. DKK-1 levels were significantly increased in IBD and were independently associated with ESR, with addi-tional correlations to inflammatory markers and disease activity in subtype analyses. Per-iostin levels were reduced in IBD and independently associated by IBD status, sex, and BMI, with gender remaining a consistent determinant across analyses. Conclusions: IBD patients show distinct alterations in Wnt-pathway biomarkers, indicating increased bone turnover and disrupted osteoblast/osteocyte activity despite preserved DXA measure-ments. These findings suggest that biochemical markers may detect early bone impairment before measurable declines in BMD and highlight the utility of Wnt-related proteins as early indicators of skeletal risk in IBD.

Abstract: Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) involves insulin resistance, altered iron homeostasis, and oxidative stress. We explored changes in hepatic steatosis and cardiometabolic parameters following targeted micronutritional supplementation. Methods: In this prospective, single-center, open-label, single-arm pilot study, 15 adults with ultrasound-confirmed moderate-to-severe hepatic steatosis received two standardized micronutrient formulations for four months, alongside previously established dietary recommendations. No new structured weight-loss program was introduced. The pre-specified primary efficacy target was a ≥10% reduction in Fatty Liver Index (FLI). Secondary outcomes included ultrasound steatosis severity, metabolic and biochemical parameters, quality of life, and safety. Results: The primary efficacy target was not achieved. Mean FLI decreased by 2.55 points (59.18 ± 26.67 to 56.63 ± 27.48), corresponding to a 4.3% relative reduction (p = 0.256). Exploratory analyses showed a shift towards lower ultrasound-defined steatosis grades (nominal p = 0.010), with severe steatosis decreasing from 46.7% to 6.7%. BMI remained unchanged, while waist circumference decreased by 0.89 cm (p = 0.046). Fasting glucose (p = 0.033), insulin (p = 0.025), homocysteine (−23%; p = 0.001), and ferritin (p = 0.007) decreased, while transferrin saturation increased (p = 0.005). No serious adverse events occurred. Conclusions: Although the primary endpoint was not met, micronutritional support was associated with exploratory improvements in ultrasound-defined steatosis and selected cardiometabolic biomarkers. Larger controlled trials are warranted.

Abstract: During the progression of chronic liver disease, changes in the acidic microenvironment of liver tissue are closely correlated with the extent of pathological injury, making precise monitoring of these changes critical for disease assessment. Traditional detection methods (e.g., blood gas analysis, tissue pH electrodes) suffer from limitations such as high invasiveness and low spatiotemporal resolution, hindering dynamic reflection of hepatic acid environment evolution. PH-responsive probes (e.g., fluorescent probes, magnetic resonance probes), leveraging their non-invasive, real-time, and high-specificity advantages, have emerged as a research focus in this field. This review focuses on the application of such probes in rat chronic liver disease models: outlining their design principles and types, analyzing their quantitative detection capabilities for liver acidification levels, summarizing their value in correlating pathological processes such as liver inflammation, fibrosis, and cirrhosis, and demonstrating their ability to identify disease progression and evaluate intervention efficacy through early detection of acidic environment changes. Studies indicate that pH-responsive probes provide a tool for elucidating the mechanisms of the acidic microenvironment in chronic liver disease and lay the foundation for developing non-invasive monitoring technologies in clinical translation, holding significant academic and practical value.

Abstract: Background and aims: Serum vitamin B12 may increase during liver injury, but its association with clinical outcomes in acute hepatitis remains incompletely characterized. We evaluated admission vitamin B12 in relation to in-hospital outcomes and explored a combined vitamin B12–ferritin index. Methods: This retrospective single-center study included 186 adults hospitalized with acute hepatitis or acute liver injury during 2018–2025. Clinical outcomes were gastroenterology ward length of stay, liver transplantation, and in-hospital mortality. Additional exploratory analyses evaluated ICU admission, recorded encephalopathy, and a composite of ICU admission, transplantation, or death. Discrimination was assessed using receiver operating characteristic analysis. Eight vitamin B12 results exceeded the assay reporting limit of 4000 pg/mL; available numerical analyses used a top-coded representation, with these observations tied at the upper limit. Results: Nine patients (4.8%) died and one (0.5%) underwent transplantation; 20 (10.8%) met the exploratory composite outcome, all of whom required ICU care. Eleven patients had recorded hepatic encephalopathy. Vitamin B12 AUCs were 0.935 (95% CI 0.891–0.979) for mortality, 0.944 (0.904–0.984) for death or transplantation, and 0.938 (0.897–0.980) for the ICU-inclusive composite. Vitamin B12 was not associated with gastroenterology ward length of stay (Spearman ρ=0.017; P=0.818). The exploratory B12–Ferritin Index had a composite-outcome AUC of 0.892, providing no demonstrated improvement over vitamin B12. Conclusions: Higher admission vitamin B12 was associated with adverse in-hospital outcomes, but not with gastroenterology ward length of stay. The limited event count, assay upper-limit censoring, and uncertain timing of sampling relative to deterioration restrict prognostic interpretation. Prospective validation is required before clinical application.

Abstract: This paper examines the inferential framework used to attribute the positive association between acid-suppressive therapy (AS) and esophageal adenocarcinoma (EAC) to confounding by gastroesophageal reflux disease (GERD), a common indication for AS. The experimental literature has proposed several mechanisms by which AS may increase the risk of EAC—either by altering the properties of refluxate or enhancing proliferation in reflux-injured tissue—and reviews of the in vivo literature have suggested that the AS–EAC association may be causal. At the same time, clinical guidelines have long maintained that the AS–EAC association reflects confounding by GERD, and cite observational studies that estimate either the AS–EAC association among those without GERD or the treatment odds ratio upon adjusting for GERD as a main-effect covariate. This paper first outlines the causal hypotheses articulated in the in vivo literature and establishes that the patient's underlying reflux burden is an effect modifier under each of these hypotheses. It then argues that the epidemiologic findings presented in clinical guidelines as reassuring evidence against causality have been widely misread, as they do not inherently distinguish confounding by GERD from the causal structures implied by any of these hypotheses.

Abstract: Background/Objectives: Immune checkpoint inhibitors (ICIs) have become part of standard systemic therapy for hepatocellular carcinoma (HCC), yet only a minority of patients achieve durable responses. The immunosuppressive tumour microenvironment (TME) is increasingly recognised as a central determinant of this resistance, but existing literature largely treats individual TME components – tumour-associated macrophages, neutrophils, myeloid-derived suppressor cells, regulatory T cells, cancer-associated fibroblasts, exhausted T cells and others – as independent contributors. This review aimed to synthesise current cellular, molecular and spatial evidence on the HCC TME into a unified, systems-level explanation of ICI resistance. Methods: A literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science Core Collection, combining terms for HCC, the TME, individual TME cell populations, and methodological/therapeutic aspects, supplemented by a snowballing search of reference lists and a direct search of ClinicalTrials.gov for relevant trials. Results: The review characterises the physiological basis of hepatic immune tolerance and its pathological co-option in HCC, the principal immunosuppressive cell populations and their intercellular network, the contribution of the gut and intratumoural microbiome, and the spatial architecture of the TME, including the invasive tumour margin. Integrating these findings, we propose five interrelated principles of TME-centred ecosystem resistance – immune exclusion, distributed robustness, functional entrapment, multiscale feedback stabilisation, and surface–depth mismatch – that jointly explain why single-checkpoint blockade is frequently insufficient. Conclusions: Overcoming ICI resistance in HCC requires combination strategies that target multiple, interacting nodes of the suppressive TME network rather than the PD-1/PD-L1 axis alone, guided by aetiology-aware, spatially resolved biomarkers.

Abstract: Background and Objectives: Metabolic and bariatric surgery improves obesity and metabolic dys-function-associated steatotic liver disease (MASLD), but its effect on the residual risk of hepatocellu- lar carcinoma (HCC) is less clearly defined. This narrative review examines the relationship between postoperative metabolic improvement, fibrosis regression, and HCC risk, with particular attention to surveillance. Materials and Methods: A targeted literature search identified clinical studies, mechanistic investigations, and professional guidance relevant to bariatric surgery, MASLD, and HCC. Results: Randomized and paired-biopsy studies support improvement in steatohepatitis, whereas observational cohorts associate surgery with lower HCC occurrence and fewer major adverse liver outcomes. These findings address different endpoints and should not be treated as interchangeable evidence of cancer prevention. Advanced fibrosis can persist despite substantial weight loss and resolution of steatohepatitis. Conversely, the absolute postoperative HCC risk among patients with documented fibrosis regression remains insufficiently characterized. The available evidence does not establish a postoperative biochemical, elastographic, or histological threshold at which surveillance can safely be stopped in patients with established cirrhosis. Conclusion: Surveillance decisions should therefore remain anchored to the underlying liver disease, treatment eligibility, and applicable guidance rather than weight loss alone. Noncirrhotic advanced fibrosis requires individualized assessment because professional recommendations differ and evidence is limited. Future studies should report HCC separately from composite liver outcomes and evaluate risk according to baseline and postoperative fibrosis, metabolic trajectories, and surveillance exposure. Bariatric surgery may modify the course of liver disease, but metabolic improvement should not be equated with elimination of carcinogenic risk.

Abstract: Gastrointestinal filling and contraction expose the gut wall to changing mechanical loads. Interstitial cells of Cajal (ICC) respond to these loads, but the channels that couple force to pacemaker activity remain incompletely defined. This narrative review examines direct recordings from ICC, proposed channel mechanisms and the epithelial, neural and muscular pathways that shape the motor response. Perfusion shear enhances NaV1.5 current in human jejunal ICC, whereas hypotonic swelling activates a Cl⁻ current in cultured murine ICC whose molecular identity remains unresolved. ANO1 converts intracellular Ca²⁺ signals into depolarization; evidence for its direct mechanical gating is lacking. Piezo1 and TRPM7 are candidate upstream mechanisms in ICC. Piezo2 instead has established functions in epithelial mechanosensing and extrinsic sensory pathways, with effects that depend on the cells and circuits involved. Within the electrically coupled smooth muscle–ICC–PDGFRα⁺ cell network, these inputs alter excitability, propagation and the timing of contraction. Increased local slow-wave frequency can therefore disrupt coordination rather than improve propulsion. Human genetics and tissue studies link channel dysfunction and ICC abnormalities to gastrointestinal motor disorders, but do not yet establish an ICC-specific mechanosensory lesion. Progress toward treatment will require experiments that connect defined mechanical stimuli, currents in identified cells and organ-level motor function.

Abstract: Surgical interventions in cirrhotic patients are a relevant problem due to the high rates of perioperative morbidity and mortality. The purpose of this review is to provide up–to-date information on the current principles of extrahepatic abdominal surgery in cirrhotic patients. They are based on stratification of patients by risk groups and a multidisciplinary individual approach to the choice of treatment strategy. The implementation of these provisions includes the use of scores for predicting perioperative risk, diagnosis and possible correction of clinically significant portal hypertension, prophylaxis of infectious complications and postoperative venous thromboembolism, monitoring of coagulopathy and cardiovascular disorders, nutritional support and etiological therapy. When choosing the optimal method of surgical treatment in urgent cases, one should strive to use minimally invasive technologies. If elective operations are considered, a thorough examination of patients is necessary to determine the risk factors for adverse outcome, resolve issues of preoperative preparation, and choice of the scope and timing of the surgical intervention. It can be assumed that the thoughtful implementation of these principles in clinical practice and, in prospect, the use of robotics and artificial intelligence will improve the safety of extrahepatic abdominal surgery in cirrhotic patients.

Abstract: Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated disorders characterized by considerable clinical and biological heterogeneity. Despite major advances in biologic therapies and small molecules, a considerable proportion of patients fail to achieve sustained clinical and endoscopic remission, highlighting the therapeutic ceiling of current treatment strategies. Increasing evidence suggests that treatment failure may result from the activation of multiple, partially overlapping inflammatory pathways that are not adequately controlled by single-agent therapy. Advanced combination therapy (ACT), defined as the concomitant use of two targeted therapies with complementary mechanisms of action, has emerged as a potential strategy to overcome these limitations, particularly in patients with refractory disease, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. This review summarizes the biological rationale, current clinical evidence, safety considerations, and practical applications of ACT in IBD. Available observational studies and emerging prospective data suggest that ACT may improve clinical and endoscopic outcomes in selected patients without a clear short-term increase in serious adverse events. However, important uncertainties remain regarding optimal patient selection, treatment sequencing, duration of therapy, de-escalation strategies, long-term safety, and cost-effectiveness.As the therapeutic landscape continues to evolve, ACT represents a promising step toward a more personalized and mechanism-based approach to IBD management. Ongoing clinical studies and the development of novel multi-target therapeutic strategies will be critical to define its future role in clinical practice.