Game changer: How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis management.

Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.

Successful treatment of Crohn's disease-related peripheral spondyloarthritis with upadacitinib: two case reports and case-based review.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease (CD), not only causes significant intestinal inflammation but also leads to extra-intestinal manifestations such as spondyloarthritis (SpA). Although the efficacy of tumor necrosis factor (TNF) inhibitors has been reported for IBD-related SpA, some cases still encounter treatment failure, highlighting the need for novel therapeutic alternatives. Recently, Janus kinase inhibitors have demonstrated their efficacy in IBD and SpA, yet their impact on CD-related SpA remains unexplored. Here we present the first two cases of CD-related peripheral SpA successfully treated with upadacitinib. Additionally, our literature review identified a reported case of CD-related peripheral SpA treated with tofacitinib. All cases achieved clinical remission of both CD and peripheral SpA with Janus kinase inhibitors, and no adverse events or disease relapses were reported during the observation period. Our cases and literature review highlight the promising potential of Janus kinase inhibitors as a novel treatment not only for intestinal inflammation of CD, but also for CD-related peripheral SpA.

Treatment With Upadacitinib in Refractory Prurigo Nodularis: A Prospective Cohort Study.

Prurigo nodularis (PN) is a chronic neuroinflammatory dermatosis with severe pruritus that has limited efficacy in various conventional treatments. This study investigated the outcomes of upadacitinib treatment in patients with refractory PN. A prospective study was conducted to screen for potential chronic infections prior to treatment. Upadacitinib was administered at a daily dose of 15 mg for 24 weeks, and the treatment response was assessed using the itch Numeric Rating Scale (NRS), investigator's Global Assessment (IGA), and Dermatology Life Quality Index (DLQI). Adverse events were monitored at each visit. Ten patients, with an average age of 48.8 years, were included in the study. All participants were treated with systemic cyclosporine before receiving upadacitinib, which yielded limited responses. At baseline, the mean prurigo severity scores assessed using the IGA, DLQI, and itch NRS were 3.4, 17.8, and 8.1, respectively; after 24 weeks of treatment, these scores significantly reduced to 1.0, 0.6, and 0.8, respectively. No severe adverse effects were observed. In conclusion, upadacitinib could be considered an alternative therapeutic option with good tolerability for refractory PN.

Advances in Targeted Therapy: Addressing Resistance to BTK Inhibition in B-Cell Lymphoid Malignancies.

B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

Advancing Treatment Options for Merkel Cell Carcinoma: A Review of Tumor-Targeted Therapies.

Although rare, Merkel cell carcinoma (MCC) is a highly aggressive and increasingly prevalent neuroendocrine cancer of the skin. While current interventions, including surgical resection, radiation, and immunotherapy have been employed in treating many patients, those who remain unresponsive to treatment are met with sparse alternatives and a grim prognosis. For this reason, it is of interest to expand the repertoire of available therapies for MCC patients who remain resistant to current primary interventions. Recently, our improved mechanistic understanding of aberrant cell signaling observed in both MCPyV-positive and -negative MCC has facilitated exploration into several small molecules and inhibitors, among them receptor tyrosine kinase inhibitors (TKIs) and somatostatin analogs (SSAs), both of which have positively improved response rates and reduced tumor volumes upon application to treatment of MCC. The introduction of such targeted therapies into treatment protocols holds promise for more personalized care tailored towards patients of diverse subtypes, thereby improving outcomes and mitigating tumor burden, especially for treatment-resistant individuals. In this review, we characterize recent findings surrounding targeted treatments that have been applied to MCC and provide an overview of emerging perspectives on translatable options that can be further developed to offer additional therapeutic avenues for patients with the disease.

Ponatinib exacerbate renal injury in systemic lupus erythematosus mouse model through PDGFR-PI3K/AKT pathway.

Lupus nephritis (LN) is a common clinical complication of systemic lupus erythematosus (SLE). Proliferative lupus nephritis represents the gravest form of LN, and since effective drugs for its treatment are still lacking, tyrosine kinase inhibitors (TKIs) find extensive clinical utility due to their notable impact on suppressing cell proliferation and may serve as potential drugs for LN treatment. However, previous studies on the effects of TKI on LN have been controversial. Ponatinib, a third-generation TKI, lacks studies on its role in LN. This study aimed to investigate the impact of the ponatinib on LN. MRL/lpr mice were evaluated for renal function, autoimmune markers and histopathological changes after oral administration of ponatinib. RNA-seq analysis was performed to explore the molecular pathways involved in ponatinib-induced kidney injury. Ponatinib uniquely exacerbated renal damage in MRL/lpr mice, evidenced by a decline in renal function and acute pathological changes, without affecting lupus-related autoimmune markers. Differential expressed genes analysis and functional enrichment implicate ponatinib-induced renal damage in MRL/lpr mice associated with adiponectin. Furthermore, we verified ponatinib signaling the PI3K/AKT pathway through PDGFRα, potentially influencing high molecular weight adiponectin (HMW ADIPOQ) expression and exacerbating renal damage. In conclusion, this study demonstrates that ponatinib can up-regulate HMW ADIPOQ expression via the PI3K/AKT pathway by inhibiting PDGFRα phosphorylation, highlighting the potential nephrotoxic effects of ponatinib in lupus-prone mice, and underscoring the importance of monitoring renal function in systemic autoimmune diseases patients receiving ponatinib.

Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis.

BACKGROUND: Treatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. METHODS: We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software. RESULTS: A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59% [95CI:0.56-0.63] at 12 months and 55% [95CI:0.52-0.59] at 24 months, and no CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (P = 0.003), and molecular response depth MR5.0 (P = 0.020). CONCLUSION: Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 62% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334).

Advancements in fourth-generation EGFR TKIs in EGFR-mutant NSCLC: Bridging biological insights and therapeutic development.

Third-generation EGFR tyrosine kinase inhibitor (TKIs) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations, with improved long-term outcomes compared to first-generation TKIs. Nevertheless, disease progression inevitably occurs, limiting osimertinib long-term efficacy. Indeed, the molecular biology underlying acquired resistance to first-line osimertinib is multifaceted and includes the emergence of on-target and off-target alterations. EGFR-C797S mutation represents the most frequent mechanism of on-target resistance and hinders drug binding to the target site. EGFR-independent resistance includes the activation of alternative signaling pathways, such as MET amplification and HER2 mutations, and histological transformation. In this setting, chemotherapy is the current therapeutic option, with modest clinical outcomes. Therefore, the development of novel therapeutic strategies to overcome resistance to osimertinib is a major challenge. In this setting, fourth-generation TKIs are emerging as an interesting therapeutic option to overcome on-target resistance. Preclinical drug development has led to the discovery of thiazole-amid inhibitors, which activity is mediated by the allosteric inhibition of EGFR, resulting in high specificity towards mutant-EGFR. Early phase 1/2 clinical trials are ongoing to elucidate their activity also in the clinical setting. Aim of this review is to provide a state-of-the-art analysis on preclinical development of fourth-generation EGFR-TKIs and promising preliminary clinical data.

New ABL1 Kinase Domain Mutations in BCR::ABL1-Positive Acute Lymphoblastic Leukemia.

BACKGROUND: Since the development of the first-generation Tyrosine Kinase Inhibitor (TKI), it has played a crucial role in the treatment of BCR::ABL1-positive acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). However, ABL1 kinase domain (ABL1 KD) mutations confer resistance to several TKIs. These mutations have been extensively studied in chronic myeloid leukemia (CML) but less so in BCR::ABL1-positive acute lymphoblastic leukemia (ALL). METHODS: Our study aimed to analyze the the ABL1 KD mutations in 97 consecutive newly-diagnosed adults with BCR::ABL1-positive ALL before therapy, in cytogenetic complete remission and at relapse with next generation sequencing (NGS). The relationship between ABL1 KD mutations and TKI selection was also analyzed. RESULTS: Previously unreported ABL1 KD mutations R239G, F401V/L, R516L and K262T were the most prevalent in pre-therapy and cytogenetic remission samples, whereas T315I/P and P-loop mutations were most prevalent in relapse samples. R239G, F401V/L, R516L and K262T are related to the BCR::ABL1 structure, whereas T315I/P and P-loop mutations directly alter kinase activity. BaF3 cells transfected with ABL1 KD F401V, K262T, R239G, or R516L mutations were resistant to imatinib but strongly inhibited by olverembatinib with IC50 values of 0.73 to 1.52nM. Meanwhile, olverembatinib had advantages in increasing complete molecular response (CMR) and good prognosis. CONCLUSION: Overall, our findings indicate the prevalence and impact of new ABL1 KD mutations in BCR::ABL1-positive ALL patients, highlighting the necessity for effective therapies targetingthese mutations.

Unveiling new chapters in medullary thyroid carcinoma therapy: advances in molecular genetics and targeted treatment strategies.

Medullary Thyroid Carcinoma (MTC), a neuroendocrine malignancy that arises from the calcitonin-secreting parafollicular C-cells of the thyroid, constitutes a minor yet impactful fraction of thyroid malignancies. Distinguished by its propensity for aggressive growth and a pronounced tendency for metastasis, MTC poses formidable obstacles to the early diagnosis and therapeutic intervention. The molecular genetics of MTC, particularly the role of the RET gene and the RAS gene family, have been extensively studied, offering insights into the pathogenesis of the disease and revealing potential therapeutic targets. This comprehensive review synthesizes the latest advancements in the molecular genetics of MTC, the evolution of precision therapies, and the identification of novel biomarkers. We also discuss the implications of these findings for clinical practice and the future direction of MTC research.

Comparative efficacy and safety of anti-cryptosporidial agents: an in vitro study on nitazoxanide, halofuginone lactate, KDU731, and paromomycin against Cryptosporidium parvum.

This study evaluated the in vitro effectiveness of anti-cryptosporidial agents nitazoxanide, halofuginone, the pyrazolopyridine analog KDU731, and paromomycin (PMC) in combating the significant zoonotic pathogen Cryptosporidium parvum. The study utilized HCT-8 host cells to culture C. parvum and fluorescent microscopy/quantitative PCR (qPCR) for detecting parasitic growth. The efficacy of the compounds was assessed by calculating their inhibitory concentrations (IC) against the total growth of C. parvum at 48 h post-infection. The study further investigated the impact of these compounds on early parasitophorous vacuole (PV) formation, merozoite egress, host cell viability, and cell growth cycle. KDU731 displayed the most promising profile, with low nanomolar (102 nM ± 2.28) activity and negligible host cell toxicity. This study offers new insights into the relative efficacy and safety of various anti-cryptosporidial compounds, highlighting their stage-specific effects on C. parvum and the consequential impacts on host cells. Identifying safe and effective anti-cryptosporidial agents contributes significantly to the One Health approach, which emphasizes the importance of integrated strategies in controlling zoonotic diseases.

Difficult-to-treat Takayasu arteritis: a case-based review.

Takayasu arteritis is a rare chronic inflammatory large vessel vasculitis which affects the aorta and its large branches. The diagnosis is based on the 2022 ACR/EULAR classification criteria for Takayasu arteritis. The management of this vasculitis is challenging. Although it is corticosteroid-responsive, relapses and disease progression are common. Thus, it is possible to resort to alternative conventional synthetic disease-modifying anti-rheumatic drugs and biologics, as second-line such as tumor necrosis factor-alpha inhibitors, tocilizumab, or JAK inhibitors as second-line agents is possible. Nevertheless, in some complex cases, the vasculitis remains active despite different proposed therapeutic lines, and a multitarget approach could induce sustained remission. We report herewith a case of 33-female patient with a refractory Takayasu arteritis which remained active after three different therapeutic lines with tocilizumab, then infliximab, then Upadacitinib. Finally, we consider a successful multitarget approach with a combination of infliximab, Upadacitinib, and methotrexate.

Piperlongumine in combination with EGFR tyrosine kinase inhibitors for the treatment of lung cancer cells.

Objectives: EGFR tyrosine kinase inhibitor (EGFR-TKI) therapies such as erlotinib and gefitinib are approved for the treatment of non-small cell lung cancer (NSCLC). However, the high incidence of acquired resistance to these EGFR-TKIs may preclude their effectiveness. Piperlongumine (PPL), an extract from the long pepper fruit (Piper longum), has been shown to possess anticancer properties. The purpose of the study was to investigate piperlongumine as an anticancer agent and to study a combination treatment approach with EGFR-TKIs against lung cancer cells. Methods: Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Cells were treated with PPL, ERL, GEF, and CIS alone, and in combination, cell viability was determined after 72 h. The mechanism of PPL-induced cytotoxicity was investigated via reactive oxygen species (ROS) induction, and apoptosis induction using acridine orange/ethidium bromide staining and flow cytometry. The effect of treatment on EGFR-mediated oncogenic signaling was investigated by immunoblotting for mitogenic and apoptotic markers. Results: PPL exhibited a potent cytotoxic effect in H1299 and H1975 cells compared to ERL, GEF, and CIS. Combination treatments of PPL with GEF and ERL showed significant reductions in cancer cells compared to control in both cell lines, which were associated with apoptotic induction, but without significant ROS induction. Compared to control, PPL with GEF significantly increased apoptotic cell death in H1975as confirmed with flow cytometry. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. Conclusion: PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.

Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy.

Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. However, other genetic and epigenetic abnormalities in SS do not necessarily include SS18-SSX-related events, but abnormalities are more sporadic and do not correlate well with the prognosis and response to therapy. Currently, targeted therapy for synovial sarcoma includes a limited range of drugs, and surgical resection is the mainstay treatment for localized cancer with adjuvant or neoadjuvant chemotherapy and radiotherapy. Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.

New Fusarochromanone Derivatives from the Marine Fungus Fusarium equiseti UBOCC-A-117302.

Two new fusarochromanone derivatives, deacetylfusarochromene (1) and deacetamidofusarochrom-2',3-diene (2), along with the previously reported metabolites fusarochromanone TDP-2 (3), fusarochromene (4), 2,2-dimethyl-5-amino-6-(2'E-ene-4'-hydroxylbutyryl)-4-chromone (5), fusarochromanone (6), (-)-chrysogine (7), and equisetin (8), were isolated from the marine fungus Fusarium equiseti UBOCC-A-117302. The structures of the compounds were determined by extensive spectrometric (HRMS) and spectroscopic (1D and 2D NMR) analyses, as well as specific rotation. Among them, 2 and 5 showed inhibition of three protein kinases with IC50 values ranging from 1.42 to 25.48 µM. Cytotoxicity and antimicrobial activity of all isolated compounds were also evaluated. Six fusarochromanone derivatives (1-6) exhibited diverse activities against three cell lines, RPE-1, HCT-116, and U2OS (IC50 values ranging from 0.058 to 84.380 µM). Equisetin (8) showed bactericidal activities against Bacillus cereus and Listeria monocytogenes (MBC values of 7.8 and 31.25 µM, respectively), and bacteriostatic activity against Enterococcus faecalis (MIC value of 31.25 µM). Compounds 2 and 4 showed bacteriostatic activities against Listeria monocytogenes (MIC of 125 µM).

Development and Validation of a New Eco-Friendly HPLC-PDA Bioanalytical Method for Studying Pharmacokinetics of Seliciclib.

Background and Objectives: Seliciclib (SEL) is the first selective, orally bioavailable potential drug containing cyclin-dependent kinase inhibitors. Preclinical studies showed antitumor activity in a broad range of human tumor xenografts, neurodegenerative diseases, renal dysfunctions, viral infections, and chronic inflammatory disorders. To support the pharmacokinetics and aid in therapeutic monitoring of SEL following its administration for therapy, an efficient analytical tool capable of quantifying the concentrations of SEL in blood plasma is needed. In the literature, there is no existing method for quantifying SEL in plasma samples. This study introduces the first HPLC method with a photodiode array (PDA) detector for the quantitation of SEL in plasma. Materials and Methods: The chromatographic resolution of SEL and linifanib as an internal standard (IS) was achieved on Zorbax Eclipse Plus C18 HPLC column (150 mm length × 4.6 mm internal diameter, 5 µm particle size), with a mobile phase composed of acetonitrile-ammonium acetate, pH 5 (50:50, v/v) at a flow rate of 1.0 mL min-1. Both SEL and IS were detected by PDA at 230 nm. The method was validated according to the ICH guidelines for bioanalytical method validation. Results: The method exhibited linearity in concentrations ranging from 50 to 1000 ng mL-1, with a limit of quantitation of 66.1 ng mL-1. All remaining validation parameters satisfied the ICH validation criteria. The environmental sustainability of the method was verified using three extensive tools. The proposed HPLC-PDA method was effectively utilized to study the pharmacokinetics of SEL in rats after a single oral administration of 25 mg/kg. Conclusions: The proposed method stands as a valuable tool for studying SELs for pharmacokinetics in humans. It aids in achieving the targeted therapeutic advantages and safety of treatment with SEL by optimizing the SEL dosage and dosing schedule.

Immune Indicator Changes in Hepatocellular Carcinoma Undergoing TACE Plus ICIs and Anti-VEGF Antibodies/TKIs: A Prognostic Biomarker Analysis.

Objective: To explore changing trends in circulating immune indicators of hepatocellular carcinoma (HCC) undergoing TACE plus immune checkpoint inhibitors (ICIs) and anti-VEGF antibodies/TKIs and to elucidate the relationship between immune response and tumor prognosis. Materials: This single-center retrospective study included patients with unresectable HCC undergoing TACE plus ICIs and anti-VEGF antibodies/TKIs from March 11, 2019, to February 15, 2024. Peripheral blood samples were collected at baseline and every cycle, from which blood cell counts and immune indicators were analyzed. The primary outcome was the objective response rate (ORR) at the first evaluation. According to the first evaluation based on mRECIST, patients were classified into PD, SD, and OR groups for analysis. Further subgroup analysis was performed on the OR group based on whether experiencing progression after the first evaluation. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The neutrophil-to-lymphocyte ratio (NLR) was measured by the complete blood count. Simple linear regression was employed to examine the dynamic trends. Results: A total of 63 patients were enrolled, with an ORR of 55.6% and a disease control rate (DCR) of 87.3% at the first evaluation. The median overall survival (mOS) was 27.5 months (95% CI: 22.5-32.5 months). In the OR group (n=35), more active immune responses, expressed in a decrease in CD3-CD19+ (p=0.004), CFB (p=0.027), NLR (p<0.001) and an increase in Ig λ (p=0.010), Ig κ (p=0.037), Ig A (p=0.005), Ig G (p=0.006), were related to better prognosis, while similar patterns seen in the OR-nPD subgroup. Concurrently, no significant differences were noted in the PD group (n=8). Conclusion: The combination therapy may modify the tumor microenvironment of HCC. Changing trends in circulating immune indicators and NLR can serve as potential biomarkers for predicting tumor response and guiding clinical treatment.

Investigation of the Theragnostic Role of KIT Expression for the Treatment of Canine Mast Cell Tumors with Tyrosine Kinase Inhibitors.

Several reports have indicated that canine MCTs express a mutated form of a tyrosine kinase receptor, namely KIT, that is involved in abnormal mast cell growth and differentiation. Currently, the post-surgical prognosis for MCTs is related to three different KIT immunohistochemical expression patterns. However, to our knowledge, there are few studies specifically exploring the efficacy of treatment with tyrosine kinase inhibitors related to KIT staining pattern. The purpose of this study was to investigate the potential theragnostic role of KIT expression patterns by studying their correlation to the overall survival and progression-free survival in dogs treated with only tyrosine kinase inhibitors immediately after surgery. We selected 66 cases of canine cutaneous MCTs with complete clinical background. A statistical analysis was performed to assess the overall survival status. Our data suggest an important role of KIT in the etiopathogenesis of canine MCTs and indicate that the anomalous cytoplasmatic distribution of KIT is potentially related to a lower efficacy of tyrosine kinase inhibitors, thus providing a significant prognostic information about the treatment outcome.

Cardiovascular safety of the class of JAK inhibitors or tocilizumab compared with TNF inhibitors in patients with rheumatoid arthritis: Systematic review and a traditional and Bayesian network meta-analysis of randomized clinical trials.

BACKGROUND: We aimed to compare the risk of major adverse cardiovascular events (MACE) and all-cause of death (ACD) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi) or tocilizumab (TCZ) versus tumor necrosis factor (TNF) inhibitors (TNFi). METHODS: We performed a systematic review of six medical databases until May, 2024 for phase 2-4 randomized controlled trials (RCTs) evaluating patients with RA treated with TCZ or JAKi (intervention arm) compared with controls (TNFi or placebo). The study data were independently assessed by 3 investigators. The risk of bias was assessed using the Cochrane Collaboration tool. We performed a network meta-analysis with random effects to evaluate the risk of MACE (primary outcome) and ACD (secondary outcome) compared to TNFi. We also calculated the posterior probability of increasing the primary and secondary outcomes by 15% or more (PP15%) following Bayes' theorem. RESULTS: This meta-analysis included 18 RCTs with 21,432 patients and 57,040 patient-years. JAKi were linked to a non-statistically significant increase in the risk of MACE and ACD as compared to TNFi (ORs of 1.232 [95%CI 0.86-1.76]; p = 0.56 and ORs = 1.3903[95%CI 0.94-2.07]; p = 0.10, respectively). By Bayesian analysis, a high clinical probability of more frequent MACE (PP15% of 61%) and ACD (PP15% of 84%) was found in the JAKi group than in the TNFi group. No statistical difference was found between TCZ and TNFi in relation to MACE (1.029 [95%CI 0.75 -1.40]; p = 0.86) and ACD (1.072 [95%CI 0.78-1.48]; p = 0.67]) in the traditional meta-analysis. In the Bayesian approach, the probability of a difference in clinical relevance was low (PP15% for MACE of 11% and PP15% for ACD of 25%). DISCUSSION: The main limitation of this study is the small number of events with JAKi other than tofacitinib, reflecting the importance of ORAL SURVEILLANCE. Despite this, these data reinforce the recommendations of regulatory agencies and rheumatology societies on the use of JAKi in the context of RA, but above all call for more direct comparison studies involving primary safety outcomes with JAKi, since the outcome data available are still small and heterogeneous. In both meta-analyses, no difference was found between TNFi and TCZ.

Efficacy and safety of HAIC-FOLFOX plus tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for unresectable advanced hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries. However, further investigation is necessary to assess the efficacy and safety of this triple therapy. METHOD: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies conducted within the past 5 years on HAIC combined with immunotherapy and targeted therapy as first-line treatment for advanced HCC. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted this meta-analysis. Additionally, the quality of included studies was assessed using the Joanna Briggs Institute (JBI) scale. Outcomes such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)were extracted and pooled from eligible studies. RESULT: Twelve studies involving 1072 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 65.7% (95% CI, 58.7%-72.7%) (I2 = 83%, P = 0.000) and 89.2% (95% CI, 83.9%-93.6%) (I2 = 83%, P = 0.000), respectively. When analyzing PFS, the upper limit of 95% confidence interval of PFS in one study was not reached, which could potentially impact the statistical analysis. Therefore, we analyzed the remaining 11 studies a total of 1019 patients to pool mPFS, ultimately the pooled mPFS was 9.77months (95% CI, 7.73-11.80) (I2 = 93.9%, P = 0.000). Follow-up time in some studies was insufficient, only eight studies reported OS, we systematically analyzed these eight studies and extracted the pooled mOS was 16.65 months (95% CI, 14.17-19.14) (I2 = 76.9%, P = 0.000). In terms of safety, the incidence rates of any grade AEs, ranked from high to low, were as follows: aminotransferase increased (61.3%), nausea and vomiting (40.5%), hypertension (37.8%), thrombocytopenia (37.4%), hyperbilirubinemia (36.7%), abdominal pain (35.6%), leukopenia (34.6%), hypothyroidism (19.0%), rash (14.4%). Grade 3-4 AEs ranked from high to low were as follows: aminotransferase increased (10.8%), thrombocytopenia (7.9%), hypertension (7.4%), leukopenia (5.0%). No treatment-related deaths occurred, patients receiving this triple therapy demonstrated favorable tolerability. CONCLUSION: The combination of hepatic arterial infusion chemotherapy with tyrosine kinase inhibitors and immune checkpoint inhibitors as a first-line therapy for unresectable advanced HCC demonstrates promising therapeutic efficacy and favorable safety.