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A nutritional approach could be a promising strategy to prevent or decrease the progression of neurodegenerative disorders such as Parkinson's disease (PD). The neuroprotective role of walnut oil (WO) was investigated in Drosophila melanogaster treated with rotenone (Rot), as a PD model, WO, or their combination, and compared to controls. WO reduced mortality and improved locomotor activity impairment after 3 and 7 days, induced by Rot. LC-MS analyses of fatty acid levels in Drosophila heads showed a significant increase in linolenic (ALA) and linoleic acid (LA) both in flies fed with the WO-enriched diet and in those treated with the association of WO with Rot. Flies supplemented with the WO diet showed an increase in brain dopamine (DA) level, while Rot treatment significantly depleted dopamine content; conversely, the association of Rot with WO did not modify DA content compared to controls. The greater intake of ALA and LA in the enriched diet enhanced their levels in Drosophila brain, suggesting a neuroprotective role of polyunsaturated fatty acids against Rot-induced neurotoxicity. The involvement of the dopaminergic system in the improvement of behavioral and biochemical parameters in Drosophila fed with WO is also suggested.

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BACKGROUND: Automated analysis of lung computed tomography (CT) scans may help characterize subphenotypes of acute respiratory illness. We integrated lung CT features measured via deep learning with clinical and laboratory data in spontaneously breathing subjects to enhance the identification of COVID-19 subphenotypes. METHODS: This is a multicenter observational cohort study in spontaneously breathing patients with COVID-19 respiratory failure exposed to early lung CT within 7 days of admission. We explored lung CT images using deep learning approaches to quantitative and qualitative analyses; latent class analysis (LCA) by using clinical, laboratory and lung CT variables; regional differences between subphenotypes following 3D spatial trajectories. RESULTS: Complete datasets were available in 559 patients. LCA identified two subphenotypes (subphenotype 1 and 2). As compared with subphenotype 2 (n = 403), subphenotype 1 patients (n = 156) were older, had higher inflammatory biomarkers, and were more hypoxemic. Lungs in subphenotype 1 had a higher density gravitational gradient with a greater proportion of consolidated lungs as compared with subphenotype 2. In contrast, subphenotype 2 had a higher density submantellar-hilar gradient with a greater proportion of ground glass opacities as compared with subphenotype 1. Subphenotype 1 showed higher prevalence of comorbidities associated with endothelial dysfunction and higher 90-day mortality than subphenotype 2, even after adjustment for clinically meaningful variables. CONCLUSIONS: Integrating lung-CT data in a LCA allowed us to identify two subphenotypes of COVID-19, with different clinical trajectories. These exploratory findings suggest a role of automated imaging characterization guided by machine learning in subphenotyping patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04395482. Registration date: 19/05/2020.

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BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) can lower the risk of first decompensation in patients with cirrhosis and clinically significant portal hypertension (CSPH) (identified by a hepatic venous pressure gradient ≥10 mmHg) with active etiology. Our aim was to examine the effect of NSBB on first decompensation occurrence in patients with cirrhosis and enduring CSPH after etiological treatment. METHODS: Patients with compensated cirrhosis and clinical evidence of CSPH (gastroesophageal varices -GEV- and/or spontaneous portosystemic collaterals- SPSS) after two years from etiological treatment. Primary endpoint was first decompensation (occurrence of variceal bleeding, ascites, or hepatic encephalopathy) in patients on-NSBB vs. off-NSBB. RESULTS: Final cohort included 406 patients. Baseline characteristics of patients on-NSBB (n=187) and off-NSBB (n=219) were comparable, except for signs of PH that were more pronounced in the on-NSBB group. During a mean follow-up of 32 months, 127 (31%) patients decompensated, with ascites being the most common (77%) decompensating event. Decompensation rates were lower in patients on-NSBB (16% vs 44%, p<0,0001). The benefit of NSBB on decompensation was maintained in patients with small GEV (17% vs 43%, p<0,0001), in those with SPSS only (8% vs 43%, p=0,003) and in each different etiology, including HCV-cured cirrhosis (9% vs 32%, p<0,0001). At Cox regression analysis, Hemoglobin, Child-Pugh, MELD-Na, diabetes at baseline and previous bacterial infections were independent predictors of decompensation, while NSBB-use had a protective effect (HR 0,32, 95% CI 0,20-0,49; p<0,0001). NSBB-use significantly reduced bacterial infection rates (HR 0,36, 95% CI 0,22-0,58; p<0,0001). CONCLUSION: NSBB decrease the risk of first decompensation in patients with cirrhosis and enduring CSPH after etiological treatment.

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BACKGROUND: Lung perfusion defects, mainly due to endothelial and coagulation activation, are a key contributor to COVID-19 respiratory failure. COVID-19 patients may also develop acute kidney injury (AKI) because of renal perfusion deficit. We aimed to explore AKI-associated factors and the independent prediction of standardized minute ventilation (MV)-a proxy of alveolar dead space-on AKI onset and persistence in COVID-19 mechanically ventilated patients. METHODS: This is a multicenter observational cohort study. We enrolled 157 COVID-19 patients requiring mechanical ventilation and intensive care unit (ICU) admission. We collected clinical information, ventilation, and laboratory data. AKI was defined by the 2012 KDIGO guidelines and classified as transient or persistent according to serum creatinine criteria persistence within 48 h. Ordered univariate and multivariate logistic regression analyses were employed to identify variables associated with AKI onset and persistence. RESULTS: Among 157 COVID-19 patients on mechanical ventilation, 47% developed AKI: 10% had transient AKI, and 37% had persistent AKI. The degree of hypoxia was not associated with differences in AKI severity. Across increasing severity of AKI groups, despite similar levels of paCO2, we observed an increased MV and standardized MV, a robust proxy of alveolar dead space. After adjusting for other clinical and laboratory covariates, standardized MV remained an independent predictor of AKI development and persistence. D-dimer levels were higher in patients with persistent AKI. CONCLUSIONS: In critically ill COVID-19 patients with respiratory failure, increased wasted ventilation is independently associated with a greater risk of persistent AKI. These hypothesis-generating findings may suggest that perfusion derangements may link the pathophysiology of both wasted ventilation and acute kidney injury in our population.

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Introduction: Lung carcinoids (LCs) are a type of neuroendocrine tumor (NET) that originate in the bronchopulmonary tract. LCs account for 20-25% of all NETs and approximately 1-2% of lung cancers. Given the highly vascularized nature of NETs and their tendency to overexpress vascular growth factor receptors (VEGFR), inhibiting angiogenesis appears as a potential therapeutic target in slowing down tumor growth and spread. This study evaluated the long-term antitumor activity and related mechanisms of axitinib (AXI), a VEGFR-targeting drug, in LC cell lines. Methods: Three LC cell lines (NCI-H727, UMC-11 and NCI-H835) were incubated with their respective EC50 AXI concentrations for 6 days. At the end of the incubation, FACS experiments and Western blot analyses were performed to examine changes in the cell cycle and the activation of apoptosis. Microscopy analyses were added to describe the mechanisms of senescence and mitotic catastrophe when present. Results: The primary effect of AXI on LC cell lines is to arrest tumor growth through an indirect DNA damage. Notably, AXI triggers this response in diverse manners among the cell lines, such as inducing senescence or mitotic catastrophe. The drug seems to lose its efficacy when the DNA damage is mitigated, as observed in NCI-H835 cells. Conclusion: The ability of AXI to affect cell viability and proliferation in LC tumor cells highlights its potential as a therapeutic agent. The role of DNA damage and the consequent activation of senescence seem to be a prerequisite for AXI to exert its function.

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BACKGROUND AND AIMS: Baveno VII consensus suggests that screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa as they have a low probability of high-risk varices (HRV). Conversely, screening endoscopy is required in all patients with porto-sinusoidal vascular disorder (PSVD). This study aimed to evaluate the performance of SSM-VCTE to rule out HRV in patients with PSVD and signs of portal hypertension. APPROACH AND RESULTS: We retrospectively included patients with PSVD, ≥1 sign of portal hypertension, without a history of variceal bleeding, who underwent an SSM-VCTE within 2 years before or after an upper endoscopy in 21 VALDIG centers, divided into a derivation and a validation cohort. One hundred fifty-four patients were included in the derivation cohort; 43% had HRV. By multivariable logistic regression analysis, SSM-VCTE >40 kPa and serum bilirubin ≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL had a sensitivity of 96% to rule out HRV and could spare 38% of screening endoscopies, with 4% of HRV missed, and a 95% negative predictive value. In the validation cohort, including 155 patients, SSM combined with bilirubin could spare 21% of screening endoscopies, with 4% of HRV missed and a 94% negative predictive value. CONCLUSIONS: This study gathering a total of 309 patients with PSVD showed that SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL identifies patients with PSVD and portal hypertension with a probability of HRV <5%, in whom screening endoscopy can be spared.

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Untargeted tandem mass spectrometry (MS/MS) has become a high-throughput method to measure small molecules in complex samples. One key goal is the transformation of these MS/MS spectra into chemical structures. Computational techniques such as MS/MS library search have enabled the reidentification of known compounds. Analog library search and molecular networking extend this identification to unknown compounds. While there have been advancements in metrics for the similarity of MS/MS spectra of structurally similar compounds, there is still a lack of automated methods to provide site specific information about structural modifications. Here we introduce ModiFinder which leverages the alignment of peaks in MS/MS spectra between structurally related known and unknown small molecules. Specifically, ModiFinder focuses on shifted MS/MS fragment peaks in the MS/MS alignment. These shifted peaks putatively represent substructures of the known molecule that contain the site of the modification. ModiFinder synthesizes this information together and scores the likelihood for each atom in the known molecule to be the modification site. We demonstrate in this manuscript how ModiFinder can effectively localize modifications which extends the capabilities of MS/MS analog searching and molecular networking to accelerate the discovery of novel compounds.

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Venovenous bypass (VVB) use during liver transplantation (LT) is notably variable among the centres and it is actually restricted to surgically complex cases, severely unstable recipients or grafts from high-risk donors. Historically, VVB was associated with the classical LT with caval cross clamping, while not much is known about the safety of this technique applied to piggyback LT. This retrospective observational study evaluated the effects of VVB applied to piggyback LT on mortality, hospital outcomes, postoperative graft and other organ dysfunction. We retrospectively collected data about recipient status, surgical complexity and graft quality of all the piggyback LTs performed at the Transplant Unit of IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy, from January 2012 to December 2022. A propensity score (PS) was built taking into account the variables possibly associated with either VVB choice and the investigated outcomes with the average treatment overlap method. PS-weighted general linear models (GLMs) were developed to investigate the adjusted effect of VVB use on the selected outcomes. The final analysis included 874 LT cases, of whom 74 (8.5%) underwent VVB. The effective sample sizes after PS-weighting were 280.2 and 64.3 patients in the no-VVB and VVB groups, respectively. PS-weighted GLMs did not show any differences regarding hospital and graft-related outcomes. However, significantly higher odds ratios for serum creatinine > 2 mg/dL and AKIN stage 2 or 3 during the first 24 h after ICU admission together with a higher renal replacement therapy need during ICU stay were reported for VVB exposure in the weighted analyses. This study suggests similar mortality and length of stay but a higher risk for postoperative acute kidney injury in patients undergoing piggyback LT with VVB.

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Covering: 1995 to 2023Advances in bioanalytical methods, particularly mass spectrometry, have provided valuable molecular insights into the mechanisms of life. Non-targeted metabolomics aims to detect and (relatively) quantify all observable small molecules present in a biological system. By comparing small molecule abundances between different conditions or timepoints in a biological system, researchers can generate new hypotheses and begin to understand causes of observed phenotypes. Functional metabolomics aims to investigate the functional roles of metabolites at the scale of the metabolome. However, most functional metabolomics studies rely on indirect measurements and correlation analyses, which leads to ambiguity in the precise definition of functional metabolomics. In contrast, the field of natural products has a history of identifying the structures and bioactivities of primary and specialized metabolites. Here, we propose to expand and reframe functional metabolomics by integrating concepts from the fields of natural products and chemical biology. We highlight emerging functional metabolomics approaches that shift the focus from correlation to physical interactions, and we discuss how this allows researchers to uncover causal relationships between molecules and phenotypes.

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BACKGROUND: Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. AIM: We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. METHODS: In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. RESULTS: From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). CONCLUSIONS: Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death.

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Contour (Stryker, Kalamazoo, MI) is a relatively new endosaccular device for the treatment of intracranial aneurysms.1 2 Its unique cup-like shape permits treatment of most lesions, including wide-necked, irregular, and shallowed-shaped aneurysms. The sizing of the device only requires two parameters: neck size and equatorial plane (width). It must be positioned at the neck of the aneurysm with the device proximal marker in the parent artery. In our experience, dual antiplatelet therapy is usually not required for intrasaccular devices and this is also an advantage of the Contour device. We report two illustrative cases of wide-neck aneurysms in the anterior and posterior circulation, respectively (video 1). In this video we demonstrate the feasibility of this treatment in a middle cerebral artery bifurcation with atypical triangular shape and typical tip-basilar aneurysm. neurintsurg;16/3/225/V1F1V1Video 1 .

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BACKGROUND: Seeing the importance of healthy diet after liver transplant (LT), our study aimed to evaluate the adherence to Mediterranean diet (MD) in a large population of LT recipients. METHODS: The present multicenter study was developed in clinically stable, liver transplanted patients, from June to September 2021. Patients completed a survey about adherence to MD, Quality of Life (QoL), sport, and employment. To analyze the correlations, we computed Pearson's coefficients; while to compare subgroups, independent samples t-tests and ANOVAs. We used a multivariable logistic regression analysis to find the predictors of impaired adherence to MD. RESULTS: The questionnaire was administered to 511 patients. They were males in 71% of cases with a mean age of 63.1 years (SD±10.8). LT recipients coming from central Italy displayed higher adherence to the MD (M=11.10±1.91) than patients from northern (M=9.94±2.28, P<0.001) or southern Italy (M=10.04±2.16, P<0.001). Patients from central Italy showed a significantly higher consumption of fruit, vegetables, legumes, cereals, olive oil, fish and a significantly lower intake of dairy products than patients resident in the other Italian areas. At multivariate analysis, recipients from central Italy were 3.8 times more likely to report adherence to the MD. Patients with a high physical health score were more adherent to MD, as well as patients transplanted at an earlier time. CONCLUSIONS: We demonstrated that place of stay, time from transplant and physical dimension of QoL significantly influences the adherence to MD. Continuous information campaigns about a correct diet and lifestyle would be necessary.

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BACKGROUND: Mechanical thrombectomy for acute ischemic stroke is effective and includes different technical approaches. Operators use direct aspiration, a stent retriever, or a combination of both. Direct aspiration can be performed with various catheters of different sizes depending on the diameter of the occluded vessel. PURPOSE: We studied the relationship between the catheter diameter in regards to the occluded vessel diameter and the rate of successful recanalization. MATERIALS AND METHODS: We conducted a retrospective, monocentric study on a series of consecutive patients treated with mechanical thrombectomy. For each procedure, we extracted each attempt that used direct aspiration and rated the attempt as successful or unsuccessful. We also measured the occluded artery diameter and calculated the ratio between the occluded artery and the aspiration catheter diameters. We tested the association between the diameter ratio and the recanalization status. We also performed inter-rater agreement for the arterial diameter measurement between three interventional neuroradiologists. RESULTS: We included 119 patients with 201 attempts of direct aspiration. A higher diameter ratio was associated with a higher recanalization rate. The analysis in terciles showed that the odds of success were 4.80 higher when the ratio was >0.71 vs <0.54 (p < 0.01). Inter-rater agreement showed near-perfect intraclass correlation with 0.93 (0.91-0.94) consistency and 0.92 (0.90-0.94) absolute agreement. CONCLUSIONS: We demonstrated an association between higher recanalization and a diameter of ratio >0.71 between the aspiration catheter and the occluded artery. These results could guide intraoperative decisions regarding the appropriate selection of aspiration catheters during mechanical thrombectomy increasing the rate of successful recanalisation. A larger study could provide additional data to further specify the optimal ratio.

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Alpha-lipoic acid (ALA) is a natural antioxidant dithiol compound, exerting antiproliferative and antimetastatic effects in various cancer cell lines. In our study, we demonstrated that ALA reduces the cell growth of prostate cancer cells LNCaP and DU-145. Western blot results revealed that in both cancer cells, ALA, by upregulating pmTOR expression, reduced the protein content of two autophagy initiation markers, Beclin-1 and MAPLC3. Concomitantly, MTT assays showed that chloroquine (CQ) exposure, a well-known autophagy inhibitor, reduced cells' viability. This was more evident for treatment using the combination ALA + CQ, suggesting that ALA can reduce cells' viability by inhibiting autophagy. In addition, in DU-145 cells we observed that ALA affected the oxidative/redox balance system by deregulating the KEAP1/Nrf2/p62 signaling pathway. ALA decreased ROS production, SOD1 and GSTP1 protein expression, and significantly reduced the cytosolic and nuclear content of the transcription factor Nrf2, concomitantly downregulating p62, suggesting that ALA disrupted p62-Nrf2 feedback loop. Conversely, in LNCaP cells, ALA exposure upregulated both SOD1 and p62 protein expression, but did not affect the KEAP1/Nrf2/p62 signaling pathway. In addition, wound-healing, Western blot, and immunofluorescence assays evidenced that ALA significantly reduced the motility of LNCaP and DU-145 cells and downregulated the protein expression of TGFß1 and vimentin and the deposition of fibronectin. Finally, a soft agar assay revealed that ALA decreased the colony formation of both the prostate cancer cells by affecting the anchorage independent growth. Collectively, our in vitro evidence demonstrated that in prostate cancer cells, ALA reduces cell growth and counteracts both migration and invasion. Further studies are needed in order to achieve a better understanding of the underlined molecular mechanisms.

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Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder characterized by benign tumor growth in multiple organs, including the brain, kidneys, heart, eyes, lungs, and skin. Pathogenesis stems from mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR pathway, a critical regulator of cell growth and proliferation. Disruption of the tuberin-hamartin complex leads to overactivation of mTOR signaling and uncontrolled cell growth, resulting in hamartoma formation. Neurological manifestations are common in TSC, with epilepsy developing in up to 90% of patients. Seizures tend to be refractory to medical treatment with anti-seizure medications. Infantile spasms and focal seizures are the predominant seizure types, often arising in early childhood. Drug-resistant epilepsy contributes significantly to morbidity and mortality. This review provides a comprehensive overview of the current state of knowledge regarding the pathogenesis, clinical manifestations, and treatment approaches for epilepsy and other neurological features of TSC. While narrative reviews on TSC exist, this review uniquely synthesizes key advancements across the areas of TSC neuropathology, conventional and emerging pharmacological therapies, and targeted treatments. The review is narrative in nature, without any date restrictions, and summarizes the most relevant literature on the neurological aspects and management of TSC. By consolidating the current understanding of TSC neurobiology and evidence-based treatment strategies, this review provides an invaluable reference that highlights progress made while also emphasizing areas requiring further research to optimize care and outcomes for TSC patients.

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Lung carcinoids (LCs) comprise well-differentiated neuroendocrine tumors classified as typical (TCs) and atypical (ACs) carcinoids. Unfortunately, curative therapies remain elusive for metastatic LCs, which account for 25-30% of cases. This study evaluated the antitumor activity of axitinib (AXI), a second-generation tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) in human lung TC (NCI-H727, UMC-11, NCI-H835) and AC (NCI-H720) cell lines. In vitro and in vivo (zebrafish) assays were performed following AXI treatment to gather several read-outs about cell viability, cell cycle, the secretion of proangiogenic factors, apoptosis, tumor-induced angiogenesis and migration. AXI demonstrated relevant antitumor activity in human LC cells, with pronounced effects observed in UMC-11 and NCI-H720, characterized by cell cycle perturbation and apoptosis induction. AXI significantly hindered tumor induced-angiogenesis in Tg(fli1a:EGFP)y1 zebrafish embryos implanted with all LC cell lines and also reduced the invasiveness of NCI-H720 cells, as well as the secretion of several proangiogenic factors. In conclusion, our study provides initial evidence supporting the potential anti-tumor activity of AXI in LC, offering a promising basis for future investigations in mammalian animal models and, eventually, progressing to clinical trials.

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Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines.

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Inflammaging is a low-grade inflammatory state that can be considered an adaptive process aimed at stimulating appropriate anti-inflammatory response. Frailty is determined by the accumulation of molecular and cellular defects accumulated throughout life; therefore, an appropriate frailty computation could be a valuable tool for measuring biological age. This study aims to analyse the association between inflammatory markers and both chronological age "per se" and frailty. We studied 452 persons aged 43-114 years. A Frailty Index (FI) was computed considering a wide range of age-related signs, symptoms, disabilities, and diseases. Plasma concentrations of inflammatory cytokines and peripheral markers of neuroinflammation were analysed by next-generation ELISA. The mean age of the cohort was 79.7 (from 43 to 114) years and the median FI was 0.19 (from 0.00 to 0.75). The concentrations of most inflammatory markers increased significantly with chronological age, after adjustment for sex and FI. Interferon-γ was significantly affected only by FI, while interleukin (IL)-10 and IL-1ß were associated only with chronological age. In conclusion, we described different associations between inflammatory components and chronological vs. biological age. A better characterization of the molecular signature of aging could help to understand the complexity of this process.

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A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the neonatal period because of initial misdiagnosis of biliary atresia. Laboratory investigations showed hyperbilirubinemia (total bilirubin 1.76 mg/dL [<1.2 mg/dL]; conjugated 1.06 mg/dL [<0.3 mg/dL]) and cholestasis (GGT 78 U/L [<50 U/L]; ALP 200 U/L [<50 U/L]). Transabdominal ultrasound was limited by aerobilia due to the cholecystojejuno-anastomosis. Subsequent basal CT scan revealed an impacted stone within the patient's native common bile duct (CBD). Aerobilia in intrahepatic bile ducts and gallbladder was reported. Magnetic Resonance cholangiopancreatography confirmed the gallstone in the CBD compressing cystic duct and common hepatic duct, with dilation of the upstream bile ducts. Furthermore, the native CBD was obstructed by other gallstones. In Mirizzi syndrome, gallstones impacted in gallbladder's Hartmann's pouch or cystic duct extrinsically compress CBD. We suggest naming the present condition "Reverse Mirizzi Syndrome" (Renzulli Matteo Syndrome, RMS) because it is the exact opposite of Mirizzi syndrome.

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Safety data on MET inhibitors in patients with advanced NSCLC harboring MET exon 14 mutation and treated with frontline immune checkpoint inhibitors (ICIs) are still limited. Here, we describe clinical characteristics, liver biopsy features, and management of liver injury of two patients with a diagnosis of MET exon 14-mutant NSCLC receiving capmatinib after ICI failure. On the basis of histologic findings and exclusion of other potential causes, a diagnosis of drug-induced liver injury (DILI) associated with portal fibrosis was made in both cases. The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization. To provide a global safety perspective, we queried the Food and Drug Administration Adverse Event Reporting System and detected a robust disproportionality signal. Out of the 918 total reports with capmatinib from the Food and Drug Administration Adverse Event Reporting System database, DILI was recorded in 43 cases (4.7%), mostly serious (93.0%) with hospitalization and death recorded in 25.6% and 16.3% of the cases, respectively. The median time to onset was 42 days, with discontinuation and positive dechallenge documented in 41.9% and 39.5% of the cases, respectively. Anti-programmed cell death protein-1 agents were coreported in 11 DILI cases. Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.