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Purpose: To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS / BRAF wild-type (wt) metastatic colorectal cancer (mCRC)., Patients and Methods: IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS / BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test., Results: Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B., Conclusion: Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Study Aims: Despite lower patient adherence, the overnight split-dose (SD) intestinal preparation regimen is currently recommended for early morning colonoscopies. Using low-volume preparation, we compared performance of a "day before late" (DBL) regimen, with the whole preparation taken between 8.30 pm and midnight on the day before the endoscopic procedure vs the overnight SD regimen for colonoscopies scheduled between 8 am and 10 am., Patients and Methods: Patients were randomized to the DBL group (n = 162) or SD group (n = 158). The SD group took the second dose 5 hours before colonoscopy. Successful bowel cleansing, defined as an overall Boston Bowel Preparation Score ≥ 3, safety, compliance and tolerability were assessed in the two groups., Results: The DBL regimen failed to demonstrate non-inferiority compared with the SD regimen in terms of successful bowel cleansing (DBL, 88.2 % vs SD, 98.1%, P < 0.001). Subgroup analysis on colonoscopies before 9 am showed BBPS ≥ 3 rates of 94.6% and 100% in the DBL and SD groups, respectively P = 0.126). The two regimens showed similar compliance and tolerability. Compared with SD patients (25.5%), a lower proportion of DBL patients (13.9%) reported fear of incontinence during the journey to the hospital ( P = 0.01)., Conclusions: Albeit more tolerable, the DBL regimen was less effective than the SD regimen with regard to successful bowel cleansing for colonoscopies between 8 am and 10 am. Subgroup analysis on colonoscopies scheduled before 9 am showed that the two regimens have similar efficacy, suggesting that the DBL regimen may be a valuable alternative to the SD regimen for very early morning colonoscopies., Competing Interests: Conflict of Interest Giuseppe Grande, MD (corresponding author) is: - consultant for: Olympus, ERBE, Boston Scientific - conference speaker for: Alfa Sigma spa; Mayoly All other authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The endocannabinoid system (ECS), composed of receptors, endocannabinoids, and enzymes that regulate biosynthesis and degradation, plays a fundamental role in the physiology and pathology of the gastrointestinal tract, particularly in the small and large intestine and liver. Specifically, cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), located principally in the nervous system and immune cells, orchestrate processes such as intestinal motility, intestinal and hepatic inflammation, and energy metabolism, respectively. The main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), influence appetite, body weight regulation, and inflammatory states and thus have implications in obesity, non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS). Recent studies have highlighted the therapeutic potential of targeting the ECS to modulate gastrointestinal and metabolic diseases. In particular, peripheral CB1R antagonists and CB2R agonists have shown efficacy in treating intestinal inflammation, reducing hepatic steatosis, and controlling IBS symptoms. Moreover, the ECS is emerging as a potential target for the treatment of colorectal cancer, acting on cell proliferation and apoptosis. This review highlights the opportunity to exploit the endocannabinoid system in the search for innovative therapeutic strategies, emphasizing the importance of a targeted approach to optimize treatment efficacy and minimize side effects.

Irritable bowel syndrome (IBS) is a chronic and recurrent disorder characterized by gastrointestinal (GI) symptoms and psychological disorders. Individuals with an external locus of control (LoC), a personality trait influencing one's actions and outcomes, are more vulnerable to IBS. Physical activity can deal with GI symptoms, preserving mental and physical health. In this context, our study aimed to investigate differences in symptom and psychological profiles among IBS patients classified by internal or external LoC when patients engaged in an aerobic exercise program (AEP). Each IBS patient was administered the International Physical Activity Questionnaire-Short Form (IPAQ-SF) before treatment, and the Physical Capacity Assessment Tests were applied before and after treatment. Participants filled out a GI symptom questionnaire before and after the intervention and some validated psychological tests to evaluate the changes induced by AEP. The AEP consisted of 180 min of moderate-intensity aerobic walking activity a week. Fifty-four IBS patients completed the 12-week study; 37 belonged to the internal LoC group and 17 to the external one. The internal LoC subgroup had a higher percentage of physically active subjects and a better physical capacity at baseline than those with external LoC. Only patients with an internal LoC achieved a statistically significant increase in physical capacity as the effect of the AEP. However, there was no statistically significant difference when Delta was considered. The somatic and psychological health status of IBS patients in the external LoC group was poorer than that of the internal LoC group at the baseline, particularly abdominal pain, psychosocial functioning, and emotional distress. After AEP, patients showed significant improvement in scores on the IBS-related and psychological scales, regardless of whether they belonged to the external or internal LoC. The present study confirmed the importance of considering both the GI symptoms and the psychological profile when dealing with IBS. AEP organized in walking groups has shown significant improvements for all IBS patients. Since external LoC was associated with poorer health status, individually tailored interventions should be planned to increase patients' self-motivation to treatment.Trial registration: registration number NCT05453084. First Posted Date 12/07/2022., Competing Interests: Declarations. Competing interests: The authors declare that they have no competing interests. Ethics approval: Informed consent was obtained from all subjects involved in the study. Consent for publication: All authors have read and agreed to the published version of the manuscript., (© 2025. The Author(s).)

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.

Background: Diffuse intrinsic pontine glioma [DIPG] is a fatal pediatric disease characterized by a post-translational modification, a replacement of lysine by methionine in position 27 of the N-terminal [H3K27M] tail of histone 3 isoform-1 [H3.1] or histone 3 isoform-3 [H3.3], respectively, expressed in the DIPG-36 and DIPG-50 cells. We investigated the role of cation channels in DIPG cells for the first time and the effects of ATP-sensitive K + [KATP] and TRPV1 channel modulators., Methods: Experiments were performed using "in vitro" cytotoxic assays combined with the patch clamp technique, RT-PCR, Western blot, and flow cytometry assays., Results: The most effective anti-proliferative drugs were repaglinide and glibenclamide after short and long-term incubation [6-96 h]. These drugs reduced macroscopic currents of the DIPG cells recorded in whole-cell patch clamp. Repaglinide concentration dependently enhanced the target protein H3K27ac in Western blotting after 48 h of incubation. This drug reduced cell diameter and enhanced cleaved caspase-3 in DIPG cells; total AKT/mTOR levels and phospho-mTOR were downregulated in DIPG-36., Conclusions: KATP and TRPV1 channels are functionally expressed, and sulphonylureas are effective antiproliferative upregulating H3K27ac with apoptosis in DIPG cells and the sub-micromolar concentrations in DIPG-50.

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive tumor with limited treatment options. Zolbetuximab, a monoclonal antibody against the tight junction protein Claudin 18.2 has recently been developed. At present, few and conflicting data have been reported regarding the clinical-pathological features of Claudin 18.2 expression in PDA. The present study investigated the expression of Claudin 18.2 in histological samples from PDA patients with the aim of verifying its utility as a therapeutic biomarker. Claudin 18.2 immunoreactivity was assessed by immunohistochemical staining on 70 formalin-fixed, paraffin-embedded PDA specimens (28 surgical specimens and 42 fine needle aspiration biopsies). The results obtained were associated with the clinicopathological characteristics and the survival rate of patients. Claudin 18.2 was detected only in neoplastic cells, not in normal pancreatic tissue. Claudin 18.2 was positive in 50% of samples and a higher expression was associated with well- and moderately-differentiated tumors and lymph node-negative status. The high expression of Claudin 18.2 in neoplastic tissue and absence in normal cells suggested that this protein had an attractive role in PDA as both a diagnostic and a prognostic-therapeutic marker. High expression of Claudin 18.2 in neoplastic tissue was associated with more favorable prognostic parameters and the high percentage of positive samples obtained suggests that Zolbetuximab may be suitable for a large number of patients., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2025 Valentini et al.)

Navelina oranges ( Citrus sinensis ) are rich in phytonutrients and bioactive compounds, especially flavonoids like hesperidin. This study investigates the anti-inflammatory and anti-fibrotic properties of hesperidin (HE) and a polyphenol mixture from Navelina oranges (OE) in human hepatocytes (Hepa-RG) and hepatic stellate cells (LX-2), in order to elucidate the underlying molecular mechanisms. In Hepa-RG cells, HE treatment increased expression of cannabinoid receptor 2 (CB2R), which was associated with down-regulation of p38 mitogen-activated protein kinases (p38 MAPK) but had minimal impact on cyclooxygenase-2 (COX-2) and transforming growth factor-β (TGF-β) levels. Conversely, OE treatment not only enhanced CB2R levels and reduced p38 MAPK, but also promoted a significant reduction in both COX-2 and TGF-β levels, suggesting that OE might be more effective in mitigating inflammatory and fibrotic processes than HE. In LX-2 cells, HE treatment caused a notable decrease in both COX-2 and TGF-β levels, reflecting its efficacy in targeting fibrosis-associated inflammation. OE treatment, on the other hand, reduced Nuclear Factor-Kappa B p65 (NF-κB) expression, a critical transcription factor involved in inflammatory responses, though it did not significantly affect COX-2. LX-2 cells induced to fibrosis with TGF-β and treated with HE and OE showed a reduction in the expression levels of several fibrosis markers. In addition, HE and OE showed antioxidant effects by increasing protein levels of Cu, Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and catalase (CAT) and influencing the state of lipid peroxidation. Further research is needed to explore the effects of the treatments in activated hepatic stellate cells and in vivo liver disease models.

Background/Objectives : Endometrial cancer (EC) is the second most frequent gynecological malignant tumor in postmenopausal women. Pathogenic mechanisms related to the onset and development of the disease are still unknown. To identify dysregulated proteins associated with EC we exploited a combined in vitro/in silico approach analyzing the proteome of exosomes with advanced MS techniques and annotating their results by using Chymeris1 AI tools. Methods : To this aim in this pilot study, we performed a deep proteomics analysis with high resolution MS (HRMS), advanced computational tools and western blotting for proteomics data validation. Results : That allowed us to identify 3628 proteins in serum albumin-depleted exosomes from 10 patients with EC compared to 10 healthy controls. This is the largest number of proteins identified in EC serum EVs. After quantification and statistical analysis, we identified 373 significantly ( p < 0.05) dysregulated proteins involved in neutrophil and platelet degranulation pathways. A more detailed bioinformatics analysis revealed 61 dysregulated enzymes related to metabolic and catabolic pathways linked to tumor invasion. Through this analysis, we identified 49 metabolic and catabolic pathways related to tumor growth. Conclusions : Altogether, data shed light on the metabolic pathways involved in tumors. This is very important for understanding the metabolism of EC and for the development of new therapies.

Chrono-nutritional factors may play a significant role in glucose regulation and the risk of type 2 diabetes (T2D). We investigated the association between breakfast skipping (BS) and fasting plasma glucose (FPG) levels in a non-diabetic cohort of the ABCD project (nutrition, cardiovascular wellness and diabetes) representing the general population of Palermo, Italy Among the 623 participants included in the analysis, 118 individuals were identified as BS. In men, BS was associated with higher values of FPG ( p  < .05), glycated haemoglobin ( p  < .01), triglycerides ( p  < .05) and insulin ( p  < .005). Among women, no significant differences were observed between BS and non-skippers. Multivariate regression analysis confirmed that BS was an independent predictor of higher FPG levels in men ( p  < .01); waist circumference emerged as the primary predictor of FPG in women ( p  < .001). This study supports the importance of dietary habits in glycaemic control and T2D risk.