Search Results (6,914)

Background: This study addresses an important vulnerability in the treatment of high-risk neuroblastoma (NB). NB is characterized by high rates of metastasis, drug resistance, relapse, and treatment-related toxicities. Current treatments, which include intensive chemotherapy, surgical removal of tumors, and stem cell transplants, have less than 50 percent survival rates among high-risk NB patients, demonstrating the need for novel targeted treatment approaches. CXC chemokine receptor 2 (CXCR2), a G-protein-coupled receptor, has been implicated in promoting cancer cell proliferation, invasion, metastasis, angiogenesis, chemoresistance, and maintaining cancer stem cells. Methods: We analyzed transcriptomic data from 1,464 primary NB patient samples to evaluate the prognostic significance of CXCR2 expression. Pharmacological inhibition of CXCR2 using SB225002, a selective small-molecule antagonist, was evaluated to determine its effects on cell growth, colony formation, apoptosis, and cell cycle progression in different NB cell lines. Three-dimensional (3D) spheroid models were used to examine tumor growth under physiologically relevant conditions. Mechanistic studies included gene expression analyses and immunoblot validation of key signaling regulators. Results: High CXCR2 expression was found to be inversely correlated with overall survival in patient datasets, suggesting a role in NB pathogenesis. Treatment with SB225002 significantly inhibited NB proliferation and colony formation while inducing apoptosis and cell cycle arrest in a dose-dependent manner. In 3D spheroid models, SB225002 significantly impaired spheroid formation and growth, confirming its potent anti-tumor efficacy. Mechanistically, CXCR2 blockade inhibited the expression of key pathway targets, including GLIPR1, BACH2, JUN, CHEK1, AKT1, and CXCR2 itself. Immunoblot analysis confirmed significant inhibition of CXCR2 and GLIPR1 protein levels in response to SB225002 treatment. Conclusions: Taken together, our findings demonstrate that pharmacological inhibition of CXCR2 using SB225002 effectively inhibits NB tumor cell growth and tumorigenicity by modulating oncogenic signaling networks. This study provides strong evidence for elucidating CXCR2-targeted therapies as an attractive treatment option for NB. These findings support the development of CXCR2-targeted therapies for high-risk NB. Full article

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite harmful consequence, and long-lasting changes in the brain. The reward system, which involves dopaminergic circuits, plays a key role in addiction. Dopamine levels have been described to fluctuate throughout the day, in a circadian fashion, and the effects of drugs have been shown to depend on the time when they are used. Hence, due to its important role in the control of circadian rhythms, the orexinergic system seems to have a role in the regulation of addiction. This system is composed by the orexin receptors 1 and 2 (OX₁R and OX₂R), the ligands orexin A (OXA) and orexin B (OXB) and their respective enzymes for degradation or synthesis. Here, we explore how orexin receptors and orexin peptides are involved in addiction. For instance, OX₁R has been shown to be strongly involved in specific behaviors such as drug-seeking for stimulants, alcohol and other addiction problems, whereas OX₂R appears to be linked with arousal and stress responses. We also investigate how the orexinergic system may regulate drug-seeking behavior by interaction with other brain systems such as the dopaminergic, cannabinoid or opioid systems. Finally, the potential of receptor complexes as new therapeutic targets to treat drug addiction is explored. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are often complicated by immune-related adverse events, particularly colitis. With increasing ICI use, understanding the clinical course and management of ICI-induced colitis is essential. Objectives: To characterize the clinical, endoscopic, and histological features of ICI-induced colitis and evaluate treatment outcomes, focusing on the use of corticosteroids and second-line biologicals (infliximab and vedolizumab) in a real-world setting. Methods: A retrospective cohort study was conducted at Ghent University Hospital, including 77 adult patients diagnosed with ICI-induced colitis in between 2012 and 2023. Clinical, biochemical, endoscopic, and histological data were analyzed, along with treatment response and safety outcomes. Results: Patients with ICI-induced colitis received anti-PD-1/PD-L1 (64.9%), anti-CTLA-4 (9.1%), or combination of both (26.0%). In patients with normal endoscopic findings, histological signs of colitis were observed in 88.0%. Combination ICI therapy was associated with higher Mayo scores (p = 0.029) and increased need for biologicals (p = 0.011) compared to anti-PD-1/PD-L1 monotherapy. Clinical response rates were 79.6% with corticosteroids and 100.0% with biologicals. Rechallenge with ICIs lead to a 17.4% relapse rate. No colitis-related deaths were observed. Conclusions: In this retrospective study, we demonstrate that random colon biopsies reveal microscopic ICI-induced colitis in most patients with absence of endoscopic disease. Combination ICI therapy predicts a corticosteroid-refractory course, supporting the need for early escalation to biologicals. ICI rechallenge appears feasible, as relapse rates were relatively low and colitis morbidity remained manageable. Prospective studies are needed to refine therapeutic strategies and improve patient outcomes. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality worldwide. This study evaluates the predictive value of Carcinoembryonic Antigen (CEA) in identifying CRC recurrence following surgical resection. Methods: This retrospective study was realized in the Oncology Institute in Cluj-Napoca and included 88 patients diagnosed with CRC. Clinical, demographic, and tumor-specific data were collected, including TNM staging, tumor histology. CEA levels were recorded before surgery. Receiver Operating Characteristic (ROC) analysis was performed to determine the diagnostic accuracy of CEA in predicting tumor relapse, and the sensitivity and specificity of various CEA cut-off values were assessed. Results: Most patients presented with advanced-stage tumors (T3/T4, 80.6%). CEA levels were significantly higher in patients with lymphatic and perineural invasion and in those with metastases (mean CEA: 45.0 ng/mL for M1 vs. 13.2 ng/mL for M0, p = 0.032). ROC analysis revealed an area under the curve (AUC) of 0.877 (95% CI: 0.763–0.949). A CEA cut-off value of 11.73 ng/mL yielded 100% sensitivity and 74.5% specificity for detecting recurrence; Conclusions: CEA is a valuable non-invasive biomarker for predicting CRC relapse, with high sensitivity and acceptable specificity. Regular CEA monitoring post-surgery can facilitate early detection of recurrence, improving prognosis. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that affects women more frequently than men. This sex gap has widened over the past century, and appears to be shaped by lifestyle factors more than biological factors. This narrative review examines the evidence for sex-specific differences in lifestyle risk factors and their impact on both MS susceptibility and disease progression, with implications for diagnosis, monitoring, and treatment. Smoking, obesity, vitamin D deficiency, ultraviolet radiation exposure, and Epstein–Barr virus infection all interact with sex-related biological pathways to influence MS risk. Women appear to be more vulnerable to the pathogenic effects of smoking and obesity, both independently and in synergy with genetic risk alleles, while vitamin D and UV exposure confer stronger protective effects in females than in males. EBV infection also exhibits sex-dependent immune responses, shaped by hormonal regulation and host–virus genetic interactions. Sex-related lifestyle factors also modulate MS progression. Women experience more inflammatory activity and relapses, whereas men more often develop a progressive phenotype with greater neurodegeneration. Hormonal changes during female reproductive phases, such as pregnancy, breastfeeding, menopause, and hormone-based therapies, critically influence disease activity and progression in MS. Obesity, smoking, vitamin D status, diet, and gut microbiota further interact with sex hormones and genetic background, contributing to variable disease trajectories, also modulated by social determinants such as education level. These findings underscore the need to integrate into clinical practice the evaluation of lifestyle factors in a sex-specific way for diagnosis, monitoring, and treatment of MS. Full article

Acute myeloid leukemia (AML) accounts for 15–20% of childhood leukemia cases; however, it is characterized by very high aggressiveness and has the highest mortality rate among leukemias, with relapse rates ranging from 34% to 38%. It is a disease characterized by high molecular diversity, and the frequency of specific genetic alterations in children is different from that in adults. Furthermore, mutations and rearrangements vary with age within the pediatric population. To date, a wide spectrum of genetic alterations has already been studied, but the molecular landscape of each patient is unique. An analysis of rearrangements and mutations specific to children of different ages appears to be crucial in order to individualize diagnosis and therapy appropriately. The aim of the following review is to analyze the molecular landscape of pediatric AML by age in detail in order to prioritize therapeutic strategies dedicated to specific age groups. Full article

Background: Antimicrobial drugs are used to treat bacterial diseases in livestock production systems, including bovine respiratory disease (BRD) in feedlot cattle. It is recommended that therapeutic antimicrobial use (AMU) in food animals be informed by diagnostic tests to limit the emergence of antimicrobial resistance (AMR) and preserve the effectiveness of available drugs. Recent evidence demonstrates preliminary support for the pen as a prospective target for AMR testing-based interventions in higher-risk cattle. Methods: A previously reported agent-based model (ABM) was modified and then used in this study to investigate the potential for different pen-level sampling and laboratory testing-informed BRD treatment strategies to favorably impact selected antimicrobial stewardship and management outcomes in the western Canadian context. The incorporation of sample testing to guide treatment choice was hypothesized to reduce BRD relapses, subsequent AMU treatments and resultant AMR in sentinel pathogen Mannheimia haemolytica. The ABM was extended to include a discrete event simulation (DES) workflow that models the testing process, including the time at sample collection (0 or 13 days on feed) and the type of AMR diagnostic test (antimicrobial susceptibility testing or long-read metagenomic sequencing). Candidate testing scenarios were simulated for both a test-only control and testing-informed treatment (TI) setting (n = 52 total experiments). Key model outputs were generated for both the pen and feedlot levels and extracted to data repositories. Results: There was no effect of the TI strategy on the stewardship or economic outcomes of interest under baseline ecological and treatment conditions. Changes in the type and number of uses by antimicrobial class were observed when baseline AMR in M. haemolytica was assumed to be higher at feedlot arrival, but there was no corresponding impact on subsequent resistance or morbidity measures. The impacts of sample timing and diagnostic test accuracy on AMR test positivity and other outputs were subsequently explored with a theoretical “extreme” BRD treatment protocol that maximized selection pressure for AMR. Conclusions: The successful implementation of a pen-level sampling and diagnostic strategy would be critically dependent on many interrelated factors, including the BRD treatment protocol, the prevalences of resistance to the treatment classes, the accuracy of available AMR diagnostic tests, and the selected “treatment change” thresholds. This study demonstrates how the hybrid ABM-DES model can be used for future experimentation with interventions proposed to limit AMR risk in the context of BRD management. Full article

Background: Idiopathic granulomatous mastitis (IGM) is a rare, benign, chronic inflammatory breast condition that poses diagnostic and therapeutic challenges. While corticosteroids are standard first-line therapy, some patients require additional immunomodulation, such as methotrexate. Predictive factors for step-up therapy remain poorly characterized. This study aimed to identify clinical, imaging, and pathological factors predictive of step-up therapy in IGM and evaluate associations between treatment approach and outcomes. Methods: A retrospective cohort study of women diagnosed with IGM was conducted between May 2022 and June 2024 at a tertiary center in Singapore. Data on demographics, clinical presentation, imaging, histopathology, and treatment were extracted. Step-up therapy was defined as methotrexate use following corticosteroids. Primary outcome was predictors of step-up therapy; secondary outcomes included treatment success, relapse, surgery, and time to remission. Statistical analyses included chi-square/Fisher’s exact tests, Cox models, and Kaplan-Meier analysis. Results: Fifty-two women (median age 39 years) were included; 26 (50%) required step-up therapy. Predictors included oral contraceptive (OCP) use (RR 1.92; 95% CI 1.45–2.53; p < 0.001), smoking (RR 2.00; 95% CI 1.49–2.69; p < 0.001), flares (RR 2.33; 95% CI 1.44–3.79; p = 0.002), and percutaneous aspiration (RR 2.10; 95% CI 1.53–2.88; p = 0.025). Patients receiving methotrexate had lower relapse rates (RR 1.23; 95% CI 1.12–1.36; p < 0.001) but longer time to remission (adjusted HR 0.09; 95% CI 0.02–0.46; p = 0.004). Conclusions: OCP use, smoking, flares, and aspiration need may predict step-up therapy in IGM. Early identification could guide a more personalized, potentially top-down treatment. Full article

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant therapeutic challenge, particularly when multiple resistance mechanisms, such as metallo-β-lactamases (MBLs) and Klebsiella pneumoniae carbapenemase (KPC), coexist. Case description: We describe a case of a 51-year-old male with a post-sternotomy surgical site infection and concurrent bacteremia caused by a CRKP. Sternal swab and mediastinal liquid culture results highlighted CRKP harboring bla_NDM and bla_KPC genes, while the blood isolate showed bla_CTX and bla_KPC, indicating phenotypic resistance to ceftazidime-avibactam. All the strains exhibited phenotypic susceptibility to meropenem-vaborbactam (MEV), despite having a high minimum inhibitory concentration. Following clinical failure of MEV-based therapy, combination treatment with aztreonam (ATM) and imipenem/cilastatin/relebactam (IMI/REL), plus gentamicin, was initiated. Therapy was well tolerated and resulted in microbiological eradication and full clinical recovery. The patient completed 49 days of ATM and IMI/REL without relapse over a 3-month follow-up period. This is, to the best of our knowledge, the first reported case of IMI/REL being used in combination with ATM. Full article

Pediatric-type diffuse high-grade gliomas (pHGGs) tend to have a dismal prognosis. Some of these gliomas feature alterations in genes such as ROS1, ALK, MET, and NTRK1–3. Despite development of targeted agents, the therapeutic application of these agents in pHGGs is still unclear. The aim of this retrospective case series is to report the outcome of two patients with pHGGs who were treated at Arkansas Children’s Hospital with targeted agents (Cabozantinib for a MET fusion in patient 1 and Lorlatinib for an ALK fusion in patient 2) with an initial, objective response followed by treatment resistance. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. In both cases, relapse occurred while on targeted inhibition. Recurrent tumor sequencing for patient 2 revealed a MET copy gain suggesting a mechanism of resistance in this patient. Pediatric high-grade gliomas with targetable alterations can show objective responses to pathway inhibition. Relapse after initial response may warrant additional surgical samples to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and earlier integration of these agents may be beneficial. Full article

Adult patients affected by acute myeloid leukemia who fail to achieve remission after two cycles of intensive chemotherapy based on a combination of anthracyclines and cytarabine are considered chemorefractory and are unlikely to benefit from further induction attempts. Characterized by a poor prognosis, they may still benefit from allogeneic hematopoietic stem cell transplantation, even if long-term survival rarely exceeds 20–30%. Still, the use of sequential high-dose chemotherapy followed by reduced-intensity conditioning, with transplantation performed during aplasia, and the optimization of the alloreactivity of donor leukocytes against leukemia (i.e., the graft-versus-leukemia effect) may ameliorate these results. Optimization of alloreactivity against leukemic cells can be achieved by proper donor selection, by the early withdrawal of immunosuppressive therapy, by post-transplant administration of donor lymphocyte infusions as prophylaxis of leukemia relapse, and by several other maintenance and preemptive therapies. Far from being the final stage of consolidation therapy, allogeneic hematopoietic stem cell transplantation is now considered as the moment when a unique immunological platform can be established in these patients, to be used for additional post-transplant measures. In this study we will critically review the different pre- and post-transplant strategies used in clinical trials to improve long-term survival in adult patients transplanted with chemorefractory leukemia. Full article

Background: The Comprehensive Geriatric Assessment (CGA) has proven to be a valuable tool for providing a more comprehensive health evaluation of allogeneic stem cell transplantation (allo-SCT) recipients. Methods: We prospectively developed and tested a new Simplified Geriatric Score-4 (SGS-4) on 135 consecutive patients aged ≥50 years who underwent allo-SCT between 2020 and 2023. Each CGA component was individually analyzed for its association with overall survival (OS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR). Then, we performed a two-factor analysis (FA) using oblimin rotation and Bartlett estimation on all CGA components and sex. Based on component weights, a simplified geriatric score-4 score (SGS-4) was created: [Gait Speed] + 2 × [Hand Grip] + Geriatric 8 + 1.5 × [Sex]. ROC analysis defined three fitness groups, frail (≤13), prefrail (>13–22.5), and fit (>22.5). Results: Reduced hand grip strength and impaired mini mental state examination (MMSE) were associated with worse OS and higher NRM. Vulnerable Elders Survey (VES-13) and Fondazione Italiana Linfomi (FIL) scores also indicated poorer OS, though with uneven group sizes. Other CGA domains and the Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI) showed no significant prognostic value. The SGS-4 effectively stratified patients into three fitness groups, with those in the frail category experiencing lower OS and an increased risk of relapse. Conclusions: The new Simplified Geriatric Score-4 (SGS-4) based on three CGA domains (gait speed, hand grip, Geriatric 8) and sex effectively predicts OS and CIR risk in patients aged ≥50 years undergoing allo-SCT. The study’s small sample size and disease heterogeneity warrant further validation in larger cohorts. Full article

Background: Seborrheic dermatitis (SD) is a chronic, recurrent inflammatory dermatosis that primarily affects seborrheic areas such as the scalp, face, and upper trunk. Its etiology is multifactorial, involving sebaceous gland activity, immune dysregulation, skin barrier dysfunction, and alterations in the microbiome, particularly an overgrowth of Malassezia spp. Objective: This review provides an updated overview of the pathophysiological mechanisms of seborrheic dermatitis and critically examines current therapies and emerging treatments. Methods: A narrative review of the recent literature was conducted, including preclinical studies, clinical trials, and real-world evidence regarding SD pathogenesis and therapy. Special attention was paid to molecular pathways, microbiome-modulating strategies, and novel therapeutic agents. Results: Advances in transcriptomic and microbiome profiling have revealed a complex immunoinflammatory environment in SD, involving predominantly Th1, Th17, and Th22 axes. Conventional therapies are mainly based on antifungals, topical corticosteroids, and calcineurin inhibitors. However, new therapeutic approaches are under investigation, including PDE4 inhibitors (roflumilast, crisaborole, and apremilast), topical and oral JAK inhibitors, probiotics, and microbiome-targeted therapies. These agents offer promising results in selected patients, particularly those with refractory disease or facial involvement. Conclusions: SD remains a challenging condition due to its relapsing course and limited long-term therapeutic options. Emerging therapies represent a valuable opportunity to address unmet clinical needs, particularly in patients with severe, recurrent, or treatment-resistant forms. Full article

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) worldwide. Currently, approximately sixty percent of patients are cured with R-CHOP as frontline treatment, while the remaining patients experience primary refractory or relapsed (R/R) disease. Recently, the introduction of Pola-R-CHP as front-line therapy has represented a major advance in the management of DLBCL, resulting in improved outcomes. Prognosis of R/R DLBCL patients is poor, particularly for those eligible neither for chimeric antigen receptor (CAR) T-cell therapy nor autologous stem cell transplantation (ASCT), representing a significant unmet clinical need. The advent of bispecific monoclonal antibodies (BsAbs), such as bispecific T-cell engagers (BiTEs), dual affinity retargeting (DART) molecules and IgG-like bispecific antibodies, offers a novel promising therapeutic approach in the treatment of DLBCL, both as frontline treatment and in the R/R setting. BsAbs simultaneously engage two different antigens, a tumor-associated antigen and an immune cell antigen, redirecting T-cells against malignant cells and enhancing the immune response. Most BsAbs developed for the treatment of NHLs engage T-cells via CD3 and malignant B-cells via CD20, a surface antigen expressed on most lymphomatous cells. Engagement of malignant B-cells by BsAbs activates T-cells, leading to the release of multiple cytokines and potentially to two characteristic adverse events: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The most extensively studied BsAbs, in both the frontline and relapsed/refractory (R/R) settings, include epcoritamab, glofitamab, mosunetuzumab, and odronextamab. Epcoritamab and glofitamab have received FDA and EMA approval for R/R DLBCL after two or more systemic line of therapies. EMA has also approved glofitamab in combination with gemcitabine and oxaliplatin (GemOx) for patients with R/R DLBCL ineligible for ASCT, whereas this indication has not been approved by FDA. Odronextamab is approved by EMA for R/R DLBCL and FL in patients who have received at least two prior lines of therapy, but it has not been approved by FDA. Mosunetuzumab is approved by both agencies—but only for R/R follicular lymphoma (FL). BsAbs represent a breakthrough therapy in the treatment of DLBCL, especially in R/R diseases. The purpose of this article is to review the landscape of BsAbs in DLBCL. Full article

Recurrent erysipelas is a common and clinically significant condition that poses challenges for both patients and healthcare systems. Each episode may damage lymphatic vessels, leading to chronic lymphedema, which perpetuates the risk of further relapses. Recurrence rates remain high, ranging from 11% in outpatients during the first year to up to 46% of hospitalized patients within three years. The lower limbs are the most frequent site, although recurrences may also occur in other regions, such as the upper limb after mastectomy with lymph node dissection. This review summarizes current knowledge on risk factors, preventive measures, and chemoprophylaxis in recurrent erysipelas. Modifiable risk factors such as obesity, diabetes, venous insufficiency, tinea pedis, and poor hygiene play an important role, while non-modifiable factors include age, sex, and a history of prior episodes. Non-pharmacological strategies—weight reduction, glycemic control, smoking cessation, compression therapy, and meticulous skin care—form the cornerstone of prevention and may reduce the need for long-term antibiotics. Antibiotic prophylaxis, most commonly with oral penicillin V or intramuscular benzathine penicillin, has been shown to lower recurrence rates. However, efficacy may be reduced in patients with chronic edema or severe obesity. Macrolides serve as alternatives in penicillin-allergic patients, but concerns remain about resistance, adverse effects, and drug–drug interactions. In conclusion, recurrent erysipelas requires a multifaceted approach. While antibiotic prophylaxis is effective, its long-term success depends on simultaneous management of underlying conditions. Further studies are needed to define optimal regimens, treatment duration, and non-antibiotic alternatives. Full article