The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition.

BACKGROUND: Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution. METHODS: 187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected. RESULTS: An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16-5, p = 0.02, and HR:5.931, CI:2-17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1-T2 Δ) was demonstrated. CONCLUSIONS: The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.

Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with high mortality due to early metastatic dissemination and high chemoresistance. All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. METHODS: For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pHe 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine. RESULTS: We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. CONCLUSIONS: We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and Delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5,492 HBsAg-positive enrolled patients, 4,152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age≤40 years vs. 2.1%; p<0.001), more often females (males 43.0% vs. 68.6%; p<0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.

Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

Non-small cell lung cancer: an update on emerging EGFR-targeted therapies.

INTRODUCTION: Current research in EGFR-mutated NSCLC focuses on the management of drug resistance and uncommon mutations, as well as on the opportunity to extend targeted therapies' field of action to earlier stages of disease. AREAS COVERED: We conducted a review analyzing literature from the PubMed database with the aim to describe the current state of art in the management of EGFR-mutated NSCLC, but also to explore new strategies under investigation. To this purpose, we collected recruiting phase II-III trials registered on Clinicaltrials.govand conducted on EGFR-mutated NSCLC both in early and advanced stage. EXPERT OPINION: With this review, we want to provide an exhaustive overview of current and new potential treatments in EGFR-mutated NSCLC, with emphasis on the most promising newly investigated strategies, such as association therapies in the first-line setting involving EGFR-TKIs and chemotherapy (FLAURA2) or drugs targeting different driver pathways (MARIPOSA). We also aimed at unearthing challenges to achieve in this field, specifically the need to fully exploit already available compounds while developing new ones, the management of new emerging toxicities and the necessity to improve our biological understanding of the disease to design trials with a solid scientific rationale and to allow treatment personalization such in case of uncommon mutations.

Melanocortin 3,5 receptors immunohistochemical expression in colonic mucosa of inflammatory bowel disease patients: A matter of disease activity?

BACKGROUND: Melanocortin 3 and 5 receptors (i.e., MC3R and MC5R) belong to the melanocortin family. However, data regarding their role in inflammatory bowel diseases (IBD) are currently unavailable. AIM: This study aims to ascertain their expression profiles in the colonic mucosa of Crohn's disease (CD) and ulcerative colitis (UC), aligning them with IBD disease endoscopic and histologic activity. METHODS: Colonic mucosal biopsies from CD/UC patients were sampled, and immunohistochemical analyses were conducted to evaluate the expression of MC3R and MC5R. Colonic sampling was performed on both traits with endoscopic scores (Mayo endoscopic score and CD endoscopic index of severity) consistent with inflamed mucosa and not consistent with disease activity (i.e., normal appearing mucosa). RESULTS: In both CD and UC inflamed mucosa, MC3R (CD: + 7.7 fold vs normal mucosa, P < 0.01; UC: + 12 fold vs normal mucosa, P < 0.01) and MC5R (CD: + 5.5 fold vs normal mucosa, P < 0.01; UC: + 8.1 fold vs normal mucosa, P < 0.01) were significantly more expressed compared to normal mucosa. CONCLUSION: MC3R and MC5R are expressed in the colon of IBD patients. Furthermore, expression may differ according to disease endoscopic activity, with a higher degree of expression in the traits affected by disease activity in both CD and UC, suggesting a potential use of these receptors in IBD pharmacology.

Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease.

BACKGROUND AIMS: Metabolic dysfunction associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of hepatocellular carcinoma (HCC). Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD. METHODS: We considered individuals with MASLD-HCC (n=208) and controls with (n=414) and without (n=259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with VAF ≥2%. RESULTS: CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 and ASXL1, and correlated with age (p<0.0001) and advanced liver fibrosis (p=0.001). Higher AST levels predicted non-DNMT3A-CHIP, in particular with variant allele frequency (VAF)≥10% (OR 1.14, 1.03-1.28 and OR 1.30, 1.12-1.49, respectively, p<0.05). After adjustment for sex, diabetes and a polygenic risk score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30-3.15, p=0.02), and with HCC even after further adjustment for cirrhosis (OR 1.81, 1.11-2.00, 1.30-3.15, p=0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non-DNTM3A-CHIP and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR 2.45, 1.35-4.53; OR 4.8, 1.60-17.0, p=0.02). CONCLUSIONS: We observed an independent association between CHIP, particularly related to non-DNTM3A and TET2 genetic lesions, and MASLD-HCC.

Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are typical and recurrent, but the underlying mechanisms and clinical implications of these patterns are poorly understood. Here, we investigated structures of > 8,000 kinase fusions and explore their generative mechanisms by applying newly developed experimental framework integrating high-throughput genome-wide gene fusion sequencing and clonal selection called Functionally Active Chromosomal Translocation Sequencing (FACTS). We discovered that typical oncogenic TK fusions recurrently seen in patients are selected from large pools of chromosomal rearrangements spontaneously occurring in cells based on two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies, as well as a shorter progression-free survival (PFS) and overall survival (OS) compared to patients with typical TK fusions. These findings highlight the principles of oncogenic TK fusion formation and their selection in cancers, with clinical implications for guiding targeted therapy.

The JAK-STAT Pathway as a Therapeutic Strategy in Cancer Patients with Immune Checkpoint Inhibitor-Induced Colitis: A Narrative Review.

Immunotherapy has emerged as a pivotal component in the treatment of various malignancies, encompassing lung, skin, gastrointestinal, and head and neck cancers. The foundation of this therapeutic approach lies in immune checkpoint inhibitors (ICI). While ICIs have demonstrated remarkable efficacy in impeding the neoplastic progression of these tumours, their use may give rise to substantial toxicity, notably in the gastrointestinal domain, where ICI colitis constitutes a significant aspect. The optimal positioning of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibitors in the therapeutic management of ICI colitis remains unclear. Numerous reports have highlighted notable improvements in ICI colitis through the application of pan-JAK-STAT inhibitors, with tofacitinib, in particular, reporting evident clinical remission of colitis. The precise mechanism by which JAK-STAT inhibitors may impact the pathogenetic process of ICI colitis remains inadequately understood. However, there is speculation regarding their potential role in modulating memory resident CD8+ T lymphocytes. The elucidation of this mechanism requires further extensive and robust evidence, and ongoing JAK-STAT-based trials are anticipated to contribute valuable insights.

Navigating challenges in EGFR exon 20 insertions: The PAPILLON trial unravels the promise of amivantamab-chemotherapy.

The PAPILLON trial showed that adding amivantamab to carboplatin-pemetrexed for advanced non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations is more effective than chemotherapy. Although safety concerns may arise, this study highlights the need for alternative therapeutic strategies beyond chemotherapy for this subtype of NSCLC.

Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer.

PURPOSE: Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown. METHODS: Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls. RESULTS: We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts. CONCLUSION: These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.

Effective retreatment with osimertinib in CNS-relapsed epidermal growth factor receptor-mutant non-small cell lung cancer patient following resection and adjuvant osimertinib.

For years, adjuvant chemotherapy has been the only standard treatment for resected non-small cell lung cancer patients (NSCLC), offering a dismal survival improvement at 5 years. Following the outstanding results of the recent ADAURA trial, osimertinib has become a new standard treatment for resected epidermal growth factor receptor (EGFR)-mutant non-squamous NSCLC, regardless of the administration of chemotherapy. For patients whose disease relapses after completion of the adjuvant therapy, there is no consensus about the optimal treatment. Herein, we report the case of a 74-year-old woman diagnosed with stage IIIA non-squamous NSCLC, harboring the EGFR p.L858R mutation. After complete tumor resection, the patient received adjuvant chemotherapy with cisplatin and vinorelbine, followed by osimertinib 80 mg daily for 3 years within the ADAURA trial. Brain disease relapse was documented 18 months after treatment completion by computed tomography scans. The patient was then retreated with osimertinib obtaining a deep intracranial partial response, which is still lasting after 21 months. The retreatment with osimertinib in patients whose disease relapsed following adjuvant therapy with the third-generation EGFR inhibitor might be a valid option, especially in patients with intracranial disease relapse. Studies are warranted to confirm this finding and to define the impact of the disease-free interval in this regard.

Predicting de-novo portal vein thrombosis after HCV eradication: A long-term competing risk analysis in the ongoing PITER cohort.

BACKGROUND & AIMS: Sustained virological response (SVR) by direct-acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non-tumoral PVT in patients with cirrhosis after HCV eradication. METHODS: Patients with HCV-related cirrhosis, consecutively enrolled in the multi-center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan-Meier and competing risk regression analyses were performed. RESULTS: During a median time of 38.3 months (IQR: 25.1-48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count ≤120,000/µL, albumin levels ≤3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB-4, and RESIST scores were significantly different (p < 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33-24.99) and pre-treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36-13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p < 0.001) versus pre-treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p > 0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16-27.53 and subHR: 5.50; CI 95% 1.67-18.13, respectively). CONCLUSIONS: In patients with HCV-related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

Inflammatory bowel diseases patients suffer from significant low levels and barriers to physical activity: The "BE-FIT-IBD" study.

BACKGROUND: The place regular physical activity (PA) should occupy in managing patients with inflammatory bowel diseases (IBD) is unclear. AIM: To assess PA levels and barriers in a southern Italian IBD population. METHODS: IBD patients with non-severe disease activity [assessed with partial Mayo score for ulcerative colitis (UC) and Harvey-Bradshaw index for Crohn's disease] were approached to receive an anonymous online questionnaire to assess PA levels using the International Physical Activity Questionnaire (IPAQ) and to assess disease activity as patient-reported outcomes 2 (PRO-2) and finally to assess habits, beliefs and barriers in conducting regular PA. Clinical, anthropometric and demographic data of patients were also collected. PA was expressed as continuous units of resting metabolic rate (Met) in min/wk. Three PA groups were identified: Inactive (< 700 Met min/wk), sufficiently active (700-2500 Met min/wk) and health enhancing PA (HEPA) (i.e., HEPA active, > 2500 Met min/wk) patients. RESULTS: Included patients (219) showed overall PA levels of 834.5 Met min/wk, with a large proportion (94, 42.9%) classified as inactive while only a minority (9, 4.1%) as health-enhancing PA. Patients without dyslipidaemia (P < 0.0001) or on biologics therapy (P = 0.022) showed better IPAQ scores in moderate activities. UC PRO-2 correlated negatively with IPAQ intense activities scores (τ = -0.156, P = 0.038). PRO-2 did not show notable sensitivity/specificity in predicting IPAQ inactivity (AUC < 0.6). IBD activity did not differ between active and inactive patients (P > 0.05). Active patients expressed the need to discuss PA with their gastroenterologist. Some barriers (e.g., diagnosis of IBD and fear of flare-ups after PA) are significantly more reported by inactive patients. CONCLUSION: A significant rate of physical inactivity was recorded in this setting. IPAQ showed good feasibility. PA should be an element of discussion in IBD visits assessed quickly with non-invasive questionnaires.

Environmental bisphenol A exposure triggers trained immunity-related pathways in monocytes.

Introduction: Trained Immunity represents a novel revolutionary concept of the immunological response involving innate immune cells. Bisphenol A is a well-known endocrine disrupter, widely disseminated worldwide and accumulated in the human body. Due to the increased interest regarding the effects of plastic-derived compounds on the immune system, our purpose was to explore whether BPA was able to induce trained immunity in human primary monocytes in vitro using low environmental concentrations. Materials and methods: We extracted BPA from the serum of 10 healthy individuals through a liquid-liquid extraction followed by a solid phase extraction and measured the concentration using an HPLC system coupled to a triple quadrupole mass spectrometer. In parallel, monocytes were isolated from whole blood and acutely stimulated or trained with BPA at three different concentrations (1 nM, 10 nM, 20 nM). Pro- and anti-inflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-10) production were assessed after 24 hours of acute stimulation and after Lipopolysaccharide (LPS) rechallenge. A comprehensive overview of the metabolic changes after BPA acute stimulation and trained immunity induction was assessed through extracellular lactate measurements, Seahorse XFb metabolic flux analysis and ROS production. Results: Monocytes primed with BPA showed increased pro- and anti-inflammatory cytokine responses upon restimulation, sustained by the modulation of the immunometabolic circuits. Moreover, we proved the non-toxic effect of BPA at each experimental concentration by performing an MTT assay. Additionally, correlation analysis were performed between pro- and anti-inflammatory cytokines production after LPS acute stimulation or BPA-mediated trained immunity and BPA serum concentrations showing a significant association between TNF-α and BPA circulating levels. Discussion: Overall, this study pointed out for the first time the immunological effects of an environmental chemical and plastic-derived compound in the induction of trained immunity in a healthy cohort.

Neutrophil-to-Lymphocyte Ratio (NLR) in NSCLC, Gastrointestinal, and Other Solid Tumors: Immunotherapy and Beyond.

In the era of immunotherapy, identifying biomarkers of immune system activation has become a high-priority challenge. The blood neutrophil-to-lymphocyte ratio (NLR) has been largely investigated as a biomarker in several cancer types. NLR values have been shown to mirror the tumor-induced inflammatory status and have been demonstrated to be a reliable prognostic tool across stages of disease and therapeutic approaches. When integrated with other biomarkers of response to immunotherapy, such as PD-L1, tumor mutational burden, and tumor-associated immune cells, the NLR may allow to further stratify patients with different likelihoods of deriving a significant clinical benefit. However, despite its accessibility, low cost, and easy interpretation, the NLR is still poorly used as a prognostic tool in daily clinical practice. In this review, we analyze the role of the NLR in defining the relationship between cancer and the immune system, its usefulness in daily clinical practice, and its relationship with other established or emerging biomarkers of immunotherapy outcomes.

Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications.

Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.

Amplification of Wild-Type RET Represents a Novel Molecular Subtype of Several Cancer Types With Clinical Response to Selpercatinib.

PURPOSE: RET rearrangements and RET activating point mutations represent targetable genomic alterations in advanced solid tumors. However, the frequency and clinicopathologic characteristics of wild-type RET amplification in cancer and its potential role as a targetable oncogenic driver are not well-characterized. METHODS: In two institutional cohorts of patients with solid cancers from the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC) whose tumors underwent next-generation sequencing (NGS), the frequency and clinicopathologic features of wild-type RET amplification in the absence of RET rearrangements or activating mutations was assessed. The findings were validated using merged data from The Cancer Genome Atlas (TCGA), Genomics Evidence Neoplasia Information Exchange (GENIE), and China Pan-Cancer data sets. RESULTS: The frequency of wild-type RET amplification across all solid cancers was 0.08% (26 of 32,505) in the DFCI cohort, 0.05% (26 of 53,152) in the MSKCC cohort, and 0.25% (71 of 28,623) in the cohort from TCGA, GENIE, and China Pan-Cancer. Cancer types with RET amplification included non-small-cell lung cancer (NSCLC), hepatobiliary cancer, prostate cancer, breast cancer, and others. The median RET copy number in RET-amplified cases was 7.5 (range, 6-36) in the DFCI cohort and 5.7 (range, 4-27.7) in the MSKCC cohort. Among 11 RET-amplified NSCLCs, eight had no other concurrent driver mutations. Finally, we report on a 69-year-old man with recurrent NSCLC harboring high-level wild-type RET amplification (22-28 copies) as the only identified putative genomic driver who experienced both a systemic and intracranial confirmed response to the RET inhibitor selpercatinib. CONCLUSION: Amplification of wild-type RET represents a novel, targetable molecular subset of cancer.