The multifaceted landscape behind imatinib resistance in gastrointestinal stromal tumors (GISTs): A lesson from ripretinib

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal sarcomas and the gold-standard treatment is rep-resented by tyrosine kinase inhibitors (TKIs). Unfortunately, first-line treatment with the TKI imatinib usually promotes partial response or stable disease rather than a complete response, and resistance appears in most pa-tients. Adaptive mechanisms are immediately relevant at the beginning of imatinib therapy, and they may rep-resent the reason behind the low complete response rates observed in GISTs. Concurrently, resistant subclones can silently continue to grow or emerge de novo, becoming the most representative populations. Therefore, a slow evolution of the primary tumor gradually occurs during imatinib treatment, enriching heterogeneous ima-tinib resistant clonal subpopulations. The identification of secondary KIT/PDGFRA mutations in resistant GISTs prompted the development of novel multi-targeted TKIs, leading to the approval of sunitinib, regorafenib, and ripretinib. Although ripretinib has broad anti-KIT and-PDGFRA activity, it failed to overcome sunitinib as second-line treatment, suggesting that imatinib resistance is more multifaceted than initially thought. The present review summarizes several biological aspects suggesting that heterogeneous adaptive and resistance mechanisms can also be driven by KIT or PDGFRA downstream mediators, alternative kinases, as well as non -coding RNAs, which are not targeted by any TKI, including ripretinib. This may explain the modest effect observed with ripretinib and all anti-GIST agents in patients.& COPY; 2023 Elsevier Inc. All rights reserved

Arbutus unedo L. Fractions Exhibit Chemotherapeutic Properties for the Treatment of Gastrointestinal Stromal Tumors

Novel treatments in gastrointestinal stromal tumors (GISTs) are essential due to imatinib resistance and the modest results obtained with multi-target tyrosine kinase inhibitors. We investigated the possibility that the hydroalcoholic extract from the leaves of Arbutus unedo L. (AUN) could harbor novel chemotherapeutics. The bio-guided fractionation of AUN led to a subfraction, FR2-A, that affected the viability of both imatinib-sensitive and -resistant GIST cells. Cells treated with FR2-A were positive for Annexin V staining, a marker of apoptosis. A rapid PARP-1 downregulation was observed, although without the traditional caspase-dependent cleavage. The fractionation of FR2-A produced nine further active subfractions (FRs), indicating that different molecules contributed to the effect promoted by FR2-A. NMR analysis revealed that pyrogallol-bearing compounds, such as gallic acid, gallic acid hexoside, gallocatechin, myricetin hexoside, and trigalloyl-glucose, are the main components of active FRs. Notably, FRs similarly impaired the viability of GIST cells and peripheral blood mononuclear cells (PBMCs), suggesting a non-specific mechanism of action. Nevertheless, despite the lack of specificity, the established FRs showed promising chemotherapeutic properties to broadly affect the viability of GIST cells, including those that are imatinib-resistant, encouraging further studies to investigate whether pyrogallol-bearing compounds could represent an alternative avenue in GISTs

New insights into irritable bowel syndrome pathophysiological mechanisms: contribution of epigenetics

Irritable bowel syndrome (IBS) is a complex multifactorial condition including alterations of the gut-brain axis, intestinal permeability, mucosal neuro-immune interactions, and microbiota imbalance. Recent advances proposed epigenetic factors as possible regulators of several mechanisms involved in IBS pathophysiology. These epigenetic factors include biomolecular mechanisms inducing chromosome-related and heritable changes in gene expression regardless of DNA coding sequence. Accordingly, altered gut microbiota may increase the production of metabolites such as sodium butyrate, a prominent inhibitor of histone deacetylases. Patients with IBS showed an increased amount of butyrate-producing microbial phila as well as an altered profile of methylated genes and micro-RNAs (miRNAs). Importantly, gene acetylation as well as specific miRNA profiles are involved in different IBS mechanisms and may be applied for future diagnostic purposes, especially to detect increased gut permeability and visceromotor dysfunctions. In this review, we summarize current knowledge of the role of epigenetics in IBS pathophysiology

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Effect of visual stimuli of pain on empathy brain network in people with and without Autism Spectrum Disorder

The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some\u2014but not all\u2014previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD

Timing of Cholecystectomy After Moderate and Severe Acute Biliary Pancreatitis

IMPORTANCE Considering the lack of equipoise regarding the timing of cholecystectomy in patients with moderately severe and severe acute biliary pancreatitis (ABP), it is critical to assess this issue.OBJECTIVE To assess the outcomes of early cholecystectomy (EC) in patients with moderately severe and severe ABP.DESIGN, SETTINGS, AND PARTICIPANTS This cohort study retrospectively analyzed real-life data from the MANCTRA-1 (Compliance With Evidence-Based Clinical Guidelines in the Management of Acute Biliary Pancreatitis) data set, assessing 5304 consecutive patients hospitalized between January 1, 2019, and December 31, 2020, for ABP from 42 countries. A total of 3696 patients who were hospitalized for ABP and underwent cholecystectomy were included in the analysis; of these, 1202 underwent EC, defined as a cholecystectomy performed within 14 days of admission. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality and morbidity. Data analysis was performed from January to February 2023.MAIN OUTCOMES Mortality and morbidity after EC.RESULTS Of the 3696 patients (mean [SD] age, 58.5 [17.8] years; 1907 [51.5%] female) included in the analysis, 1202 (32.5%) underwent EC and 2494 (67.5%) underwent delayed cholecystectomy (DC). Overall, EC presented an increased risk of postoperative mortality (1.4% vs 0.1%, P <.001) and morbidity (7.7% vs 3.7%, P < .001) compared with DC. On the multivariable analysis, moderately severe and severe ABP were associated with increased mortality (odds ratio [OR], 361.46; 95% CI, 2.28-57 212.31; P = .02) and morbidity (OR, 2.64; 95% CI, 1.35-5.19; P = .005). In patients with moderately severe and severe ABP (n = 108), EC was associated with an increased risk of mortality (16 [15.6%] vs 0 [0%], P < .001), morbidity (30 [30.3%] vs 57 [5.5%], P < .001), bile leakage (2 [2.4%] vs 4 [0.4%], P = .02), and infections (12 [14.6%] vs 4 [0.4%], P < .001) compared with patients with mild ABP who underwent EC. In patients with moderately severe and severe ABP (n = 108), EC was associated with higher mortality (16 [15.6%] vs 2 [1.2%], P < .001), morbidity (30 [30.3%] vs 17 [10.3%], P < .001), and infections (12 [14.6%] vs 2 [1.3%], P < .001) compared with patients with moderately severe and severe ABP who underwent DC. On the multivariable analysis, the patient's age (OR, 1.12; 95% CI, 1.02-1.36; P = .03) and American Society of Anesthesiologists score (OR, 5.91; 95% CI, 1.06-32.78; P = .04) were associated with mortality; severe complications of ABP were associated with increased mortality (OR, 50.04; 95% CI, 2.37-1058.01; P = .01) and morbidity (OR, 33.64; 95% CI, 3.19-354.73; P = .003).CONCLUSIONS AND RELEVANCE This cohort study's findings suggest that EC should be considered carefully in patients with moderately severe and severe ABP, as it was associated with increased postoperative mortality and morbidity. However, older and more fragile patients manifesting severe complications related to ABP should most likely not be considered for EC