First-line Treatment Research Articles

Adalimumab Use in Severe Recalcitrant Vulval Lichen Sclerosus and Vulval Lichen Planus.

This case series aims to evaluate the demographic features, disease characteristics, and treatment outcomes of 8 patients receiving subcutaneous (SC) adalimumab for severe, refractory vulval lichen sclerosus (VLS) and/or vulval lichen planus (VLP). Both conditions are chronic inflammatory dermatoses that significantly impair quality of life, and although first-line treatment typically involves potent to ultrapotent topical corticosteroids, managing severe cases is challenging due to a lack of FDA-approved systemic therapies. Adalimumab, a TNF-α inhibitor, may offer a promising alternative by targeting the inflammatory cytokine implicated in the pathogenesis of both conditions. Eight patients received SC adalimumab for VLS and/or VLP at a tertiary referral vulvar disorders clinic from September 2020 to June 2024. Among the 8 patients, 4 had VLS/VLP clinical overlap, 2 had VLP, and 2 had VLS. Evaluation included patient-reported outcome measures (PROMs) namely the vulval life quality index (VLQI) and numerical rating scales for itch and pain, and objective clinical severity was assessed by a vulvar dermatologist based on cutaneous signs and architectural features. Adalimumab was well tolerated by 6 of 8 patients who received treatment for at least 9 months. Varying degrees of clinical improvement were observed in cutaneous signs and PROMs, including significant reductions in vulval life quality index scores for 6 patients. Architectural changes remained stable throughout treatment for all patients. This case series indicates that SC adalimumab may be a treatment option for patients with severe, refractory VLS and VLP, as demonstrated by significant improvements in PROMs. The observed clinical benefits suggest that adalimumab targets key inflammatory pathways in these conditions. Controlled trials are necessary to further validate these findings and define adalimumab's role in managing severe refractory VLS and VLP. Future research should also investigate long-term efficacy and safety, as well as potential predictors of treatment response, to optimize care for this challenging patient population.

Relaxin-2 improves type I diabetes mellitus-induced erectile dysfunction in rats by protecting cavernous endothelial and smooth muscle function, and inhibiting penile fibrosis and apoptosis.

Diabetes mellitus-induced erectile dysfunction (DMED) responds poorly to first-line treatments, necessitating the development of new therapeutic strategies. Relaxin-2 (RLX-2) plays a crucial role in protecting vascular endothelium, vasodilatation, and antifibrosis in various diseases. However, its effects and mechanisms on DMED remain unclear. To investigate the effects and mechanisms of RLX-2 on DMED rats in vivo and vitro. For in vivo research, 30 Sprague-Dawley rats were allocated into three groups: control, DMED, and DMED + RLX-2. The induction of DMED in the rats was achieved through intraperitoneal administration of streptozotocin, with confirmation of ED status being conducted via the apomorphine test. Rats in the DMED + RLX-2 group received continuous RLX-2 treatment by osmotic pump. Following a 4-week treatment period, assessment of erectile function was carried out using cavernous manometry, and samples of corpus cavernosum tissues were procured for subsequent analysis. For in vitro research, human cardiac microvascular endothelial cells (HCMECs) were allocated into three groups: control, high glucose (HG, 40mM), and HG + RLX-2. HCMECs were cultured for 6 days and treated with RLX-2 for 48h before collection for subsequent experiments. In DMED rats, RLX-2 treatment partially improved erectile function. We observed relatively normalized functions of endothelial and smooth muscle cells with decreased levels of apoptosis and fibrosis in the penis. In vitro experiments also demonstrated the antihyperglycemic effects of RLX-2. RLX-2 can protect endothelial and smooth muscle function, and inhibit aberrant apoptosis and fibrosis in the corpus cavernosum, thereby improving erectile function in DMED rats. This may provide a novel treatment for DMED.

Musculoskeletal immune-related adverse events of PD-(L)1 inhibitors in melanoma: a systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) are first-line treatment for melanoma. The incidence of musculoskeletal immune-related adverse events (MSK irAEs) remains unclear. To estimate the relative risk of MSK irAEs in melanoma patients treated with ICIs targeting programmed cell death-1 or its ligand PD-(L)1 as compared to placebo. We performed a systematic literature review including phase III randomized controlled trials of adult melanoma patients comparing a PD-(L)1 inhibitor to a placebo arm. Outcomes of interest included arthralgias, arthritis, back pain and myalgias. Meta-analysis was performed to estimate the pooled relative risk of MSK irAEs over the treatment course. Four RCTs met the inclusion criteria (n = 3,041 subjects). Use of PD-(L)1 inhibitors was associated with an increased risk of developing arthralgias (RR 1.30 [95% CI: 1.13-1.49]) and myalgias (RR 1.48 [95% CI: 1.17-1.87]) as compared to placebo. Back pain and arthritis were not reported. Use of PD-(L)1 inhibitors is associated with a significantly increased risk of arthralgias and myalgias in melanoma patients. The risk of back pain and arthritis is unknown. MSK irAEs can impact quality of life and should be considered, particularly in the adjuvant setting when risks and benefits are carefully weighed.

Assessment of the American College of Surgeons Surgical Risk Calculator (ACS-SRC) for Prediction of Early Postoperative Complications in Patients Undergoing Cytoreductive Surgery for Ovarian Peritoneal Carcinomatosis.

Ovarian cancer (OC) is diagnosed at a locally advanced stage in two-thirds of cases. The first line of treatment consists of cytoreductive surgery (CRS) combined with neoadjuvant and/or adjuvant chemotherapy. However, CRS can be associated with high rates of postoperative complications (POCs), and detection of fragile patients at high risk of POCs is important. The American College of Surgeons Surgical Risk Calculator (ACS-SRC) provides a predictive model for early POCs (30 days) for any given surgical procedure. This study aimed to evaluate the performance of the ACS-SRC in predicting the occurrence of early POCs for patients undergoing CRS for OC. This was a retrospective study that included patients undergoing CRS for advanced OC between January 2010 and December 2022. Early POCs were reviewed, and the rate of POCs was compared with those predicted by the ACS-SRC to evaluate its accuracy (i.e., discrimination and calibration). A total of 218 patients were included, 112 of whom underwent extensive surgery/resection. A total of 94 complications were recorded. This cohort demonstrated correct calibration of the ACS-SRC for the prediction of surgical site infection, readmission, and the need for nursing care post-discharge (NCPD; transfer to revalidation center or need for nursing care at home). Using both the discrimination and calibration methods, the score only predicted NCPD. In this study, the ACS-SRC was shown to be of little value for patients undergoing cytoreductive surgery for ovarian peritoneal carcinomatosis, as it only accurately predicted NCPD.

Talazoparib plus enzalutamide versus olaparib plus abiraterone acetate and niraparib plus abiraterone acetate for metastatic castration-resistant prostate cancer: a matching-adjusted indirect comparison.

Without head-to-head trials between talazoparib+enzalutamide (TALA + ENZA), olaparib+abiraterone acetate (OLAP + AAP), and niraparib plus AAP (NIRA + AAP) the ability to evaluate their relative efficacy as first-line (1 L) treatment in metastatic castration-resistant prostate cancer (mCRPC) is limited. The objective of this study was to assess the relative efficacy between TALA + ENZA (TALAPRO-2) versus OLAP + AAP (PROpel) and NIRA + AAP (MAGNITUDE) in 1 L mCRPC via a matching-adjusted indirect treatment comparison (MAIC). Patient-level data from TALAPRO-2 and published data from PROpel and MAGNITUDE were used. TALAPRO-2 data were reweighted to satisfy the eligibility criteria for PROpel and MAGNITUDE. Talazoparib (0.5 mg/day) plus enzalutamide (160 mg/day) was compared to olaparib (300 mg twice daily) plus abiraterone acetate (1000 mg/day) and niraparib (200 mg/day) plus abiraterone acetate (1000 mg/day). Hazard ratios (HRs) were calculated for radiographic progression-free survival (rPFS) and overall survival (OS), and odds ratios (ORs) for prostate-specific antigen (PSA) response and objective response rate (ORR). Additional efficacy outcomes were assessed. In all-comers, TALA + ENZA was statistically superior to OLAP + AAP for rPFS (HR: 0.727; 95% confidence interval [CI]: 0.565, 0.935) and PSA response (OR: 1.663; 1.101, 2.510), and numerically favored for OS (HR: 0.847; 0.667, 1.076) and ORR (OR: 1.109; 0.646, 1.903). In patients with homologous recombination repair mutations (HRRm), relative to NIRA + AAP, TALA + ENZA was statistically superior for rPFS (HR: 0.460; 0.280, 0.754), and numerically favored for OS (HR: 0.601; 0.347, 1.041) and ORR (OR: 1.524; 0.579, 4.016). Results suggest that TALA + ENZA may provide improvements in clinical outcomes relative to OLAP + AAP and NIRA + AAP in 1 L mCRPC; however, inherent limitations associated with the complexity of the analyses must be considered.

Relentless Angina of a Scarred Heart

Refractory anginal pain affects nearly 5-10% of stable coronary artery disease patients, and maximizing the anti-ischemic medical therapy is the standard first-line treatment. The presence of a scarred myocardial territory of the epicardial coronary chronic total occlusion (CTO) limits the implementation of other modalities, such as angioplasty and surgical bypass. Accordingly, this subset of patients, who show poor response to medical treatment with the absence of considerable reversible ischemia, bears an additional burden of persistent angina besides the structural and functional complications resulting from their scarred hearts. In this report, a patient, with compensated ischemic cardiomyopathy, complaining of disabling stable angina was indicated for diagnostic coronary angiography that showed a chronic total occlusion (CTO) at the mid-segment of the left anterior descending coronary artery (LAD) and otherwise no significant stenoses in the epicardial coronary tree. After the failure of maximized anti-ischemic medical therapy, the patient underwent elective percutaneous intervention (PCI) to the left anterior descending coronary artery (LAD) chronic total occlusion (CTO) with 2 overlapping drug-eluting stents that yielded a favorable outcome on patient follow-up even though a myocardial perfusion imaging failed to show considerable reversible ischemia at the left anterior descending coronary artery (LAD) territory. The report points out that elective chronic total occlusion (CTO) revascularization may alleviate anginal pain, despite the absence of a considerable macroscopic ischemia, after failure of a maximized anti-ischemic medical regimen.

Evaluation of In Vitro Inhibition of β-Hematin Formation: A Step Towards a Comprehensive Understanding of the Mechanism of Action of New Arylamino Alcohols.

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1-3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of β-hematin-the synthetic counterpart of hemozoin formation-was determined for each compound. Antimalarial activity against W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.

Antimicrobial Susceptibility Profiles of Commensal Enterococcus spp. Isolates from Chickens in Hungarian Poultry Farms Between 2022 and 2023.

Background: The global spread of antimicrobial resistance (AMR) represents one of the most significant challenges of our generation. It is crucial to continuously monitor AMR, not only by investigating clinical, pathogenic strains but also by monitoring commensal bacterial strains, as they can serve as natural reservoirs of resistance. Infections caused by Enterococcus species are increasingly recognized as emerging threats to both animal and public health. Among economically important livestock, poultry as a major source of animal protein for humans is a frequent carrier of enterococci, and also of sporadically detected clinical disease. Methods: This study aimed to determine the antimicrobial susceptibility profile of Enterococcus strains (n = 499) isolated from chicken farms in Hungary. The minimum inhibitory concentration (MIC) was determined for 15 antibiotics, including 10 with established clinical breakpoints. Results: The strains exhibited good sensitivity to amoxicillin, one of the first-line treatments for Enterococcus infections in veterinary medicine, with only 20.8% showing resistance. However, we observed an alarming 27.9% resistance rate to vancomycin, which is reserved to treat infections caused by multidrug-resistant strains in humans. A comparison of our findings with Hungarian hospital records revealed that the resistance patterns of poultry-derived Enterococcus faecalis strains were very similar to those of human isolates, particularly regarding penicillins and aminoglycosides. Conclusions: Overall, the increasing rates of AMR reinforce the importance of conducting periodic studies to establish long-term trends. For multidrug-resistant strains, next-generation sequencing is recommended to elucidate the genetic basis of resistance.

Effectiveness of dry needling combined with eccentric strength training in lateral epicondylalgia with trigger points

IntroductionLateral epicondylalgia (LE) is commonly presented with myofascial trigger points (MTrPs) among adults. Dry needling (DN) is used less frequently as a first-line treatment in LE with trigger points, and the short and long-term effectiveness of DN in these populations were not studied. Hence, this study compared the effectiveness of DN with conventional physiotherapy in the population of LE with myofascial trigger points.MethodsFor four weeks, the experimental group (<i>n</i> = 19) received DN with weekly one session, and the control group (<i>n</i> = 19) received therapeutic ultrasound combined with deep friction massage for 2 sessions per week at the active sites of active MTrPs. Both groups performed two eccentric exercises sessions from the 5th to the 6th week. Handgrip, pain and disability scores of patient rated tennis elbow evaluation (PRTEE) at baseline, 4th week, 6th week, and follow-up of 12th week were analysed.ResultsHandgrip strength, pain, and disability scores were significantly improved for the experimental group at 4th week (SMD of 1.21 kg in handgrip, 12.26 in PRTEE scores) and 6th week (SMD of 1.58 kg in handgrip, 10.15 in PRTEE scores) compared to the control group. However, no significant group differences (p > 0.05) after 12th week either grip strength (SMD = 0.84) or PRTEE scores (SMD = 3.74) were obtained.ConclusionsDry needling with exercise produced greater short-term improvements in grip strength and disability compared to the control group. However, no significant difference in outcomes was found between groups over a 12-week follow-up period.

Real-world efficacy and safety of combined first-line treatment with PARP inhibitors and novel hormonal therapy in mCRPC patients with HRR gene mutations.

This study evaluated the real-world efficacy and safety of combining PARP inhibitors with novel hormonal therapy (NHT) as a first-line treatment in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations. We enrolled 41 mCRPC patients who received at least 1month of combined treatment with PARP inhibitors and NHT. Patients were divided into two groups: Cohort A (mutations in BRCA1, BRCA2, or ATM genes) and Cohort B (mutations in other HRR genes). The primary endpoint was imaging-based progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS), PSA50 response, and adverse events (AEs). To ensure accurate research results and control confounding factors, we will employ multivariate Cox proportional hazards models to evaluate key variables affecting mCRPC patient survival outcomes. This study enrolled 41 patients, 22 in Cohort A and 19 in Cohort B. The median PFS for all patients was 21.8months, and the median OS had yet to be reached. The overall ORR was 48.8%, and the DCR was 61.0%. Specifically, the median PFS for Cohort A was 21.8months compared to 14.5months for Cohort B. The median OS had yet to be reached for either cohort. Regarding efficacy, 81.8% of patients in Cohort A and 73.7% in Cohort B achieved a PSA50 response. Imaging assessments showed ORRs of 54.6% for Cohort A and 42.1% for Cohort B, with DCRs of 72.7% and 47.4%, respectively. 85.4% of patients experienced grade 1 or 2 adverse events, and 51.2% encountered grade 3 or 4. In the multivariate Cox regression analysis focusing on PFS, the Gleason score was identified as a significant predictor (HR = 5.8, 95% CI: 1.65-20.2, p = 0.006). Combined first-line treatment with PARP inhibitors and NHT is effective and well-tolerated in mCRPC patients with HRR gene mutations, particularly those with BRCA1, BRCA2, or ATM mutations. These findings underscore the potential of this therapeutic combination in managing mCRPC in the Chinese population, suggesting a favorable outcome for those with specific genetic backgrounds.

Standardized Response Assessment in Patients with Advanced Cholangiocarcinoma Treated with Personalized Therapy.

Background/Objectives: Current guidelines recommend Cisplatin/Gemcitabine/Durvalumab as first-line treatment for inoperable or recurrent cholangiocarcinoma (CCA). Molecular tumor boards (MTB) have the expertise to support organ-specific tumor boards with evidence-based treatment recommendations for subsequent lines of treatment, based on genomic tumor data and scientific evidence. This study evaluates the adoption of an MTB at a comprehensive cancer center in Germany and whether actionable genetic alterations are associated with specific imaging phenotypes. Methods: Patients with CCA referred to MTB were enrolled from May 2019 to September 2021. For comparison, a cohort of patients from a second center was included. Data on treatment recommendations, regimens, and survival were collected from prospective registries. Baseline and follow-up contrast-enhanced CT were analyzed according to RECIST 1.1. The chi-square test and t-test were used to compare categorical and continuous variables. Results: 583 patients were referred to the MTB, and 92 patients (47 female/51%) with a mean age of 60.3 ± 11.2 were referred for CCA treatment. 65/92 patients harbored 1-3 targetable mutations. Liver metastases were more frequently observed in patients with targetable mutations (84% vs. 62%). Metastasis to the liver and lung was associated with increased sums of diameters (93 mm and 111 mm vs. 40/73 mm in patients with no liver/lung metastasis). The number of metastases in individual organs was unrelated to treatment targets. Follow-up was available for 25 patients with a median time until imaging progression of 23 weeks. Progression occurred as target progression in 63%, nontarget progression in 13%, and appearance of new lesions in 63%. Conclusions: Most patients with CCA harbored targetable mutations, some were related to disease patterns on imaging. The pattern of treatment response and progression was as diverse as the metastatic spread.

Insights on treatment of adult ITP: algorithm for management and role of multimodal therapy.

The management of immune thrombocytopenia (ITP) is continuously evolving with the development and introduction of newer therapies and a better understanding of the disease. Corticosteroids still represent the cornerstone of first-line treatment. Patients who fail to achieve remission with a short course of corticosteroids require subsequent therapy. Most guidelines recommend starting with either a thrombopoietin receptor agonist (TPO-RA), rituximab, or fostamatinib since these agents have been investigated in randomized trials and have well-characterized efficacy and safety profiles. Patients' involvement to reach a shared decision regarding choice of therapy is essential as these treatments have different modes of administration and mechanisms of action. Less than 10% will fail to respond to and/or be intolerant of multiple second-line therapeutic options and thus be considered to have refractory ITP and require a third-line therapeutic option. Such patients may require drugs with different targets or a combination of drugs with different mechanisms of action. Combining a TPO-RA and an immunomodulatory agent may be an appropriate approach at this stage. Many studies have been conducted during the last 2 decades investigating the efficacy and safety of combinations strategies for first and later lines of therapies. Yet none of these are recommended by current guidelines or have gained wide acceptance and consensus.

To consolidate or not to consolidate: the role of autologous stem cell transplantation in MCL.

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions. However, ASCT is also hampered by acute and delayed toxicity. Thus, alternative first-line treatment strategies without ASCT but including novel agents are under investigation. With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care. Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined. In addition, it remains unclear how effective Bruton's tyrosine kinase inhibitor (BTKi) therapy will be in the relapsed setting for patients who received BTKi as part of first-line therapy. It also remains unclear whether the TRIANGLE data can be extrapolated to other BTKi, which is particularly relevant considering it is no longer FDA approved for MCL. Until then, individual patient characteristics and preferences, disease biology, and estimation of risk of toxicity needs to be taken into account when deciding about the addition of ASCT to an ibrutinib-containing induction therapy. For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.

Predicting prognosis prior to the combination of atezolizumab and bevacizumab on unresectable HCC: Analysis and comparison of tumor heterogeneity at CT and Gd-EOB-DTPA hepatobiliary MR imaging.

Since 2007, the combination of atezolizumab and bevacizumab, comprising an immune checkpoint inhibitor and a molecularly targeted agent, has become the first-line treatment for advanced hepatocellular carcinoma (HCC). Predicting prognosis prior to systemic chemotherapy remains a critical concern. This study included 84 advanced HCC patients who underwent enhanced computed tomography (CT) and Gd-EOB-DTPA magnetic resonance imaging (MRI) before the systemic therapy were included. In CT, the 2 radiologists measured mean CT Hounsfield unit (CTHU) value by drawing region of interest at the largest diameter of the tumor on arterial phage. The HU values were categorized into 5 groups: ≤ 0, 0 < HU ≤ 50, 50 < HU ≤ 100, 100 < HU ≤ 150, and HU > 150. The percentage of the entire tumor in each category was calculated. On MRI, hepatobiliary phase imaging features and relative enhancement ratio (RER) were also evaluated by 2 radiologists. Prognostic factors associated with progression-free survival were identified using statistical analysis. RER on HBP MRI correlated with prognosis in systemic chemotherapy. Conversely, other image features on HBP MRI and CT histogram provided consistent treatment effect.

Anidulafungin exposure and population pharmacokinetics in critically ill patients with invasive candidiasis.

Anidulafungin is recommended as a first-line treatment for invasive Candida infections in critically ill patients. Pharmacokinetic (PK) variability is large in critically ill patients, potentially compromising pharmacokinetic-pharmacodynamic (PKPD) target attainment under standard dosing. We aimed to assess anidulafungin exposure, PKPD target attainment, and population (pop)PK in critically ill patients. Adult ICU patients receiving standard anidulafungin dosing [200mg on day 1, then 100mg daily] were included (NCT04045366). We performed rich blood sampling on an early (day 2 ± 1) and/or late (day 5 ± 1) treatment day. Using total anidulafungin plasma concentrations, we developed a popPK model (NONMEM7.5) and conducted Monte Carlo simulations (n = 1,000 per virtual patient) to evaluate the impact of patient factors on PKPD target attainment (AUC24h target 83.5mg×h/L). Twenty patients contributed 188 anidulafungin concentrations. PKPD target attainment was 45% and 65% on early and late sampling days, respectively. A two-compartment popPK model with first-order elimination described the data. Anidulafungin clearance increased with bodyweight and central volume of distribution increased as serum albumin decreased. Both bodyweight and serum albumin had a clinically relevant impact on PKPD target attainment at day 1 (area under the ROC curve; AUROC 0.82 and 0.62, respectively), and bodyweight on PKPD target attainment at day 14 (AUROC 0.94). Standard anidulafungin dosing regimen fails to achieve adequate target attainment throughout the treatment period. Standard anidulafungin dosing is insufficient for achieving adequate exposure in critically ill patients. An interactive simulation tool is provided to aid dose-finding research and explore different dosing strategies and targets.

Large granular lymphocyte leukemia: a clonal disorder with autoimmune manifestations.

Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or natural killer lymphocytes. Neutropenia-related infections and anemia represent the main manifestations. LGL leukemia is frequently associated with autoimmune disorders such as rheumatoid arthritis, Sjögren's syndrome, autoimmune endocrinopathies, vasculitis, or autoimmune cytopenia. Recent advances in the phenotypic and molecular characterization of LGL clones have underscored the pivotal role of a chronic antigenic stimulation and a dysregulation of the Jak/STAT signaling pathway in the pathophysiology linking leukemic-cell expansion and autoimmunity. In more than half of patients, there is a somatic STAT3 mutation. The disease is characterized by an indolent course, but approximately half of all patients will eventually require therapy. The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.

Survival Outcomes of Durvalumab in Combination with Cisplatin and Gemcitabine in Advanced Biliary Tract Cancer: Real-World Results from a Single Italian Institution

Introduction: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combinationʼs real-world efficacy and tolerability, we conducted a retrospective analysis of its first-line treatment outcomes. Methods: We included patients with unresectable, locally advanced, or metastatic BTC treated with cisplatin, gemcitabine, plus durvalumab. The primary endpoint was overall survival (OS). Results: Thirty-three patients were enrolled. Median OS was NR and median progression free survival (PFS) was 7.6 months, after a median follow-up of 13.5 months. The investigator-assessed overall response rate was 34.5%, with stable disease in 53.0% of patients. High baseline CEA levels were associated with poor survival. Any grade adverse events (AEs) occurred in 97% of patients. Immune-related AEs (irAEs) occurred in 16% (grade >2: 6%). Presence of TP53 mutation was related to a worse OS; conversely the presence of ARID1A genomic alteration was related to a better PFS. A tendence toward a better OS was found for BRCAness patients which did not reach the statistical significance. On the other hand, BRCAness patients showed significantly higher PFS compared to no BRCAness patients. Conclusion: This real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

Zolbetuximab for Unresectable and Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma: A Review of Literature.

This article comprehensively reviews the working, efficacy, and safety profile of zolbetuximab. Zolbetuximab is a pioneering chimeric monoclonal antibody designed to target Claudin 18.2 (CLDN18.2), a tight junction protein frequently overexpressed in various gastrointestinal cancers, including gastric (G) and gastroesophageal junction (GEJ) adenocarcinomas. This drug has captured attention in the treatment of unresectable and metastatic G/GEJ cancer, especially in HER2-negative patients whose tumours express CLDN18.2.Zolbetuximab is a drug that binds to CLDN18.2, and its binding initiates an immune response that attacks and kills the cancer cells. It is typically co-prescribed with fluoropyrimidine and platinum-containing chemotherapy. The drug (formerly IMAB362), brand name Vyloy, was developed by Astellas Pharma, Tokyo, Japan. After multiple rounds of clinical trials, it was approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment for locally advanced, unresectable cancer, establishing itself as a promising option for advanced G/GEJ cancers. Studies reveal that it targets CLDN18.2 for the selective killing of cancer cells while sparing most healthy tissues. Zolbetuximab has demonstrated a significant improvement in progression-free survival (PFS) when combined with chemotherapy (like mFOLFOX6 or CAPOX). Also, it showed prolonged PFS compared to chemotherapy alone in previously untreated, CLDN18.2-positive, HER2-negative patients. Zolbetuximab has also shown improvements in overall survival (OS), regardless of whether the cancer progresses. This is a crucial benefit for patients with advanced G/GEJ adenocarcinomas. Additionally, zolbetuximab's dual action triggers antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).This enhances the immune system's ability to destroy cancerous cells and results in highly potent tumour destruction compared with chemotherapy alone. Zolbetuximab is a relatively safe drug with a few adverse effects. The most frequently reported side effects were gastrointestinal, namely nausea, fatigue, vomiting, decreased appetite, diarrhea, neutropenia, anemia, and thrombocytopenia, potentially due to specific CLDN18.2 expression in the gastric mucosa. Its side effects are generally manageable, with no unexpected toxicity beyond those typically seen in patients receiving chemotherapy.

P20 A case of erythrodermic psoriasis successfully treated with ixekizumab combined with low-dose methotrexate to ensure sustained clearance: a case report

Abstract Erythrodermic psoriasis (EP) is a severe type of psoriasis that requires immediate and effective treatment. Although recommended as first-line treatment, systemic immunomodulators such as methotrexate and/or cyclosporine can sometimes be ineffective or undesirable, hence the use of biologics. However, in cases of refractory disease, biologics may be combined with methotrexate to boost efficacy and optimize outcomes without compromising safety and tolerability. A 16-year-old Filipino male was seen at a tertiary hospital for generalized erythema with scaling. He had chronic plaque psoriasis since age 11 and was previously treated with methotrexate 10 mg weekly, folic acid supplementation, and alternate courses of topical clobetasol and calcipotriol every 2 weeks until near remission was achieved. He was then lost to follow-up and never went through phototherapy. The patient was diagnosed with EP and was treated simultaneously with methotrexate at a maximum of 17.5 mg/week and cyclosporine at 2.75 mg/kg/day. After 6 months of continuous treatment with no reported adverse effects, the patient still exhibited minimal improvement. The patient was then started with ixekizumab 80 mg subcutaneous injections every 4 weeks in an off-label indication and dose for his age in the Philippines. The biologic was given alongside low-dose methotrexate at 7.5 mg/week; cyclosporine was discontinued. After 12 weeks of ixekizumab in combination with low-dose methotrexate, the patient achieved PASI75. The patient received his last dose of ixekizumab at Week 20 in combination with methotrexate of the same dose with good response at PASI100, achieving complete skin clearance. Since discontinuation of ixekizumab, the patient remains lesion-free with low-dose methotrexate at Week 32, with no reported adverse effects. In a resource-constrained setting such as the Philippines, payments for treatment are largely out-of-pocket. Government subsidies for effective but expensive treatments such as biologics are limited, forcing physicians to revert to a more affordable but not necessarily more effective treatment. Methotrexate has been found to have moderate to good efficacy in the treatment of psoriasis. Its acceptable safety profile and affordable cost make it a favourable treatment option for patients with psoriasis in the Philippines. Due to its nature of being a slow starter, the concomitant use of low-dose methotrexate for at least 12 weeks provides a treatment reserve that will allow continuous efficacy once the biologic drug is discontinued. This case illustrates the effective and safe use of ixekizumab combined with methotrexate in the treatment of EP, a strategy employed to overcome limitations in management secondary to finances in a resource-constrained setting such as the Philippines.

Prescribing patterns before the initiation of novel antidiabetic medicines in public, occupational, and private healthcare: a register study reflecting the guidelines of care in type 2 diabetes

BackgroundDisparities in access to healthcare has been implied before in Finland, a country with universal healthcare but de facto tiered primary care. Less is however known about the content of care provided in different settings. Previous studies indicate potential disparities in prescribing newer medicines between healthcare sectors. We compared the preceding prescribing patterns of patients who initiated a sodium-glucose co-transporter 2 (SGLT2) inhibitor or a glucagon-like peptide-1 (GLP-1) analogue in public, occupational, and private healthcare.MethodsWe used logistic models and patient-level register data from the city of Oulu, Finland, during 2014–2018. Among patients who initiated SGLT2 inhibitors or GLP-1 analogues, we studied whether it was a first-line treatment or if other antidiabetic medicines preceded the use. In addition, prior use of statins (a lipid-lowering medicine) and insulins were studied. Clinical guidelines for type 2 diabetes recommend in most cases metformin in first-line, and insulin only at later stages or in case of severe hyperglycaemia. Using a lipid-lowering medicine is typically recommended for all.ResultsThe examined novel antidiabetic medicines were seldom initiated in first-line, and no significant differences were observed for preceding statin use across sectors, net of patient characteristics. However, patients in the public sector were more likely to have used insulin previously compared to patients in occupational sector.ConclusionsBefore the initiation of the examined novel antidiabetic medicines, no marked differences across sectors in the use of other antidiabetic medicines or statins were observed. The higher likelihood of prior insulin use in the public sector might reflect initiation at a later stage and/or unobserved differences in clinical characteristics across patient populations.